Lewis Acids in Organic Synthesis, Volume 1

Johann Casteiger (Ed.) Handbook of Chemoinformatics

Further Titles of Interest:

M. Beller, C. Bolm (Eds.) Transition Metals for Organic Synthesis Building Blocks and Fine Chemicals 2 Volumes, 1998, ISBN 3-527-29501-1

F. Diederich, P. J. Stang (Eds.) Templated Organic Synthesis 2000, ISBN 3-527-29666-2

F. Diederich, P. J. Stang (Eds.) Metal-catalyzed Cross-couplingReactions 1999, ISBN 3-527-29421-X

U. Diederichsen, T. K. Lindhorst, B. Westermann, L. A. Wessjohann (Eds.) Bioorganic Chemistry Highlights and New Aspects

1999. ISBN 3-527-29665-4

Lewis Acids in Organic Synthesis Edited by Hisashi Yamamoto

@WILEY-VCH Weinheim . New York . Chichester . Brisbane . Singapore . Toronto

Prof. Dr. H. Yamamoto Graduate School of Engineering Nagoya University, CREST (JST) Furo-cho, Chikusa Nagoya 464-8603 Japan

This book was carefully produced. Nevertheless, authors, editor and publisher do not warrant the information contained therein to be free of errors. Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate.

1st Edition 2000

1st Reprint 2002

Library of Congress Card No. applied for British Library Cataloguing-in-Publication Data: A catalogue record for this book is available from the British Library Die Deutsche Bibliothek - CIP-Cataloguing-in-Publication Data: A catalogue record for this book is available from Die Deutsche Bibliothek

0WILEY-VCH Verlag GmbH, D-69469 Weinheim (Federal Republic of Germany), 2000 ISBN 3-527-29579-8 Printed on acid-free paper. All rights reserved (including those of translation in other languages). No part of this book may be reproduced in any form - by photoprinting, microfilm, or any other means - nor transmitted or translated into machine language without written permission from the publishers. Registered names, trademarks, etc. used in this book, even when not specifically marked as such, are not to be considered unprotected by law.

Cover design: Gunther Schulz, D-67136 Fussgonheim Composition: Kiihn & Weyh, D-79111 Freiburg Printing: Strauss Offsetdruck, D-69509 Morlenbach Bookbinding: Wilhelm Osswald & Co., D-67433 Neustadt (WeinstraBe)

Preface The designation of electron-pair donors and acceptors as Lewis bases and Lewis acids is firmly and fittingly ingrained in the language of chemistry. G. N. Lewis laid the foundation for this important theory approximately 80 years ago and Lewis acids have since become increasingly important because of their central role in synthetic organic chemistry. This is clearly illustrated by an ever-increasing number of publications and books. This volume focuses on different areas of Lewis acid chemistry, selected because they have developed significantly and, in some cases, even completely in the last two decades. Each is treated in more depth than would be possible in a volume that attempted to cover all Lewis acid chemistry comprehensively. The authors are knowledgeable about the area reviewed, have contributed to its development, and are uniquely able to provide valuable perspectives. I was fortunate that these distinguished chemists were willing to devote the time and effort required to write these contributions. These chapters demonstrate the abundance of significant developments of Lewis acid reagents and related areas. It is hoped that this handbook will serve as a catalyst to encourage the dissemination of their (so far untapped) full potential in organic synthesis throughout the twenty-first century. Hisashi Yamamoto, Nagoya

Contents

Volume 1 Preface V List of Authors XVII

1

Introduction Hisashi Yamamoto 1

References 7

2

Li(I), Na(I), and K(1) Lewis Acids Susumu Saito 9

2.1 2.2 2.3

2.4

3

Introduction 9 General Properties of Alkali Metal Salt 10 2.2.1 Lewis Acidic Properties of Alkali Metal Salt 10 2.2.2 Alkali Metal Halide Effect 17 Application to Synthetic Organic Chemistry 28 2.3.1 Cycloaddition Reactions 28 2.3.2 Substitution Reactions 39 2.3.3 Nucleophilic Addition to the C=O Double Bond 45 2.3.4 Conjugate Addition 47 2.3.5 Rearrangement 50 2.3.6 Oxirane Ring-Opening Functionalization 52 Closing Remarks 55 References 55

Mg(1I) and Zn(I1) Lewis Acids YukihiroMotoyama and Hisao Nishiyama 59

3.1 3.2 3.3

Introduction 59 The Diels-Alder Reaction 59 3.2.1 Control of Diastereoselectivity 60 3.2.2 Chiral Lewis Acid Complexes 62 Radical-Mediated Reactions 67 3.3.1 Control of Diastereoselectivity 67 3.3.2 Asymmetric Reactions using Chiral Auxiliaries 69

VIII 3.4 3.5

4

Contents

3.3.3 Enantioselective Reactions Other Reactions 75 Concluding Remarks 85 References 85

Achiral B(II1) Lewis Acids Kazuaki Ishihara

4.1 4.2 4.3

4.4

4.5

4.6

5

5.3 5.4 5.5 5.6 5.7

89

Introduction 89 H3B03-promoted Reactions 90 B13-, BBr3-, or BC13-promoted Reactions 91 4.3.1 Cleavage of Ethers, Acetals, and Esters 91 4.3.2 Glycosidation of Glycals 95 4.3.3 Synthesis of Organoboron Reagents 95 BF3-Promoted Reactions 96 4.4.1 Cleavage of Ethers 96 4.4.2 Friedel-Crafts Alkylation Reactions 97 4.4.3 Friedel-Crafts Acylation Reactions 98 4.4.4 Cyclizations 99 4.4.5 Rearrangement Reactions 101 4.4.6 Diels-Alder Reactions 104 4.4.7 Desilylation Reactions 106 4.4.8 Destannylation Reactions 107 4.4.9 Acylation Reactions of Ketones and Nitriles 107 4.4.10 Addition Reactions 109 4.4.11 Aldol Reactions 111 4.4.12 Miscellaneous Reactions 112 Arylboron Compounds as Lewis Acid Catalysts 114 4.5.1 Triarylboron 114 4.5.2 Diarylborinic Acid 121 4.5.3 Arylboronic Acid 126 Conclusions 130 References 130

Chiral B(II1) Lewis Acids Kazuaki Zshihara

5.1 5.2

71

135

Introduction 135 Enantioselective Carbo Diels-Alder Reactions 135 5.2.1 Chiral Lewis Acids as Stoichiometric Reagents 135 5.2.2 Chiral Lewis Acids as Catalytic Reagents 137 Enantioselective Hetero Diels-Alder Reactions 160 Enantioselective Mukaiyama Aldol Reactions 162 5.4.1 Chiral Lewis Acids as Stoichiometric Reagents 163 5.4.2 Chiral Lewis Acids as Catalytic Reagents 169 Enantioselective Sakurai-Hosomi Allylation Reactions 176 Enantioselective Claisen Rearrangement 179 Enantioselective Hydrocyanation of Aldehydes 180

Contents

5.8 5.9 5.10

Enantioselective Mannich-Type Reactions 180 Other Enantioselective Aza-Reactions 185 Chiral Boron Receptors 187 References 188

6

Achiral Al(II1) Lewis Acids Takashi Ooi and Keiji Maruoka

6.1 6.2 6.3 6.4 6.5

7

191

Introduction 191 Aluminum Halides 191 Aluminum Alkoxides 194 Alkyl Aluminums 202 6.4.1 Trialkyl Aluminums and Alkylaluminum Halides 202 6.4.2 Heteroatom-Substituted Alkylaluminums 234 Modified Organoaluminums 238 References 277

Chiral Aluminum Lewis Acids in Organic Synthesis WilliamD. Wulff 283

7.1 7.2 7.3 7.4 7.5 7.6

Introduction 283 Aldol Reactions 284 Carbonyl Additions and Reductions 286 Claisen Rearrangements 292 [2 + 21 and [2 + 11 Cycloadditions 297 Diels-Alder Reactions 302 7.6.1 Aluminum Catalysts from Chiral Alcohols 302 7.6.2 Aluminum Catalysts from Chiral Diols, Sulfonamides, and P-Hydroxysulfonamides 306 7.6.3 Aluminum Catalysts from Axially Chiral Bis-Phenols 314 7.6.4 Aluminum Catalysts from Bis-Sulfonamides 320 7.7 Ene Reactions 325 7.8 Epoxide-Opening Reactions 327 7.9 Free-Radical Reactions 329 7.10 Friedel-Crafts Reaction 333 7.11 Heteroatom Diels-Alder Reactions 334 7.12 Michael Addition Reactions 339 7.13 Strecker Reaction 350 Acknowledgment 352 References 352

8

Silicon(1V) Lewis Acids Masataka Oishi 355

8.1 8.2

Introduction 355 Preparation of Organosilicon Lewis acids 355 8.2.1 Trimethylsilyl Triflate (la) [5c] 357

IX

X

8.3

8.4 8.5

9

Contents

8.2.2 Trimethylsilyl bis(Trifluoromethanesulfony1)imide (7) [9a] 357 8.2.3 Trimethylsilyl Perchlorate (6a) [lob] 357 8.2.4 Iodotrimethylsilane [70] 357 8.2.5 Trimethylsilyl tetrakis(Trifluoromethanesulfony1)borate [11] 357 Reactions Promoted or Catalyzed by Silicon-Based Lewis Acids 358 8.3.1 Aldol-Type Reactions, Allylation and Related Reactions 358 8.3.2 Intramolecular Aldol-Type Reaction and Allylation 366 8.3.3 Ring Construction 368 8.3.4 Isomerization and rearrangement 374 8.3.5 Glycosidation 378 8.3.6 Reduction and Oxidation 380 Reactions via Hypervalent Silicon Species 382 Conclusions 389 References 389

Sn(I1) and Sn(1V) Lewis Acids Kazuaki Zshihara 395

9.1 9.2 9.3

9.4

10

Introduction 395 SnX2-Catalyzed Reactions 396 9.2.1 Sn(I1) Halide-Catalyzed Reactions 396 9.2.2 Sn(OTf)2-Catalyzed Reactions 400 SnX4-Catalyzed Reactions 408 9.3.1 SnC14-CatalyzedReactions 408 9.3.2 SnC14-ZnC12-CatalyzedReactions 427 9.3.3 Carbornetalation Reactions of Organotin Compounds Generated Using SnC14-Bu3N 429 9.3.4 SnC14-BH (Bronsted Acid)-catalyzed Reactions 430 Organotin(1V)-catalyzed Reactions 443 9.4.1 Esterification 443 9.4.2 Transformation to Carbamate 444 9.4.3 Preparation of Cyclic Thioacetals 444 9.4.4 Chemoselective Michael and Aldol Reactions 445 9.4.5 Allylation 447 References 448

Preparation and Lewis-Acid-Promoted Addition Reactions of Allylic and Allenic Tin and Indium Reagents James A. Marshall

10.1 10.2 10.3 10.4 10.5 10.6 10.7 10.8

453

Introduction 453 Toxicity 454 Preparation of Allylic Trialkylstannanes 455 Additions of Trialkyl Allylic Stannanes to Aldehydes and Ketones 456 Lewis Acid Catalysis of Allyltin Additions 466 Catalysis by Chiral Lewis Acids 470 Additions that Proceed by Transmetalation 474 Additions of Allylic Halostannanes to Aldehydes 479

Contents

10.9 Additions of Achiral and Racemic Oxygenated Allylic Stannanes to Aldehydes 480 10.10 Enantioenriched Oxygenated Allylic Stannanes 484 10.10.1 a-Oxygenated Allylic Stannanes 484 10.10.2 y-Oxygenated Allylic Stannanes 487 10.11 Reactions with Chiral a-Oxygenated Aldehydes 491 10.12 Transmetalations of Chiral Oxygenated Allylic Stannanes 495 10.12.1 SnC14 495 10.12.2 InC13 499 10.12.3 Intramolecular Reactions 503 10.13 Preparation of Allenylstannanes 507 10.14 Addition of Allenyl and Propargyl Stannanes to Aldehydes 509 10.15 Intramolecular Additions 514 10.16 Transmetalations 514 10.16.1 SnC14 514 10.16.2 InC13 518 10.17 Concluding Remarks 520 Acknowledgments 520 References 520

Volume 2 11 Sb(II1) and Sb(V) Lewis Acids Kazuaki Ishihara

523

11.1 Introduction 523 11.2 SbX3-Catalyzed Reactions 523 11.3 SbX5-Catalyzed Reactions 525 11.3.1 Friedel-Crafts and Related Chemistry 525 11.3.2 Isomerization and Rearrangements 528 11.3.3 Other Reactions 529 11.4 HX-SbF5-Catalyzed Reactions 530 11.4.1 Generation of Stable Carbocations 530 11.4.2 Friedel-Crafts and Related Chemistry 531 11.4.3 Isomerization and Rearrangements 532 11.4.4 Cyclization 533 11.4.5 Formation of Aromatic Sulfoxides 534 11.4.6 Formylation and Carboxylation 534 11.4.7 Oxyfunctionalization of Hydrocarbons 535 11.4.8 Other Reactions 537 References 538

12

Copper Lewis Acids in Organic Synthesis Mukund F! Sihi and Gregory R. Cook 543

12.1 Introduction 543 12.2 Dehydration 544

XI

XI1

Contents

12.3 Hydrolysis 546 12.4 Alcoholysis/Acylation etc. (Acetal Formation, Ester Formation, Amide Formation) 549 12.5 Elimination 553 12.6 Friedel-Crafts 553 12.7 Epoxide and Aziridine Ring Opening 555 12.8 Decarboxylation 556 12.9 Activation of Transition Metal Catalysts 556 12.10 Rearrangements 557 12.11 Free-Radical Reactions 557 12.12 Nucleophilic Addition to C=O and C=X Double Bonds 558 12.13 Conjugate Additions 561 12.14 Cycloadditions 562 12.15 Ene Reactions 570 12.16 Conclusions 571 References and Footnotes 571

13 Ag(I), Au(1) Lewis Acids Akira Yanagisawa 575

Introduction 575 Achiral Silver(1)-Catalyzed Carbon-Carbon Bond-Forming Reactions 575 BINAP . Silver(1)-Catalyzed Asymmetric Reactions 581 Gold and Silver-Catalyzed Asymmetric Aldol Reactions of a-Isocyanocarboxylates 586 13.5 Rate Enhancement of Catalytic Asymmetric Reactions by Silver(1) Salts 591 13.6 Summary and Conclusions 594 References 595 13.1 13.2 13.3 13.4

14

Transition Metal Lewis Acids: From Vanadium to Platinum E. Peter Kiindig and Christophe M . Saudan 597

14.1 Introduction 597 14.2 Ethers, Acetals (Including Thioacetals), Carboxylic Acid Derivatives, and Epoxides 598 14.2.1 Cleavage and Formation of Ethers 598 14.2.2 Reactions Involving Acetals 600 14.2.3 Transformation of Carboxylic Acid Derivatives 606 14.2.4 Epoxides 608 14.2.5 Aziridines 615 14.3 Lewis Acid-Promoted Additions to C=O, C=N and CN Bonds, Including Conjugate Additions 616 14.3.1 Reduction, Alkylation, Allylation, Cyanation, and Phenylation of Aldehydes and Ketones 616 14.3.2 Conjugate Additions 619 14.3.3 Mukaiyama Aldol Reactions 622 14.3.4 Carbene Additions to Aldehydes and Imines 623

Contents

14.3.5 Other Addition Reactions to Imines 624 14.3.6 Lewis Acid Activation of Nitriles 626 14.4. Cycloaddition Reactions 631 14.4.1 Diels-Alder Reactions 631 14.4.2 Hetero-Diels-Alder Reactions 640 14.4.3 Ene and Hetero-Ene Reactions 645 14.4.4 1,3-Dipolar Cycloadditions 647 References 648

15

Titanium(1V) Lewis Acids Hirokazu Urabe and Fumie Sat0 653

15.1 15.2 15.3 15.4 15.5 15.6 15.7 15.8 15.9 15.10 15.11 15.12 15.13

Introduction 6.53 Aldol and Related Reactions 656 Reaction of Allylsilane and -Stannane and Related Compounds 676 Reduction with R3SiH or R3SnH 705 Diels-Alder, Ene, and Related Reactions 709 Friedel-Crafts and Related Reactions 725 Esterification, Acetalization, and Related Reactions 747 Preparation of Imines and Enamines 758 Epoxidation and Aziridination 762 Ring-Opening of Epoxides 766 Deprotection of Functional Groups 776 Titanium Lewis Acids in Radical Reactions 779 Miscellaneous 780 Endnote 784 References 784

16

Chiral Ti(1V) Lewis Acids Koichi Mikami and Masahiro Teruda

16.1 16.2 16.3 16.4 16.5 16.6 16.7 16.8 16.9 16.10 16.11 16.12 16.13 16.14

799

Introduction 799 Carbonyl Addition Reaction 800 Carbonyl-Ene Reaction 805 Asymmetric Catalytic Desymmetrization 809 Kinetic Optical Resolution 809 Positive Non-Linear Effect of Non-racemic Catalysts 810 Enantiomer-Selective Activation of Racemic Catalysts 813 Ene Cyclization 814 Aldol Reaction 817 Michael Reaction 825 (Hetero) Diels-Alder Reactions 826 [2 + 21 and [2 + 31 Cycloaddition Reactions 833 Cyanohydrin Formation 836 Miscellaneous Reactions 838 Acknowledgments 840 References and Notes 840

XI11

XIV

17

Contents

Hf-Centered Lewis Acids in Organic Chemistry Keisuke Suzuki and Shigeo Yamanoi 849

17.1 17.2 17.3 17.4 17.5

18

Introduction 849 Use of Cp2HfC12in Carbohydrate Synthesis 849 Use of HfC14 and Hf(OTf)4 858 Hydro- and Carbometalation and Polymerization 861 Miscellaneous Reactions 862 References 863

Zirconium Lewis Acids Ryuichiro Hara and Tamotsu Takahashi 865

18.1 Introduction 865 18.2 Zirconium Enolates and Aldol Reactions [l] 865 18.2.1 Diastereoselective Aldol Reactions via Zirconium Enolates 865 18.2.2 Asymmetric Aldol Reactions via Zirconium Enolates [3] 866 18.2.3 Cross-Aldol Reactions Mediated by Zr(O-t-Bu)4 867 18.2.4 Zirconium-Catalyzed Mukaiyama Aldol Reactions 867 18.2.5 Ring-Opening Aldol-Type Reaction of 2,2-Dialkoxycyclopropanecarboxylic Ester [7] 868 18.2.6 Aldol Reactions of a-Naphthol [8] 869 18.2.7 Mannich-Type Reactions 869 18.2.8 Robinson Annelation Reaction 869 18.3 Friedel-Crafts Type Reactions 870 18.3.1 Acylation and Alkylation Reactions 870 18.3.2 Fries Rearrangement 870 18.4 Allylation Reactions Using Allylsilanes and Allylstannanes 871 18.5 Open-Ring Addition to Oxiranes and Aziridines 872 18.6 Diels-Alder and Hetero-Diels-Alder Reactions 873 18.7 [2 + 21 Cycloaddition Reactions 875 18.8 Zirconium-Catalyzed and -Mediated Oxidation and Reduction Reactions [30] 875 18.9 Hydrometalation Reactions Catalyzed by Zirconium Complexes 876 18.9.1 Hydroalumination of Olefins (Eq. 31) [35] 877 18.9.2 Hydrostannation of alkyne (Eq. 32) [36] 877 18.9.3 Carbometalation of alkynes 877 18.10 Miscellaneous Reactions 877 References 880

19

Sc(II1) Lewis Acids Shu Kobayashi 883

19.1 Introduction 883 19.2 Reactions in Organic Solvents 883 19.2.1 Aldol Reactions 883 19.2.2 Michael Reactions 885 19.2.3 Mannich-Type Reactions 885

Contents

XV

19.2.4 Mannich-Type Reactions Using Hydrazones 887 19.2.5 Friedel-Crafts Acylation and Fries Rearrangement 887 19.2.6 Diels-Alder Reactions 888 19.2.7 Aza Diels-Alder Reactions 890 19.2.8 1,3-Dipolar Cycloadditions 891 19.2.9 [2 + 21-Cycloaddition Reactions of Imines with Alkynyl Sulfides 892 19.2.10 Asymmetric Catalysis 892 19.2.11 Miscellaneous Reactions 895 19.3 Reactions in Aqueous Media 896 19.3.1 Aldol Reactions 896 19.3.2 Allylation Reactions 898 19.3.3 Mannich-Type Reactions 899 19.3.4 Strecker Reactions 900 19.3.5 Diels-Alder Reactions 901 19.4 Reactions in the Solid Phase 901 19.4.1 Aldol Reactions Using Polymer-Supported Silyl Enol Ethers 901 19.4.2 Mannich-Type Reactions Using PSSEE 904 19.4.3 Michael Reactions Using PSSEE 905 19.4.4 Aldol-Type Reactions Using PSSEE 905 19.5 Conclusions 905 Acknowledgments 907 References 907

20

Lanthanide Lewis Acids Catalysis Masakatsu Shihasaki, Ken-Ichi Yarnada, and Naoki Yoshikawa 911

20.1 20.2

20.3

20.4

Introduction 911 Achiral Catalysis by Lanthanide Lewis Acids 911 20.2.1 Lanthanide Triflate-Promoted Reactions in Aqueous Media [2] 911 20.2.2 Selectivities 914 20.2.3 Other Reactions Catalyzed by Lanthanide Lewis Acids 93 8 Chiral Lanthanide Lewis Acid Catalysis 922 20.3.1 Introduction 922 20.3.2 Catalytic Asymmetric Diels-Alder Reactions and Hetero Diels-Alder Reactions Promoted by Chiral Lanthanide Catalysts 923 20.3.3 Catalytic Asymmetric Aza Diels-Alder Reactions Promoted by Chiral Ytterbium Catalysts 927 20.3.4 Catalytic Asymmetric Id-Dipolar Cycloaddition Reactions Promoted by Chiral Yb Catalysts 929 20.3.5 Enantioselective Mukaiyama Aldol Reaction Promoted by Chiral Lanthanide Complexes 931 Lanthanides Containing Multifunctional Heterobimetallic and Heteropolymetallic Asymmetric Catalysis 931 20.4.1 Introduction 931 20.4.2 Heterobimetallic Asymmetric Catalysis 932 References 942

XVI

21

Contents

Polymer-Supported Metal Lewis Acids Shinichi Itsuno 945

21.1 21.2 21.3 21.4 21.5 21.6 21.7 21.8 21.9 21.10 21.11 21.12

Introduction 945 Polymer-Supported Aluminum Chloride 946 Polymer-Supported Ti(IV) 948 Polymer-Supported Fe(II1) Complex 950 Polymer-Supported Boron Derivatives 951 Polymer-Supported SnC14 952 Polymer-Supported Cu(I1) 953 Polymer-Supported Oxazaborolidines 953 Polymer-Supported Dialkylzinc 957 Polymer-Supported Diels-Alder Catalysts 965 Polymer-Supported Asymmetric Aldol Catalysts 972 Polymer-Supported Rare Earth Metal Catalysts 975 References 977

Index 981

List of Authors Gregory R. Cook Department of Chemistry North Dakota State University Fargo, ND 58105-5516 USA

James A. Marshall Department of Chemistry University of Virginia McCormick Road Charlottesville, VA 22901 USA

Ryuichiro Hara Catalysis Research Center and Graduate School of Pharmaceutical Sciences Hokkaido University Sapporo 060-0811 Japan

Keiji Maruoka Department of Chemistry Graduate School of Science Kyoto University Sakyo, Kyoto 606-8502 Japan

Kazuaki Ishihara Research Center for Advanced Waste and Emission Management Nagoya University Furo-cho, Chikusa Nagoya 464-8603 Japan Shinichi Itsuno Department of Materials Science Toyohashi University of Technology Tempaku-cho Toyohashi 441-8580 Japan Shu Kobayashi Graduate School of Pharmaceutical Sciences The University of Tokyo Hongo, Bunkyo-ku Tokyo 113-0033 Japan Peter Kiindig Department of Organic Chemistry University of Geneva 30 Quai Ernest Ansermet 1211 Geneva 4 Switzerland

Koichi Mikami Department of Chemical Technology Tokyo Institute of Technology Meguro-ku Tokyo 152-8552 Japan Yukihiro Motoyama School of Material Science Toyohashi University of Technology Tempaku-cho Toyohashi 441-8580 Japan Hisao Nishiyama School of Material Science Toyohashi University of Technology Tempaku-cho Toyohashi 441-8580 Japan Takashi Ooi Department of Chemistry Graduate School of Science Hokkaido University Sapporo, 060-0810 Japan

Masataka Oishi Graduate School of Engineering Nagoya University CREST, Japan Science and Technology Corporation (JST) Chikusa Nagoya, 464-8603 Japan Susumu Saito Graduate School of Engineering Nagoya University Chikusa Nagoya 464-8603 Japan Fumie Sat0 Department of Biomolecular Engineering Tokyo Institute of Technology 4259 Nagatsuta-cho, Midori-ku Yokohama Kanagawa, 226 -8501 Japan Christophe M. Saudan Department of Organic Chemistry University of Geneva 30 Quai Ernest Ansermet 1211 Geneva 4 Switzerland Masakatsu Shibasaki Graduate School of Pharmaceutical Sciences The University of Tokyo 7-3-1, Hongo, Bunkyo-ku Tokyo 113-0033 Japan Mukund P. Sibi Department of Chemistry North Dakota State University Fargo, ND 58105-5516 USA

Keisuke Suzuki Department of Chemistry Tokyo Institute of Technology 0-okayama, Meguro-ku Tokyo 152-8551 Japan Tamotsu Takahashi CREST, Science and Technology Corporation (JST) Sapporo 060-0811 Japan Masahiro Terada Department of Chemical Technology Tokyo Institute of Technology Meguro-ku Tokyo 152-8552 Japan Hirokazu Urabe Department of Biomolecular Engineering Tokyo Institute of Technology 4259 Nagatsuta-cho, Midori-ku Yokohama Kanagawa, 226 -8501 Japan William D. Wulff Department of Chemistry Michigan State University East Lansing, MI 48824 USA Ken-Ichi Yamada Graduate School of Pharmaceutical Sciences The University of Tokyo 7-3-1, Hongo, Bunkyo-ku Tokyo 113-0033 Japan Hisashi Yamamoto Graduate School of Engineering Nagoya University Chikusa Nagoya, 464-8603 Japan

Shigeo Yamanoi Department of Chemistry Tokyo Institute of Technology 0-okayama, Meguro-ku Tokyo 152-8551 Japan Akira Yanagisawa Graduate School of Engineering Nagoya University CREST, Japan Science and Technology Corporation (JST) Chikusa Nagoya 464-8603 Japan Naoki Yoshikawa Graduate School of Pharmaceutical Sciences The University of Tokyo 7-3-1, Hongo, Bunkyo-ku Tokyo 113-0033 Japan

Lewis Acids in Organic Synthesis Edited bv Hisashi Yamarnoto Copyright 0WILEY-VCH Verlaa GmbH.2000

1 Introduction Hisashi Yamamoto

The purpose of this handbook is to review the use of Lewis-acid catalysts in modern organic synthesis. Activity in this area has grown by leaps and bounds in the past few decades, as is clearly shown below. The commercial availability of many of these Lewis-acid reagents should encourage further development of new chemistry in this area. This topic has been the subject of several previous reviews (Fig. 1) [l]. 1200

1000

800

Number of references

ir

Achiral Lewis Acid Chiral Lewis Acid

600

400

200

0 1979

1981

1983

1985

1987

1989

1991

1993

1995

1997

Year

Figure 1. References to Lewis acids in the literature.

In this volume I have attempted to cover this field of metals comprehensively. In the recently published Encyclopedia of Reagents for Organic Synthesis, edited by Paquette, the reagent function index listed metals widely used as Lewis-acid reagents [2]: aluminum, antimony, boron, cadmium, cerium, cobalt, copper, europium, germanium, hafnium, iron, lanthanum, lithium, magnesium, molybdenum, nickel, palladium, phosphorus, silicon, silver, sulfur, thallium, tin, titanium, vanadium, ytterbium, zinc, and zirconium. A wide variety of elements can thus be used as Lewis-acid reagents and each metal has its own characteristic features. We therefore decided in this book to classify these reagents according to their metal. It need not be pointed out that Lewis acid-promoted carbon-carbon bond formation is one of the most important processes in modern organic synthesis. Classically, the Friedel-Crafts reaction, the ene reaction, the Diels-Alder reaction, and the Mukaiyama aldol synthesis are catalyzed by ordinary Lewis acids such as AICI3, TiC14, BF,.OEt,, or SnC14.These classical Lewis acids activate the functional groups of substrates, and the reactions proceed with relatively low stereo-, regio-, or chemoselectivity. When coordinated with a well-designed ligand(s), a Lewis acid has substantially different reactivity. Furthermore, designer Lewis acids lead to isolation of mono-

2

Yamamoto

meric Lewis-acid species with structural features that can be easily understood and extended to selective new designer chiral catalysts for asymmetric syntheses. Thus, metal ligand tuning is the most essential component in the design of Lewis-acid reagents (Fig. 2).

,

I

Lewis Acid Catalysts (AIC13, BF3oOEt2, SnC14,TiC14)

Classical Organic Synthesis (Carbon-Carbon Bond Formation)

I-

Diels-Alder reaction Aldol synthesis Ene reaction Friedel-Crafts reaction, etc

1 Modification of ligands _ _ ~

1 I I

Designer Lewis Acid Catalysts

1

-+

I1

I ~

Modern Organic Synthesis Stereo-, Regio- and Chemo selective reactions

r

Introduction of chiral ligand

Chiral Lewis Acid Catalysts

~~~~

JJ L

Asymmetric synthesis

I

Figure 2. Tuning of Lewis-acid reagents.

During the last decade the uninterrupted expansion of this field has continued. New Lewis-acid research is targeting more versatile, more selective, and more reactive catalysts. Each research direction synergistically helps and influences all the others. The full potential of Lewis-acid catalysts, however, is not yet realized. Today it is nearly impossible to read a single issue of a journal devoted to organic chemistry without finding that a new Lewis acid has been developed as an essential tool for synthetic transformations (Fig. 3).

more reactive

t

J more selective Figure 3. Development of Lewis-acid reagents.

Introduction

3

More reactive Lewis-acid catalysts can be obtained with more electronegative ligands. For example, the shift from TMS-C1 to TMS-OTf or TMSNTf2 gave us a much more reactive catalyst for a variety of reactions. Another example is the shift from Ar02Al-Me to ArO,AI-CL to Ar02Al-OTf and then to Ar02A1-NTf2 [3].The following concepts of ligand improvement (Eq. 1; Tf = CF3S02) are frequently used to design more reactive Lewis-acid catalysts. Me3SiC1+ Me3SiOTf i Me3SiNTf2

(1)

An even more reactive Lewis-acid catalyst can be generated by Lewis acidBrernsted acid and Lewis acid-Lewis acid combinations [4]. Anhydrous HF-BF3 and HCl-AlC13 have been classically widely used for organic synthesis as combined acid reagents. Much stronger acid systems, comprising a pentafluoride of a Group 5 element, particularly SbF5 and a strong Bransted acid such as FS03H, a well-known magic acid, have also been created [5]. Coordination of HOCH2CH2CH2NMe2 with aluminum via oxygen rather than nitrogen suggests that the alcohol hydrogen atom is a stronger acid than the aluminum. The unusually short A1-0 bond length in the structure of (‘Bu)~AI [O(H)CH2CH2CH2NMe2]suggests that instead of the alcohol-tertiary amine form, 1, the Zwitterionic alkoxide--ammonium+ form, 2, should be considered [6].

1

2

The deactivation of Lewis acids through association is well known. Thus the attachment of bulky ligand often leads to even more reactive Lewis-acid reagents because of the freeing of the reagent from steric interactions. Electron-deficient metal compounds can be significantly activated as electrophiles by dimeric association with either the same or different electrophiles. For example, coordinatively unsaturated monomers 4 are far more Lewis acidic than doubly bridged coordinatively saturated dimers 3. The same compound can, in principle, however, readily generate a species that is even more Lewis acidic than the monomer by formation of a singly bridged dimer 5 (Eq. 2) [7].

3

4

5

4

Yamamoto

How can we generate an even more versatile Lewis-acid catalyst? This is probably the ultimate goal of synthetic chemists. The recently developed chemistry of lanthanide catalysts, for example, scandium and ytterbium reagents, might be one recent achievement in this field. The catalyst can even be used in the aqueous phaseobviously not possible with classical Lewis-acid reagents [S]. Another example is pentafluorophenylborane reagents; their reactivity and selectivity are similar to those of BF3 but they can be used as true catalysts in many reactions (Eq. 3). Their unique feature comes from relatively stable pentafluorophenyl ligand in the presence of Lewis bases [9].

quantitative

How can highly selective processes be developed using Lewis-acid reagents? I would like to offer one typical example in this field of research-the chemistry of bulky aluminum reagents (Eqs 4 and 5 ) [lo].

Me- <
Me,AI

-.

A' Me- g O , T l , O p M e

Me MAD

d

O

Ph

H

-

Me3AI

.

(4)

Introduction

5

Lewis acid-mediated reactions can be classified into two groups (Fig. 4). In the first (type 1) the complex between substrate and Lewis-acid reagent produces the product. Claisen rearrangement promoted by a Lewis-acid catalyst is a typical example of this type. Some complexes formed between Lewis acids and substrates are, however, stable enough to react with a variety of reagents from outside the system to generate the product (type 2). The Diels-Alder reaction between Lewis acid-activated unsaturated carbonyl compounds and dienes is an example of type 2 reactions.

Claisen Rearrangement

->

I

Diels-Alder Aldol Esterfrcation Amidation Michael Reaction

- -___

I

~

Figure 4. Type 1 and Type 2 Lewis acid-mediated reactions.

Benzaldehyde and the bulky aluminum reagent ATPH, for example, form a relatively stable complex which when exposed to an alkyllithium reagent from outside the system generates the cyclohexadiene derivative in high yield. The reaction proceeds not via the usual 12-addition pattern but through the unique 1,6-addition process, which is very difficult in the absence of such a bulky Lewis-acid catalyst (Eq. 6) [ll].

r\'

U4LR, 0

1) ATP Hholuene, 2) Bu'LiTTHF 3) conc. HCI -78 "C

0

R = H 181% = Me: 93 %

A Lewis basic carbonyl group can be activated by coordination with a metal-centered Lewis acid, with profound reactivity and stereochemical consequences. In the context of asymmetric synthesis many Lewis acid-mediated reactions are known to proceed with better stereoselectivity than their non-catalyzed counterparts-very recently a variety of chiral Lewis acids have been shown to be remarkably efficient

6

Yamamoto

catalysts for carbonyl addition processes. Although the origins of many of the effects brought about by Lewis acids are still poorly understood, it is clear that the conformational preferences of the Lewis acid carbonyl complex are ultimately responsible for determining the stereochemical course of Lewis acid-mediated reactions [12]. In 1985 we reported a new cyclization process employing a chiral zinc reagent derived from dimethylzinc and optically active binaphthol [13]. The reaction proceeds smoothly at low temperature to generate the cyclization product with reasonable asymmetric induction. Since then many chiral Lewis-acid catalysts have been reported in the literature and the resulting process is now an essential tool for many asymmetric syntheses (Eq. 7).

I

I-

li

, \

? CHO

I

x

(7)

I

\

CHzCls -78-0 "C

91%yield

,

'OH

90%ee

Are enzymatic reactions really good models for laboratory chemical reactions? An enzyme is a giant molecule, large enough to support a substrate, whereas chemical reagents are much smaller molecules. Still, the much smaller molecular apparatus of man-made reagents is expected to induce reactions with selectivity comparable with that of a large enzyme. Clearly, the design of new reagents requires careful abstraction and simplification of the true mechanism of an enzyme, much like the design of an aircraft might be based on the aerodynamics of a bird. A case in point is the important role of hydrogen-bonding during enzymatic reactions. In the course of such processes, the giant template of the enzyme will specify quite accurately the position and direction of a proton for hydrogen bonding, before and after the reaction. A proton by itself cannot, however, behave in this fashion. A perfect sphere, it has no directional selectivity for hydrogen-bonding outside the domain of the enzyme, thus it is unable to act as a 'delicate finger' in an ordinary organic reaction as it does in the enzymatic transformation. It is natural to wonder whether an appropriate substitute for the proton might induce man-made reactions capable of selectivities comparable with those afforded by enzymes. A Lewis acid is an excellent candidate as a proton substitute. Thus, because an organometallic compound would have several ligands around the metal, the structural design of such a catalyst could be quite flexible. The goal, then, was to engineer an artificial proton with a special shape, which could be utilized as an effective tool for chemical reactions, by harnessing the high reactivity of the metal atom towards oxygen. In fact, throughout this handbook, we can see a number of useful processes using designer Lewis-acid reagents.

Introduction

7

References 1. (a) Yamamoto, H. Ed., Lewis-acid reagents, A Practical Approach, Oxford University Press, 1999; (b) Santelli, M.; Pons, J.-M., Lewis Acids and Selectivity in Organic Synthesis, CRC Press, Boca Raton, New York, London, Tokyo, 1996, (c) Methods of Organic Chemistry (Houben-Weyl), Additional and Supplementary Volume to the 4th Edition., Vol. E 21b; Stereoselective Synthesis (Eds Helmchen, G.; Hoffmann, R. W.; Mulzer, J.; Schaumann, E.), Thieme, Stuttgart, 1995; (d) Schinzer, D. (Ed.), Selectivities in Lewis Acid Promoted Reaction, Kluwer Academic Publishers, Dordrecht, Boston, London, 1988. 2. Paquette, L. A,, Ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley & Sons, Chichester, New York, Brisbane, Toronto, Singapore, 1995. 3. Marx, A,; Yamamoto, H., Angew. Chem. Int. Ed. 39,178 (2000) 4. Yanagisawa, A.; Ishihara, K.; Yamamoto, H., Synlett., 1997,411. 5. Kilpatrick, M.; Luborsky, F. E., J. Am. Chem. SOC.,76, 5863 (1954); Gillespie, R. J.; Peel, T. E., J. Am. Chem. Soc., 95,5173 (1973). 6. Barron, A. R. In his lecture during International Symposium of Lewis Acid Catalysis for Selective Organic Synthesis,Nagoya, 1999. 7. Negishi, E. Chem. Eur. J. 5,4112 (1999) 8. Kobayashi, S.; Ishitani, H., Chem. Rev., 99,1069 (1999) 9. Ishihara, K.; Yamamoto, H. Eur. J. Org. Chem. 527, (1999). 20. Saito, S.; Yamamoto, H.,J. Chem. Soc. Chem. Commun., 1585 (1997). 11. Maruoka, K.; Ito, M.; Yamamoto, H.,J. Am. Chem. Soc., 117,9091 (1995). 12. Shambayati, S; Crowe, W. E.; Schreiber, S. L, Angew. Chem. Int. Ed. Engl., 29, 256 (1990), Denmark, s. E.; Almstead, N. G., J. Am. Chem. SOC.,115,3133 (1993). 13. Sakane, S; Maruoka, K.; Yamamoto, H., Tetrahedron Lett., 26,5535 (1985).

Lewis Acids in Organic Synthesis Edited bv Hisashi Yamarnoto Copyright 0WILEY-VCH Verlaa GmbH.2000

2 Li(I), Na(I), and K(1) Lewis Acids Susumu Saito

2.1 Introduction Compared with representative, conventional Lewis acids such as A1Cl3, TiC14, and SnC14, etc., alkali metal Lewis acids are relative newcomers to the group of Lewis acids used for synthetic organic chemistry, and have been found to be interesting catalysts with inherent and milder Lewis acidity. A variety of metal perchlorates including LiC104, NaC104, and KC104 were synthesized during the 1920s [l], and the solubility and other physical properties of LiC104 solution were investigated in detail [2]. Later Pocker, Weinstein, and others focused on the astonishing behavior of concentrated LiC104 as a reaction promoter not only in aprotic but also in protic solvents [3]. Its Lewis acidic nature has also been highlighted both experimentally and theoretically [4]. In 1986 Braun and Sauer discovered the enhanced endo selectivity in the Diels-Alder reaction of methyl acrylate (MA) with cyclopentadiene (CP) with a concentrated solution of lithium perchlorate (LiC104) in EtzO, THF or DME [5]. Four years later Grieco et al. described a similar solvent system, 5.0 M LiC104 in Et20, with comparable, perhaps greater, accelerating effect on the Diels-Alder reaction; it has been widely used in cycloaddition reactions [6]. After these preliminary discoveries, other useful transformations involving LiC104 have been reported-for example sigmatropic rearrangements, Mukaikama aldol and Michael additions, ring-opening functionalization of oxiranes, and some substitution reactions. With the continuous and tremendous effort applied especially by Grieco and co-workers, LiC104 has become a most popular and powerful reagent, with the diverse utility of all the alkali metal Lewis acids. Grieco first suggested that LiC104Et2O (LPDE) solutions, by analogy with water, generate an internal pressure that presses organic reactants together. Dailey later presented evidence that the rate accelerations observed in some Diels-Alder reactions with LPDE are consistent with lithium ion catalysis [7]. Much of this chapter will be devoted to the demonstration of the vast synthetic utilities of LiC104. It is widely accepted that perchlorates are potentially explosive and should be handled with special care. In fact, the decomposition of LiC104 starts at ca 400 "C and becomes rapid at 430 "C, yielding LiCl and O2 [S]. A violent explosion has, furthermore, been reported after contact of cyclooctatetraene with LiC104 in Et2O under reflux [9], and under other conditions also [lo]. Attendant safety and stability are highly required. Later, lithium hexafluorophosphate (LiPF6) [I 11, lithium tetrafluoroborate (LiBF4) [12], lithium trifluoromethanesulfonate (lithium triflate; LiOTf) [13], and lithium bis(trifluor0methanesulfonamide) (LiNTf2) [14] proved to be more useful and safer variants in similar carbon-carbon bond-forming reactions. All these lithium reagents are now commercially available and each has its characteristic advantages, although their synthetic utility is rather limited and still being pursued. Although the sodium and potassium salts, NaC1O4 and KC104, have also been employed as Lewis acids in organic syntheses, their synthetic potential and versatility are so poorly understood, so far as we know, that very few attractive cases are included in this chapter. Na(NTf2) has also been synthesized [15], but its synthetic application remains unexplored.

10

Saito

Alkali metal halide salts have weaker Lewis acidity than those of other alkali metal salts containing the counter anions C10, and B E , and thus contribute less to the direct promotion of chemical processes, resulting in poor synthetic efficacy. Their Lewis acidic behavior, however, has unique characteristics, and their critically important roles are featured in Section 2.2.2. Organolithium compounds and lithium amides have found tremendous application in selective organic syntheses [16], and these reagents are regarded as either strong bases or nucleophiles. It also seems that the lithium in these species contributes in the reaction as a Lewis acid. Recent impressive applications are also highlighted later, in Section 2.2.1.2.

2.2 General Properties of Alkali Metal Salt 2.2.1 Lewis Acidic Properties of Alkali Metal Salt 2.2.1.1 Relative Lewis Acidity Because LPDE is an important and versatile catalyst, it is of great value to assess the Lewis acidity of this medium. There are a variety of ways in which Lewis acidity can be evaluated [17]. That the corresponding counter-anion can affect the Lewis acidity of Li+ was documented in the early work of Pushin et al., who showed that catalytic activity of a series of lithium salts decreased in the order of C104 > Br- > C1- [18]. Pagni, Kabalka, and co-workers defined the Lewis acidity of LPDE by its ability to catalyze reactions and to regulate its regio- and stereochemical pathways [19]. The regioselectivity of the [4 + 21 addition of isoprene with MA, and the diastereoselectivity in the reaction of CP with (-)-dimenthy1 fumarate were investigated (Sch. 1).Compared with the relatively strong Lewis acids A1C13 and Et2AlC1, this selectivity is moderate, irrespective of the concentration of LPDE. Childs and co-workers examined the effect of Lewis acids on the 'H and 13C NMR chemical shifts of conjugated aldehydes and ketones [20]. Unlike the examples cited by Childs, in which the complexa-

1,9substituted

1,Csubstituted

6.OM LPDE : 1:3.4 AIC13 : 1:19

C02R* de % 3.OM LPDE : 20.6 38.3 AICIdEt20 Et2AICl/toluene : 91

Scheme 1

C02R*

Li(I), Na(I), and K(I) Lewis Acids

11

tion of typical Lewis acids with crotonaldehyde is essentially irreversible (large equilibrium constant), LiC104 reversibly coordinates not only to crotonaldehyde, but also to Et20. According to Childs the magnitude of the induced shift is a direct reflection of Lewis acidity. The equilibrium constant (Kcq) and induced limiting chemical shift (Ad,) for the formation of the complex of crotonaldehyde in LPDE at -20 “C were estimated to be K,, = 3.20 and Ad, = 0.760.02. The latter value is considerably smaller than those resulting from BBr3 (Ad, = 1.49), BF3 (Ad, = 1.17), and AIC13 (Ad, = 1.23) in CH2C12.From these data, the lithium ion in LPDE seems to be a relatively modest or weak Lewis acid. The rate of reaction of the LiC104-catalyzed hetero-Diels-Alder reactions was investigated by varying the solvent (Sch. 2) [21]. For the solvents tested (Et,O, MeCN, acetone, MeOH, and isopropanol), it was demonstrated that the catalytic species was the lithium cation and that its active concentration depended upon the solvating power of each solvent. The effect in E t 2 0 was significant, indeed, a 2.16 M LPDE solution (kcat)gives a rate that is 300 times that in pure Et20 (ksolv)at 20 “C. Apparently the rate (kcat) at a same concentration increases in the order E t 2 0 > MeCN > methanol > isopropanol > acetone. In contrast, the relative rate enhancement (kcat/ ksolv)increases in the order Et2O > MeCN > acetone > methanol > isopropanol.

Nd

ca 0.5M L i C Q in:

+

’’z,OEt

I

Ph

Ph

Phl

Et20 MeCN MeOH i-PrOH acetone

rate constant at 20 oc : 61.5 x lo4 M-‘s-’ :35.9x 1O4M-’s‘’ : 25.6 x lo4 M-’s-’ : 23.5 x lo4 M-’s-’ : 9.6 x 1O4 M-’s”

Scheme 2

Continuous effort by Righetti et al. was devoted to investigation of the effect of different metal salts on the rate of the Diels-Alder and hetero-Diels-Alder reaction in acetone solution (Sch. 3) [22]. LiC104, NaC104, Ba(C104)2, and Mg(C10& were compared to evaluate the distinctive Lewis acidic nature of each species. When the effect of different cations is compared at the same concentration, Na is 2-3 times less effective than Li, which is 2-3 times less effective than Ba. The outstanding result, however, is that Mg is ca

x+@-* 0

21-

N. N

Ph

Scheme 3

rate constant at 30°C

.. 0

0

Pi

0

1.4M 1.4M 1.4M 1.4M

NaC104 : 7.1 x lo5 M-’s-’ : 14.6 x lo5 M-’s-’ LiC104 Ba(C104)2 : 74.9 x lo5 M - k ’ Mg(CIO& : 324 x lo5 M-’s-‘

rate constant at 20°C 1.4M 1.4M 1.4M 1.4M

NaC104 LiC104 Ba(C104)2 Mg(CIO,&

: 2.1 x lo6 M-’s-’ : 9.0 x 1 lo6 M-’s-’ : 12.1 x lo6 M-’s-’ : 59.6 x lo6 M-’s-’

12

Saito

10-20 times more efficient than Li. The rate increases with increasing charge density of each cation, because the order of the chargehadius values (Mg' > Ba+ M Li' > Na+)parallels the order of reactivity. Pocker and Ellsworth showed that the allylic rearrangement of 1-phenylallyl chloride to cinnamyl chloride in aprotic solvents undergoes substantial rate enhancement on addition of LiC104 (Sch. 4) 1231. For example, at 25 "C the first-order rate constant of this isomerization in pure E t 2 0 is k = 2.5 x 10" s-l whereas in 3.39 M LPDE, it is k = 2.14 x s-l -an overall 85 600-fold increase. In the other solvents the results are indicative of varying catalytic efficiency: THF (0.0-1.53 M LiClO,; 266-fold), propylene oxide (0.0-3.01 M LiC104; 40-fold), diethyl carbonate (0.0-3.02 M LiC104; 9300-fold), and DMF (0.0-3.01 M LiC104; 40-fold). Pocker also hypothesized on the coordination of LPDE-at concentrations below 4.25 M LPDE solutions exist as dietherate ions, Lif(OEt2)2C10,, whereas the dietherate and monoetherate Li'(OEt2)C10, coexist at concentrations above 4.25 M. The concentration of the latter species increases until the solubility limit is reached.

6'"e CI

(J+-"'

Scheme 4

An enormous rate acceleration in LPDE was also reported for the ionization of p methoxyneophyl p-toluenesulfonate 1241. In the absence of LiC104, the rate of the ionization in AcOH ( k = 11.9 x lo5 s-l at SO "C) exceeds that in EtzO (0.5 x lo3 s-' at 75 "C) by a factor of 2 x lo4, and is also much faster in other solvents such as DMSO (18.2 x lo's-' at 75 "C), acetone (0.857 x lo5 s-l at 75 "C), and EtOAc (0.113 x 10's-1 at 7.5 "C). E t 2 0 becomes a better ionization medium than AcOH, however, when concentrations of LiC104 exceed 0.036 M (at SO "C). Finally, the rate in E t 2 0 is increased by a factor of 10' by 0.1 M LPDE. Similarly, the rate of ionization of spirodienyl p-nitrobenzoate was further examined to account for the remarkable effects of LPDE 1251.

2.2.1.2 Lewis Acidic Functions in LithiumAmide and Organolithium Several Lewis acid-base interactions between alkali metal cations and heteroatomcontaining molecules are indispensable in the promotion of reactions involved in critically important and fundamental transformations-deprotonation with lithium amides at the a-hydrogens of carbonyl or imino compounds and the addition of organolithium compounds to such electrophilic substrates. Because it is impossible to cover the multitude of these and other closely related subjects, this chapter describes only briefly general aspects of current interest.

Proton Abstraction with LithiumAmide and Organolithium The importance of open dimers in organic reactions has received widespread attention in recent years (Fig. 1). Determination of the crystal structural of an open dimer of lithium amide also led to the proposal that the coordinatively unsaturated open dimer is a critical intermediate [26]. Collum and co-workers used MNDO calculations in which extensive studies of monomer- (M-1) and open-dimer (OD-1)-based pathways afforded insight into mechanisms [27].

Li(I), Na(I), and K(I) Lewis Acids

13

S = solvent OD-1:open-dimer (eight-membered transition state)

M-1: monomer (six-membered transition stare)

Figure 1

In general, ketones are predicted to metalate via the open dimer pathway whereas imine metallations proceed more readily via monomers. By contrast, increased steric demands of the substrates promote the monomer pathways. It is reasonable to ascribe this to a decrease in congestion in monomers relative to open dimers. Indeed, for metallation of imine 2 with LDA in THF (4 must be a real species) the rate behavior was consistent with the mechanism specified by M-1. When 2:2 TMEDA-LDA complex 1 was used for deprotonation of 3, a solvent-free open dimer proved to be a plausible reactive intermediate (Sch. 5 ) [28]. Accordingly, the rate of imine metalation depends strongly on the solvent and substrate used [29]. Kinetic evidence obtained in the enolization experiment with sterically demanding ester 5 showed disolvated LDA monomers to be the reactive form, providing the first direct support for Ireland’s hypothesis of cyclic transition state structures in LDA-mediated enolizations (Sch. 6) [30].

N

A

I

2

1

Scheme 5

4

14

Saito

-d[5]/dt = k[THF][5][(LDA*THF)2]1’2

Scheme 6

A very recent ‘slick’ investigation by Majewski and Nowak also supports Collum’s theoretical and experimental results. They measured decreases in optical purity of (R)-6, originally in the optically pure form, during the course of deprotonation and provided the rate of the enolization (Sch. 7) [31]. Lithiation of bulky ketone 6 with LDA is first-order in the ketone and 0.5-order in the base. This result is consistent with a spectroscopically invisible dimer-monomer pre-equilibrium of LDA which is also suggested by Collum’s results. Fractional order in LDA suggests a pathway involving the monomer of the amide and rate-determining proton transfer. Most notably, a combination of both monomer and dimer pathways is possible, especially for substrates less sterically hindered. OLi

Scheme 7

Beak and coworkers reported the asymmetric deprotonation and subsequent electrophilic alkylation of Boc-pyrrolidine 7 by using of the i-PrLi-(-)-sparteine complex as an alternative deprotonating agent [32]. The structure of i-PrLi-(-)-sparteine in E t 2 0 is in agreement with 8, established by NMR spectroscopy. They demonstrated that prelithiation complex C is involved before rate-determining deprotonation. The reaction is first-order in 7 and zero order in i-PrLi. From this and other information, they concluded that the complexation-decomplexation equilibrium is rapid relative to the deprotonation, and the equilibrium constant (K,) is heavily shifted to the side of complex C (Sch. 8) [33]. Although complex 9 is consistent with the data, prelithiation structures, open dimer 11 and monomer 10 cannot be excluded because of the high enantiomeric excess (ee), possibly induced by a close contact between chiral species and 7.

Li(I), Na(I), and K(I) Lewis Acids

15

o + $010 7

10

11

Scheme 8

Nucleophilic Addition with Organolithium

There is similar controversy over whether the monomer (M-2) or open-dimer (OD-2) transition state governs the mode of addition of organolithium compounds to carbonyl compounds (Fig. 2). Although a four-center transition state M-2 involving the monomer has long been believed to participate in the alkylation [34], some ab initio calculation evidence shows that an open dimer OD-2 or related dimeric structure is more likely to be involved in the reactions, especially when (MeLi)2 participates [35, 361. McGarrity and co-workers showed that the dimer of n-BuLi is tenfold more reactive than the tetramer toward benzaldehyde in THE Even at high dilution there is no detectable concentration of the monomer [37]. Sn

OD-2 open dimer (six-membered transition state)

Figure 2

M-2 monomer (four-membered transition state)

16

Saito

Three possible mechanisms have been proposed for the nucleophilic alkylation of a&unsaturated ketones: (i) contact ion pair (CIP) with Li+ assisting; (2) separated ion pair (SIP) with Li+ assisting (SIP-1); (3) SIP with no Li+ catalysis (SIP-2) (Fig. 3).

0 Li(HMPA),

CIP Cle Li-assisted 1,2-adduct

SIP-1 Sle Li-assisted 1,2- and 1,4-adduct

SIP-2

SIe no Li-assisted 1,4-adduct

Figure 3

Cohen has proposed that the regioselectivity (1,2- relative to 1,4-addition) is influenced by whether the Li+-catalyzed CIP or SIP mechanism (CIP or SIP-1, respectively) is involved, the former being consistent with 1,2-addition, and the latter with 1,4-addition [38]. Reich and Sikorski recently focused their interest on the regiochemical outcome of the HMPA-organolithium system when reacted with 2-cyclohexene1-one (12) (Sch. 9) [39]. They found several examples illustrating the lack of a direct correlation between the CIP/SIP-1 ratio and 1,2:1,4-addition. Experimentally, (bis(3,5-bis(trifluoromethyl)phenylthio)methyllithium (13), which is almost fully separated in THF, actually resulted in a preponderance of 1,Zaddition (61 YO)in 3:2 THF-Et20. In contrast, the reaction, which is 34 % complete in 30 s at -120 "C in THF-Et20, proceeded to less than 3 YO in 1 h when HMPA (4 equiv.) was present i.e. the rate decreased by a factor of 1800. Enhancement of 1,Cselectivity is generally achieved by combined use of HMPA and organolithium compounds. They hypothesized that rate-retarding and conjugate addition-enhancing effects of HMPA arise in part from suppression of a lithium-catalyzed process, in accord with mechanism SIP-2.

13 (= RLi) \

12

1.4-adduct

1,Fadduct

F3C

Li 13

Et90 : <1:>99 THFIEGO : 1,Z- 21 ,Cadduct THF/EtZO/HMPA : >99:<1

Scheme 9

CF3

Li(I), Na(Z), and K ( I ) Lewis Acids

17

2.2.2 Alkali Metal Halide Effect 2.2.2.1 Salting-Out Effect It has been suggested that hydrophobic effects are the principal forces responsible for enhancement of the rate of Diels-Alder reactions performed in aqueous medium. In aqueous solution organic solutes tend to aggregate to reduce their contact with the aqueous solvent. This hydrophobic packing gives rise to a large acceleration of the rate. LiCl is a salting-out agent which makes organic substrates less soluble in water and in doing so enhances the hydrophobic effect, leading to rate acceleration. An interesting relationship between the rate of the aqueous Diels-Alder reaction of anthracene-9-carbinol (14) with N-ethylmaleimide (15) and the size of the counter anion of a series of sodium salts (NaX) has been reported (Sch. 10). The rate is linearly related to the crystallographic radii of the anions-the rate of the Diels-Alder reaction in water diminishes as the radius of the anion increases (Cl- < Br-< BF;; < C10, < P& < As&), thus approximating a Hofmeister series (lyotropic series) [40].

& ( -& E: 45°C

+

/

/

14

/

1

15

NEt

water

rate constant

water only : 230 x 103 ~ - 1 s - 1 ::298x103M-’s-’ 308 x 103 M-1s-1

,

,/

OH

NaBF4 NaC104 NaPF6 NaAsF6

: 224 x 1o3 M-ls-l l o 3 M-’s-’ : 190 x 1O3 M-’s-’ : 179 x l o 3 M-’s-’ : 205 x

Scheme 10

Closely related to these investigations, Breslow and co-workers studied the DielsAlder reaction of CP with methyl vinyl ketone (MVK) in ‘water-like’ solvents, ethylene glycol and formamide, in the presence of lithium salts. They found clear differences and similarities between water and these two solvent systems. In the absence of Li salts, the second-order rate constant for the reaction at 20 “C increased in formamide (k2 = 3184 x lo5 m-l s-’), and even more in ethylene glycol (480 x lo5 m-’ s-l), relative to a polar solvent such as methanol (75.5 x lo5 m-’ s-l) or non-polar solvent such as isooctane (5.940.3 x lo5 m-’ s-’). The reactions in both polar solvents were faster in the presence of LiC104 than in the presence of LiC1, although the perchlorate ion has less salting-out effect than chloride ion in water [41].

2.2.2.2 Complexation with Enolate and Metal Amide LiX is a weak Lewis acid that forms mixed aggregates with lithium dialkylamides, enolates, alkoxides [42], peptides and related ‘hard Lewis bases’(LiX effect). Aggregates of LiX with either lithium amides or enolates have been characterized by X-ray crystallography [43]. Mechanistic studies by semi-empirical methods [44] and by NMR analysis combined with kinetic investigation also shed light on the elusive behavior of the LiX-enolate aggregates in the solution state. LiX, therefore, often has a dramatic effect on reactions involving these species. The generation of lithium eno-

18

Saito

lates of tert-butyl5-hydroxyhexanoate (16) is accelerated by LiOTf or LiI. Thus ester 16 was converted to the enolate intermediate 1-1 by Et2NLi (3 equiv.) in the presence of LiOTf (3 equiv.) at -100 "C in THF-HMPA, then treatment with acetone to give the aldol adducts syn- and anti-17 (91:9) in 92 % yield (Sch. 11) [45]. Without LiOTf, the diastereoselectivity and the yield of the products are disappointingly lower. Et2NLi (3 eq) TfOLi or Lil THF-HMPA

=Ot-Bu

Ot-Bu

16 syn-17

anti-17

LiOTf : 92% (919) Lil : 79% (88:12) none : 53% (86:14) 1-1

Scheme 11

In the enolization of 3-pentanone by lithium 2,2,6,6-tetramethylpiperidide (LTMP), kinetic EIZ selectivity normally obtained in THFat low temperature is only about 51, whereas in the presence of 0.3-0.4 equiv. LiCl, this ratio increases to 50-6O:l. Surprisingly, with large quantities of LiCl (1 equiv.), the selectivity returned to ca 1O:l (Sch. 12) [46]. Li-arnide

18

-;!,

Me3SiCl

Z EZ LTMP (no LiCI) : 5:l LTMP-LiCI (0.3-0.4 eq) : 50-6O:l : 1O:l LTMP-LiCI (1 eq)

Scheme 12

Collum and co-workers investigated the aggregation structure of LDA with LiX. At high LiCl concentrations the mixed-dimer structure MD-1 is the major LDA species; at lower concentrations two distinctive structures are possible, the mixed-cyclic trimer MCT-1 and the ladder-trimer LT-1 (Fig. 4) [47]. Rigorous establishment of the presence of LTMP-LiX aggregates has not been forthcoming, because the various LTMP

MCT-1 mixed-cyclic-trimer

LT-1 ladder trimer

at lower [LiCI]

Figure 4

MD-1 mixed-dimer at higher [LiCI]

Li(I), Na(I), and K(I) Lewis Acids

19

aggregates adopt a variety of conformations [48]. They also confirmed the presence of a limited concentration of mixed dimers MD-2 and MD-3 when 1 equiv. LDA was treated with 1.0 equiv. of the lithium enolates of pinacolone and pyrrolidine propionamide, respectively (Fig. 5). The X-ray crystal structures of the mixed aggregates of lithium and sodium amides with enolates have also been discussed [49]. Me.

MD-2

MD-3

v

Figure 5

There are several examples of the effect of LiX on enolate aggregation leading to increased enantiomeric excess in asymmetric chemical events. Koga and co-workers developed an efficient enantioselective benzylation of the lithium enolate of 19 by using a stoichiometric amount of chiral ligand 22 with LiBr in toluene [50].The chiral lithium amide 22 was prepared by treatment of a mixture of the corresponding amine 21 and LiBr in toluene with a solution of n-BuLi in hexane. Sequential addition of ketone 19 and benzyl bromide gave rise to 20 in 89 YOyield and 92 YO ee. The amount

APh

0

?IOnOMe

19

21 : X = H 22 : X = L i

20

OSiMe3

8

S

MeLi-LiBr

21 t

_ j

EQO-DME

t-Bu

equatorial attack

(s)-23

24

25

26

27

69% (12.5:0.5:9.5:77.5)

r

OSiMe3

1

t

toluene 20

Scheme 13

+

26

+

75% (88:4:0.5:7.5)

L

MeLi-LiBr

25

axialattack

1) 30, -78 "C

&M~

2) AcOH

J

88% 91% ee

29

0APh HNxOnNMe2 30

27

20

Saito

of asymmetric induction is highly dependent on the solvent and on the Li salt used. Among several Li salts tested (LiF, LiCl, LiBr, LiI, LiOBut, and LiOTf), LiBr gave the best result. Another way of generating the lithium enolate-LiBr aggregate, starting from silyl enolates and an Et,O solution of the MeLi-LiBr complex, is applicable with equal success in a similar asymmetric processes. This method of forming the enolate was used to investigate the stereochemical course of the alkylation of ketone enolate 23 [51]. The results revealed that (R)-23 gave 24 preferentially via axial attack, whereas (S)-23 led to 27 via equatorial attack. The different diastereoselectivities observed strongly suggest that the structural influence of 22 dominates the stereoelectronic effect on stereoselective alkylation. Use of a stoichiometric amount of chiral reagent 30 and similar LiX concepts results in asymmetric protonation of 28. The effect of LiX is remarkable-without the use of LiBr the product 29 is completely racemic (Sch. 13) [52]. Similar enhancement of ee is also observed in the asymmetric protonation of prochiral enolates, for instance 31, by use of a chiral imide 32 with LiBr or LiCl as additive; LiC104, LiI, or NaBr are ineffective [53]. In terms of high ee EtZO is generally superior to THF as solvent when used with LiBr (Sch. 14). A mixed aggregate of MD4 is probably formed as an intermediate, because higher concentrations of LiBr suppress the generation of a monomeric lithium enolate to give exclusive formation of an enolate-LiBr mixed aggregate [54]. This effect of LiBr works negatively, however, in the protonation of enolate 33. 0

SiMe3 n-BuLi, MX, -4. - 8

II

32

I

solvent

u

-78"C, 2h *

v""mb5n11 . . _ I ,

31

MX, (equiv)

none THF none Et20 LiBr (1) THF LiBr (1) Et20 LiBr (2) Et20 LiBr (5) EtpO LiBr (10) Et20 LiCl (5) EtPO LiC104 (5) Et20 Lil (5) THF NaBr (5) THF

32

&RC5HII MD-4

Scheme 14

solvent

% ee

* 33

63 74

79 83 85

90 88 77 72 40 65

Li(I), Na(I), and K(I) Lewis Acids

21

33

Enantioselective benzylation of ketone 19 gives further insight into the LiX effect (Sch. 13). In the absence of LiBr, the amount of ee is time-dependent, increasing as reaction time is increased. This phenomenon can be rationalized in terms of the effect of LiX which is gradually formed as the reaction proceeds, and which is assumed to involve conversion of a poorly selective aggregate into a much more selective mixed aggregate. Detailed NMR analysis by Koga [55] and by Collum and others [56, 571 have afforded some clarification of this critical issue. The diverse structures of lithium enolate-LiX aggregates in solution were partially elucidated (Sch. 15): (i) under otherwise identical conditions the ee of product 23 depends on the silylating agent usedfor Me3SiX (X = C1, Br, I) ee decreases in the order Me3SiC1 > Me3SiBr > Me3SiI; (ii) In the presence of LiX ee decreases in the order LiCl > LiBr > LiI, because of the behavior of Me3SiX, and is temperature-dependent-LiBr and LiI resulted in lower ee at -114 "C than at -78 "C; (iii) in the absence of LiX, the structure of 35 is consistent with homo-dimer HD-1.

(Rq-35 MeaSiX THF, -78 "C IQ method

t-Bu

X = CI : 71 %, 90% ee X = Br : 86%, 65% ee x = I : 97%, 31Yoee t-Bu

(5)-23

34

(R,R)-35,LiX 34

* (5)-23 Me3SiX THF, temperature EQ method

LiCl (3.6 eq) LiBr (3.6 eq) Lil (3.6 eq)

-78 "C 88% ee 86% ee 43% ee

-114°C 91 Yo ee 71% ee 37% ee

Scheme 15

When LiCl or LiBr is exposed to 35, two new mixed aggregates LT-2 and MD-5 seem to be formed. Although the latter species is considered to be responsible for high enantioselectivity (Fig. 6), structure MD-5 is very minor species when 1 equiv. LiBr is employed, and the homo-dimer HD-1 can be detected in a reasonable amounts even in the presence of 3 equiv. LiBr. LiI has the least influence on the deformation of HD-1, and does not, therefore, result in detection of mixed aggregate MD-5 on the NMR time-scale. The effect of the contribution of HD-1 (X = Br) to the depro-

22

Saito

tonation is not as small as that of HD-1 (X = Cl). To whichever species, MD-5 or HD1, the equilibrium shifts, catalysis that involves the latter species must predominate to preserve high ee.

HD-1

homo-dimer

LT-2

MD-5

ladder-trimer

Figure 6

Substantial improvements of the ee of another desymmetrization process are also observed in the presence of LiCl (Sch. 16). Results obtained for formation of enol silane 36 show that when a base is reacted with the ketone before Me3SiC1 treatment (external quench: E Q method), the ee is low (33 YO).Under the external quench technique in the presence of LiCl (10 mol YO),however, the ee is enhanced to 84 %, comparable with the 82 YOee obtained by an internal quench technique (IQ method: addition of Me3SiC1 before treatment with 35). It should be noted that unlike the EIZ ratios and ee mentioned above (Sch. 12), no subsequent drop in ee is seen when 1 equiv. or more LiCl is used. Further experiments involving the LiC1-assisted aldol reaction of tropinone 37 also resulted in increased ee [57].

IQ method : 82%ee EQ method, LiCl (0.1 eq) : 84% ee Me N

1) (S,S)-35 THF

37 EQ method (no LiCI) : 24% ee EQ method, LiCl (0.5 eq) : 78% ee

Scheme 16

In the development of chiral lithium amides which result in higher ee, the effect of a diverse set of substituents R and R1 in 38 was examined. It was shown that ee increases as the size of substituent R' becomes bulkier, and also as the amount of fluorine in R increases. In THF, 38a occurs as a monomeric structure M-38a in either the presence or absence of HMPA. Fluorinated base 38b has also been shown to be monomeric in THF, consistent with structure M-38b where the fluorine atoms do not act as internal chelating ligands. In the presence of LiC1, the solution structure of labeled 38b was examined by 6Li and "N NMR in THF-d8. The 6Li-1sN coupling patterns showed that mixed dimer MD-6 was formed, as also illustrated with 38a. The absolute configuration of the products renders the OD-1 structure of transition state TS-1 most likely (Fig. 7 ) [58].

Li(I), Na(I), and K(1) Lewis Acids

23

Q C N e N , R MD-6

TS-1

38a : R = cH2t-B~; R' = H 38b : R = CHzCF3 ; R' = H

Figure 7

An attempt to use a catalytic amount of chiral ligand 40 in a similar asymmetric benzylation process resulted in equal success (Sch. 17). To promote catalysis effectively, N,N,W,N'-tetramethylethylenediamine (TMEDA) or the analogous amine 41 was added to trap LiBr which otherwise strongly complexes with the catalytic amount of the chiral ligand 40, thereby suppressing the desirable benzylation. In 1,2-dimethoxyethane (DME), the use of 0.05 equiv. ligand 40 with 2.0 equiv. 41 is sufficient to achieve a maximum ee of 96 %. The benzylation rate of 39 is considerably greater, as a result of complexation with tetradentate chiral ligand 40 rather than with bidentate achiral ligand 41, thus enabling the preferable asymmetric catalysis [59].

OSiMe3 MeLi-LiBr (1.O eq) EtzO

40(20 additive ma'%:

&,,,,

BnBr

~fiA~'g~NMe~~

/

40

39 additive

= ~TvEDA = M~~""./'NM~~ 41

: 89%, 86% ee : 83%, 92% ee

Scheme 17

The behavior of the bidentate amines 38aH and 38bH is not only interesting but also completely different on treatment with lithium amide 43. As shown in Sch. 18, the equilibrium is shifted to the left for 38aH, but to the right for 38bH. The ketone-enolization utilizing tridentate amides proved sluggish because the Lewis acidity of Li' in 43 is substantially lower owing to complexation with the additional internal amine. It is thus possi-

38bH

Scheme 18

38b

24

Saito

ble to discover another catalytic cycle that utilizes a catalytic amount of chiral amine 38bH (30 mol YO) by considering these distinctive characteristics of the three amines (Sch. 19). In the presence of other additives such as HMPA (2.4 equiv.) and DABCO (1.5 equiv.), the desymmetrization of 34 proceeds giving (R)-23 in 83 YOyield with 79 YO ee [60].Most notably, LiX is not required in this catalytic process.

Scheme 19

LiX affects the course of the Wittig reaction and its modified versions in many important ways. In 1984 Masamune, Roush and co-workers reported that lithium halides are effective in the generation of carbanions such as 45 in the Horner-Wadsworth-Emmons (HWE) reaction involving base-sensitive substrates and weak bases such as amines [61]. Li' probably forms a tight complex with the carbanion derived from phosphonate 44,thereby enhancing the acidity of the latter. Treatment of aliphatic, a$-unsaturated, and aromatic aldehydes with triethyl phosphonoacetate and LiC1-i-PrzNEt (or DBU) in MeCN leads to high yields of E configured unsaturated esters. The mild conditions used in this procedure occasionally become critically important; for example, base-sensitive substrate 46 and aldehyde 47 undergo HWE coupling to afford ketone 48 in 95 YO yield, with no evidence of epimerization at the chiral a-position, or self-condensation of the aldehyde (Sch. 20). When Et3N is used as a weaker base LiBr or MgX2 (X = C1, Br) is more effective than LiCl [62].

44

45

OHC7

LiCI, DIPEA, MeCN 24h,rt

Scheme 20

n

25

Li(I), Na(I), and K(I) Lewis Acids

2.2.2.3 Complexation with Peptide To achieve selective functionalization at a specific site of polypeptide derivatives, it would be most attractive to introduce new selectivity by electrophilic alkylation. This is hampered because many acidic protons in polypeptides are subject to deprotonation. Problems with limited solubility of oligopeptides and proteins in aprotic solvents are serious obstacles which must be overcome, because most useful and reactive organic reagents such as RLi or R2NLi are only compatible with these solvents. Seebach and coworkers found that LiCl and other alkali metal salts (LiBF4, LiI, LiBr, and NaBr) disrupt peptide aggregation and increase the solubilities of peptides in ethereal solvents, often 100-fold or more [63]. The potential of peptides for forming complexes with alkali and alkaline earth metal cations has been shown for amino acids and peptides in crystals [64] and in solution [65]. The same effect can be produced by use of excess LDA for peptide deprotonation. These solubilizing effects are interpreted as the result of a deaggregation of cross-linked aggregates between the polylithiated species to form mixed dimers MD-7 and MD-8 (Fig. 8). OLi

R

Li:

-

R

":

-1

,Li 0

I

I/o\ Li, ,Li J,

MD-7

-

excess R2NLi

Li,/o\,Li

Li:

,Li

0

0 -I-

x,

LiX -1

I-

*

I

I/ox Li, ,Li X

I

" Li/O

MD-8

Li/O

Figure 8

These effects render LiCl a useful additive in the chemical modification of peptides. For example, deprotonation and methylation of 49 occurs regioselectively at the methylene of the glycine moiety, showing that the yield can be increased by addition of LiCl and n-BuLi (Sch. 21) [66]. LiCl, indeed, renders the reaction mixture homogenous and more easily stirred. The effect of n-BuLi is worthy of comment-complexes of Li-enolate aggregates A-1 with i-Pr2NH might be present. These aggregates were sometimes responsible for 'reprotonation' which leads to formation of starting material upon the addition of electrophile [67]. Thus 're-deprotonation' of i-Pr2NH as a result of addition of n-BuLi, and subsequent reaggregation to mixed dimer MD-9, might result in increased yield (Fig. 9).

49 (Boc-Ala-Sar-MeLeu-OH)

Scheme 21

80% ( D L = 3.7:l)

26

Saito

I

A-1

MD-9

Figure 9

To learn how and to what extent peptide-forming reactions are tolerant of such Li salt additives, Seebach demonstrated the effect of some LiX (X = C1, Br, C104, BF4) on yields, by-product formation, racemization, and kinetics of peptide-coupling reactions in solution [68]. As exemplified by a model synthesis of peptide Phe-Ala from Ac-Phe-OH and H-Ala-OMe.HC1, the potential of typical condensation agents (mixed or symmetrical anhydrides, DCCI, DCCI-HOBt, BOP agent, TBTU agent) together with LiXs was tested (Sch. 22). Most reactions generally suffer from considerable racemization and poor yields in the presence of LiXs, except for a few examples using less basic LiBF4, the salt recommended for stereochemical reasons. The possibility of using 2-protection at the a-N atom was also studied in this model coupling, for which no salt effects (i.e. racemization) are observed in the course of coupling using active esters 51a, b and symmetrical anhydride 51c. It is, therefore, suggested that both these methods are applicable for stepwise coupling. The effect that

NMM, LiX DMF -40 - -20 "C 50: HCI-H-Ala-O( t-Bu)

Z-Phe-Ala-O(t-Bu)

no LiX additive LiCl (6 eq) LiBF4 (6 eq)

(L,L:D,L) : 87% (>97:<3) : 92% (>97:<3) : 89% (>97:<3)

0

0

51a (Z-Phe-ONp)

rP$

m;;NH

CI

CI

0 51b (Z-Phe-OPcp) active esters

Scheme 22

51c

0

symmetrical anhydride

Li(I}, Na(I}, and K(I} Lewis Acids

27

salts have on the reaction rate of coupling of the active ester 51a with 50 was studied further. LiCl and LiBr accelerate the reaction in DMF, but not in THE LiBF4 and LiC104 had no effect in DMF at room temperature. With KSCN and NaC104 the rate was slightly lower than under salt-free conditions. LiCl has shown promise as an additive in solid-phase peptide synthesis, enhancing resin swelling and improving efficiencies of otherwise difficult coupling steps [69]. By choosing coupling conditions described above which proved tolerant to the addition of Li salts, H-(Ala)5-Phe-(resin) was coupled to Fmoc-Ala-OH or Fmoc-Ala-OPfp (Pfp = pentafluorophenyl) with or without active esters, respectively. In general, use of more polar resins such as poly(ethy1ene oxide) on polystyrene (PEO-PS) or poly(N,N-dimethylacrylamide)on Kieselguhr (PDMAA-KG) support, results in better coupling yields and reaction rate; these are further improved by LiX additives (Sch. 23). Coupling reactions can be brought close to completion by the addition of LiCl in NMP, DMPU, or DMF-CH2C12 for PEO-PS resin, and LiCl in DMPU for PDMAA-KG resin.

Ph 0 -"$N@"' O;~$NHH

=

0

(PEO-PS)-O-Phe-(Ala)5-H

PEO-PS (polyethyleneoxide)on (PSI1%DVB)

0

Scheme 23

r

+

Frnoc'

F Fmoc-Ala-OPfp

PDMAA-KG (poly(N,N-dirnethylacrylarnide) on 'Kieselgur'

28

Saito

2.3 Application to Synthetic Organic Chemistry 2.3.1 Cycloaddition Reactions 2.3.1.1 Achiral Diels-Alder Reaction

Although the rate-accelerating effect of LPDE is not universal, Diels-Alder adducts that hitherto were inaccessible via conventional means can be realized in this remarkable medium. The [4 + 21 cycloaddition of the aza-diene 52 with MA is complete after 5 h in 5.0 M LPDE, resulting in 80 YOyield of the cycloadduct, whereas the same reaction in benzene requires 72 h at 60 "C to realize 74 YOyield. Of particular note is that furan, a poor diene, because of its aromaticity, which generally requires pressure in the range 10-20 kbar to effect cycloaddition, is also compatible with this medium. Whereas the reaction of trans-piperylene with 2,6-dimethylbenzoquinone (53) in 5.0 M LPDE is complete within a few minutes, the corresponding reaction in water is extremely sluggish (Sch. 24). Note that all reactions using LPDE are homogeneous and were conducted at ambient temperature and pressure [70].

TBDMsoq +

&C02Me

TBDMSO &7HN 0

Co2Me + TBDMSO & t: &C02Me

OTBDMS

52

5.OM LPDE ; rt, 5h : 80% (1:3.7) 2.5M LiNTf2-Et20 ; rt,l.5h : 97% (<1:>99)

o+

s$o

* 0

; rt, 9.5h : 70% (5.7:l) 5.OM LPDE 4.OM LiNTf2-acetone;40 "C, 13h : 82% ( 2.4:l)

0

53

5.OM LPDE ; rt, 30 min : 94% 4.OM LiNTf2-acetone ; rt, 30 min : 84%

Scheme 24

For more practical reasons, concentrated acetone or EtzO solutions of LiNTfz (2.54.0 M) is used as a similar medium. Under identical conditions (room temperature, 1 h), comparable results were obtained for 4.0 M LiNTfz-acetone and 5.0 M LPDE. Of interest is that the reaction of 2-azadiene 52 with N-methylmaleimide or MA in 2.5 M LiNTfz-EtzO gave rise to preferential or predominant ex0 selectivity. The

Li(I), Na(I), and K(I) Lewis Acids

29

pseudo-first-order rate constant for various concentrations of LiNTf2-acetone and Et,O, and for LPDE were measured; in general the acceleration of rate observed with these LiNTf2 media is closely comparable with the dramatic rate acceleration observed with 5.0 M LPDE [71]. A clearly apparent disadvantage of such reaction media is the environmental problem associated with disposal of excess catalyst and the possibility of perchlorate explosions. To address these problems, Reetz and co-workers utilized a catalytic amount of LiC104 (ca 7-30 mol %) suspended in CH2C12.Nevertheless, the amount of acceleration is modest (22 “C, 18 h, 100 YO conversion, endo:exo = 6.0) in the reaction of CP and MA (Sch. 25). This compares favorably with the result obtained by performing the reaction in 5.0 M LPDE (room temperature, 5 h, yield 93 %, endo:exo = 8.0). In these catalytic versions it has also been suggested by the authors that the effect of internal pressure-compression of the reactants and confined solute movement -is not operating [72].

CP

MA

endo

C02Me

ex0

LiC104 (25 mol%)-CHzC12,-15 “C, 24h : 75% (7.3:l) relative kobs = none :1 LiNTfz :2 Zn(NTfzh Mg(NTf2)2 : 1440 La(NTf2)pH20

;1”2”5”

Scheme 25

Another alternative, LiNTf,, was also employed as Lewis acid catalyst (1 mol %) in the Diels-Alder reaction of CP with MVK in CH2C12. The rate enhancement was moderate compared with that obtained with the other alkali earth and lanthanide metal imides Mg(NTf2)2,La(NTf2)3.H20, and Zn(NTf2)2(Sch. 25) [73]. A similar rate enhancing effect was observed for intramolecular Diels-Alder reactions using 5.0 M LPDE, which, after room temperature for 24 h, resulted in a poor (3:l) cis:truns ratio of the two diastereomers (Sch. 26) [74]. In contrast, the reaction was dramatically further accelerated by addition of ca 1.0 mol YO of camphorsulfonic

t

54

H cis-55 5.0~ LPDE

H trans-55 : rt, 30h : 71% (3.0:l)

5.0M LPDE : rt, 3.5h: 77% (3.7:l) CSA (1.O mol%)

Scheme 26

30

Saito

acid (CSA) -and all the reactions studied occurred with significantly improved diastereoselectivity . It should be noted that when LiC104 (30 mol %)-CH2C12 was used in place of 5.0 M LPDE, only a trace amount of 55 was produced. The product distribution in these intramolecular reactions using LPDE-CSA seems to depend not only on the substitution pattern of both the dienoic and dienophilic moieties in the starting materials but also on the relative capability of cyclization (Sch. 27). For example, the formation of 58 undoubtedly arises via competitive protonation of the terminal diene and subsequent loss of a proton leading to the migrated diene 57 which undergoes very facile cyclization compared with 56 (Sch. 28) [75]. Taking into consideration the use of Me2AlC1,which necessitates slow addition of the substrate, the LPDE-CSA medium seems more convenient.

6 1& CSA 5.OM (10LPDE mol%)

0

__t

@

rt, 6h

56

b\\\\ a 58 64%

57

Scheme 27

&

b \ \ \ \ O

5.OM LPDE CSArt, (10 18h mol%) *

/

+

Me-59 40%

59

&

10%

1.OM LiCIO4-benzene-acetonitrile : rt, 48-72h : no reaction 1.OM LiBF4-benzene-acetonitrile : rt, 72h : 299% (>99:<1) : 78'X0 (>99:<1) 5.OM LPDE-CSA (10 mol%) : rt, 4h 5.OM LPDE CSArt, (10 18h mol%)

H 81% (6:l)

5.OM LPDE

*

CSA (10 mol%) rt, 18h

Scheme 28

H

10%

H

57

/

/

H

H

0

88% (44:l)

Li(I), Na(I), and K(I) Lewis Acids

31

The potential use of 1.0 M LiBF4 in benzene-MeCN as Lewis acid catalyst was also investigated in a similar intramolecular sequence. When trienone 59 was used, a bicyclic product was formed quantitatively after 72 h at room temperature. In contrast, LiC104 (1.0 M)-benzene-MeCN resulted in merely quantitative recovery of the starting material (room temperature, 48-72 h) (Sch. 29). Subsequent results implied, however, that LiBF4 functioned as a slow-releasing source of BF3, rather than working as a cationic lithium species [76].

4.0 M LPDE t

1.O mol% CSA rt, 30 min

H 96%

4.0 M LPDE; no reaction n

g J

f i n

5.0 M LPDE

1.O mol% CSA rt. 1.5h 94%

60

.H.

61

Scheme 29

For some reason a$-unsaturated ketones are less reactive species as dienophiles. In comparison, the corresponding ketals undergo facial ionic (Gassman-type) DielsAlder reaction [77] in 4.0 M LPDE containing 1.0 mol YO CSA. The use of 4.0 M LPDE or CSA consistently furnished ketals only. Note that cycloadditions readily occur ar room temperature and 0 "C in contrast to the low temperatures required under Gassman conditions (2 mol % TfOH, CH2C12-Cl2FCCFzC1, -78 "C). Ketal 60 was also subjected to the same conditions, giving cisdl in 94 YOyield (Sch. 29). This result is in clear contrast with the similar reaction with ketone Me-59, which leads to three different products with low selectivity. The harsh conditions required for a trienoate, coupled with the lack of endolexo selectivity, can be overcome by employing the corresponding orthoester 62 (Sch. 30) [78].

A

& 62

5.0 M LPDE 5.0 mol% CSA rt, 21 h

..

76%

Scheme 30

One of the most striking features of these LPDE-promoted reactions compared with those using other typical Lewis acids is that the presence of a broad range of functional groups is appreciably tolerated. This significant characteristic advantage is

32

Saito

very useful in the preparation of complex organic molecules, because it enables shorter synthetic routes as a result of the avoidance of tedious protection-deprotection steps and interconversions of functional groups. Also, with water-sensitive substrates reaction generally proceeds smoothly in excellent yields. By taking advantage of the tolerance of many functional groups, the intermediates for the proxiphomin [79] and quassinoid families [80], and the pyrrolophenanthridine alkaloids [81] were synthesized efficiently (Sch. 31-33) .

0

0

1

R = Ph : 99% (15.6:l) R = bPr:92% (41:l)

TFA

Ph Ph’ proxiphomin

Scheme 31

R = Et : benzene, reflux 72h R = Na : H20, rt, 5h R = H : LiCIOa-EtOAc, rt

23%

67% 0% 0%

OH H0,o

0 (-)-chaparrinone

Scheme 32

Li(I), Na(I), and K ( I ) Lewis Acids

33

C02Me 5.OM LPDE

*

100 "C, 36-42h

Me0

J

I

Me0

oxoassoanine

80%

Scheme 33

Very recently a new concept has been introduced that utilizes bimetallic species for activation of carbonyl groups (A). The low Lewis acidity of Li' can be compensated for by simultaneous coordination of two Li' ions; these are oriented intramolecularly, at an appropriate distance, with the two oxygen lone-pairs of one carbonyl group. In fact, exposure of bidentate lithium Lewis acid 63 to cyclization of MVK with CP in toluene gives rise to the cycloadduct in 71 % yield. Analogous Lewis acid 64 proved less effective, and monodentate analog 65 gave poor results (Sch. 34). Another advantage of this doubly-activating system is the high solubility of 63 in nonpolar solvents [82].

t

-

B

u

w

t-Bu

t

-

B

u

t-BU

t

-

B /u

t / - B

u

t-BU$

t-BU

t-BU

t-BU

63

A

w

64

MVK

CP

toluene 0°C to rt

65

0

ex0

63 :71%(89:11) 64 : 67% (85115) 65 : 19% (80120)

Scheme 34

34

Saito

2.3.1.2 Asymmetric Diels-Alder Reaction Asymmetric [4 + 21 cycloadditions of an optically active diene, or dienophile with chiral sulfinyl groups, with a quaternary sulfur center have succeeded in the LiC104CHZC12 medium. When chiral dienophile 66 and CP were subjected to cyclization, neither the endolexo ratio nor the enantiofacial selectivity of endo adducts was high [83]. In the reaction of chiral diene 67 with MA, the best catalyst was LiC104CH2C12; this gave only endo isomers endo-68a and endod8b in 70 % yield in the ratio of 96:4, presumably via TS-2 (Sch. 35) [84].

31 Yo

48%

?-

?-

?-

R * / ‘ V

COpMe OMe ende68a

w=

q0.

?-

+ R ” ” n ,

A

21%

+

9’

R ‘ / s p

. “C02Me OMe ende68b

+

R ‘ / s o

”’CO2Me OMe exo-68a

:

C02Me

OMe exo-68b

LiC104-CHpC1p: rt, 7h : 70% (96:4:0:0)

‘SH

TS-2

Scheme 35

LPDE media promote the asymmetric cyclization of chiral diene 69 with maleic anhydride to give endo-70 highly selectively. A gradual increase in n-facial selectivity is observed when the homoallylic hydroxy group of the diene is endowed with a large protecting group. LPDE was found to be the most effective Lewis acidic medium in terms of high asymmetric induction. These effects were rationalized by proposing a model based on significant 1,3-allylic strain (1,3-A-strain) involved in transition state TS-3, consequently leading to preferred TS-4 (Sch. 36) [85]. The difficulties encountered in the development of asymmetric alkali metal catalysts are easily envisaged because a chirally designed counter-anion is required while maintaining the Lewis acidity of metal cations. Shibasaki and co-workers discovered an asymmetric catalysis, presumably involving the participation of a Lewis acidic lithium cation, during the course of their elegant approach to heterobimetallic catalysts [86]. In the course of the reaction between CP and oxazolidinone 74, they examined catalysts with the general formula of LnLi$ris((R)-6,6’-dibromobinaphthoxide) where Ln denotes a lanthanide trivalent metal. The enantioselectivity progressively improved in the order Yb < Gd < Dy = Sm < Pr < La, reaching optimum when the catalyst had La as the central metal (Sch. 37). It was proposed that one side of the n-

Li(I), Na(I), and K(I) Lewis Acids

35

Cbz TBDPSO

+ endo-epi-70

1

1

0

Cbz =

TBDPSO

TBDps8 I H

H ""COpH 49% (91.518.5)

TS-4

TS-3

TBDPSO

?92

HN Cbz

0

e

o

J

minor

endo-epi-70

major

J. O+O

1,3-A-strain

endo-70

Scheme 36

face of 74 would be concealed by the binaphthyl ring of the complex on coordination with Li. Worth mentioning is that non-polar or non-coordinative solvents such as toluene and CHzC12 must be used to induce high ee. Because mono- and dilithium salts of 6,6'-dibromobinaphthol (72 and 73)-catalyzed Diels-Alder reactions proceeded with low enantioselectivity, an asymmetric environment constructed by heterobimetallic catalysts was essential for high enantiofacial control [87]. A similar [4 + 21 cyclization between 74 and CP was also conducted with a CH2C12 solution of A1Li3tris(binaphthoxide)(75) [87, 881. Catalyst 75 has a saturated coordination number with respect to the aluminum atom, which thus no longer has vacant orbitals for further complexation with other incoming Lewis bases. Whereas the ee of the adduct was very low (16 % ee), this result strongly suggests the possibility that lithium ions in 75 serve as Lewis acids in non-polar solvents.

36

Saito

71 : R 1 = R 2 = H 72 : R1 = H; R2 = Li

73 : R 1 = R 2 = L i

qN7 0

0

+

0

catalyst (10 toluene, -20"C

74

R La Pr Sm Gd DY

Yb

time (h)

yield ("A)

endo:exo

ee of endo adduct f%)

20 20 48 48 48 48

100 94 92 92 97 100

36:1 25:l 18:l 18:l 22:1 19:l

86 79 70 68 70 58

Scheme 37

2.3.1.3 Hetero-Diels-Alder Reaction There are a few reports of hetero-Diels-Alder Reactions promoted by LPDE. Intriguing stereoselectivity is observed for the [4 + 21 cyclization between Danishefsky's diene 77 and a-heteroatom-substituted aldehydes. For example, reaction of 77 with N Boc-protected a-aminoaldehyde with 76 gave the threo isomer selectively, a result in keeping with a chelation-controlled process. In contrast, the threo diastereoselectivity observed could be reversed by changing the amino protecting group from N-Boc to N,N-dibenzyl. In this instance, the erythro isomer was generated exclusively via a nonchelation-controlled transition state (Sch. 38) [89]. A 15-25 mol % LiC104-CH2C12 medium gave cycloadducts with similar success. Imine 78 also participates in this catalytic process. It was also pointed out that for 2benzyloxylaldehyde 79, the rate of cycloaddition is considerably higher than that observed for benzaldehyde. A high level of chelation control is also observed (Sch. 39) [72]. The investigation of the Diels-Alder reaction of 2-substituted-a,P-unsaturated hydrazones in a concentrated solution of LiNTf2 in MeCN revealed a spectacular rate increase when the reaction of 80 with N-phenylmaleimide (81) was run in this media (2.5 M LiNTf2-MeCN) (Sch. 40). These conditions also enable cycloadditions to be performed with less reactive dienophiles such as dimethyl fumarate or malate; such cycloadditions result in stereospecific cyclizations [90].

37

Li(I),Na(I), and K(I) Lewis Acids

OBn

+I

B

n

O

B"OQo

(

0.5M LiC104-Et20 *

5 C H O NHBOC

o +

rt, 1.5h

OTBDMS

76

NHBOC

77

threo

3.OM LiCl04-EtpO t T C H O

+

77

NHBOC 64% (2.5:l) . .

BnO*

B

n

erythro 0

G

o

o +

rt

NBn2

NBn2

NBnp 66% (1:>99)

Scheme 38

PhhNr\Ph

78

p Ph h - n O 54%

+

Me3Si0

rt, 20h

77

no

1) LiC104 (15 mol%) PhCHpO 79

+ 77

CH2CI2;rt, 2h 2) HOAc

* PhHpCO

+

P h H p C O a o

295x5

Scheme 39

4.OM LiNTf2-CH3CN NC

rt, 3h

0 80

81

G : - P h

N

NC

O

/N,

82%

Scheme 40

2.3.1.4 Other Cyclizations

The cationic [5 + 21 cycloaddition was also conducted both inter- and intramolecularly. Exposure of 82 in 5.0 M LPDE or LiClO4-EtOAc to 2,3-dimethyl-Zbutene at room temperature did not yield the expected bicyclo[3.2.l]octenedione. After extensive studies, it was found that 1.05 equiv. Me3SiOTf in 3.0 M LiC104-EtOAc promotes the cationic [5 + 21 cyclization (Sch. 41). Control experiments demonstrated that both the Me3SiOTf and the polar medium are crucial for the success of this reaction. Indeed, treatment of a 0.2 M solution of 82 in EtOAc containing 3.0 equiv, Me3SiOTf at -23 "C afforded a 17 % yield only of the desired 83, which was accompanied by substantial amounts of benzoquinone 84 (37 YO)and benzopyran 85 (16 YO)[91].

38

Saito

Me0 OMe

0

Me3SiOTf (1.05 eq)

OMe

0 82

+ )1 Ph

3.OM LiCI04-EtOAc -23 "C, 5 min

jyMe 0

W

M

0

OMe e

85

84

Scheme 41

A intramolecular version of this potential process was conducted with equal success. In addition, a formal synthesis of the angular triquinane isocomene was highlighted (Sch. 42) [92]. 0

Me0 OMe

-& L

Me3SiOTf (1.05 eq)

3.OM LiCI04-EtOAc -23 "C,5 rnin

I

,Me

OMe

I

86%

Me'

",

isocomene

Scheme 42

Allylic cations 1-2 are successfully generated by treatment of a-chloro-a'-methoxy or a-chloro-a'-alkylated ketones with LPDE and amines [93]. This observation was extended to the cationic inter- and intramolecular [4 + 31 cycloadditions via 1-2 to give the fused 5,8 ring system found in many interesting natural products (Sch. 43) [94].

16:l)

1-2

Scheme 43

Li(I), Na(I), and K(I) Lewis Acids

39

2.3.2 Substitution Reactions 2.3.2.1 Allylic Substitutions The transition metal-catalyzed allylation of carbon nucleophiles was a widely used method until Grieco and Pearson discovered LPDE-mediated allylic substitutions in 1992. Grieco investigated substitution reactions of cyclic allyl alcohols with silyl ketene acetals such as Si-1 by use of LPDE solution [95]. The concentration of LPDE seems to be important. For example, the use of 2.0 M LPDE resulted in formation of silyl ether 88 with 86 and 87 in the ratio 2:6.4:1. In contrast, 3.0 M LPDE afforded an excellent yield (90 YO) of 86 and 87 (5.8:1), and the less hindered side of the allylic unit is alkylated regioselectively. It is of interest to note that this chemistry is also applicable to cyclopropyl carbinol89 (Sch. 44).

oTBDMs

,C02Me

Si-1 3.OMLPDE rt, 15 min

89

75% (4:l)

Scheme 44

Unfortunately, attempts to perform this substitution reaction on cyclohexenol and geraniol led to the exclusive formation of the corresponding silyl ethers. It thus would seem that one requirement for effective carbon-carbon bond formation is that allylic alcohols be secondary and have possess y,y-disubstitution. Pearson, however, discovered a method with less restriction on the nature of the substrate; he used allylic acetates with y-mono-substitution or primary alcohols [96]. Not only ketene silyl acetals but also a diverse set of nucleophiles including allyl silane, indoles, MOM vinyl ether, trimethylsilyl azide, trimethylsilyl cyanide, and propargyl silane participate in the substitution of y-aryl allylic alcohol 90 to give allylated 91 (Sch. 45). Further experimental evidence suggests that these reactions proceed via ionization to allylic carbocations- alcohols 90 and 92 both afforded the identical product 93. Grieco improved the above methods, developing a general allylation method for indoles employing y,y-disubstituted allylic alcohols. Allylic alcohol 94 underwent no reaction under conditions similar to those affording effective allylation of 95 by use of y-aryl allylic alcohol 90. By contrast, in an LPDE solution containing a catalytic amount of AcOH (1 mol YO), the rapid consumption of 94 proceeded to give the indole substitution product 96 in 77 Y yield. Particularly noteworthy is that the iso-

40

Saito

propylsilyl and thioethers (97 and 98) survive the reaction conditions (Sch. 46). The iterative use of this allylation of indoles was highlighted during the course of the total synthesis of Yuehchukene (Sch. 47) [97].

90

NU = Me3S.CN, Me3SiN3,e

eo-o',

Q

GOSiMe3 ,

n Ar

SiMe3

S i M e 3 ,

OSiMe3

OTBDMS

90 3.OM LPDE

A

C02Me

93

r w OH 92

Scheme 45

3.OM LPDE

AcOH (1 mol%) Ic

94

95

""W 77%

NH

96

Scheme 46

The synthesis of the C(l)-C(18) fragment 101 of Scytophycin C also features a highly stereoselective carbon Ferrier-type reaction in polar LPDE media between acetyl-4-deoxyglucal 99 and the silyl enol ether of acetaldehyde Si-2 (Sch. 48) [98]. The reaction is best performed with 3.0 M LiClO,-EtOAc, which rather attenuated the polar nature, but proved fruitless with 5.0 M LPDE. Equally disappointing is the use of other Lewis acids such as MgBr2, ZnC12, or (i-Pr0)2TiC12, which gave rise to substantial amounts of oligomeric structure 100.

Li(I),Na(I), and K(I) Lewis Acids

41

3.OM LPDE

HO

AcOH (1 rnol%) rt, 1.5h 86%

H

OH

. .

OH

rt, 3h 86%

H

Yuehchukene

Scheme 47

AcO

AcO

Lo

3.y:;;;;

99

rt. 16h

CHO

si-2

90%

101

AcO with 5.OM LiC104-Et20:oligorner

100

Scheme 48

An attempt to obviate the need to employ excess catalyst in addition to highly polar media was also made with a novel Lewis acid, lithium cobalt-bis(dicarbollide), [LiCo (B9C2H11)2](102), in which the lithium ion is weakly coordinated to the C O ( B ~ G H ~ ~ ) ~ ~ anion. Reagent 102 was introduced as an effective soluble catalyst in non-polar solvents. The counter anion would presumably coordinate to the Li cation more weakly than other anions such as P E , B E , and ClOj, thus imparting enhanced Lewis acidity to the cationic metal complex. Treatment of isophorol 94 in dichloroethane with 10 mol Yo 102, then addition of ketene silyl acetal Si-1 afforded substitution product 103 in 51 % yield after 24 h at room temperature. When the acetate 104 is employed in place of 94, however, 81 YO yield of 103 is obtained after 15 min (Sch. 49) [99]. More intriguing is the case of 3-methylindole-the reaction rate is considerably slowed because allylation proceeds via facile kinetically favored attack at C(3) leading to regioisomeric indolenine 105. This kinetic product slowly rearranges via a WagnerMeerwein type process to give the thermodynamically more stable C(2) allylated indole 106 (Sch. 50). This chemistry is especially suitable for use with polyoxygenated substrates.

42

Saito 102 (10 mol%)

94 : R = H 104 : R = A c

103 102: LiCo(B9C2H12)2

Scheme 49

Scheme 50

An even more interesting result, recently obtained with LiA1[OC(Ph)(CF3)2]4 (107), is applicable to similar allylic substitutions. Reagent 107 is readily prepared by treatment of a toluene suspension of LiAlH4 with 4 equiv. HO-C(Ph)(CF3)2 under reflux conditions. The X-ray crystal structure of 107 shows that the lithium is hexacoordinated with two internal oxygen and four internal fluorine atoms. By use of 10 mol % 107, cyclohexenyl acetate 108 and Si-3 were coupled successfully to furnish 109 in 92 % yield (Sch. 51) [loo].

Scheme 51

Li(I), Na(I), and K(I) Lewis Acids

43

2.3.2.2 Glycosidation and other Substitutions

Mukaiyama and co-workers revealed that Li salts play a significant role in controlling the novel stereochemical preference that is involved in the glycosidation with ribofuranose derivatives (Sch. 52). In particular, LiC104 [101-1051 and LiNTfi [lo51 were found to be effective additives in the stereocontrolled synthesis of a-D-ribofuranosides and several alcohols, whereas p anomers were from 2,3,5-tri-O-benzyl-~-ribofuranose formed in the absence of the lithium salts. Sch. 52 shows several examples that emphasize general characteristics with or without the addition of lithium salts. In the most recently advanced system (Sch. 53), a hypothetical mechanism of this reverse stereocontrol to yield 110 with the influence of lithium salt is also discussed. In the presence of 10 mol % TrC104, both pure a anomer 110 (a$ = >99:<1) and p anomer 111 (a$ = <1:>99) isomerized to afford a p anomer-rich mixture (a$ = 6:94).

a-anomer

p-anomer

SnCI4, Sn(OTf)2 (10 mol%), LiC104 (100 mol%) : 64 (>99:<1) SnCI4, Sn(OTf)2 (10 mol%), LiC104 (100 mol%), Na104 (10 mol%) : 86 (>99:<1)

'nab

OH

B n o b O H

+

0

CH2C12

:Oboehex

Oc-hex

BnO OBn

Brio OBn

BnO OBn

a-anomer

p-anomer

Ph2Sn=S (150 mol%),Tf20 (120 mol%), LiC104 (30eq), NEt3, CsF: >99% (99:l)

OTMS

OTMS

+

Bnob yobOc-hex

*

0-

CH2C12

BnO OBn

Ochex

rt

Brio OBn

BnO OBn

a-anomer

p-anomer

Ph2Sn=S (150 mol%), TMSOTf (3mol%) Ph2Sn=S (150mol%), TMSOTf (3mol%), LiC104 (300mol%)

: 299% (2:98) : >99% (97:3)

bo,,

BnO

CHzCl2

BnO OBn

rt

'

+BnoQoyPh

BnO OBn

Ph

a-anomer

AgC104 : 73% (37:68) AIC104 (10 mol%) /LiC104 (300rnol%) : 96% (96:4)

Scheme 52

BnO OBn p-anomer

44

Saito

T T ( BLi-salt C ~ F(10 ~ )mol%) ~ B n o b o H

+

(OH

Drierite CHzCIz rt

BnO OBn

Bno@oc-hex

+ B n O y h e x

BnO OBn 110: a-anorner Liclo4 : LiOTf : LiBF4 : LiNTfP :

90% 80% 85% 94%

BnO OBn 111: p-anorner

(955) (32:68) (40:60)

(>!%:I)

Scheme 53

The situation is completely different in the presence of 150 mol % LiNTf2. Indeed, whether isomer 110 or 111 is used, the formation of a anomer 110 predominates (a$ = >99<1). It has been proposed that the intermediate oxocarbenium ion 1-3 is involved in the anomerization mechanism. In the presence of the trityl cation, the equilibrium between anomers 110 and 111 might shift to the more thermodynamically stable 4, anomer 111.The significant role of perchlorate and bis(su1fonimide)anions has been consistently claimed. Thus, intermediate 1-3 would be efficiently stabilized by these anions located at the sterically less-encumbered,4 side of anomeric centers, achieving nucleophilic attack from the a side. It is also suggested that the Li cation is likely to effect the selective stabilization of product a anomer 110 by forming coordination complexes as exemplified by putative chelated structures C-1and C-2 (Fig. 10).

1-3

c-1

c-2

Figure 10

LiC104 catalyzes substitutions of /3-phenylsulfonyl-y-oxo arenebutanenitriles by organomagnesium reagents (Sch. 54). This interesting reactivity seems to be peculiar to Grignard reagents; organolithium and organocerium reagents do not give the substitution. Additives other than LiC104 have been tested but only ZnClz occasionally gives comparable results. Strongly electrophilic catalysis by lithium cation that activates the S=O bond of the sulfone is highly likely [106]. LiCIO4 (1 eq) -Et20-benzene (1 :5) A r G C N Ph/s=O 0

RMgX (4eq)

* A r h C N

R

R = Me, Et, n-Bu, n-Pr, Me3SiCH2-, kPr, s-Bu, c-Hex, etc.

Scheme 54

Li(I), Na(I), and K(I) Lewis Acids

45

2.3.3 Nucleophilic Addition to the C=O Double Bond 2.3.3.1 Aldol Reaction The aldol reaction of ketene silyl acetals with several aldehydes (Mukaiyama aldol reaction) assisted by Li' has been described briefly by Reetz et al. Wirth 5.0 M LPDE a clean reaction began within 1 h with the sole formation of the silylated aldol 112, whereas the use of a catalytic amount (3 mol YO) of LiC104 in Et,O (3 mol YOLPDE) required a reaction time of 5 days for 86 YO conversion. As observed in the heteroDiels-Alder reaction of a-alkoxyaldehyde, the higher rate of reaction of 79 compared with that of benzaldehyde can be attributable to chelation. Indeed, the use of 3 mol YO LPDE required only 20 h at room temperature for complete uptake of 79 with a diastereoselectivity (syn-113/anti-113)of >96 YO (Sch. 55). S ~ - ~ B D M S ~

OMe fl

CHO

112

C02Me OTBDMS

5 . 0 LPDE ~ ; 1h : >99% conversion LPDE ; 5 days : 86% conversion 3 molyo OBn OBn -/,+ .O

Si-1

*

3 mol% LPDE

79

-30 iC, 6h

OBn

+ /\(-'C02Me

+C02Me OTBDMS syn-113

OTBDMS anti-113

67% (>98:2)

Chelation control

-.

68:32

Scheme 55

LiC104 was shown to be a more compatible Lewis acid for chelation in an ethereal solvent -when TiCI4, a typical chelation agent for a-alkoxyaldehydes, was used in EtzO for alkylation of 79, moderate diastereoselectivity (68:32) was obtained. Rapid injection NMR studies of the TiC14-promoted chelation-controlled Mukaiyama aldol reaction and the Sakurai reaction show that an acyclic transition state must be involved in which the silyl groups never reach the carbonyl oxygen atom. In LPDEmediated enolsilane additions silylated products predominate. Obviously, the mechanism is different-it is a group-transfer aldol reaction [107]. LiC104 (3 mol %) in CHZCl2had a similar chelation tendency leading to rate acceleration, giving syn-113 preferentially. In the non-coordinative solvent, as expected, the aldolization between 79 and Si-1 led to complete conversion to 0-silylated products, 113, within 15 min at room temperature (Sch. 56), in striking contrast with the low reactivity of 3 mol YOLPDE as mentioned above (5 days, room temperature, 86 YO conversion).

46

Saito

The relative rate increase with LiC104 (3 mol %) in CH2C12 was also observed in a case involving the aldolization of N,N-dibenzyl-protectedaminoaldehyde, where anti-product predominates, as a result of non-chelation control. When attempted in Et20,the transformation is successful only when 5.0 M LPDE is used. Moreover, a reaction time of 18 h at room temperature sufficed for complete conversion of iso-butyraldehyde, while reacting less rapidly to the desirable product [lOS].

OBn

OBn OMe

,/A,@

LiC104(3 mol%)-CH2CI2 -30 "C, 6h

79

OBn

+ /\(\C02Me

*C02Me

OR

R = H, TBDMS

OR

84% (92:8)

Chelation control

NBn2

A

pn2

Si-1

p n 2

*

+ /\(\C02Me

0 LiC104(3 mol%)-CH2CI2 /\/\C02Me rt, 6h

OR

OR

58% (1:>99)

non-Chelationcontrol

Scheme 56

Carreira conducted a mechanistic study of the Mukaiyama aldol reaction employing benzaldehyde and hydrocinnamaldehyde with a selection of Lewis acids, including LiC104 and other typical examples. The results of experiments performed with doublylabeled ketene silyl acetals implicate a Lewis acidic silicon species when at least these two aldehydes are used. Thus, two ketene silyl acetals Si-4 and Si-5 were prepared, and a crossover experiment was performed. A 1:lmixture of Si-4 and Si-5 was left to react with benzaldehyde or hydrocinnamaldehyde in CH2C12 at -78 "C in the presence of 20 mol % LiC104. This gave a mixture of almost equal amounts of 114,115,116, and 117, reproducibly, and suggests that silicon-mediated catalysis is highly probable; if not, at least intermolecular silicon transfer participates (Sch. 57). The rate enhancement and high diastereoselectivity with a-alkoxyaldehydes using LiC104 described above poses questions, however, if only a silicon Lewis acid is operating [109].

f

CH2C12 -78 "C, <30 min

. f

I

t

AOEt si-5 R = Ph, PhCH2CH2-

116

Scheme 57

117

Li(I),Na(I), and K(I) Lewis Acids

47

2.3.3.2 Allylation and other C-C Bond Formation The addition of allylstannanes to a-benzyloxyaldehyde 118 with 5.0 M LPDE has been shown to proceed with high diastereoselectivity and via chelation control. Exposure of the corresponding TBDMS-ether 119 to trimethylallylstannane afforded a 1.2:l ratio of the products, indicating that the Lewis basicity of the a-ether oxygen lone pairs is an important factor in controlling the selectivity of the reaction. It is of interest to note that P-chelation control seems not to be operational. The synthetic potential and functional-group tolerance of LPDE are well featured in the allylation of polyoxygenated compounds including dialdose derivatives (Sch. 58) [110].

5.0 M LPDE

OH

118 : R =CH*Ph 119 : R =TBDMS

The LiC104 (3 mol %)-CH2C12 medium also proved to be a catalyst for the addition of trimethylsilyl cyanide (Me3SiCN) to aldehyde 79. Unfortunately, the diastereoselectivity was low (syn:anti= 57:43); this might be attributed to the reversibility of the reaction (Sch. 59) [108]. OBn OBn 1)TMSCN / i . & ,+.YCN LiC104(3 rnolYo)-CH2CI2 OH OH 79 rt, 16h 2) 2N HCI-THF 87% (57:43)

oBn

-

+

qCN

Scheme 59

2.3.4 Conjugate Addition Several ketene silyl acetals add in a conjugate fashion to a&unsaturated carbonyl compounds (Mukaiyama-Michael reaction) in the presence of LiC104. The more sterically demanding the ketene silyl acetals used, the greater is the concentration of LPDE required. For example, ketene silyl acetal Si-2 subjected to an LPDE solution (1.0 M) of 2-cyclohexen-1-one (12) gave 87 YOof the 1,4 adduct whereas Si-3 required

48

Saito

the use of 5.0 M LPDE for sufficient acceleration of the reaction (Sch. 60). 2.5 M LPDE also catalyzed the conjugate addition of Si-2 to d-lactone 120, but 1.0 M LPDE resulted in an appreciable decrease in the rate. To achieve the sterically demanding conjugate addition to P&disubstituted conjugated ketones, the corresponding a-positions are preferably appended with another electron-withdrawing group (Sch. 61). This system is even more applicable to highly functionalized, sterically hindered substrates. When 121 was used as conjugated substrate, LPDE medium of widely different concentration proved totally disappointing, giving a mixture of the 1,2 and 1,4 adducts. Exclusive formation of the 1P-addition product could be realized by employing 1.0 M LiC104-DME, although the rate of reaction was appreciably slower in DME [ l l l ] .

6

OTBDMS Si-1 +OTBDMS

*

bOMe

12

1.OM LPDE ; rt, 1.2h : 95% LiCo(B9C2H11)2 (10 mol%)-CICH2CH2CI; rt, 5 min : 97% LiC104 (3 mol%)-CH2C12 ; rI, l h : >97%

Q 12

rt 1.6h

-

C02Me Si-6

5.OM LPDE : 76% 1.OM LPDE : no reaction

Scheme 60

The greater activity of LiC104 (3 mol %)-CH2C12 enables conjugate addition of Si2 to 12. Complete and regioselective conversion to the desirable 1,4-adduct was, in fact, achieved within 1 h (>97 YOisolated yield), presumably via a group transfer-type process (Sch. 60) [72]. The use of catalytic amounts of [LiCo(B9C2HI1)2](102) had several practical advantages (Sch. 60 and 61): (i) The conjugate addition of Si-1 to 12 proceeds equally fast ( 5 min) in Et,O, dichloroethane, or CH2C12in the presence of 10 mol % 102. (ii) In contrast to the above mentioned dependence on the concentration of the LPDE system, in this reaction any of the substrates Si-1, Si-3, or Si-6 can be used under identical conditions using 10 mol % 102, except that reaction times range from 5 min to 1 h. (iii) When sterically encumbered substrates such as 122 are used, the combined use of equimolar amount of HMPA and 102 (10 rnol YOeach) dramatically enhances lP-selectivity [1121. Very recent applications of the reagent LiA1[OC(Ph)(CF3)2]4(107) in conjugate additions have been described (Sch. 62). The capacity of 107 to catalyze sterically demanding additions in toluene obviates the necessity of using either highly polar media (5.0 M LPDE) or ultra high pressure [loo].

Li(I), Na(I), and K(I) Lewis Acids

49

OTBDMS T O M e si-1 TBDPSO

It

85%

<0.25h 120

-9 TBDPSO

2.5M LPDE

0

0

Ll'y 0

:

121

-

OTBDMS Si-1 I

122

1.OM LPDE ; rt, l h L ~ C O ( B ~ C ~ H(10 ,,)~ mol%)-CICH2CH2CI-HMPA(10 mol%) ; It, 86h

Scheme 61

&+

73% 97%

-* OTBDMS

107 (10 mol%) TMEDA

+ITMS

toluene

OAc

Si-1

1%

C02Me

OAc

107: LiAl[-OC(Ph)(CF&]d

Scheme 62

LPDE solution also catalyzes the conjugate allylation of quinones. This is an important reaction in the preparation of biologically active isoprenoid quinones such as vitamin E, vitamin K, coenzyme Q1, and plastoquinones. If 123 is reacted with the allylsilane in 5.0 M LPDE for 15 h at 40 "C, allylhydroquinone 124 is obtained in 73 % yield, together with non-allylated hydroquinone 125 (Sch. 63) [113].

50

Saito

0

?SiMe3

OSiMe3

OSiMe3

OSiMe3

5.OM LPDE

SiMe3

*

40 "C, 15h I

0 123

124 73%

125 12%

Scheme 63

2.3.5 Rearrangement The effect of LPDE on the rate of rearrangement of allyl vinyl ether has been examined. Exposure of 126 to 1.0 M LPDE for 24 h resulted in one major product which was not the product of the expected [3,3]-sigmatropic rearrangement, but instead the result of an exclusive [1,3]-sigmatropic rearrangement (Sch. 64) [114]. The rearrangement of 126 is best performed in 3.0 M LPDE. The [1,3]-rearrangement is likely to take place cleanly with the substrates bearing geminal substituents at the y-positions of allylic moieties. In fact, use of deuterated allyl vinyl ether 129 with the protonated y-carbon on the allylic unit resulted in a 1:l mixture of [1,3]- and [3,3]-rearrangement products (Sch. 65). -0

,CHO 3.OM LPDE

HO"'

~

HO' 90% (511)

Scheme 64

3.OMLPDE R'

I

k2

OHC

H

55%-60% 3.OM LPDE

L

J

1-4

Scheme 65

Li(Z),Na(I), and K(I) Lewis Acids

51

This observation and further evidence that the identical product was obtained from 127 and US shed light, in part, on the mechanistic aspects of the rearrangement, suggesting that ion dissociation and recombination are involved via the ion pair 1-4 [115]. The reaction rate for the [1,3] rearrangement depends on the concentration of lithium ions. The rearrangement of 130 (0.2 M) in 1.8 M and 1.0 M LiC104-acetone occurred with rate constants of 8.31 x 10” and 2.05 x s-l, respectively (Sch. 66). In 5.0 M LiC104-acetone the rearrangement was so fast that only a lower limit for the reaction rate (ca 2.46 x lO-’s-’) could be established. Other factors might thus account for the greater than 1000-fold increase in reaction rate.

g; 130

LiCI04-acetone

s-’ 1.8M : 8.31 x 1.OM : 2.05 x 1o-55.’

Scheme 66

The epoxide 131 rearranges to afford a-hydroxyethylene-2-indanone(132) in moderate yield when heated under reflux in LiC104-toluene (Sch. 67). The proposed mechanism is lithium ion-promoted epoxide cleavage then 12-aryl migration to afford a relatively stable oxonium ion which cleaves to furnish a benzylic carbocation with subsequent 12-hydride shift affording the P-ketoaldehyde. An attempt to bring about this transformation with BF3.0Et2proved problematic [116].

..

132 R

131 R

R = H:

LiCI04-toluene : 57% BF3 : 10%

R = Me:

~ i ~ ~ ~ ~ - t :o>99% ~uene : 99% BF3

Scheme 67

LiBr acts as a Lewis acid which rearranges epoxides. The reactions afforded aldehydes leading to ring contractions (Sch. 68) [117]. LiBr-HMPA benzene 80 “C

* O C H O

95%

Scheme 68

LiBF4 promotes a high-yield rearrangement of oxaspiropentanes to cyclobutanones, and in this regard, is reported to be superior to LiC104 (Sch. 69) [118].

52

Saito

99% Scheme 69

2.3.6 Oxirane Ring-Opening Functionalization Crotti and co-workers extensively studied the ring-opening functionalization of oxiranes using a variety of alkali-metal salts. Several oxiranes were reacted with ammonium halides [119], KCN [120], NaN3 [121], lithium acetylide [122], amines [123], and ketone enolates [124] in the presence of alkali-metal salts to afford the formation of the corresponding ,B-functionalized alcohols; and some of the results are listed in Table 1. Several key issues must be discussed. Unfortunately, NaC104 and KC104 totally lack catalytic activity in the azidolysis and cyanidolysis that utilize relatively weak nucleophiles (entries 7, 8, 18, and 19); whereas the former led to modest activation of oxirane when used with acetylides (entry lo), the latter was totally ineffective. (ii) KC104 and KBF4, although readily soluble in MeCN, did not seem to exert any catalytic effect on the aminolysis of oxiranes. (iii) Activation with LiOTf, although moderate, eventually led to high yields of products (entries 11 and 33). Considerable rate enhancement was observed in aminolysis with LiBF4 and NaC104 (entries 24 and 28), although the latter was used in non-homogeneous solution because of its lack of solubility in MeCN. In all respects, LiC104 proved to be the most prominent and general agent for the ring-opening functionalization of oxiranes. (iv) In some instances, metal ion-catalyzed aminolysis could be performed with toluene, acetone, or E t 2 0 as solvent although all of these led to lower reaction rates than the analogous reactions in MeCN. (v) The reactions are highly regioselective, with the attack of the nucleophiles on the less substituted carbon, except for styrene oxide. (vi) In general, the results are consistent with anti stereoselectivity, as shown by several examples in which trans isomers predominate. (vii) It seems that the effective catalysts in these additions are the metal cations, as a result of their ability to coordinate with oxirane oxygen.

(i)

53

Li(I), Na(I), and K(I) Lewis Acids Table 1. Ring-opening functionalization of epoxides

Entry

Attack at the Attack at the Reagents and solvent Conditions more-hindered less-hindered Yield (%) ("C, h) side side

Epoxide

1

2 J

3 4 5 6 7 8 9 10 11 12

Ph

LiC10JNH4CI/MeCN LiC10JNH4Br/MeCN LiC10JNH41/MeCN NaC10JNH4CI/MeCN LiClOJNaNdMeCN LiClOJKCN/MeCN NaClOJKCN/MeCN KClOJKCN/MeCN LiCIOJPhC=CLi/THF NaC104/PhC= CLi/THF LiOTf/C5H1lC=CLi/THF LiCIOJHzNBn/MeCN

80,4 80,4 rt, 3 80,4 80,s 70,24 70,48 70,48 rt, 24 rt, 24 50,48 rt, 2

45 55 33 40 18 77

92 96 96 50 92 95

2 10 40

94 98 90 60

96 38 97 98

50,24

9

91

95

65,24 65,16 rt, 2 80,5 80,24 80,24 80,5 70,4 rt, 24 rt, 26 rt, 1

<1 <1 <1 <1

>99 >99 >99 299

95 96 94 97

<1

>99 299 >99 >99 >99

92 98 97 90 95

25,24

<1

299

90

rt, 2

99 90 94

55 45 67 60 82 23 no reaction no reaction 6

OLi LiCIOflHF

13

Af-Bu

0

14 15 Ph 16 17 18 19 20 21 22 23 24

LiCIOJNH4CI/MeCN LiCIOJNH4Br/MeCN LiC10JNH41/MeCN LiClOJNaNdMeCN NaCIOJNaNdMeCN KC104/NaNdMeCN LiOTWNaNdMeCN LiClOJKCN/MeCN LiClOJPhC =CLi/THF LiCIOJHNEtz/MeCN NaCIOJHNEtz/MeCN

no reaction no reaction

<1 <1 <1 <1

OLi LiCIOflHF

25

26 27 28

>

Me

29

30 31 32 33 34

0

%HI3

&-Bu

LiC1O4/NH4I/MeCN LiC104/KCN/MeCN LiBFJH NEtz/MeCN OLi LiCIOflHF

70,8

<1 3.5

rt, 0.5

<1

>99 95 >99

25,72

<1

>99

98

LiClOJNaN$MeCN LiClOJKCN/MeCN LiClOJPhC =CLi/THF LiOTf/C5H11 = CLi/THF LiC1OJHNEtz/MeCN

80,24 70,8 rt, 24 50,24 rt, 1.5

7.5 1.8 <1 <1 <1

92.5 97.0 >99 >99 >99

96 95 96 66 98

54

Saito

Table 1. Ring-opening functionalization of epoxides (continued).

Entry

Epoxide

Reagents and solvent

Attack at the Attack at the Conditions more-hindered less-hindered Yield ("h) ("C, h) side side

35 36 37 38 39 40 41 42 43 44

LiC10JNH4CI/MeCN LiC10JNH4Br/MeCN LiC10JNH41/MeCN LiC104/NaNdMeCN LiClOJKCN/MeCN LiC104/PhC=CLi/THF LiC10JH2NBn/MeCN LiC10JH2NPh/MeCN LiCIOJHNi-Pr2/MeCN LiC10JHNt-Bu2/MeCN

65,24 65,24 65, 16 80,36 70,24 50,72 rt, 20 rt, 38 80,64 rt, 18

75 80 82 95 96 80 95 97 86 95

45

LiCIOflHF

50,72

80

OLi A t - B u

46 47 48 49 50 51

52 53 54 55 56 57

0

LiClOJNH4CVMeCN LiCIOJNH4BdMeCN LiC10JNH41/MeCN LiCIOJNaNdMeCN LiClOJKCN/MeCN LiCIOJPhC=CLi/THF

65, 65 65,46 65,24 80,18 70, 8 rt, 24

<1 <1 <1 <1 <1 <1

299 >99 299 >99 299 >99

54 40 90 95 95 92

LiC10JNH4CI/MeCN LiC10JNH4Br/MeCN LiC10JNH41/MeCN LiCIOJNaNdMeCN LiClOJKCN/MeCN LiC10JH2NBn/MeCN

65, 24 65,24 rt, 16 80,48 70,48 rt, 64

8 2 <1 19 1 <1

84 86 >99 81 99 >99

95 94 90 92 95 80

The aminolysis of oxiranes occurs with similar success in the presence of LiOTf (Sch. 70). As mentioned above, it is usually recommended that the reactions are conducted in MeCN. Acetone and THF, however, gave similar results in terms of reaction rate. LiOTf is poorly soluble in CHZC12 or toluene and the aminolysis must thus be investigated at low concentrations, when the salt is completely soluble [125].

Li(I), Na(I), and K(I} Lewis Acids

55

LiOTf (50 mol%), Et2NH

R0

MeCN

NEt2

rt,ll.5h

OH

OH NEt2

87% (2.8:l)

83% (>99:1)

Scheme 70

2.4 Closing Remarks In contrast with the spectacular improvement of ligand design which led to an enormous variety of typical Lewis acids (i.e. AI(III), Ti(IV), Sn(IV), B(III), etc.), progress in the development of alkali metal Lewis acids has been appreciably slower because of intrinsic limitations which result from modification of the counter anions. A solution of alkali metal species must often be concentrated before use, to compensate for the low Lewis acidity. This, even while synthetically viable, leads to some inevitable practical disadvantages. As shown in several instances involving the preparation of 63, 75, 102, and 107, however, novel strategic candidates for alkali metal Lewis acids are beginning to appear. These reagents have enhanced Lewis acidity, achieve catalysis, and construct an effective anionic environment where even asymmetric templates can be reasonably created. As exemplified by the wide range of tolerance of Li salts toward various functional groups, and by attractive Lewis acidic behavior of LiX, their synthetic potential seems infinite, and the examples described here are only a few of the possibilities available. Thus, the search for new and practical approaches to the design of alkali metal Lewis acids remains a challenge in selective organic synthesis.

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9. R. A. Silva, Chem. Eng. News, Dec. 2 (1992). 10. R. Jasinski, S. Carroll, J. Electrochem. Soc., 117,218 (1970); G. H. Newman, R. W. Francis, L. H. Gaines, B. M. L. Rao, J. Electrochem. Soc., 127,2025 (1980). 11. See reference 7. CAS-registry number: [21324-40-31 12. P. J. Coleman in Encyclopedia of Reagents for Organic Synthesis,Vol. 5, L. A. Paquette, Ed., John Wiley & Sons Ltd., Chichester, 1995, p. 3164. CAS-registry number: [14283-07-91 13. See references 122 and 125. CAS-registry number: [33454-82-91 14. See references 71,73, and 90. 15. J. Foropoulos, Jr, D. D. DesMarteau, Inorg. Chem., 23,3720 (1984). 16. B. M. Trost, I. Fleming, Comprehensive Organic Synthesis, vol. 1, 2, and 3, Pergamon, Oxford, 1991. 17. S. L. Schreiber in Comprehensive Organic Synthesis, vol. I, B. M. Trost, I. Fleming, Eds., Pergamon, Oxford, 1991,p. 283; G. A. Olah, G. K. Surya Prkash, J. Sommer, Superacids, John Wiley & Sons, Ltd., New York, 1985 and references cited therein. 18. A. N. Pushin, S. E. Tkachewko, L. V. Martynov, Dokl. Akad. Nauk SSSR,299,154 (1988). 19. R. M. Pagni, G. W. Kabalka, S. Bains, M. Plesco, J. Wilson, J. Bartmess, J. Org. Chem., 58, 3130 (1993). 20. R. F. Childs, D. L. Mulholland, A. Nixon, Can. J. Chem., 60,801 (1982). 21. G. Desimoni, G. Faita, P. P. Righetti, G. Tacconi, Tetrahedron, 47,8399 (1991). 22. A. Casaschi, G. Desimoni, G. Faita, A. G. Invernizzi, S. Lanati, P. Righetti, J. Am. Chem. SOC., 115,8002 (1993). 23. Y. Pocker, D. L. Ellsworth,J. Am. Chem. SOC.,99,2276 (1977). 24. S. Winstein, S. Smith, D. Darwish, J. Am. Chem. Soc., 81,5511 (1959). 25. S. Weinstein, E. C. Friedrich, S. Smith, J. Am. Chem. SOC.,86,305 (1964). 26. P. G. Williard, Q.-Y. Liu, J. Am. Chem. Soc., 115,3380 (1993). 27. F. E. Romesberg, D. B. Collum, J. Am. Chem. Soc., 117,2166 (1995). 28. M. P. Bernstein, D. B. Collum, J. Am. Chem. Soc., 115,789 (1993); M. P. Bernstein, D. B. Collum, J. Am. Chem. Soc., 115,8008 (1993). 29. X. Sun, S. L. Kenkre, J. F. Remenar, J. H. Gilchrist, D. B. Collum, J. Am. Chem. Soc., 119, 4765 (1997). 30. R. E. Ireland, R. H. Mueller, A. K. Willard, J. Am. Chem. Soc., 98,2868 (1976). 31. M. Majewski, P. Nowak, Tetrahedron Lett., 39,1661 (1998). 32. S. T. Kerrick, €! Beak, D. J. Am. Chem. Soc., 113, 9708 (1991); P. Beak, S. T. Kerrick, S. Wu, J. Chu, J. Am. Chem. Soc., 116, 3231 (1994); D. J. Gallagher, S. T. Kerrick, P. Beak, J. Am. Chem. Soc., 114,5872 (1992). 33. J. Gallagher, P. Beak, J. Org. Chem., 60,7092 (1995). 34. E. Kaufmann, P. R. Schleyer, K. N. Houk, Y.-D. Wu, J. Am. Chem. Soc., 107, 5560 (1985); S. M. Bachrach, A. Streitweiser, J. Am. Chem. SOC.,108,3946 (1986). 35. M. Nakamura, E. Nakamura, N. Koga, K. Morokuma, J. Am. Chem. Soc., 115,11016 (1993). 36. E. Kaufmann, P. von R. Schleyer, K. N. Houk, Y.-D. Wu, J. Am. Chem. Soc., 107,5560 (1985). 37. J. F. McGarrity, C. A. Ogle, Z. Brich, H.-R. Loosli, J. Am. Chem. SOC.,107,1810 (1985). 38. T. Cohen, W. D. Abraham, M. Myers,J. Am. Chem. Soc., 109,7923 (1987). 39. H. J. Reich, W. H. Sikorski, J. Org. Chem., 64,14 (1999). 40. C. J. Rizzo, J. Org. Chem.,57,6832 (1992). 41. R. Breslow, T. Gao,J. Am. Chem. SOC.,110,5613 (1988). 42. L. M. Jackman, E. F. Rakiewicz, J. Am. Chem. Soc., 113,1202 (1991). 43. K. W. Henderson, A. E. Dorigo, Q.-Y. Liu, P. G. Williard, P. von R. Schleyer, P. R. Bernstein, J. Am. Chem. Soc., 118,1339 (1996). 44. F. E. Romesberg, D. B. Collum, J. Am. Chem. Soc., 116,9187 (1994). F. A.-Hasanayn, A. Streitwieser,J. Am. Chem. Soc., 118,8236 (1996). 45. K. Narasaka, Y. Ukaji, K. Watanabe, Chem. Lett., 1755 (1986). 46. P. L. Hall, J. H. Gilchrist, D. B. Collum, J. Am. Chem. Soc., 113,9571 (1991). 47. A. S. Galiano-Roth, Y-J. Kim, J. H. Gilchrist, A. T. Harrison, D. J. Fuller, D. B. Collum, J. Am. Chem. Soc., 113, 5053 (1991). 48. P. L. Hall, J. H. Gilchrist, A. T. Harrison, D. J. Fuller, D. B. Collum, J. Am. Chem. Soc., 113, 9575 (1991); D. B. Collum, Acc. Chem. Res., 26, 227 (1993); For an influence of HMPA on lithium amides-LiX or --nolate mixed aggregates, see: F. E. Romesberg, D. B. Collum, J. Am. Chem. Soc., 116,9198 (1994). 49. P. G. Williard, M. J. Hintze, J. Am. Chem. Soc., 112,8602 (1990). 50. M. Murakawa, M. Nakajima, K. Koga, J. Chem. Soc., Chem. Commun., 1657 (1990); K. Koga, Pure Appl. Chem., 66,1487 (1994). 51. Y. Hasegaw, H. Kawasaki, K. Koga, Tetrahedron Lett., 34,1963 (1993).

Li(Z), Na(I), and K(I) Lewis Acids

57

52. T. Yasukata, K. Koga, Tetrahedron: Asymmetry,4,35 (1993). 53. A. Yanagisawa, T. Kikuchi, H. Yamamoto, Synlett, 174 (1998). 54. F. Abu-Hasanayn, A. Streitwieser,J. Am. Chem. Soc., 118,8136 (1996). 55. K. Sugasawa, M. Shindo, H. Noguchi, K. Koga, Tetrahedron Lett., 37,7377 (1996). 56. C. Fehr, Angew. Chem. Int. Ed. Engl., 35, 2566 (1996); U. Gerlach, T. Haubenreich, S. Hunig, Chem. Ber., 127, 1981 (1994); E. Juaristi, A. K. Beck, J. Hansen, T. Matt, T. Mukhopadhyay, M. Simons, D. Seebach, Synthesis, 1271 (1993); D. Seebach, Angew. Chem. Int. Ed. Engl., 27, 1624 (1988). See also reference 28 and 54. 57. B. J. Bum, N. S. Simpkins, J. Org. Chern., 58, 533 (1993); other reports on discussion of LiX effects are also cited therein. 58. K. Aoki, H. Noguchi, K. Tomioka, K. Koga, Tetrahedron Lett., 34,5105 (1993). 59. M. Imai, A. Hagihara, H. Kawasaki, K. Manabe, K. Koga, J. A m . Chem. SOC.,116,8829 (1994). 60. T. Yamashita, D. Sato, T. Kiyoto, A. Kumar, K. Koga, Tetrahedron Lett., 37,8195 (1996). 61. M. A. Blanchette, W. Choy, J. T. Davis, A. P. Essenfeld, S. Masamune, W. R. Roush, T. Sakai, Tetrahedron Lett., 25,2183 (1984). 62. M. W. Rathke, M. Nowak, J. Org. Chem., 50,2624 (1985). 63. D. Seebach, A. Thaler, A. K. Beck, Helv.Chem. Acta., 72,857 (1989). 64. W. N. Setzer, P. von R. Schleyer, Adv. Organornet. Chem., 24,353 (1985); H. Schmidbaur, I. Bach, D. L. Wilkinson, G. Muller, Chem. Ber., 122,1427 (1989). 65. K. Kessler, M. Gehrke, J. Lautz, M. Kock, D. Seebach, A. Thaler, Biochem. Pharmacol., 40, 169 (1990); V. Madison, M. Atreyi, C. M. Deber, E. R. Blout, J. Am. Chem. Soc., 96,6725 (1974); L. G. Pease, C. Watson, J. A m . Chem. SOC.,100, 1279 (1978); L. Radiccs, M. Hollosi, Tetrahedron Lett., 21,4531 (1980); H. Kessler, W. Hehlein, R. Schunk, J. Am. Chem. SOC.,104,4534 (1982). 66. D. Seebach, H. Bossler, H. Grundler, S. Shoda, R. Wenger, Helv. Chem. Acta., 74,197 (1991). 68. A. Thaler, D. Seebach, F. Cardinaux, Helv. Chem. Acta., 74,617, (1991). 69. A. Thaler, D. Seebach, F. Cardinaux, Helv. Chem. Acta., 74,628, (1991). 70. P. A. Grieco, J. J. Nunes, M. D. Gau1,J. Am. Chem. SOC.,112,4595 (1990). 71. S. T. Handy, P. A. Grieco, C . Mineur, L. Ghosez, Synlett, 565 (1995). 72. M. T. Reetz, A. Gansauer, Tetrahedron, 49,6025 (1993). 73. H. Kobatashi, J. Nie, T. Sonoda, Synlett, 307 (1995). 74. P. A. Grieco, S. T. Handy, J. P. Beck, Tetrahedron Lett., 35,2663 (1994). 75. P. A. Grieco, J. P. Beck, S. T. Handy, N. Saito, J .F. Daeuble, Tetrahedron Lett., 35,6783 (1994). 76. D. A. Smith, K. N. Houk, Tetrahedron Lett., 32,1549 (1991). 77. P. G. Gassman, D. A. Singleton, J. J. Wilwerding, S. P. Chavan, J. Am. Chem. SOC., 109, 2182 (1987); P. G. Gassman, S. P. Chavan, J. Org. Chem., 53,2392 (1988). 78. P. A. Grieco, J. L. Collins, S. T. Handy, Synlett, 1155 (1995). 79. P. A. Grieco, J. P. Beck, Tetrahedron Lett., 34,7367 (1993). 80. P. A. Grieco, J. L. Collins, E. D. Moher, T. J. Fleck, R. S. Gross, J. A m . Chem. Soc., 115, 6078 (1993). 81. A. Padwa, M. Dimtroff, A. G. Waterson, T. Wu, J. Org. Chem., 63,3986 (1998). 82. T. Ooi, A. Saito, K. Maruoka, Tetrahedron Lett., 39,3745 (1998). 83. I. Alonso, M. B. Cid, J. C. Carretero, J. L. C. Ruano, M. A. Hoyos, Tetrahedron: Asymmetry,2, 1193 (1991). 84. M. C. Aversa, A. Barattucci, P. Bonaccorsi, P. Giannetto, J. Org. Chem., 62,4376 (1997). 85. G. T. Grisp, M. G. Gebauer, J. Org. Chem., 61,8425 (1996). 86. M. Shibasaki, H. Sasai, T. Arai, Angew. Chem. Int. Ed. Engl., 36,1236 (1997). 87. T. Morita, T. Arai, H. Sasai, M. Shibasaki, Tetrahedron: Asymmetry,9,1445 (1998). 88. T. Arai, H. Sasai, K. Yamaguchi, M. Shibasaki, J. Am. Chem. SOC.,120,441 (1998). 89. P. A. Grieco, F. D. Moher, Tetrahedron Lett., 34,5567 (1993). 90. R. Tamion, C. Mineur, L. Ghosez, Tetrahedron Lett., 36,8977 (1995). 91. J. L. Collins, I? A. Grieco, J. K. Walker, Tetrahedron Letf.,38,1321 (1997). 92. P. A. Grieco, J. K. Walker, Tetrahedron, 53,8975 (1997). 93. B. Fohlisch, D. Krimmer, E. Gehrlach, D. Kashammer, Chem. Ber., 121,1585 (1988). 94. M. Harmata, S. Elahmad, Tetrahedron Lett., 34,789 (1993). 95. P. A. Grieco, J. L. Collins, K. J. Henry, Jr., Tetrahedron Lett., 33,4735 (1992). 96. W. H. Rearson, J. M. Schkeryantz,L Org. Chem., 57,2986 (1992). 97. K. J. Henry, Jr., I? A. Grieco, J. Chem. Soc., Chem. Commun.,510 (1993). 98. P. A. Grieco, J. D. Speake, Tetrahedron Lett., 39,1275 (1998). 99. P. A. Grieco, W. J. DuBay, L. J. Todd, Tetrahedron Lett., 37,8707 (1996). 100. T. J. Barbarich, S. T. Handy, S. M. Miller, 0.P. Anderson, P. A. Grieco, S. H. Strauss, Organometalhcs, 15,3776 (1996). 101. T. Mukaiyama, N. Shimomura, Chem. Lett., 781 (1993).

58 102. 103. 104. 105. 106. 107. 108. 109. 110. 111. 112. 113. 114. 115. 116. 117. 118. 119. 120. 121. 122. 123. 124. 125.

Saito T. Mukaiyama, K. Matsubara, Chem. Lett., 1041 (1992). T. Mukaiyama, K. Matsubara, S. Suda, Chem. Lett., 981 (1991). T. Mukaiyama, T. Shimpuku, T. Takashima, S. Kobayashi, Chem. Lett., 145 (1989). H. Uchiro, T. Mukaiyama, Chem. Lett., 271 (1996); H. Uchiro, T. Mukaiyama, Chem. Lett., 79 (1996). R. Giovannini, M. Petrini, Synlett, 1001 (1996). M. T. Reetz, B. Raguse, C. F. Marth, H. M. Hiigel, T. Bach, D. N. A. Fox, Tetrahedron, 48, 5731 (1992). M. T. Reetz, D. A. Fox, Tetrahedron Lett., 34,1119 (1993). E. M. Carreira, R. A. Singer, Tetrahedron Lett., 35,4323 (1994). K. J. Henry, Jr., P. A. Grieco, C. T. Jagoe, Tetrahedron Lett., 33,1817 (1992). I? A. Grieco, R. J. Cooke, K. J. Henry, J. M. VanderRoest, Tetrahedron Lett., 32,4665 (1991). W. J. DuBay, P. A. Grieco, L. J. Todd, J. Org. Chem., 59,6898 (1994). J. Ipaktschi, A. Heydari, Angew. Chem. Int. Ed. Engl., 31,313 (1992). P. A. Grieco, J. D. Clark, C. T. Jagoe, J. Am. Chem. Soc., 113,5488 (1991). N. Palani, K. K. Balasubramanian, Tetrahedron Lett., 34,5001 (1993). L. G. French, E. E. Fenlon, T. P. Charlton, Tetrahedron Lett., 32,851 (1991). B. Rickborn, R. M. Gerkin, J. Am. Chem. SOC.,93,1693 (1971). B. M. Trost, M. Preckel, J. Am. Chem. Soc., 95,7862 (1973). M. Chini, P. Crotti, C. Gardelli, F. Macchia, Tetrahedron, 48,3805 (1992). M. Chini, P. Croti, L. Favero, F. Macchia, Tetrahedron Lett., 32,4775 (1991). M. Chini, P. Crotti, F. Macchia, Tetrahedron Lett., 31,5641 (1990); M. Chini, P. Crotti, L. Favero, F. Macchia, Tetrahedron Lett., 32,6617 (1991). M. Chini, P. Crotti, F. Macchia, Tetrahedron Lett., 32,4661 (1990). M. Chini, P. Crotti, L. Favero, M. Pineschi, Tetrahedron Lett., 32,7583 (1991); M. Chini, P. Crotti, L. A. Flippin, F. Macchia, J. Org. Chem., 55,4265 (1990). J. AugC, F. Leroy, Tetrahedron Lett., 37,7715 (1996).

Lewis Acids in Organic Synthesis Edited bv Hisashi Yamarnoto Copyright 0WILEY-VCH Verlaa GmbH.2000

3 Mg(I1) and Zn(I1) Lewis Acids YukihiroMotoyama and Hisao Nishiyama

3.1 Introduction Magnesium and zinc halides are inherently milder Lewis acids than the traditionally used boron, aluminum, titanium and tin atoms. They can, however, supply two vacant sites of substrates of Lewis bases, for example carbonyl, alkoxy, or amine functionality. Bidentate setting, chelation, of the hetero-atom substrates on Mg or Zn often results in a hindered and rigid stereochemical arrangement around the active intermediates, leading to high expectation of stereo- and enantioselectivity. In the last decade, a variety of Lewis acid catalysts based on magnesium and zinc complexes with high quality auxiliaries has been applied to many reactions with highly demanding synthetic goals.

3.2 The Diels-Alder Reaction The Diels-Alder reaction is one of the most powerful and efficient processes for formation of six-membered rings with the potential of controlling the relative and absolute stereochemistry at four newly created stereogenic centers [I]. Relative stereochemistry is usually well-defined because of the formation of a cyclic transition state arising from suprafacial-suprafacial interaction, with endo approach [2]. The reaction can be accelerated by Lewis acids, high pressure, or radical cations. Diels-Alder reactions catalyzed by Lewis acids are generally more regio- and stereoselective than their thermal counterparts [3]. Certain reactive and electron-rich 1,3-dienes, such as Danishefsky’s diene [4] or Brassard’s diene [5] (Fig. I) bearing alkoxy or silyloxy substituents, react readily with a wide range of aldehydes in the presence of Lewis acid catalysts to give substituted ypyrones [6] or d-lactones [7]. There is, however, some limitations on using strong Lewis acids such as TiC14, A1C13, or SnC14, because decomposition of such acid-labile dienes or products occurs readily during reactions. To preserve valuable functionalities in the reactants and the adducts, milder Lewis acid catalysts, such as MgBr2, ZnC12, or lanthanide complexes [S] have been used.

TMSO Danishefsky’s Diene

Figure 1

Me0 Brassard’s Diene

60

Motoyama/Nishiyama

3.2.1 Control of Diastereoselectivity Danishefsky et ul. [9] reported that stereochemical outcome of cyclocondensation of aldehydes and siloxy dienes was highly dependent on the nature of Lewis acid catalysts. When the reaction of diene 1 and benzaldehyde 2 was performed using BF3. OEtz consistent trans (threo) selectivity was observed (cis-3ltruns-3 = 1:3) (Sch. 1). High cis specificity was, however, observed in the presence of MgBr, or ZnClz (cisltruns = 38:l and 39:1, respectively). Lewis acid (I equiv)

0

CF3CO2H *

+ HAph

TMSO<Me 1

qph oT +

0

2

BF3*OEt2 MgBr2 ZnC12

CH2C12 THF THF

-78 "C rt rt

91% 50% 80%

"Ph

cis-3

trans-3

1 38 39

3 1 1

Scheme 1

This diastereoselectivity was explained as follows. The reactions catalyzed by MgBr, or ZnCl, were true pericyclic reactions via an all-carbon framework of the classical Diels-Alder processes. The phenyl group of benzaldehyde, bound to the Lewis acid, was located in an endo orientation I relative to the diene (Sch. 2). Intermediate 4 from the pericyclic pathway with the cis stereochemistry at the 5- and 6positions, which was actually isolated, was smoothly converted to the final cis pyrone 3 by treatment with trifluoroacetic acid [lo]. OMe

L

4

cis-3

endo transition state I

Scheme 2

A threo-selective siloxonium (aldol-like) pathway I1 was favored when BF3. OEt, was used as catalyst (Sch. 3) [ll]. The reaction of benzaldehyde by quenching after 5 min resulted in 48 % yield of the final cyclic products 3 (1:8 cisltruns ratio) and 46 % yield of the Mukaiyama-like aldol products 5 (1:2 threolerythro ratio). When either threo or erythro adduct was re-subjected to trifluoroacetic acid media, each underwent conversion to the corresponding y-pyrones 3.

Mg(l1) and Zn(ZI) Lewis Acids OMe

61

OMe

erythra5

three5

cis3

trans-3

1

8

Scheme 3

In the reaction of a-alkoxyaldehydes the stereochemical outcome is different reactions in the pericyclic mode now lead preferentially to the 5,6-anti product. The reaction of chiral a-benzyloxyaldehyde 6 under the influence of MgBr2 afforded a single pyrone 7, which was consistent with a chelation-control product [9b,12]. A chelated complex was formed, and the ex0 transition state III was preferred because of steric repulsion between the diene and the chelated ring (Sch. 4).

MgBr2 (1 equiv) THF TMSO$Me+ 1

O B n , ,$fH ,

Et

AcOH (68%)

6

chelation-exo 111 Scheme 4

~

0

OBn Et 5,6-anti-7

62

Motoyama/Nishiyama

3.2.2 Chiral Lewis Acid Complexes The first example of use of chiral magnesium catalysts for the Diels-Alder reaction was reported by Corey and Ishihara [13]. They performed the cycloaddition of 3-acryloyloxazolidin-2-one 9 and cyclopentadiene 8 catalyzed by 10 mol % of a chiral cationic Mg complex, prepared in-situ from chiral bis(oxazo1ine) ligand 10 and MgI2 in the presence of I2 (co-catalyst). The Diels-Alder adduct 11 was obtained in 82 YO yield with 91 YOee (endolexo = 97:3) (Sch. 5). The cationic complexes prepared from bis(oxazoline), MgC12, and NaBPh4 or bis(oxazoline), Mg12, and AgSbF6 were both effective (97 YOendo, 91 YOee and 98 YOendo, 91 Yo ee, respectively). The same reaction using bis(oxazo1ine) 10 and MgI2 (no co-catalyst), however, afforded the adduct 11 with lower enantioselectivity (81 % ee). They proposed a model for the transition state IV, the oxazolidinone 9 binds in the s-cis geometry to the magnesium atom with a tetrahedral arrangement, with the re face of the dienophile 9 exposed to the diene 8, because the si face was masked by a phenyl substituent on the oxazoline ring.

0

(S,S)-10 + Mglp + (10 CH2C12 rnol%)

N \nO

+

K 0

0 9

8

-80 "C, 24 h (82%)

12

-

&NKO

n

0 0 (24-endo-ll 97% endo 91% ee

\

Ph

I

Ph

(S,S)-10

Scheme 5

Subsequent systematic investigation of bis(oxazo1ine)-derived complexes such as cationic Mg(II), Zn(II), and Cu(I1) species were continued. Firstly, Desimoni et al. [14] reported the enantioselective synthesis of both Diels-Alder enantiomers with the same (R,R)-bis(oxazo1ine) 12/Mg(C104)2 system. The chiral magnesium complex, prepared from Mg(C104)2 (10 mol YO)and (R,R)-12,catalyzed the reaction of oxazolidinone 9 with cyclopentadiene 8 at -50 "C to give (S)-endo-11with 68-70 YOee (Table 1).The sense of the asymmetric induction can be rationalized by assuming a tetrahedral complex V (Sch. 6). When two equiv. water were added to the tetrahedral complex V the (R,R)-12/Mg(C104)2 system gave the opposite enantiomer (2R)-endo11with 59-65 YOee. They explained this phenomenon in terms of the reaction proceeding via a trans-octahedral intermediate VI in which two water molecules were

Mg(I1) and Zn(I1)Lewis Acids

63

coordinated on the magnesium atom in the axial positions. If the water molecules were in the equatorial and axial positions, again the (S)-cyclic adduct would be expected as the major enantiomer. Table 1

(S,S)-12

(R,R)-12

catalyst (10 molYo)

tetrahedral V

s

q

(

N 0

p 0

11

conditions

(R,R)-12 / Mg(C104)2 (R,R)-12 / Mg(CI04)2 / 2 H20 (S,S)-12 / Zn(SbF& (S,S)-13 / Cu(SbF&

p

(S,S ) - l 3

-50°C, 3 h -50 “C, 3 h -78”C, 8 h -78”C,4 h

%yield >98 >98 >90 >95

Yo endo 93 93 98 96

12+

trans-octahedral VI

QNT0 0

0

(2S)-endoll

t

square planar VII

Scheme 6

Yo ee 68-70 59-65 92 >98

tetrahedral Vlll

(2s) (2R) (2R) (2s)

64

Motoyama/Nishcyama

Next, Evans et al. [15] reported that Cu-based catalysts were superior in the DielsAlder reaction of the oxazolidinone 9 with cyclopentadiene 8. The (S,S)-bis(oxazoline)-Cu(I1) and -Zn(II) complexes were very effective catalysts of the reaction. The optimum tert-butyl ligand 13-Cu(II) complex afforded (2S)-endo-ll with > 98 % ee. In contrast, the optimum catalyst system for the phenyl-substituted ligand 12-Zn complex afforded the enantiomeric ( R ) product, (2R)-endo-ll, with 92 YOee. The different direction of asymmetric induction was explained in terms of the geometry of catalyst-dienophile complexes at the corresponding metal centers. The bis(oxazo1ine)Zn(I1) complex-catalyzed reaction proceeded via the tetrahedral chiral Zn-dienophile complex VIII, in a manner similar to the bis(oxazo1ine)-Mg catalyst reported by Corey [13], whereas the reaction catalyzed by the cationic bis(oxazo1ine)-Cu complex proceeded via the square-planar Cu(I1)-dienophile intermediate VII, so the diene preferred to approach from the opposite si face of the bound dienophile with s-cis configuration, avoiding steric repulsion by one of the tert-butyl substituents on the oxazoline rings. In 1995, Fujisawa et al. [16] reported that the chiral Mg complex prepared by treatment of a (sulfony1amino)oxazoline ligand 14 with Grignard reagent (MeMgI) and I2 (co-catalyst) is effective in the Diels-Alder reaction of oxazolidinone 9 with cyclopentadiene 8. endo-11 was obtained exclusively in high enantiomeric excess (92 YOee) when the stoichiometric amount of the chiral Mg complex was used, but reducing the amount of the complex to 20 or 10 mol '30 reduced the enantioselectivity (80 YOee and 51 YOee, respectively; Table 2). The 'H and 13CNMR spectra showed EtZO coordinated to the magnesium atom. Because of this the high enantioselectivity was explained as arising from the octahedral arrangement IX (rather than a tetrahedral arrangement, as in Corey's catalyst [13]) with the chiral ligand 14 and the bidentate dienophile 9 in the s-cis configuration in the equatorial plane, and two molecules of the ether located at the apical positions.

Table 2

Ph 14 Mg cat.

100 mol% 50 mol% 20 mol% 10 mol%

(PFI)-endo-ll %yield 69 81 82 95

% ee

92 91 80 51

IX

Llera et al. [17] reported a new chiral hydroxysulfoxide 15, the chiral MgI2 complex of which catalyzed the reaction of the oxazolidinone 9 with cyclopentadiene 8 at 78 "C to give (2S)-ll in 95 YOyield (>98 YOendo) with 84 YO ee. They proposed two reactive species X and XI to explain the mode of asymmetric induction in the preceding reaction. Transition states X and XI differ in the arrangement of the oxazolidinone

Mg(II) and Zn(II) Lewis Acids

65

around the magnesium. In both instances the si face of the dienophile 9 is hindered either by the axial phenyl ring in X or by the large naphthyl group attached to the sulfur in XI (Fig. 2).

p[fy-,s,-Naphthyl l

6

HO

15

(2S)-endo-11 >98% endo 84% ee

X

XI

Figure 2

0

+

K

N \ mO

0 8

95% yield 87% ee (25) (endo/ ex0 = 2.5 : 1)

catalyst (20 mol%)

q r N T o 0

0

0

16

(S,S)-l8

(S,S)-13

+

+

Zn(OTf)2

CU(0Tf)Z

99% yield 78% ee (25) (endo/exo = 8 : 1)

90% yield 76% ee (25) (endo/exo = 6.7 : 1)

Scheme 7

Takacs et al. [18] then examined a series of chiral bis(oxazo1ine) ligands, differing in the length of the chain connecting the chiral oxazoline moieties, using triflate complexes of Mg(II), Zn(II), and Cu(I1) in the reaction of N-crotonyloxazolidinone 16

66

Motoyama/Nishiyama

with cyclopentadiene 8 (Sch. 7 ) .The best Mg(OTf)2 catalyst was derived from the 1,3bis(oxazo1ine) ligand 10 (87 YOee). In contrast to the Mg catalyst, the 1,4-bis(oxazoline) ligand 18 afforded the best catalysts with Zn(OTf)2, although enantioselectivity of the endo adduct 17 was slightly reduced (78 YOee). The enantioface selectivity observed in the reaction with bis(o~azoline)-Mg(OTf)~ and -Zn(OTf)2 was the opposite of that reported by Corey [13] and Evans [15]. They explained these results by suggesting that that the triflate ligands did not become detached from the metal in the reaction medium, and that reaction proceeded via the trans-octahedral intermediate XI1 rather than the tetrahedral intermediate (Fig. 3).

trans-octahedral XI1

Figure 3

Very interestingly, a non-C2-symmetric mono(oxazo1ine) 19 was reported as an efficient chiral ligand for the magnesium-catalyzed Diels-Alder reaction of 2-benzoylacrylate 21 with cyclopentadiene 8. Yamauchi et al. [19] reported that the enantioselectivity (87 % ee) of the reaction with the mono(oxazo1ine)-derived Mg complex, prepared by the Corey's procedure [13] in acetonitrile under reflux, was almost equal to or slightly higher than that with the C2-symmetric bis(oxazo1ine) 20-derived product (85 % ee) (Sch. 8), although the mechanism of the reaction giving high diastereoand enantioselectivity was unclear.

21

8

19

Scheme 8

-90 "C (88%)

20

22a

22b

>99 (87% ee)

1

67

Mg(II) and Zn(II) Lewis Acids

Whiting et al. [20] found the catalytic system for an aza Diels-Alder reaction by the use of a combinatorial approach to catalyst selection. When methyl glyoxylate-derived aldimine 25 was reacted with Danishefsky's diene 24 in the presence of the chiral magnesium catalyst (10 mol YO), prepared in-situ from chiral diphenylethylenediamine 23, Mg12, and 2,6-lutidine, the Diels-Alder product 26 was obtained in 64 YOyield with 97 % ee (Sch. 9).

PhyNH2 + Ph"''

Mgl2

f!+Meon 23 NH2

N

TMSO 24

HKC02Me 25

F

2,6-lutidine

ND

O

M

e

(10 mol%) *

CH3CN rt, 18 h then hydrolysis (64%)

0-C02Me 26 97% ee

Scheme 9

3.3 Radical-Mediated Reactions Radical reactions can often be rationalized on the basis of frontier orbital considerations for intermediate radical species, the reactivity and stereochemistry of which can certainly be regulated with Lewis acid additives [21-231. The first appearance of Lewis acids in radical reactions was in polymerization reactions resulting in alternation of copolymers different from that obtained without Lewis acids [24-261. This concept, Lewis acid-directed radical reactions, has been applied to reductions and alkylations of organic halides or olefins, and has resulted in highly stereospecific processes.

3.3.1 Control of Diastereoselectivity Guindon et al. [27] reported the first example of a chelation-controlled radical reaction. Completely reversed stereochemistry was observed in radical reduction of a 2iodo-3-phenylpropionate 27 with Bu3SnH (Sch 10) performed in the presence and absence of Mg Lewis acid catalysts. Even a catalytic amount of MgBr2.0Et2 (0.25 equiv.) maintained such high diastereoselectivity (28; erythrolthreo 2 25:l). In addition, no radical initiator was required for the reaction to proceed. The initiation step probably occurred via a single electron-transfer (SET) process between Bu3SnH and the electron-deficient chelate complex of the substrate 27 and magnesium species. In the absence of Lewis acid the stereochemical outcome was controlled by the conformation of the starting radicals XI11 (Sch. 11). Divalent Lewis acids such as MgBrz or MgIz could alter the structure of the transition state XIV to the bidentate chelate, thus changing the diastereofacial selectivity of the addition reaction. Similar results were obtained with chelation-controlled allylation mediated by radicals (Sch. 12) [28]. In the presence of MgBr2.0Etz, the reaction of 2-iodopropionate 29a with allyltributyltin 30 proceeded more readily even at a low temperature (-78 "C) than the reaction under reflux in hexane in the absence of the catalyst. The

68

Motoyama/Nishiyama

addition of MgBr2. OEt2 (3 equiv.) gave excellent diastereofacial selectivity for anti31 (antilsyn = 38:l). syn-31 was formed preferentially in the absence of the Lewis acid (antilsyn = 1 5 ) [28a]. Lewis acid Bu3SnH

0

Me0

P h v O M e Me I

P : v O M e Me

*

27

none Mg12 (1.O equiv) MgBrpOEt2 (1.O equiv) MgBr2*OEt2(0.25 equiv)

0

Me0 -t

PhuOMe Me

erythre28

three28

1 >25 >25 >25

>25

90% 78% 84% 81Y' o

1 1 1

Scheme 10 In the absence of Lewis acid

Me0 H

H-SnBu3

three28

XI"

In the presence of Mg salts as Lewis acid

I

&ze

Me

H-SnBu3

o---'2

Ph

Me

M M :e+ ;& :,],

Ph

H

2+

Mg

H erythre28

LTS\Bure XIV

Scheme 11 Et3B or

30

29a

none MgBrpOEt2 (3.0 equiv) Scheme 12

82% 80%

anti-31

syn-31

1 38

5 1

69

Mg(II) and Zn(II) Lewis Acids

Guindon et al. [28b] also found that allylsilane 32 was more effective in the allylation reaction than the allyltin reagent (Sch. 13). The reaction proceeded via an atomtransfer process. To prove the reaction mechanism, they examined the bromo- and phenylselenide substrates (29b and 29c) as starting materials and succeeded in isolating the intermediate phenylselenide 34c as a 4:l mixture of isomers, epimeric at the pcarbon to the silyl group. The final product 31 was obtained in an antilsyn ratio 2 1OO:l. A similar intermediate 34b derived from the bromo substrate 29b was also detected in the reaction mixture, although the corresponding iodide intermediate 34a could not be trapped to cause the subsequent rapid elimination to 31. The inclusion of MgBrz. OEt, also seems to improve the efficiency of the overall atom-transfer process for /3-alkoxy substrates 29. Coordination of the Lewis acid would make the /3-alkoxy group sufficiently electronegative to reduce the SOMO energy of the intermediate radical 33, thus enabling better overlap with the HOMO of the allylsilane. MgBrpOEt2 (1 .O equiv)

0

Me0 Ph-OMe

+

-SiMe3

Et3B

(0.2 equiv)

CH2C12

x

-

Ph-OMe

-w

-78"C

29a: X = I b: X = Br c: X = SePh

X=I

32

0

Me0

87% yield

31 anti/syn = 42 : 1

X-SiMe3

Me0

Me0

'T)

Ph-OMe

--I 0

Ph-OMe

x

'*SiMe3 X

-SiMe3

x'>Meo,Ms. dOMe Ph

Scheme 13

.

33

Med M g"0 2+

x*q

32 * Ph-OMe

34a: X = I b: X = Br c: X = SePh

y S i M e 3

3.3.2 Asymmetric Reactions using Chiral Auxiliaries The use of chiral auxiliaries proved to be particularly efficient for the preparation of optically pure materials via radical reactions [29]. Yamamoto et al. [3O] examined the free-radical reaction of an a-bromoglycine derivative 35 having a chiral auxiliary with allyltributyltin 30 to give allylated product 36 (Sch. 14). Although the use of 0.1 equiv.

70

Motoyarna/Nishiyama

ZnCI2.OEt2 accelerated the reaction sufficiently, high diastereofacial selection needed 2 equiv. Lewis acid. It was noted that ethereal zinc halides acted both as radical initiators and as chelating agents, whereas BF3.OEt2 and SnC14 did not show such activity.

7i-prh e S n B u 3 30

+

Me02C$N , KNY0

Me02CyN'fN'fo Br 0 0 -78 CH2C12 "C,1 h * v- 0 35 none ZnCI2*OEt2(0.1 equiv) ZnC12*OEt2(2.0 equiv)

0% 65% 85%

0

Me02C

JNYNYO 0 0

(1 R)-36

(1 5)-36

67 87

33 13

Scheme 14

Lewis acid (2 equiv) Et3B

Ph phA,,

Ph

Ph

0 2

0

CHzClz -78 "C, 2 - 3 h

0 37

30 none BF,*OEtz ZnC12 MgBrz

Phl

Phl

A

0

0

0

(1S)-38

(1R)-38

1

93% 85% 95%

6

1.8 1.4 1

94%

2100

1

1

0

B

ii -

XVI

-

xv Scheme 15

71

Mg(II) and Zn(II) Lewis Acids

Sibi and Ji [31] reported extremely high diastereofacial selectivity for a chiral oxazolidinone 37 derived from diphenylalaninol (Sch. 15). In the absence of Lewis acids the allylation reaction was not stereoselective (SIR = 1:l.S) because of the occurrence of at least four rotamers of the radical intermediates (A-D, XV). The use of Lewis acids capable of chelation, especially MgBr2, resulted in higher selectivity ( S / R 2 1OO:l) than given by single coordination (e.g. BF3.0Et2), with the opposite stereoselectivity. The observed (S) stereochemistry was explained in terms of coordination with MgBr2 leading to the chelated intermediate XVI with s-(Z)orientation of the C-Me group (Me is located syn to the carbonyl group); addition of the allyltin reagent then occurs from the face opposite to the large diphenylmethyl substituent on the oxazolidinone ring. The diphenylalaninol-derived oxazolidinone skeleton was thus effective as a chiral auxiliary, and was then applied to the ,&radical addition of the u,P-unsaturated compound 39 (Sch. 16) [32]. The high diastereofacial selectivity of the /?-radical addition can be explained by a chelation model XVII similar to XVI for the preceding allylation reaction. Lewis acid (2 equiv) Et3B (10 equiv)

Ph PhA*,.

Ph PhA*

Bu3SnH (5 equiv)

0

0

* P h w N K O

i-Pr

-78 "C

39 ZnCIz MgBr2

H

PhA,

"n P h T N , O "n

0 2

CH2C12/ Hex / Et20

Ph

70% 90%

e

0

0

+

i-Pr

0

(25)-40

(2R)-40

9 20

1 1

0

2 top face addition

Ph

XVll

Scheme 16

3.3.3 Enantioselective Reactions Hoshino et al. [33] reported the first example of an enantioselective radical reaction employing a chiral Lewis acid complex. The enantioselective reduction of u-methoxymethyl-a-iodolactone 41 with tributyltin hydride (Bu3SnH) in the presence of stoichiometric amounts of the chiral complex of a chiral diamine 42 and Mg12, gave the reduced product 43 in 88 YOyield with 62 YOee (Sch. 17). Reaction using Mg(C104)2,TiC14,Zn12,

72

Motoyama/Nishiyama

AlC13, and Eu(tfc)3 did not, however, give satisfactory results. Interestingly, the amount of asymmetric induction was shown to be sensitive to the concentration of the substrate. In particular, high dilution resulted in low enantioselectivity (18 0'9 ee).

619 BnO 42 (1 equiv)

mMe I

+ (1 Bu3SnH equiv)

41

+

Mglp

(1 equiv)

CH2C12 -78 "C, 40 min

21 mmol /dm3 36 mmol/ dm3 67 mmol / dm3

43

81%

88% 83%

18% ee 62% ee 52% ee

Scheme 17

In 1995, Porter et al. [34] reported the first excellent results for free radical addition to an electron-deficient alkene by use of chiral zinc complexes. Reaction of the oxazolidinone 9 with tert-butyl iodide and allyltributylstannane 30 in the presence of Zn(0Tfh and a chiral bis(oxazo1ine) ligand 12 gave the adduct 44 in 92 % yield with 90 YO ee (Sch. 18). The chiral bis(oxazo1ine) complexes derived from ZnC12 or Mg(OTf)2 gave racemic products. In this reaction, lower allyltidalkene ratios gave substantially more telomeric products, and a [3 + 21 adduct 45 of the oxazolidinone 9 and the allylstannane 30 was obtained at temperatures above 0 "C.

73

Mg(II) and Zn(II) Lewis Acids

'/

73

+ Zn(OTf)2

0 9

30

(92%)

0

(4-44 90% ee 2+

45

[3+2]adduct

XVlll Scheme 18

Coordination of the oxazolidinone 9 with the zinc complex activated the electrophilicity of the alkene moiety toward addition of the nucleophilic radicals, but the stereodetermining step was the subsequent addition-fragmentation reaction of the intermediate radical with an allyltin reagent. A transition state XVIII similar to IV was proposed for the bis(oxazo1ine)-Mg complex-catalyzed Diels-Alder reaction reported by Corey [13]. As the conformation of the bound a-amidyl radical formed by reaction with tert-butyl radical is s-cis [29a], the back face of the prostereogenic radical in XVIII is shielded by one of the phenyl substituents on the oxazoline rings. So, the addition reaction occurred from the front face to the radical intermediate XVIII to give the ( R )product from the (R,R)ligand 12. The above bis(oxazoline)-Zn(OTf)2 system is also effective for conjugate radical additions and ally1 transfer reactions. Porter et al. [35] reported the first example of penantioselective reaction-conjugate addition of the tert-butyl radical to the oxazolidinone 16 in the presence of Zn(OTf), and (R,R)-bis(oxazo1ine) 12 afforded the adduct 46 in 90 YOyield with 82 YOee ( R )(Sch. 19). The magnesium Lewis acid complex, prepared from (S,S)-bis(oxazo1ine) 47 and MgI,, was also effective in this reaction (80 YO,74 % ee, R), and reduction of the catalyst-load to 20 mol YOresulted in a small decrease in enantioselectivity with both bis(oxazo1ine)-Zn and -Mg complexes (70 Yo ee and 66 YOee, respectively). It was noted that the stereoselectivity of the reaction was highly dependent on the substituents on the oxazoline rings-the aryl group on 12 and the alkyl on 47 gave the opposite enantiomers.

74

Motoyama/Nishiyama

n

T N y o+ 0

t-Bul

0

catalyst Bu3SnH Et3B I 0 2

y-yNyO

t

CH2CI2 -78 "C

f-BU

0

16

Ph

Ph (Rq-12

0

46

i-Bu

i-Bu (S,S)-47

12/Zn(OTf)2 (100 mot%) (20 mol%) 12 I Mg12 (100 mol%) 47 I Mg12 (100 mol%) (20 mot%)

82% ee (R) 70% ee ( R ) 47% ee (R) 74% ee (R) 66% ee (R)

(goo/) (71%) (88%) (88%) (73%)

Scheme 19

Sibi and Ji optimized the reaction (Sch. 20) [36]. Excellent enantioselectivity (97 YOee) for 49 from 48 was achieved with 30 mol YOof the catalyst prepared in-situ from ligand 50 and Mg12, and reducing the amounts of the complex to 5 mol % still maintained the high level of enantioselectivity (90 % ee). Two bis(oxazo1ine)-substrate complexes of octahedral geometry with the iodides (anionic ligands) in a trans or cis arrangement were proposed (Fig. 4; XM, XX). With complex XIX the radicals attack the less hindered si face of the substrate to give (S)49. Whereas with complex XX the opposite re face of the bound cinnamoyl oxazolidinone alkene group is exposed to the radicals, because the re-alkene face is shielded by a substituent on the oxazoline rings. (S,S)-50 / Mgl2 Bu3SnH Et3B / 0 2 CH2C12

-

-\

I

Phy-yNyo

-78 "C

i-Pr

0

0

49

100 mol% 30 mol% 10 mol% 5 mol% 1 mol%

88% 91% 88% 92% 29%

93%ee 97%ee 95%ee 90%ee 63%ee

The geometry of the complex is ligand-dependent. With the phenyl-substituted ligand, the intermediate complex adopts the trans form XIX whereas in reaction with ligands with more crowded substituents than the phenyl ring the conformation of the ligand-substrate complex changes to the cis form XX- the more Lewis-basic carbonyl oxygen is trans to the anionic ligand X [37].

Mg(II) and Zn(II) Lewis Acids

75

XIX: trans-octahedral

XX: cis-octahedral

Figure 4

The ally1 transfer reaction of N-(a-bromoa1kanoyl)oxazolidinone 51 with allyltributylstannane 30 was realized in the presence of the bis(~xazoline)-Zn(OTf)~system (Sch. 21) [38]. The enantioselectivity depended on the size of the alkyl group on the oxazoline and was up to 74 % ee for 12. The use of allylsilane as a radical trap reagent gave the allylated product 44 with enantioselectivity superior to that for reaction of the allylstannane with the (R,R)-l2-derived Zn complex (90 YOee, R). The magnesium complex, prepared in-situ from ($S)-52 and MgI2, was also effective in this reaction with allylsilane (88 YOee, R). Interestingly, bis(oxazo1ine) ligands with the opposite absolute configurations gave the product with same configuration, depending on the Lewis acid ~ s e d - Z n ( O T f ) ~or Mg12.

n

f-Bu+NyO~r

+

t i 6

M = SnMe3 SiMe3

51

Et3B J 0 2 CH7C12- pentane -78 "C

~

Ph

(Rfl-12

f-Bu

t-Bu-NKO

6 6 44

12 / Zn(OTf)2 M = SnBu3 12 / Zn(OTf)2 M = SiMe3 52/Mg12 M=SiMe3 Ph

n

A:

-M

74% ee (63%) 90% ee (88%) 88% ee (65%)

t-Bu

(S,S)-52

Scheme 21

3.4 Other Reactions The terpene menthol is widely used in organic synthesis, and serves as a chiral auxiliary for several asymmetric reactions [39]. (-)-Menthol 53 could be produced in one step from isopulegol55 by hydrogenation of the carbon-carbon double bond, and the latter compound could be prepared by a Lewis acid-induced carbonyl-ene reaction [40] of d-(R)-citronella1 54. Nakatani and Kawashima examined that the ene cyclization of citronella1 to isopulegol with several Lewis acids in benzene (Sch. 22) [41]. The zinc reagents were far superior to other Lewis acids for obtaining

76

MotoyamdNishiyama

I-isopulegol 55 selectively from d-citronellal. Treatment of d-(R)-citronella1 54 with ZnBr2 or ZnIz resulted in the formation of isopulegol 55 with high diastereoselectivity. Of the three other possible diastereomers, d-neoisopulegol56 is the main by-product and the other two isomers are formed in trace amounts. To explain this high selectivity it was suggested that isopulegol was formed via a chair-like transition state XXI in which the methyl group at C3 position, the coordinated carbonyl group, and the A637-doublebond are all equatorial.

benzene

OH

&(R)-54 Lewis acid (mole/,) BF3 (2) SnCI4 (2) Tic14 (2) ZnCI2 (100) ZnBr2 (1 00) Zn12 (100)

1-55

d-56

Yoyield I-isopulegol/ others 74 : 26 69 : 31 50 : 50 88 : 12 94 : 6 95 : 5

30 81 60 53 70 50

&OH

/ i (-)-53

Scheme 22

Yamamoto et al. [42] reported a highly enantioselective ene cyclization with a chiral zinc reagent as Lewis acid catalyst. Cyclization of 3-methylcitronellal 57 by at least 3 equiv. catalyst prepared in-situ from (R)-l,l'-bi-2-naphthol (BINOL) 58 and MezZn afforded the trans-cyclohexanol 59 in 86 % yield with 88 % ee as the sole product (Sch. 23). Reducing the amounts of the chiral zinc catalyst reduced both the chemical yield and the enantioselectivity.

3:; +

'

/'

MeaZn

58 (3 equiv)

CHzCI2 -78 "C, 20 min, then 0 "C, 20 min (86%)

57

Scheme 23

59 88% ee

77

Mg(II) and Zn(II) Lewis Acids

The system was also applicable to the cyclization of citronella1 54. Treatment of ( R ) - and (S)-citronella1 with the chiral zinc reagent derived from (R)-and (S)-BINOL 58 afforded the exclusive formation of I- and d-isopulegol 55, respectively. The asymmetric induction is totally controlled by the C-3 chiral center on the substrates and is independent of the chirality of the BINOL. The Simmons-Smith reaction is an efficient and powerful method for synthesizing cyclopropanes from alkenes [43]. Allylic alcohols are reactive and widely used as substrates, whereas a$-unsaturated carbonyl compounds are unreactive. In 1988, Ambler and Davies [44] reported the electrophilic addition of methylene to a&-unsaturated acyl ligands attached to the chiral-at-metal iron complex. The reaction of the racemic iron complex 60 with diethylzinc and diiodomethane in the presence of ZnClz afforded the cis-cyclopropane derivatives 61a and 61b in 93 YO yield in 24:l ratio (Sch. 24).

-

ZnClp (4 equiv) Et2Zn (1.5 equiv)

fi

oc-$

%,,,,

Ph3P

0

i-Pr

(R7-60

CH212(4 equiv) toIuene 20 “C

(93%)

-

0 oc-$

,,,,,,,

0

Ph3P

+ i-Pr

-

oc--

,1,,,,,

0

Ph3P

FP-( 17, s’)-61a

kPr

ff-(s’,ff)-61b

24

1

Scheme 24

The rate acceleration and the Jt-face selectivity were explained in terms of the coordination of the Lewis acid to the acyl oxygen atom. The binding Lewis acid moiety interacts with the cis-P-substituent, which forces the olefinic bond to adopt the conformation XXII, approximately orthogonal to the acyl group. The olefinic bond is thus rendered more nucleophilic, accounting for the rapid reaction, and the electrophile E preferentially approaches the face not shielded by the iron auxiliary (Sch. 25).

4

Ph3P (R7-60

XXll

Scheme 25

Friedrich et al. [45] discovered that a catalytic amount of titanium(1V) chloride as a Lewis acid greatly facilitates cyclopropanation reactions of alkenes by the system CH2Br2-Zn-CuC1. The Lewis acid catalyst might bind to the oxygen atom of the allylic alcohol present as the (iodomethy1)zinc alkoxide, and thus increase the electrophilicity of the methylene group [46].

78

Motoyama/Nishiyama

XXlll

65

Figure 5

In 1992 Kobayashi et al. [47] reported the first catalytic and enantioselective cyclopropanation using the Furukawa modification [48] of the Simmons-Smith reaction of allylic alcohols in the presence of a chiral bis(su1fonamide)-Zn complex, prepared in-situ from the bis(su1fonamide) 63 and diethylzinc. When cinnamyl alcohol 62 was treated with Et2Zn (2 equiv.), CH212 (3 equiv.), and the bis(su1fonamide) 63 (12 mol %) in dichloromethane at -23 "C, the corresponding cyclopropane 64 was obtained in 82 YOyield with 76 Yo ee (Sch. 26). They proposed a transition state XXIII (Fig. 5) in which the chiral zinc complex interacts with the oxygen atom of the allylic alkoxide and the iodine atom of iodomethylzinc moiety. They also reported the use of the bis(su1fonamide)-alkylaluminum complex 65 as the Lewis acidic component catalyzing the Simmons-Smith reaction [49]. S02Ar

62

-23 "C, 5 h (82%)

64 76%ee

Scheme 26

Denmark et al. [50] subsequently optimized the reaction protocol for the Simmons-Smith variation of Kobayashi's method on the basis of structural studies of the species present in solution and X-ray crystallographic analysis of bis(iodomethy1)zinc compounds [51]. They found that the rate and the selectivity of the cyclopropanation of cinnamyl alcohol 62 were highly dependent on the order of addition of the reagents. Separate preparation of the ethylzinc cinnamyl oxide and bis(iodomethy1)zinc was very crucial. In addition, an early induction period was observed for this catalytic system; little conversion during this period was followed by rapid production of cyclopropane. This result implies autocatalytic behavior as a result of the generation of Zn12, the only by-product of the reaction. Finally, addition of 1equiv. Zn12, prepared in-situ from I2 and Et2Zn, eliminated the induction period and increased the enantioselectivity to 89 % ee (Sch. 27).

Mg(II) and Zn(II) Lewis Acids

Zn(CH21)2 +

-

Zn12

79

2 ICH2Znl

66

S02Me

Ph++o /.-H

+

+ Et2Zn

S02Me (10 mol%) (1.1 equiv)

62

CH212 (2 equiv)

0,;; 63

+

Et2Zn (1 equiv)

-

1

I

(92%)

64 89% ee

Scheme 27

The role of Zn12 is that an equimolar quantity of the compound drives the Schlenk equilibrium from the reagent bis(iodomethy1)zinc to (iodomethy1)zinc iodide, which is the actual cyclopropanation catalyst and has high reactivity and stereoselectivity [5Oc,52]. The structure of the active catalyst, Zn-bis(su1fonamide) complex XXIV, was characterized by 'H NMR analysis and X-ray study of the structure of its bipyridyl complex 66 (Sch. 28) [53].The Zn-bis(su1fonamide) complex XXIV aggregates in solution and functions as a divalent Lewis acid. The intermediate proposed for this reaction system comprises the monomeric substrate alkoxide and the active reagent (ICH2ZnI) bound with the zinc-bis(su1fonamide) complex in tetrahedral geometry (Sch. 29). Activation of ICH2ZnI is achieved by coordination of the zinc-bis(su1fonamide) species (bond a in XXV). This serves to increase the reactivity of the reagent. Internal interaction with the iodine of the iodomethyl group (bond b in XXV) then makes the methylene more reactive, which accounts for the rate acceleration. The alkoxide oxygen might be used to fill the

80

Motoyama/Nishiyama

remaining sites on the zinc of the sulfonamide moiety (bond c in XXV) and the reagent (bond d in XXV). The alkoxide zinc binds to the one of the more proximal sulfonyl oxygens (bond e in XXV). S02Me

0”;. ‘VN’

+

EtZnO

+

IZnCH21

*Ph

I

S02Me Et

\

Me

xxv Scheme 29

The allylation of a-alkoxy aldehydes with allylstannanes has been shown [54] to proceed with high diastereofacial selectivity in the presence of Zn12 or MgBrz via a chelation-controlled nucleophilic addition process. Keck et al. [SS] studied the reactions of the a-benzyloxy aldehyde 67 and allyltributylstannane 30 when treated with several Lewis acids (Sch. 30). Using Lewis acids such as ZnIz or MgBr2, which are capable of forming bidentate chelates (Fig. 6, XXVI), mainly threo (syn)-68 was obtained (Zn12: 97:3; MgBr2: > 2S0:1, respectively). Moderate selectivity was, however, observed in the formation, by use of the monodentate Lewis acid BF3 * OEt2, of the ‘Cram product’ with erythro (unti)-68 stereochemistry (Fig. 6, XXVII). -SnBu3

30

Lewis acid (1.el .1 equiv)

QBn t

CH2C12 67

BF3oOEt2 ZnC12 MgBr2

Scheme 30

85% 92%

three68

erythre68

39

61 3

97 >250

1

81

Mg(1l) and Zn(l1) Lewis Acids

XXVll

XXVl

Figure 6

Umani-Ronchi et al. [56] investigated the asymmetric allylation of aldehydes with allylstannane in the presence of chiral bis(oxazo1ine) ligands and several metal salts (Sch. 31). Combination of zinc halides and the bis(oxazo1ine) ligand 70 gave the allylated product 71 with moderate enantioselectivity (40 % ee), while other metal salts afforded either no product or racemic products. Because the formation of an allylzinc-bis(oxazo1ine) species was excluded on the basis of the NMR experiments, the reaction was considered to proceed by a Lewis acid-mediated pathway.

oY-Yo cI\1 L,) + I

"-C7H15yH

+ - s ~ B ~ ~

0 69

30

Ph

70

Pi,

metal salt (10 mol%)

n-C7H15\/\/

CH2C12 24 "C, 18 - 24 h

MgBr2 SnCI2 CU(OTf)2 ZnBr2 Zn12

/

OH 71 0%

60% 63%

54% 78%

0% ee 0% ee 40% ee 40% ee

Scheme 31

The 1,3-dipolar cycloaddition reaction [57] between alkene and nitrone [58] is an effective procedure for generating new chiral centers attached to heteroatoms. Jorgensen et al. [59a] found that remarkably high endo selectivity was induced in the 1,3dipolar reaction by use of a phenanthroline-coordinated Mg(I1) catalyst prepared in the presence of I2 as a co-catalyst (Sch. 32). By reaction of 74, an alkene bearing a chiral oxazolidinone, with benzylidenephenylamine N-oxide 73 in the presence of the Mg(I1)-phenanthroline catalyst (10 mol %), one of the four possible diastereomers of the isoxazolines 75 was formed exclusively in an almost quantitative yield.

82

Motoyama/Nishiyama

0 O ,:P h , HUPh

73

+

j - " h

'

-IfNK0 0 0 74

MS 4A CH2C12 rt, 48 h (99%)

75 single isomer

XXVlll Scheme 32

Attempts were then made to perform asymmetric catalytic reactions using chiral Lewis acid catalysts [.59]. Reaction of the nitrone 73 and the oxazolidinone 76 with 10 mol % of the bis(oxazo1ine) U-Mg(I1) catalyst, prepared by Corey's method [13], in the presence of 4-A molecular sieves afforded the cycloadduct 77 in high yield (>9.5 YO)and high (> 95 YO)endo selectivity and 82 YOee (Sch. 33). The presence of activated powdered 4-A molecular sieves was essential to the endo and enantioselectivity of the reaction; in their absence they were 65 % and < 2 YO,respectively. The reaction proceeded via an intermediate XXIX, proposed by Corey [13], in which the bis(oxazo1ine) ligand 12 and the oxazolidinone 76 are both bidentately coordinated to the magnesium and addition to the re face is favored because the si face of the bound oxazolidinone is masked by one of the phenyl substituents on the oxazoline rings. In 1993 Corey et al. [60] reported a new enantioselective method for synthesis of chiral cyanohydrins [61] from aldehydes and trimethylsilyl cyanide (TMSCN) by the use of a pair of synergistic chiral reagents. Reaction of cyclohexane carbaldehyde 78 and trimethylsilyl cyanide (TMSCN) 79 in the presence of 20 mol YOchiral magnesium complex 80 afforded the cyanohydrin TMS ether 81 in 85 YO yield with 6.5 YOee. This modest enantioselectivity was further enhanced to 94 YOee by addition of a further 12 mol YOof the bis(oxazo1ine) 70 (Sch. 34).

Mg(Z1) and Zn(1I) Lewis Acids 1

I

-to

TMSCN

TMSO CN

R

R L

xxx Scheme 35

0

n

Ph,f,O

+ n-Pr-Tf

HKPh

76

73

XXlX

Scheme 33

0

NT o 0

Ph

,2

Ph

(10 mol%)

MS 4A CHzC12 rt. 14 davs

83

84

MotoyamaINishiyama

I

CI

+

78

TMSCN

79

80

(20 mol%)

70 (12 mol%)

EtCN / CH2C12 -78 "C (94%)

TMSO GN @H

81 94% ee

Scheme 34

To explain this catalytic system it was proposed that the active CN source is not TMSCN but HCN, which can be expected to be present in reaction mixtures containing TMSCN as a result of hydrolysis caused by an adventitious trace of water. The chiral Lewis acid catalyst in turn captures the aldehyde and subsequent reaction proceeds with a 'chiral cyanide donor' derived from the bis(oxazo1ine) 70 and HCN as shown in XXX. Finally, the cyanohydrin, produced as primary product is converted to the cyanohydrin TMS ether and HCN (Sch. 35). Evans et al. [62] reported that the chiral magnesium-bis(su1fonamide) complex was the effective catalyst for the combined enolization and enantioselective amination [63] of N-acyloxazolidinones. When the oxazolidinone 82 was reacted with ditert-butylazodicarboxylate 83 in the presence of the catalyst (10 mol YO),generated by treating ($S)-bis(su1fonamide) 84 with dimethylmagnesium, and N-methyl-p-toluenesulfonamide (20 mol Y) at -75 "C, the aminated product 85 was obtained in 92 YO yield with 86 % ee (Sch. 36). The sense of asymmetric induction in the preceding reaction can be explained by proposing the intermediate of the chelated tetrahedral magnesium enolate complex XXXI. Important structural attributes of this complex include (Z)-enolate geometry [64] and the conformational rigidity enforced by chelation of both the enolate and the bis(su1fonamide) ligand to the tetrahedral Mg ion. Gearing between the aryl group resident within the diamine backbone and the arylsulfonylamide residues forces one aromatic ring to project over the enolate TC-systern [65], exposing the si enolate a-carbon diastereoface to the incoming electrophile. In this catalytic process N-methyl-p-toluenesulfonamideaccelerates the reaction, but the role of this addend has not yet been completely elucidated.

Mg(II) and Zn(II) Lewis Acids

85

phxph q

2

-

:-so+

Z

+

(10 mol%)

84

0

pTsN(H)Me (20 mol%)

+ BocN=NBoc 83

Me2Mg

0

0K N L P h

CH2C12 -75 "C, 48 h (92%)

BocN, 85 86% ee

~BOC H

Scheme 36

Sibi et al. [66] reported the first examples of highly enantioselective conjugate amine additions [67]by use of catalytic amounts of a chiral Lewis acid complex. Addition of 0-benzylhydroxyamine 87 (1.1equiv.) to the pyrazole-derived crotonamide 86 proceeded smoothly in the presence of stoichiometric amounts of the chiral catalyst prepared from the bis(oxazo1ine) 50 and MgBrz. OEtz with high enantiomeric excess (96 % ee) (Sch. 37). This conjugate addition reaction was equally effective with catalytic amounts of the chiral Lewis acid (92 % ee with 30 mol %; 88 '70 ee with 10 mol YO).A re face amine addition to the s-cis substrate bound to the chiral complex with tetrahedral- or cis-octahedral arrangements XXXII and XXXIII accounts for the product stereochemistry observed (Fig. 7).

HZNOBn 87

-60 "C, 20-22 h

88 100 mol% 30 molo/o 10 mol%

Scheme 37

62% 80% 87%

96% ee 92% ee 88% ee

86

Motoyarna/Nishiyarna

-

tetrahedral XXXll

cis-octahedralXXI

Figure 7

3.5 Concluding Remarks Remarkable advances in the magnesium and zinc Lewis acid catalysts have been reviewed and considered in terms of their catalytic activity, stereoselectivity, and the assumed intermediates. Their high potential in organic synthesis has been clarified, especially in asymmetric synthesis. Increasingly sophisticated reactions with greater selectivity and catalytic performance, including overall efficiency, are to be expected.

References 1. Reviews : (a) Morrison, J. D. Asymmetric Synthesis; Academic Press: New York, 1984; Vol. 3B. (b) Oppolzer, W. Angew. Chem., Int. Ed. Engl. 1984, 23, 876. (c) Fringuelli, F.; Taticchi, A. Dienes in the Did-Alder Reaction; Wiley: New York, 1990. (d) Oppolzer, W. in Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I. Eds.; Pergamon: Oxford, 1991; Vol. 5, p 315. (e) Kagan, H. B.; Riant, 0. Chem. Rev. 1992,92,1007. (f) Oh, T.; Reilly, M. Org. Prep. Proc. Znc. 1994,26,129. 2. (a) Alder, K.; Stein, G. Angew. Chem. 1937,50,510. (b) Martin, J. G.; Hill, R. K. Chem. Rev. 1961, 61,537. (c) Hoffmann, R.; Woodward, R. B. J. Am. Chem. SOC.1965,87,4388. (d) Woodward, R. B.; Hoffmann, R. The Conservation of Orbital Symmetry;Academic Press: New York, 1970. 3. (a) Houk, K. N.; Strozier, R. W. J. A m . Chem. Soc. 1973,95,4094. (b) Fleming, 1. Frontier OrbitaO and Organic Chemical Reactions; Wiley: New York, 1976. (c) Guner, 0. F.; Ottenbrite, R. M.; Shillady, D. D.; Alston, P. V. J. Org. Chem. 1987,.52,391. 4. (a) Danishefsky, S.; Kitahara, T.; Yan, C. F.; Morris, J. J. Am. Chem. SOC.1979, 101, 6996. (b) Danishefsky, S. Acc. Chem. Res. 1981,14,400. 5. Savard, J.; Brassard, P. Tetrahedron Lett. 1979,4911. 6. (a) Danishefsky, S. J. Aldrichimica Acta 1986,19, 59. (b) Danishefsky, S. J. DeNinno, M. P. Angew. Chem., Int. Ed. Engl. 1987,26,15. (c) Danishefsky, S. J. Chemtracts 1989, 273. 7. (a) Midland, M. M.; Graham, R. S. J. Am. Chem. SOC. 1984,106,4294. (b) Midland, M. M.; Koops, R. W. J. Org. Chem. 1990,55,5058. 8. (a) Bednarsky, M.; Danishefsky, S. J. Am. Chem. Soc. 1983, 105, 3716, 6968. (b) Danishefsky, S.; Bednarsky, M. Tetrahedron Lett. 1984, 24, 721. (c) Bednarsky, M.; Danishefsky, S. J. Am. Chem. SOC.1986,108,7060. 9. (a) Danishefsky, S.; Larson, E. R.; Askin, D. J. Am. Chem. Soc. 1982,104,6457. (b) Danishefsky, S.; Pearson, W. H.; Harvey, D. F. J. Am. Chem. Soc. 1984,106,2456. 10. Larson, E. R.; Danishefsky, S. J. A m . Chem. SOC.1982,104,6458.

Mg(I1) and Zn(1I) Lewis Acids

87

11. (a) Larson, E. R.; Danishefsky, S. Tetrahedron Lett. 1982,23,1975. (b) Larson, E. R.; Danishefsky, S. J. A m . Chem. Soc. 1982, 104, 6458. (c) Danishefsky, S. J.; Larson, E. R.; Askin, D.; Kato, N. J. Am. Chem. Soc. 1985,107,1246. 12. (a) Danishefsky, S. J.; Pearson, W. H.; Harvey, D. F, J. Am. Chem. Soc. 1984, 106, 2455. (b) Danishefsky, S. J.; Pearson, W. H.; Harvey, D. F.; Maring, C. J.; Springer, J. P. J. A m . Chem. Soc. 1985,108,1256. 13. Corey. E. J.; Ishihara, K. Tetrahedron Lett. 1992,33,6807. 14. Desimoni, G.; Faita, G.; Righetti, P. P. Tetrahedron Lett. 1996,37,3027. IS. Evans, D. A,; Kozlowski, M. C.; Tedrow, J. S. Tetrahedron Lett. 1996,37,7481. 16. (a) Fujisawa, T.; Tchiyanagi, T.; Shimizu, M. Tetrahedron Lett. 1995, 36, 5031. (b) Fujisawa, T.; Ichiyanagi, T.; Shimizu, M. Tetrahedron Lett. 1995, 36, 5031. (c) Ichiyanagi, T.; Shimizu, M.; Fujisawa, T. J. Org. Chem. 1997,62,7937. 17. Ordonez, M.; Guerrero-de la Rosa, V.; Labastida, V.; Llera, J. M. Tetrahedron: Asymmetry 1996, 7, 2675. 18. (a) Takacs, J. M.; Lawson, E. C.; Reno, M. J.; Youngman, M. A.; Quincy, D. A. Tetrahedron; Asymmetry 1997, 8, 3073. (b) Takacs, J. M.; Quincy, D. A,; Shay, W.; Jones, B. E.; Ross 11, C. R. Tetrahedron: Asymmetry1997,8,3079. 19. Honda, Y.; Date, T.; Hiramatsu, H.; Yamauchi, M. Chem. Commun. 1997,1411. 20. Bromidge, S.; Wilson, l? C.; Whiting, A. Tetrahedron Lett. 1998,39, 8905. 21. (a) Giese, B. Radicals in Organic Synthesis: Formation of Carbon-Carbon Bonds; Pergamon Press: Oxford, 1986. (b) Carran, D. I? Synthesis 1988,417,489. 22. Giese, B. Angew. Chem., Int. Ed. Engl. 1983,22,753. 23. Renaud, I?; Gerster, M. Angew. Chem., lnt. Ed. Engl. 1998,37,2562, and references cited therein. 24. Bamford, C. H.; Brumby, S.; Wayne, R. P. Nature 1966,209,292. 25. Hirooka, M.; Yabuuchi, H.; Morita, S.; Kawasumi, S.;Nakaguchi, K. J. Polym. Sci. Part B 1967,5,47. 26. Penelle, J.; Padias, A. B.; Hall, J. H. K.; Tanaka, H. Adv. Polym. Sci. 1992,102,73. 27. Guindon, Y.; Lavallee, J.-F.; Llinas-Brunet, M.; Homer, G.; Rancourt, J. J. Am. Chem. Soc. 1991, 113,9701. 28. (a) Guindon, Y.; Guerin, B.; Chabot, C.; Mackintosh, N.; Ogilvie, W. W. Synlett 1995,449. (b) Guindon, Y.; Guerin, B.; Chabot, C.; Ogilvie, W. J. Am. Chem. Soc. 1996, 118, 12528. (c) Nagano, H.; Azuma, Y. Chem. Lett. 1996,845. 29. (a) Porter, N. A,; Giese, B.; Curran, D. P. Ace. Chem. Res. 1991, 24, 296. (b) Smadja, W. Synlett 1994, 1. (c) Curran, D. P.; Porter, N. A,; Giese, B. Stereochemistry of Radical Reactions; VCH, Weinheim, 1995. 30. Yamamoto, Y.; Onuki, S.; Yumoto, M.; Asao, N. J. A m . Chem. Soc. 1994,116,421. 31. Sibi, M. P.; Ji, J. Angew. Chem., Int. Ed. Engl. 1996,35,190. 32. Sibi. M. P.; Jasperse, C. P.; Ji, J. J. A m . Chem. Soc. 1995,117,10779. 33. Murakata, M.; Tsutsui, H.; Hoshino, 0.J. Chem. Soc., Chem. Commun. 1995,481. 34. Wu, J. H.; Radinov, R.; Porter, N. A. J. A m . Chem. Soc. 1995,117,11029. 35. Sibi, M. P.; Ji, J.; Wu, J. H.; Gurtler, S.; Porter, N. A. J. Am. Chem. Soc. 1996,118,9200. 36. Sibi, M. P.; Ji, J. J. Org. Chem. 1997,62,3800. 37. For an octahedral models, see: (a) Corey, E. J.; Imai, N.; Zhang, H.-Y. J. Am. Chem. Soc. 1991,113, 728. (b) Haase, C.; Sarko, C. R.; DiMare, M. J. Org. Chem. 1995,60,1777. (c) Seebach, D.; Dahinden, R.; Marti, R. E.; Beck, A. K.; Plattner, D. A,; Kuhnle, F. N. M. J. Org. Chem. 1995, 60, 1788. (d) Johannsen, M.; Jorgensen, K. A. J. Org. Chem. 1995,60,5757. (e) ref. 14. 38. (a) Wu, J. H.; Zhang, G.; Porter, N. A. Tetrahedron Lett. 1997,38,2067. (b) Porter, N. A,; Wu, J. H.; Zhang, G.; Reed, A. D. .I. Org. Chem. 1997,62,6702. 3Y. (a) Morrison, J. D.; Mosher, H. S. Asymmetric Organic Reactions, 2nd Ed., ACS: Washington, D. C., 1976. (b) Eliel, E.; Wilen, S. H. Stereochemistry of Organic Compounds, John Wiley & Sons: New York, 1994. (c) Nogradi, M. Stereoselective Synthesis, 2nd Ed., VCH: Weinheim, New York, 1995. 40. (a) Snider, B. B. Acc. Chem. Res. 1980, 13, 426. (b) Mikami, K.; Shimizu, M. Chem. Rev. 1992, M, 1021. 41. Nakatani, Y.; Kawashima, K. Synthesis 1978,147. 42. Sakane, S.; Maruoka, K.; Yamamoto, H. Tetrahedron 1986,42,2203. 43. (a. Simmons, H. E.; Smith, R. D.; J. Am. Chem. Soc. 1958,80,5323. (b) Simmons, H. E.; Cairus, T. L.; Vladuchick, S. A.; Hoiness, C. M. Org. React. 1973,20, 1. (c) Furukawa, J.; Kawabata, N. Adv. Organomet. Chem. 1974,12,83. (d) Boersma, J. Comprehensive Organometallic Chemistry; Wilkinson, G., Ed.; Pergamon Press: New York, 1984; Vol. 2, Chapter 16. (e) Zeller, K.-P.; Gugel, H. in

Wouben-Weyl: Merhoden der Organischen Chemie; Regitz. M., Ed.; Georg Thieme Verlag: Stuttgart, 1989; Band EXIXb, 195. 44. Ambler, P. W.; Davies, S. G. Tetrahedron Lett. 1988,29. 6979.

88

Motoyama/Nishiyama

45. Friedrich, E. C.; Lunetta, S. E.; Lewis, E. J. J. Org. Chem. 1989,54,2388. 46. (a) Charette, A. B.; Brochu, C. J. Am. Chem. Soc. 1995,117, 11367. (b) Nakamura, E.; Hirai, A,; Nakamura, M. J. Am. Chem. Soc. 1998,120,5844, 47. (a) Takahashi, H.; Yoshioka, M.; Ohno, M.; Kobayashi, S. Tetrahedron Lett. 1992, 33, 2575. (b) Takahashi, H.; Yoshioka, M.; Shibasaki, M.; Ohno, M.; Imai, N.; Kobayashi, S. Tetrahedron 1995, 51,12013. 48. (a) Furukawa, J.; Kawabata, N.; Nishimura, J. Tetrahedron Left.1966,3353. (b) Furukawa, J.; Kawabata, N.; Nishimura, J. Tetrahedron 1968,24,53. 49. Imai, N.: Takahashi, H.; Kobayashi, S. Chem. Lett. 1994,177. 50. (a) Denmark, S. E.; Christenson, B. L.; Coe, D. M.; O’Connor, S. P. Tetrahedron Lett. 1995, 36, 2215. (b) Denmark, S. E.; Christenson, B. L.; O’Connor, S. P. Tetrahedron Lett. 1995, 36, 2219. (c) Denmark, S. E.; O’Connor, S. P. J. Org. Chem. 1997,62,584. 51. (a) Denmark, S. E.; Edwards, J. P.; Wilson, S. R. J. Am. Chem. Soc. 1991,113,723. (b) Denmark, S. E.; Edwards, J. P.; Wilson, S. R. J. Am. Chem. Soc. 1992,114,2592. 52. (a) Charette, A. B.; Marcoux, J.-F. J. Am. Chem. Soc. 1996,118, 4539. (b) Denmark, S. E.; O’Connor, S. P. J. Org. Chem. 1997,62,3390. 53. Denmark, S. E.; O’Connor. S. P.; Wilson, S. R. Angew. Chem., Znt. Ed. Engl. 1998,37,1149. 54. Reviews: (a) Courtois, G.; Miginiac, L. J. Organomet. Chem. 1974, 69, 1. (b) Biellmann, J. E; Ducep, J. B. Org. React. 1982, 27, 1. (c) Hoffmann, R. W. Angew. Chem., Int. Ed. Engl. 1982, 21, 555. (d) Roush, W. R. in Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I.; Heathcock, C. H., Eds.; Pergamon Press: Oxford, 1991; Vol. 2, pp 1. (e) Yamamoto, Y.; Asao, N. Chem. Rev. 1993, 93,2207. (f) Bach, T. Angew. Chem., Int. Ed. Engl. 1994,33,417. (g) Hoveyda, A. H.; Morken, J. P. Angew. Chem., Inf. Ed. Engl. 1996,35,1262. 55. (a) Keck, G. E.; Boden, E. P. Tetrahedron Lett. 1984,25,265. (b) Keck, G. E.; Savin, K. A,; Cressman, E. N. K.; Abbott, D. E. J. Org. Chem. 1994,59,7889. 56. Cozzi, P. G.; Orioli, P.; Tagliavini, E.; Umani-Ronchi, A. Tetrahedron Lett. 1997,38, 145. 57. (a) Huisgen, R. Angew. Chem., Int. Ed. Engl. 1963,2, 565. (b) Huisgen, R. 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley: New York, 1984; Vol. 1 , p 1. 58. (a) Tufariello, J. J. 1,3-Dipolar Cycloaddition Chemistry; Padwa, A,, Ed.; Wiley: New York, 1984; Vol. 2, p 83. (b) Torssell, K. B. G. Nitrile Oxides, Nitrones and Nitronates in Organic Synthesis; VCH: New York, 1988. (c) Confalone, P. N.; Huie, E. M. Org. React. 1988,36,1. 59. (a) Gothelf, K. V.; Hazell, R. G.; Jorgensen, K. A. J. Org. Chem. 1996, 61, 346. (b) Gothelf, K. V.; Hazell, R. G.; Jorgensen, K. A. J. Org. Chem. 1998,63,5483. 60. Corey, E. J.; Wang, Z. Tetrahedron Lett. 1993,34,4001. 61. North, M. Synlett 1993,807. 62. Evans, D. A,; Nelson, S. G. J. A m . Chem. Sac. 1997,119,6452. 63. (a) Gennari, C.; Colombo, L.; Bertolini, G. J. Am. Chem. Soc. 1986,108, 6394. (b) Oppolzer, W.; Moretti, R. Helv. Chim. Acta 1986,69,1923. (c) Evans, D. A,; Britton, T. C.; Dorow, R. L.; Dellaria, Jr., J. F. J. Am. Chem. SOC.1986, 108, 6395. (d) Trimble, L. A.; Vederas J. C. J. Am. Chem. SOC. 1986, 108, 6397. (e) Evans, D. A,; Britton, T. C.; Dorow, R. L.; Dellaria, J. F., Jr. Tetrahedron 1988, 44,5525. 64. The Z-geometry of the alkali metal enolates of oxazolidinone-derived imides, see: (a) Evans, D. A. Aldrichirnica Acta 1982,15,23. (b) Evans, D. A,; Britton, T. C.; Ellman, J. A,; Dorow, R. L. J. Am. Chem. Soc. 1990,112,4011. (c) Evans, D. A.; Rieger, D. L.; Bilodeau, M. T.; Urpi, F. J. Am. Chem. Soc. 1991,113, 1047. 65. For a discussion of “gearing” in related bis(su1fonamide) ligands, see: (a) Corey, E. J.; Imwinkelried, R.; Pikul, S.; Xiang, Y. B. J. A m . Chem. SOC.1989, I l l , 5493. (b) Corey, E. J.; Sarsher, S. J. A m . Chem. Soc. 1992, 114, 7938. (c) Corey, E. J.; Sarsher, S.; Lee, D.-H. J. Am. Chem. Soc. 1994, 116,12089. 66. Sibi, M. P.; Shay, J. J.; Liu, M.; Jasperse, C. P. J. Am. Chem. Soc. 1998,120,6615. 67. (a) Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis; Pergamon: Oxford, 1992. (b) Matsubara, S.; Yoshioka, M.; Uchimoto, K. Chem. Lett. 1994,827. (c) Falborg, L.; Jorgensen, K. A. J. Chem. Soc., Perkin Trans. I 1996,2823.

Lewis Acids in Organic Synthesis Edited bv Hisashi Yamarnoto Copyright 0WILEY-VCH Verlaa GmbH.2000

4 Achiral B(II1) Lewis Acids Kazuaki Ishihara

4.1 Introduction The classical boron Lewis acids, BX3, RBX2 and R2BX (X = F, C1, Br, I, OTf) are now popular tools in organic synthesis. B(II1) can act as a Lewis acid because there is an empty p-orbital on the boron. Enthalpy values indicate that when pyridine is the reference base, the Lewis acidity of Group IIIB halides increase in the order A1X3 > BX3 > GaX3. The Lewis acidity of BX3 generally increases in the order fluoride < chloride < bromide < iodide, i.e. the exact reverse of the order expected on the basis of the relative o-donor strengths of the halide anions. The main reason for this anomaly is that in these BX3 compounds, the B-X bonds contain a n-component which is formed by overlap of a filled p-orbital on the halogen with the empty p-orbital on the boron. Because the latter orbital is used to form an o-bond when BX3 coordinates with a Lewis base, this n-component is completely destroyed by complex formation. The strength of the n-component now increases in the order iodide < bromide < chloride < fluoride, i.e. the amount of n-bond energy that is lost on complex formation increases as the atomic weight of the halogen decreases. Evidently, as far as the extent of complex formation is concerned, this is a more important factor than the corresponding decrease in the o-donor strength of the halogen. The BF3 and BC13 complexes of diethyl ether are less stable than those of dimethyl ether, and the same order of stability is observed for the complexes of diethyl and dimethyl sulfides. As expected, steric interaction decreases as the distance between the metal and ligand atom is increased. Thus, it decreases when the metal atom is changed from boron to aluminum, or when the ligand atom is changed from oxygen to sulfur. The major applications of BX3 Lewis acids in organic synthesis include dealkylation of ethers, condensation reactions, and as a catalyst for Friedel-Crafts-type reactions and other acid-related chemistry. In general, these are used stoichiometrically in organic transformations under anhydrous conditions, because the presence of even a small amount of water causes rapid decomposition or deactivation of the promoters. To obviate some of these inherent problems, the potential of arylboron compounds, Ar,B(OH),-3 ( n = 1-3), bearing electron-withdrawing aromatic groups as a new class of boron catalysts has recently been demonstrated. For example, tris(pentafluor0phenyl)borane, B(C6F5)3, is a convenient, commercially available Lewis acid of strength comparable with that of BF3, but without the problems associated with reactive B-F bonds. Although its primary commercial application is as a co-catalyst in metallocene-mediated olefin polymerization, its potential as a Lewis acid catalyst for organic transformations is now recognized as being much more extensive. Diarylborinic acids and arylboronic acids bearing electron-withdrawing aromatic groups are also highly effective Lewis acid catalysts. This chapter focuses on the synthetic applications of BX3 as Lewis acids and the organic transformations catalyzed by arylboron compounds bearing electron-withdrawing aromatic groups.

90

Ishihara

4.2 H3BO3-prornotedReactions Boric acid (H3B03) reacts with alcohols to form boronate esters, and catalyzes dehydration, hydrolysis, decarboxylation, and condensation reactions. Imines can be hydrolyzed in quantitative yield by use of boric acid in ethanol under reflux [l]. Imines that are susceptible to intra- and intermolecular attack in the presence of other catalysts have been successfully hydrolyzed by use of boric acid [2].The conversion of isoxazolines into P-hydroxy ketones and P-hydroxy esters involves hydrogenolysis of the N-0 bond and imine hydrolysis in a single step [3].In the presence of boric acid, racemization is inhibited (Eq. 1) [3a].

--"9

H2 (1 atm) Raney Ni .,,,

HB03 (excess)

-

YH,

0

+

OH

/J)A

(1)

MeOH-H20 100 : 0

(51)

>go%

Boric acid has been used to catalyze the decarboxylation of P-keto esters and Pimino esters [4,5]. A convenient method for producing y-keto esters from diethyl aacylsuccinates in high yield is shown in Eq. (2) [4]. The conventional method of saponification, decarboxylation, and re-esterification gives low yields.

."-c-' OEt

1. HB03 170 "C, 1.5 h *

'\OEt

2. H20 80%

0

(2)

0

Boric acid catalyzes the self-condensation of aldehydes and ketones to produce aJ-unsaturated enones [6]. The yields are much higher than those reported with other acidic or basic catalysts. Under similar conditions, aldehydes which are not readily susceptible to aldol condensation, dismutate to form esters (Tischenko reaction) [7]. A catalytic amount of boric acid-sulfuric acid mixture has been used to synthesize aryl esters in good yields (Eq. 3) [8]; this reaction was unsuccessful when mineral acids or boric acid alone were used.

RC02H

+

ArOH

H2S04, HB03 (1-5 mol%) xylene, reflux -H20 58-94%

-

RC02Ar

(3)

Achiral B(III) Lewis Acids

91

Indole can be condensed directly with a variety of carboxylic acids in the presence of boric acid [9]. Traditional methods are unsatisfactory because of low yields and the production of 3-acylated and 1,3-diacylated side products.

4.3 B13-, BBr3-, or BCls-promoted Reactions 4.3.1 Cleavage of Ethers, Acetals, and Esters All BX3 except X = F will cleave ethers with different efficacy [lo]; the nucleophilic character of iodine coupled with the strong Lewis acidity of boron makes B13 the most potent of these reagents. It is a powerful reagent for the cleavage of C=O bonds in ethers, esters, and alcohols, resulting in the formation of alkyl iodides under mild conditions. Aryl alkyl ethers are cleaved to phenols (Eq. 4). Diary1 ethers are unreactive. B13 reacts at least an order of magnitude faster than BBr3 in ether cleavages [ll]. This is especially useful in the cleavage of the ethers of higher alkyl groups (Eq. 5).

0 "C, 1.5 min

0 "C. 0.5 min

The initial products of ether cleavage are the alkyl halide and a borate ester, (R0)3B. The borate esters are usually inert to further displacement but, because the iodide is more nucleophilic than the other halides, warming the borate esters (6080 "C) in the presence of B13, will result in the complete conversion of all the alkyl residues to iodides (Eq. 6) [12].

BBr3 also coordinates to ethereal oxygens and promotes C-0 bond cleavage to an alkyl bromide and an alkoxyborane that is hydrolyzed to an alcohol during work-up (Eq. 7) ~ 3 1 .

RIOW

BBr3 * RIBr

+

Br2BOR2

. + H20

R'Br

R ~ O H (7)

92

Ishihara

BBr3 has been widely used to cleave ethers because the reaction proceeds completely under mild conditions. In a special case, BBr3 has been used to cleave acetals that cannot be deprotected by usual acidic conditions [14]. Because alkyl aryl ethers are cleaved at the alkyl-oxygen bond to give ArOH and alkyl bromides, BBr3 has been most generally used for the demethylation of methyl aryl ethers [13,15]. The presence of a carbonyl substituent facilitates selective deprotection of polymethoxyaryl compounds (Eq. 8) [16]. Br,

B o:

BBr3 *

C02Et

OMe

Br

Meow

OMe 0

CHPCI~, 0 "C 59%

OMe

M

e

C02Et

O'H-O O A

*

80%

vN'CO2Et OMe

The cleavage of mixed dialkyl ethers occurs at the more substituted carbon-oxygen bond. Methyl ethers of secondary or tertiary alcohols give methanol and secondary or tertiary alkyl bromides selectively by reacting with BBr3 [17], although the addition of NaI and 15-crown-5 ether can change this selectivity (Eq. 9) [MI. In contrast, methyl ethers of primary alcohols are generally cleaved at the Me-0 bond [19].

BBr3

high yield

(9)

BBr3 Me0 CH2C12, -30 "C 100%

HO

Kabalka and co-workers have shown that an attenuated form of B13, B13 . NEt2Ph, will cleave a variety of compounds containing C-0 single bonds at elevated temperatures [20]. Solutions of this reagent are prepared by reacting the commercially available amine-borane complex with I2 in benzene at 80 "C for several hours. This reagent cleaves ethers [21], esters [20], and geminal diacetates [21]. Esters [20] are cleaved to an activated acyl intermediate RCOX which can be used to prepare acids, other esters, and amides (Eq. 10).

Achiral B(III) Lewis Acids

93

R'=Ph, oCGH~OH,o-CgH@, C3H7, -(CH2)2-CH=CH2

R2=Me, Et, Bu, Bn H-Z=H20, MeOH, EtOH, PhNH2, PhCH2NH2

Sulfinyl and sulfonyl compounds react with B13 [22] and B13.NEt2Ph [23] to afford disulfides (Eq. 11). CHC13

9

913,

0

60 "C, 16 h

R-S-X

R-S,S-R

t

(11)

Sulfoxides are deoxygenated by B13.NEt2Ph [23]. Sulfides are also cleaved by B13. Methionine reacts to yield a complex mixture of C-S bond-cleavage products, including homocysteic acid, homoserine, and homoserine lactone [24]. BBr3 has also been used for the deprotection of carbohydrate derivatives [25] and polyoxygenated intermediates (Eq. 12) [26].

.

BBr3

,

CHzC12, -78 "C 88%

&sc

t

(12)

0

For complete cleavage, 1 mol BBr3 is required for each ether group and other Lewis-basic functional groups. Recently, modified bromoboranes such as B-bromocatecholborane [27], dialkylbromoboranes [28], bromobis(isopropy1thio)borane [29], and 9-bromo-9-borabicyclo[3.3.l]nonane[30], have been introduced to cleave C-0 bonds more selectively under milder conditions. BBr3. SMe2 is also effective for ether cleavage and has the advantage of being more stable than BBr3. Two- to fourfold excess reagent is, however, necessary to complete the dealkylation of alkyl aryl ether [31]. Amino acid-protecting groups such as benzyloxycarbonyl and t-butoxycarbonyl groups are cleaved by BBr3. BBr3 reacts with cyclic ethers to give tris(w-bromoalkoxy)boranes, which provide w-bromoalkanols when treated with MeOH (Eq. 13) [32]. Generally, ester groups survive the reaction conditions used for ether cleavage, but ring-opening of lactones proceeds under mild conditions to give w-halocarboxylic acids in good yield (Eq. 14) [33].

94

Ishihara

1. BBra (0.33 eq), CH2C12 0 "Cto heat

(j3)

* Br-OH

2. MeOH 86%

b

BBr3, CH2Cl2 rt 98%

-

BrVCO2H

(14)

Transesterification reactions of carboxylic esters or conversion into the amides is promoted by a stoichiometric amount of BBr3 [34]. BC13 is less reactive than BBr3 for ether cleavage; the type and extent of de-etherification can, however, be more easily controlled by adjustment of the ratio of substrate to BC13, and the reaction temperature and time. The transformation of (-)-P-hydrastine to (-)-cordrastine I1 is efficiently achieved by selective cleavage of the methylenedioxy group in preference to aromatic methoxy groups (Eq. 15) [35]. One difficulty with the use of BC13 arises from its tendency to fume profusely in air. The complex of BC13 with dimethyl sulfide is solid, stable in air, and easy to handle. By using a two- to fourfold excess of the reagent in 1,2-dichloroethane at 83 "C, aromatic methoxy and methylenedioxy groups can be cleaved in good yields [36]. BC13 can also be used for cleavage of highly hindered esters under mild conditions. For example, O-methylpodocarpate is cleaved at 0 "C (Eq. 16) [37].

BC13 t

OMe

rt, 6 h 81%

(15)

OMe

Achiral B(III) Lewis Acids

95

4.3.2 Glycosidation of Glycals Glycosidations of silylated glycals and alcohols using a catalytic amount of BC13 or BBr3 proceed highly stereoselectively under mild conditions to afford the corresponding 2-deoxy-u-glycosides in high yields; these compounds are often found as the glycosidic components of bioactive natural products (Eq. 17) [38]. TBDMSO

TBDMSO

q

cat. (10 molyo) TBDMS

*

TBDMSO

CH2C12, 0 "C

(17)

BBr3: 96% yield, dp=11/1 BCI3: 99% yield, dp=36ll

4.3.3 Synthesis of Organoboron Reagents Generally, the synthesis of organoboranes consists of the transmetalation reaction of organometallic compounds with boron trihalides 1391. Alkylboronic acids are most conveniently synthesized by reacting of B(OR)3 with RLi or RMgX reagents, whereas boron trihalides are most advantageous for transmetalation reactions with less nucleophilic organometallic reagents based on Pb [40], Hg 1411, Sn [42], and Zr [43] (Eqs 18 and 19). Ph&n

+

-

2BCI3

2PhBC12

+

Ph2SnCI2 (18)

Dichloroborane and monochloroborane etherates or their methyl sulfide complexes have been prepared by the reaction of borane and boron trichloride [44]. The hydroboration of alkenes with these borane reagents is, however, usually very slow because of the slow dissociation of the complex. Dichloroborane prepared in pentane from BC13 and trimethylsilane is unusually highly reactive with alkenes and alkynes; hydroboration is instantaneous at -78 "C (Eq. 20) 1451. HSiMe3 BCI3 pentane -78 "C

-

a-pinene HBC12 95%

*

aBC12

(*O)

96

Ishihara

4.4 BF3-Promoted Reactions 4.4.1 Cleavage of Ethers Carbon-oxygen bond cleavage by use of BF3 combined with a sulfide or thiol is based on the principle that a hard acid will interact with the oxygen and that the sulfur, being a soft nucleophile, will attack carbon. The combination of an aliphatic thiol such as ethanethiol and BF3.E t 2 0 has been used to remove benzyl groups. The presence of an a&unsaturated ester in the same molecule can result in Michael addition and debenzylation (Eq. 21) [46]. BF3 in the presence of Me2& which is a milder reagent, does not cause this type of complication, as shown in Eq. (22) [47]. C02Et

EtS

Et

/ /

BF30Et20

/ /

02Et

~

(2,)

/ /

/ /

EtSH

C02Et

Me0

Me0

86%

The method has also been used successfully to remove the methoxymethyl (MOM) group (Eq. 23) [48,49], and should be compared once again with the use of BF3 EtzO-ethanedithiol (Eq. 24), which was used in a total synthesis of bruceantin [50].

BF3.Et20 Me2S 90% OH

OH

'"'OH BF30Et20

0

OMoM

HSCH2CHzSH 90%

-

Lo 0

=

OH

(24)

Achiral B(III) Lewis Acids

97

The benzyloxycarbonyl (Cbz) group can be removed from nitrogen by BF3 .EtzO in the presence of either a thiol or dimethyl sulfide. The carbamates derived from secondary amines are cleaved more rapidly than those from primary amines by use of the ethanethiol method, even when using BF3.EtzO as solvent. This procedure is reasonably selective, as shown in Eq. (25) [46]. H BFsmEt20 CN '"OBn

EtSH, CH2C12 76-86%

6"1

H

+

H

OAOBn

(25)

N H

Cleavage of the tetrahydrofuran ring gave the diacetate (Eq. 26) with inversion of configuration at C-20 [51].

4.4.2 Friedel-Crafts Alkylation Reactions Alcohols react with benzene [52] or naphthalene [53] to give alkylated products. The alkylation of benzene with cyclohexanol (Eq. 27) gives moderate yields, but no other alcohols give better results. The alkylation of aromatic hydrocarbons with alkyl fluorides has also been investigated. Although the reactivity of BF3 is lower than those of other boron halides, the yields are usually better than those of other boron halides. Methyl, ethyl, propyl, isopropyl, t-butyl, and cyclohexyl fluorides have been shown to alkylate aromatic compounds in good yields. For example, benzene and cyclohexyl fluoride give the expected product in 85 % yield (Eq. 27) [52b]. Normally, alkylation does not occur with use of alkyl halides other than the fluorides-mixed halides afford products containing halogen (Eq. 28) [54].

r

c-Hex

oHyx

ot-iex X=OH: X=F:

56%

-

28% 85%

98

Ishihuru

94%

The use of alkenes as sources of electrophiles in Friedel-Crafts alkylations has also been studied. The intramolecular alkylation of 1-(2-tolyl)-(E)-pent-3-enegives 1,5dimethyl-1,2,3,4-tetrahydronaphthalene in 95 % yield [55]. BF3 has been shown to form a complex with nitromethane which is particularly effective in catalyzing protoninitiated cascade cyclization like that shown in Eq.(29) [56].

BF3, MeN02 (29)

83%

CN

BF3. E t 2 0 is useful for the condensation of allylic alcohols with enols. A classic example is the reaction of phytol in dioxane with 2-methyl-1,4-naphthohydroquinone 1-monoacetate to form the dihydro monoacetate of vitamin K1 (Eq.30), which can be easily oxidized to the quinone [57]. OR

@ OH

1. BF30Et20 dioxane -k

Hodc16H33

2. KOH

R=H or COMe

4.4.3 Friedel-Crafts Acylation Reactions Acyl fluorides and BF3 afford ketones with better regioselectivity than when AlC13 is used as the Lewis acid. The reaction of isobutyryl fluoride with 2-methylnaphthalene gives an excellent yield of the product shown in Eq.(31) [%I.

Achiral B(III) Lewis Acids

99

Carboxylic acids have reacted with phenols [59] and aryl ethers together with BF3 as catalyst. Dealkylation of an ether residue ortho to the introduced acyl group is frequently encountered, as in the synthesis of baeckeol (Eq. 32) [60].

O,H..O 0 MeO’ Me0

OMe

2.MeOH,H20

Me0

OMe

73%

Because a carboxylic anhydride and BF3 constitute a mild Friedel-Crafts acylating system, it is not surprising that nucleophilic aromatic substrates such as toluene, mesitylene, and anisole have been acetoacetylated [61]. The expected 1,3-diketones are formed when a sufficient excess of acetic anhydride is present in the reaction mixtures. The process is illustrated with anisole in Eq. (33) [61].

4.4.4 Cyclizations Several interesting cyclization reactions leading to naturally occurring polycyclic ring systems have been investigated using BF3. The cedrane ring system is formed (Eq. 34) when the enol acetate is treated with BF3 [62]. In a detailed study of the reactions of an acetoxymenthadiene (Eq. 3 9 , it was shown that racemic camphor can be obtained in 90 % yield when a 0.1 % solution in wet dichloromethane is treated with BF3 at room temperature for 10 min [63]. OAc

(34)

I

t

A \

CH2C12 90%

(35)

100

Ishihuru

Arylamines can undergo photocyclization in the presence of BF3. Et2O to give tricyclic products, e.g. 9-azaphenanthrene derivatives (Eq. 36) [64].

RmaBF30Et20

hv, CHpCl2 R

h R'

38-45%

(36) R R'

\

x

R'

R=H, Me; R'=H, OMe; X=CH, N

Substituted phenethyl isocyanates undergo cyclization to lactams when treated with BF3.Et20 [65]. Vinyl ether epoxides (Eq. 37) [66], vinyl aldehydes [67], and epoxy/3-keto esters [68] all undergo cyclization with BF3.EtZO.

BF30Et20 40-1 00%

R=H, Me

p-Silyl divinyl ketones (Nazarov reagents) in the presence of BF3.EtzO cyclize to give cyclopentenones, generally with retention of the silyl group [69]. BF3. Et2O is used for the key step in the synthesis of the sesquiterpene trichloride, which has adjacent quaternary centers, by catalyzing the cyclization of the dienone to the tricyclic ketone (Eq. 38) [70]. Trifluoroacetic acid and trifluoroacetic anhydride do not catalyze this cyclization.

BFpEt20 CH&I, heat 75-80%

Costunolide, treated with BF3. EtzO, produces the cyclocostunolide and a C-4-oxygenated sesquiterpene lactone, 4a-hydroxycyclocostunolide (Eq. 39) [71].

Achiral B(III) Lewis Acids

101

4.4.5 Rearrangement Reactions A Lewis acid-assisted fragmentation followed by a 1,2-methyl shift, driven by the enolate, is involved in the terpene rearrangement leading to the nootkatane skeleton shown in Eq. (40) [72]. Rearrangement reactions of glycidic esters have been studied using BF3 and have been found to proceed in high yields [73]. For example, ethyl pphenylglycidate gives ethyl phenylpyruvate, isolated in 80 YOyield as the 2,4-dinitrophenylhydrazone.

Many rearrangement reactions are initiated by BF3 complexes in the presence of acetic anhydride, including the synthesis of functionalized and optically active pyrans from (+)-(R,R)-diethyl tartrate (Eq. 41) [74]. Other examples include the conversion of bicyclic into monocyclic [75] and tricyclic into bicyclic systems [76], the acetolysis of glycosides resulting in the formation of the fully acetylated acyclic derivative [77], and the unusual migration of nitrogen in the dienone-phenol rearrangement of an N methoxy-P-lactam [78]. S02T0l

vMe S02T0l

-

Q.,

BF3*0Et2, A c ~ O

CH2C12, 1.5 h, 0 "C "0SO2Me 89%

(41)

OAc

The treatment of epoxides with BF3.E t 2 0 results in rearrangements to form aldehydes and ketones (Eq. 42) [79]. The carbon a to the carbonyl group of an epoxy ketone migrates to give the dicarbonyl product [SO]. The acyl migration in acyclic a& epoxyketones proceeds through a highly concerted process, with inversion of configuration at the migration terminus [81]. With 5-substituted 2,3-epoxycyclohexanes, the stereochemistry of the quaternary carbon center of the cyclopentanecarbaldehyde product is directed by the chirality of the 5-position [82]. Diketones are formed if the P-position of the a,p-epoxy ketone is unsubstituted. The 12-carbonyl migration of an a,p-epoxy ketone, 2-cycloheptylidenecyclopentanoneoxide, occurs with BF3.E t 2 0 at 25 "C to form the cyclic spiro-1,3-diketone in 1min (Eq. 43) [83].

+

BFyEt20 R1QR2 R'

RIQ R' (42)

t

R2

CHO

0 R'=Me, H; R2=Me, Ph

0

0

102

Zshihuru

Migration of the carbonyl during epoxide cleavage is used to produce hydroxy lactones from epoxides of carboxylic acids (Eq. 44) [84]. a-Acyl-2-indanones [%], furans [86], and A2-oxazolines [87] (Eq. 45) can also be synthesized by cleavage and rearrangement of epoxides with BF3.Et20.

8 &

"'OH

BF3*Et20 55%

(44)

' CO2H R' H H-\ttR2

Rg

BF3-Et20 f

0

R3CN

86%

NYo R3

*

(45)

Remotely unsaturated epoxy acids undergo fission rearrangement when treated with BF3.Et20. Hence, cis and trans ketocyclopropane esters are produced from the unsaturated epoxy ester methyl vernolate (Eq. 46) [88].

^ 0

C02Me

BF30Et20 * benzene

Epoxy sulfones undergo rearrangement with BF3. Et2O to give the corresponding aldehydes [89]. a-Epoxy sulfoxides, like other negatively substituted epoxides, undergo rearrangement in which the sulfinyl group migrates and not the hydrogen, alkyl, or aryl groups (Eq. 47) [89].

BF3*Et20 @S(

0)Ph toluene, heat

~

c

~

~

) heat P * h -PhSOH

0""" (47)

Achiral B(II1) Lewis Acids

103

a,P-Epoxy alcohols undergo cleavage and rearrangement with BF3. EtzO to form P-hydroxyketones [90]. The rearrangement is stereospecific with respect to the epoxide and generally results in anti migration. The rearrangement of epoxy alcohols with P-substituents leads to a,a-disubstituted carbonyl compounds [91]. BF3. E t 2 0 is used for the regioselective rearrangement of polyprenyl aryl ethers to yield polyprenyl substituted phenols, e.g. coenzyme Q, [92]. This reagent is used in the Fries rearrangement; for example, 5-acetyl-6-hydroxycoumaran is obtained in 96 % yield from 6-acetoxycoumaran by use of this reagent (Eq. 48) [93]. BF3oEt20 (48)

OH

AcO

Formyl bicyclo[2.2.2]octane undergoes retro-Claisen rearrangement to a vinyl ether in the presence of BF3. EtzO at 0 "C (Eq. 49), but not with HOAc at 110 "C [94].

Meo230 BF3*Et20 72% O"C

(49)

C02Me

*

BF3. Et2O is used for a stereospecific 1,2-alkyl migration to form trans-2-alkyltetrahydrofuran-3-carbaldehydesfrom 4,5-dihydrodioxepins (Eq. 50), which are obtained [95]. Similarly, a-alkyl-P-alkoxyaldeby isomerization of 4,7-dihydro-1,3-dioxepins hydes can be prepared from 1-alkenyl alkyl acetals by a 1,3-migration using BF3. Et,O as catalyst [96]. syn Products are obtained from (E)-1-alkenyl alkyl acetals and anti products from (2)-acetals.

-73 "C 90-95%

eHO

BF3 .EtzO-promoted regioselective rearrangements of polyprenyl aryl ethers provide a convenient route for the preparation of polyprenyl-substituted hydroquinones (Eq. 51) which can be oxidized to polyprenylquinones [97].

OH

OH

OH

I

'n

4.4.6 Diels-Alder Reactions Lewis acid-catalyzed Diels-Alder reactions are well known, and several examples have been studied using BF3. The regioselectivity of the reaction of unsymmetrical dienes with unsymmetrically substituted quinones can be directed in favor of either regioisomer depending on the catalyst used. A example is shown in Eq. (52) [98]. The regioselectivity has been explained on the basis that boron is capable of forming a tetracoordinate complex, whereas tin can complex via the more basic oxygen and the adjacent methoxy group.

Lewis acid t

Me0 0 MrO

+

0

JyJf (52)

MrO

0

BF3 at 0 "C, 70% 2.4:l SnCI4at -1 6 "C, 80% 1:20

Internal Diels-Alder cycloaddition of the (2)triene proceeds smoothly in the presence of BF3. Et,O to give the bicyclic ketone. The ketone is converted by epimerization, carbonyl extrusion, and homologation to the sesquiterpene (+)-a-oplopenone (Eq. 53) [99].

83%

(+)-a-Oplopenone

Solids also serve as supports for Lewis acids. It is possible, for example, to chemisorb AlC13 [loo], BF3 [loll, and ZrCL [lo21 on to alumina and silica gel. These new materials have the potential to serve as heterogeneous catalysts of the Diels-Alder reaction. Kabalka et al. have reported the synthesis and characterization of a series of highly acidic boronated aluminas and their use as catalysts in model Diels-Alder reactions [103]. Boronated alumina is prepared by reaction of BX3 (X = F, C1, Br) with alumina (Eqs 54 and 55) or by a two-step synthesis involving the reaction of BH3. MezS with alumina and then with I2 (Eq. 56). The modified aluminas, BX2/A1203,were found to have n = 3 (F), n = 1.5 (Cl), n = 1 (Br), and n = 1(I). The acidity of the solids is large and decreased in the order I-Br > C1 > F. The solids catalyzed the Diels-Alder reactions of methyl acrylate with cyclopentadiene, and of isoprene with methyl arylate, both of which proceeded in high yield and with high selectivity (Eq. 57).

Achiral B(III) Lewis Acids

-

BF3*Et20 + A1203

BFdA1203

(54)

BXJA1203

(55)

105

-Et20

BX3

+

A1203

-HX

X=CI, Br

@C02Me

+

n=l.5 (CI), 1 (Br)

toluene cat' * rt, 1 h

4

+

&C02Me

(57)

C02Me

BF3/A1203

31% yield, endo:exo=24:1

BC~l.dA~203

78% yield, endo:exo=12:1

BBr/A1203

88% yield, endo:exo=13:l

BI/A1203

47% yield, endo:exo=l6:1

Aldehydes and siloxydienes undergo cyclocondensation with BF3. E t 2 0 to form pyranones (Eq. 58) [104]. The stereoselectivity is influenced by the solvent.

-J"

TBDMSO \

PhCHO

BF3*Et20 solvent

*

qph on +

0

Ph

(58)

1:2.3 7: 1

solvent: CH2C12 toluene

BF3. Et,O is the most effective catalyst for the Diels-Alder reaction of furan with methyl acrylate, giving high endo selectivity in the 7-oxobicyclo[2.2.l]hepteneproduct (Eq. 59) [105].

0

+ @C02Me

BF30Et20 * 50 "C 76%

4

+ M e, ,& ,

(59)

C02Me 7:3

a-Vinylidenecycloalkanones, obtained by the reaction of lithium acetylide with epoxides and subsequent oxidation, undergo a Diels-Alder reaction at low temperature with BF3. EtzO to form spirocyclic dienones (Eq. 60) [106].

106

Ishihara

4.4.7 Desilylation Reactions Desilylation reactions are based on the well-known stabilization of u&carbenium centers by silicon. The conversion of allylsilanes into alkenes by use of the BF3. (ACOH)~ complex has been studied in considerable detail. The reaction occurs by protonation, followed by nucleophile-induced desilylation (Eq. 61) [107]. The stereochemical implications have also been considered in detail, and in the deuterationdesilyation sequence shown in Eq. (62) the structure shown is the major product [108]. Protonation-desilation of alkynes to give allenes in yields ranging from 70 to 97 % can evidently be considered to involve a P-vinyl cation (Eq. 63) [109].

rSiMe BF~*(AcOH)~

CHC13,20 "C, 5 min 99%

'

SiMe3

t-Bu

BF3*(AcOH)p * t-BU--

(63)

CHpClp, -5 "C

The formation of /3-silicon-stabilized cations from y-hydroxysilanes results from the normal pattern of pinacol rearrangements, where hydride and phenyl migration is common. Desilylation then also affords an alkene [110]. If the alkyl group is a ring residue, only hydride migration is observed (Eq. 64).

SiMe3

OH

BF3*(AcOH)p CHpC12,O "C

Achiral B(III) Lewis Acids

107

The phenyldimethylsilyl group can be converted in two steps into a hydroxy group, and as such can be regarded as a masked hydroxy group. The first step involves a proto-desilylation of the phenyl group, which is then followed by peracid-mediated rearrangement into a hydroxy group, with retention of configuration (Eq. 65) [lll]. This sequence works well for primary, secondary, and tertiary silanes.

1. B F ~ * ( A c O H ) ~

Ph

SiMe2Ph

2. rn-CPBA 48%

Ph

Deblocking of the anomeric position, protected as the 2-trimethylsilylethyl ether, has been achieved in high yields in examples drawn from mono-, di-, and trisaccharide chemistry [112]. An example is shown in Eq. (66). In the absence of acetic anhydride, the product with a free anomeric hydroxy group is obtained.

4.4.8 Destannylation Reactions The absence of cyclopropane formation in the silicon-based reactions reviewed above prompted an investigation of related tin chemistry. There have been many reports of the formation of cyclopropanes in high yield and with remarkable stereoselectivity [113]. The yields are high and inversion of configuration occurs at both reacting centers (Eq. 67). Ph Bu3Sn

Ph

BF~*(AcOH)~ *

phbb'"ph

97%

4.4.9 Acylation Reactions of Ketones and Nitriles The conversion of enolizable ketones into 1,3-diketones is achieved by treating a mixture of the carboxylic anhydride and ketone with a Lewis acid catalyst system on BF3 [114]. The main catalyst systems used involve (i) saturation of the reaction mixture with gaseous BF3, (ii) the use of either solid (1:l)or liquid (1:2) complexes of BF3 and acetic acid to which a protic acid, such asp-toluenesulfonic acid, is sometimes added, and (iii) the use of BF3. Et20. When different isomeric products are possible, different conditions sometimes lead to different products or product ratios. For example, in the reaction of 3-methylbutanone with acetic anhydride under different reaction conditions two possible products are formed in the proportions shown in Eq. (68) [115].

108

,K

Zshihara

- -

1. BF3 reagent Ac~O

2. NaOAc, H20, heat Reaction conditions: BF3 gas, rapid saturation, 0-10 "C BF3 gas, slow saturation, 0-10 "C BF~*(AcOH)~, 25 "C BF~*(AcOH)~, TsOH, 25 "C

7.0 3.0 3.7 6.3

'

0.2 : 9.8 0.0 : 10.0

Rapid saturation of the reaction mixture with BF3 leads to the formation of the product derived from the kinetic enol; in the presence of a protic acid, the product formed from the thermodynamic enol can be obtained exclusively. It is assumed that in the first case the nucleophile is the boron complex of the enol, whereas an enol ester is involved in the latter case (Eq. 69). In both sequences the final product is the boron difluoride complex.

t

The chemical yield of 13-diketones was improved by the rapid addition of the ketone-anhydride mixture to a solid BF3. AcOH complex. Using this method, the acetylation of cyclohexanone gave 2-acetylcyclohexanone in 86 % yield [116]. The inverse addition method also gave 2-butanoylcyclopentanone in excellent yield (Eq. 70) [116]. This method has been used for the acylation of a wide range of cyclic ketones, including five- to eight-membered ring ketones (Eq. 71) [117].

86% 0

Achiral B(III) Lewis Acids

109

The reaction between BF3 and phenylacetonitrile in the presence of aqueous acetic acid had been shown to give phenylacetamide in high yield (Eq. 72) [118].

1. BF~*(AcOH)~, 60 "C

Ph-CN

+ AcZO

(72)

ph$

*

I

0

2. aq. NaOAc 56%

A

0

4.4.10 Addition Reactions BF3. E t 2 0 facilitates the addition of moderately basic nucleophiles like alkyl-, alkenyl-, and aryllithium, imines, Grignard reagents, and enolates to a variety of electrophiles. BF3. E t 2 0 reverses the usual anti selectivity observed in the reaction of crotyl organometallic compounds (based on Cu, Cd, Hg, Sn, T1, Ti, Zr, and V, but not on Mg, Zn, or B) with aldehydes (Eq. 73a) and imines (Eq. 73b), so that homoallyl alcohols and homoallylamines, respectively, are formed [119-1241. The products are mainly syn diastereoselective. BF3. Et2O is the only Lewis acid which produces hydroxy rather than halotetrahydropyrans from the reaction of allylstannanes with pyranosides [125]. The BF3. Et20-mediated condensations of y-oxygenated allylstannanes with aldehydes (Eq. 73c) and with activated imines (Eq. 73d) give vicinal diol derivatives and 12-amino alcohols, respectively, with syn diastereoselectivity [126,127]. The activated imines are obtained from aromatic amines, aliphatic aldehydes, and a-ethoxycarbamates. The reaction of aldehydes with a-(a1koxy)-P-methylallylstannanesin the presence of BF3 - E t 2 0gives syn-(E) isomers almost exclusively [127].

Y&SnBu3

+

RyH BF,*EtzO

*

R j r ,

X

X

(a) X=O, Y=Me

(a) X=OH, Y=Me

(b) X=NR2, Y=Me

(b) X=NHR2, Y=Me (C) X=OH, Y=OMe, OTBDMS (d) X=NHR2, Y=OH or derivative

(c) X=O, Y=OMe, OTBDMS (d) X=NR2, Y=OMe, OTBDMS

(73)

or OCH20Me

a-Alkoxycarbonylallylsilanesreact with acetals in the presence of BF3. E t 2 0 (Eq. 74) [128]. The products can be converted into a-methylene-y-butyrolactones by dealkylation with iodotrimethylsilane.

110

Zshiharu

BFsoEt20

Me3Si&

+PhYoMe OMe 89%

C02Et

Et02C

Ph (74)

*

U

O

M

e

The cuprate 1,4-conjugate addition step in the synthesis of (+)-modhephene is difficult because of the neopentyl environment of C-4 in the eneone, but this can occur in the presence of BF3.EtzO (Eq. 75) [129].

Me2CuLi 70%

This reagent is used as a Lewis acid catalyst for the intramolecular addition of diazo ketones to alkenes [130]. The direct synthesis of bicyclo[3.2.l]octenones from the appropriate diazoketones using BF3.EtzO (Eq. 76) is superior to the copper-catalyzed thermal decomposition of the diazo ketone to a cyclopropyl ketone and subsequent acid-catalyzed cleavage [131].

&

BF3*Et20 * CICH2CH2CI 0 0-27 “C 30-51%

COCHN2

(76)

BF3. E t 2 0 reacts with fluorinated amines to form salts which are analogous to Vilsmeier reagents, Arnold reagents, or phosgene-immonium salts (Eq. 77) [ 1311. These salts can be used to acylate electron-rich aromatic compounds, introducing a fluorinated carbonyl group (Eq. 78). F XCHF+NRp F

BF3*Et20

F -F

89%

XCHF-(

BF4NfR2

(77)

R=Et; X=CI, F, CF 3

F XCHF-( ArH

BF4NCR2 * XCHF-(

Ar

H30+ BF4- -XCHF-( N+R2

Ar (78)

0

Achiral B(III) Lewis Acids

111

4.4.11 Aldol Reactions Although TiC14 is a better Lewis acid in effecting aldol reactions of aldehydes, acetals, and silyl enol ethers, BF3.EtzO is more effective for aldol reactions with anions generated from transition metal carbenes and with tetrasubstituted enol ethers such as ( Z ) - and (E)-3-methyl-2-(trimethylsilyloxy)-2-pentane[132,133]. One exception involves the preparation of substituted cyclopentanediones from acetals by the aldol condensation of protected four-membered acyloin derivatives with BF3 .EtzO rather than TiC14 (Eq. 79) [134]. The latter catalyst causes some loss of the silyl protecting group. The pinacol rearrangement is driven by the release of ring strain in the fourmembered ring and is controlled by an acyl group adjacent to the diol moiety.

This reagent is the best promoter of the aldol reaction of 2-(trimethylsi1oxy)acrylate esters, prepared by the silylation of pyruvate esters, to afford y-alkoxy-a-keto esters (Eq. SO) [135] These esters occur in a variety of important natural products.

UIVlt:

I

OMe 0

Drg.it*O * F h'-OEt

(80)

0

-78 "C to 0 "C 86%

BF3. EtzO can improve or reverse aldehyde diastereofacial selectivity in the aldol reaction of silyl enol ethers with aldehydes, to give syn adducts. For example, Heathcock and Flippin have reported that the reaction of the silyl enol ether of pinacolone with 2-phenylpropanal using BF3.E t 2 0 gives enhanced levels of Felkin selectivity (up to 36:l) relative to the addition of the corresponding lithium enolate [136,137]. When the a-substituents are more subtly differentiated, however, it is still difficult to achieve acceptable levels of selectivity. Davis et al. have reported that use of triisopropylsilyl enol ether and i-Pr3SiB(OTf)4results in selectivity of ca. 1OO:l with 2-phenylpropanal and a useful level of 7:l with 2-benzylpropanal (Eq. 81) [138]. Control experiments employing BF3. Et2O catalysis, and 2-benzylpropanal as substrate, are less selective (ca. 3:l), and the selectivity does not depend substantially on the bulk of the silyl group in the enolate (Eq. 81). By contrast, both levels of 1,2-asymmetric inductions in the i - P ~ - ~ s i B ( o T(5 f )mol ~ %)- and BF3.Et20 (1 equiv.)-promoted additions of silyl ketene thioacetals to a-asymmetric aldehydes are affected by the bulk of the silyl group (Eqs 82 and 83) [138].

112

Ishiham

hX

OTlPs Lewis acid* BnC ' HO

Bn

+ A P h X=Me, t-Bu, OMe, Of-Bu

+

BnC ' HO

+

ASt-Bu

(81)

0

-+ Bn&st-Bu

0

RO

(5 mol%)

RO

Cram 5.5 3.6

(82)

0

anti-Cram 1 1

hStBu

OR

+

x

hStBu

R=TIPS R=TBDMS

BnC ' HO

h

anti-Cram 1 1

i-Pr3SiB(OTf)4 * Bn

ASt-Bu

n

TIPSO

Cram 7 3

i-Pr3SiB(OTf)4 BF3mEt20

OR

0

TIPSO

B

BF3*Et20 * Bn (1 equiv)

+

0

HO

HO

Cram 13 5.8

R=TIPS R=TBDMS

13n&st-Bu

(83)

0

anti-Cram 1 1

1,5-Dicarbonyl compounds are formed by reaction of silyl enol ethers with methyl vinyl ketones in the presence of BF3.Etz 0 and an alcohol (Eq. 84) [139].

4.4.12 Miscellaneous Reactions The reduction of alcohols with a trialkylsilane in the presence of a protic acid can be complicated by skeletal rearrangement and alkene formation as a result of carbonium ion formation. This problem is significantly reduced when using BF3 as the acid (Eq. 85) [140]. Peptide isosteres (Eq. 86) can be prepared by the alkylative elimination of y-oxygenated-a$-unsaturated carboxylates by use of BF3 complexes of alkylcopper reagents [141]. BF3, Et3SiH CH2C12

-

+ P

h

H

Ph 86.5%

13.5%

(85)

Achiral B(III) Lewis Acids

OMS R ’ F C 0 2 M e

RCU(CN)MOBF3 >90% yield >98%de

HN-BOC

-

R 1 4 C 0 2 M e

113

(86)

HN-Boc

R’=alkyl, benzyl, etc; R=alkyl or benzyl; M=Li or MgX

It is clear that BF3 in the presence of a thiol will convert an aldehyde or ketone into a related thioacetal. For example, 4-benzloxyacetophenone is converted into the ethyl thioacetal of 4-hydroxyacetophenone in 84 % yield by BF3.0Et2-EtSH, whereas using BF3. OEt2-Me2S gives 4-hydroxyacetophenone in 97 YOyield [142]. The conversion of an acetal to a dithioacetal by use of, for example 1,3-propanedithiol in the presence of BF3, has also been reported; a dithiane can also converted into the related acyclic dithioacetal by using excess methanethiol and BF3 [143]. It has also been found that the double bond in substituted styrenes is cleaved by BF3.ethanethiol when an electron-withdrawing group is present at the /?-position (Eq. 87). BF3oOEt2 P h y C N C02Et

EtSH

SEt *

PhASEt

(87)

88%

BF3 . E t 2 0 is effective in the direct amidation of carboxylic acids to form carboxamides (Eq. 88) [144]. The reaction is accelerated by bases and by the azeotropic removal of water.

50-85%

BF3. E t 2 0 catalyzes the decomposition of P,y-unsaturated diazomethyl ketones to cyclopentenone derivatives (Eq. 89) [145,146].

A new method, employing O-(2-aminobenzoyl)hydroxylamine and BF3 .EtzO, has been discovered for the synthesis of nitriles from aldehydes; yields are 78-94 YO (Eq. 90) [147].

114

Ishihara

C02NH2

+ ArCHO

BF3*Et20

NH2

-

ArCN

(90)

EtOH

P-Aryl-/?-hydroxy ketones are readily cleaved by BF3 in non-protic solvents to form the corresponding styrene derivatives and a carboxylic acid. The reaction seems to proceed via a non-synchronous Grobe fragmentation pathway (Eq. 91) [148].

X=H, &I, m N 0 2 , pCF3, 0-CI, p M e R=Pr, Me R'=Bu, Ph

33-73%

58-72%

4.5 Arylboron Compounds as Lewis Acid Catalysts 4.5.1 Triarylboron B(C6F5)3is an air-stable, water-tolerant Lewis acid catalyst which can be readily prepared as a white solid by reacting boron trichloride with pentafluorophenyllithium [149,150]. This compound does not react with pure oxygen [150]. It is very thermally stable, even at 270 "C, and is soluble in many organic solvents [150]. Although B(C6F5)3 catalyzes reactions most effectively under anhydrous conditions, B(Ca5)3 exposed to air is also available (not anhydrous grade). Mukaiyama aldol reactions of various silyl enol ethers or ketene silyl acetals with aldehydes or other electrophiles proceed smoothly in the presence of 2 mol % B(C6F5)3[151a,c]. The following characteristic features should be noted: (i) the products can be isolated as /?-trimethylsilyloxy ketones when crude adducts are worked-up without exposure to acid; (ii) this reaction can be conducted in aqueous media, so that the reaction of the silyl enol ether derived from propiophenone with a commercial aqueous solution of formaldehyde does not present any problems; (iii) the rate of an aldol reaction is markedly increased by use of an anhydrous solution of B(C&5)3 in toluene under an argon atmosphere; and (iv) silyl enol ethers can be reacted with chloromethyl methyl ether or trimethylorthoformate; hydroxymethyl, methoxymethyl, or dimethoxymethyl C l groups can be introduced at the position a to the carbony1 group. These aldol-type reactions do not proceed when triphenylborane is used (Eq. 92).

Achiral B(III) Lewis Acids

R’CHO

I ) B(c6F5)3

OSiMe3

or + other electrophiles

OH 0

(2-10 mol%)

R2+p,4

R ’ v R 4

*

2) HCI or TBAF

R3

115

(92)

R2 R3

Examples

OH 0

OH 0

OH 0

P h v E t

Ph+Et

94%

P h y O M e 90%

96% OMe 0

H O q P h

M e O q P h

M e O v P h

65%

72%

65%

Conjugate addition of silyl enol ethers to a,P-unsaturated ketones proceeds regio) ~ anhydrous grade) [151a,c]. The selectively in the presence of 2 mol YOB ( C G F ~(not product can be isolated as a synthetically valuable silyl enol ether when the crude product is worked-up without exposure to acid (Eq. 93).

Examples

&C02Me 85%

% 89%

Ph

93%

The Sakurai-Hosomi allylation reaction of benzaldehyde with 2-methallyltrimethylsilane proceeds smoothly in the presence of 5 mol YOB(C6F5)3(not anhydrous grade) to afford 3-methyl-l-phenyl-3-buten-l-o1(93 YO)[151c]. Diels-Alder reaction of cyclopentadiene with 2-methyl-2-propanal also proceeds smoothly in the presence of 5 mol YOB(C6F5)3 (not anhydrous grade) to give the cyclic adducts (> 99 YO)[151c]. B(C6F5)3 (anhydrous grade) is a highly active catalyst for the aldol-type reaction between ketene silyl acetals and imines, because of its stability and comparatively low N-B bond energy and affinity toward nitrogen-containing compounds [151b,c]. N Benzylimines are useful substrates because the P-benzylamino acid esters produced are readily debenzylated by hydrogenolysis over palladium on carbon. Catalysis is performed with 0.2-10 mol YOcatalyst loading in toluene. The following characteristic features should be noted: (i) the condensation usually proceeds smoothly, even with aliphatic enolizable imines derived from primary and secondary aliphatic aldehydes,

116

Zshihara

and (ii) the synlanti stereoselectivity in these condensations of N-benzylidenebenzylamine is dependent on the geometry of the ketene silyl acetal double bond-(E)- and (2)-ketene silyl acetals give anti and syn products, respectively, as major diastereomers (Eq. 94).

(0.2-10 mol%) CH2C12

OSiMe3

2) NaHC03 aq.

B n - ~o~ *

R i v O R 4

(94)

R2 R3 Examples Bn,

Phu

Bn-NH

o

m

u

99%

0

'"XNH

Bn ,

o

NH 0

Pr U O t B u seBuu

P,Yc, >99%

>99%

o m u

>99%

The use of N-trialkylsilylimine can be advantageous, because the N-substituent can easily be cleaved from the N-trialkylsilyl B(C6F5)3-amino acid esters produced in the reaction. The borane Lewis acid B(C6F5)3is an effective catalyst for the reaction of N-trimethylsilylimines [151c]. The reaction of mono- or disubstituted ketene silyl acetals with N-trimethylsilylbenzylideneamineproceeds smoothly to give the correspondingp-amino acid ester in good yield (Eq. 95) [151c].

(10 mol%) toluene

"SiMe3

+

R 2 7 2 : R3

NH2 0 * Ph+OR4

2) HCI

(95)

R2 R3

Examples P h v O E t 82%, syn:antk84:16 (ketene silyl acetal EZ=85:15)

P

h

q

OMe

83%

N-Unsubstituted p-lactams have become very attractive synthetic targets. Most existing methods for their preparation require elaborate procedures to deblock the has been synthesized in modernitrogen atom. 3,3-Dimethyl-4-phenylazetidin-2-one ate yield by in situ treatment of the intermediate N,N-bis(trimethylsily1)-P-aminoacid ester with MeMgBr (Eq. 96) [151c].

Achiral B(III) Lewis Acids

lZMe3+

Ph

(10 mol%)

OSiMe3

Y O M e

toluene 2)MeMgBr

'$

117

(96)

* Ph

The protic or Lewis acid-promoted rearrangement of epoxides to carbonyl compounds is a well known synthetic transformation. BF3. EtZO seems to be the most widely used Lewis acid for this purpose [152]. This is often consumed or altered in the course of these reactions, and is thus a reagent rather than a catalyst, although an amount less than equimolar is effective in some instances. We have found B(C6F5)3 to be a highly efficient catalyst in the rearrangement of epoxides [153]. The rearrangement of trisubstituted epoxides readily takes place in the presence of catalytic amounts of B(C6F5)3 (anhydrous grade) resulting in a highly selective alkyl shift to give the corresponding aldehydes. The exceptional bulkiness of B ( C G F ~might ) ~ play a role in ensuring the high selectivity of this process. In contrast, treatment of a solution of pentylidenecyclohexane oxide in benzene with BF, .EtZO affords a diastereomeric mixture in 33:67 ratio (alkyl shift:hydride shift) (Eqs 97 and 98). B(C6F5)3 Bu%

t

(97)

toluene, 60 "C

(alkyl shift)

(hydride shift)

>99% (alkyl shifthydride shift=98 : 2)

(1 mol%) P~+OTBDMS

toluene, 60 0;

oHCz~~~ (98)

(alkyl shift)

73% (alkyl shifthydride shift=s99:1)

Hydrosilylation of carbon-oxygen bonds is a mild method for selective reduction of carbonyl functions. Parks and Piers have found that aromatic aldehydes, ketones, and esters are hydrosilylated at room temperature in the presence of 1 4 mol % B(C6F5)3 and 1 equiv. Ph3SiH [154]. On the basis of kinetic experiments the authors suggested that the reduction takes place by an unusual nucleophilic/electrophilic mechanismthe substrate itself serves to nucleophilically activate the Si-H bond, and hydride transfer is facilitated by the borane Lewis acid (Eq. 99).

118

Zshiharu

B(C6F5)3 (1-4 mol%) Xd

R + HSiPh3

6-

&

OSiPh3

t

rt

R

X

(99)

,B(c6F5)3

H'

'

A synthetically useful and convenient method for the B(C6F5)3-catalyzedhydrostannylation of alkynes with tributyltin hydride, prepared in situ from easily handled and inexpensive chlorostannane and hydrosilane, has been developed by Yamamoto and his colleagues [155]. The hydrostannylation of monosubstituted alkynes proceeds in a regiospecific manner to give the P-hydrostannylation products exclusively (Eq. 100). The reaction is trans stereoselective. This method can also be applied to the hydrostannylation of allenes and alkenes (Eqs 101 and 102).

+

R-R'

Bu3SnCl

+

B(C6F5)3 (10 mol%) Et3SiH

*

toluene 0 "C to rt

major

minor

B(c6F5)3

7+

Ph

Bu3SnCI

+

Et3SiH

(10 mol%) toluene 0 "C to rt

*

ph+ Bu~SU

(101)

51Yo yield

(1 0 mol%) Ph/=

+

Bu3SnCI

+

Et3SiH

* phn./suBu3

toluene 0 "C to rt

(102)

70% yield

Maruoka and his colleagues reported that B(C6F5)3 is capable of forming a pentacoordinate complex in the reduction of alkoxy-substituted carbonyl compounds with Bu3SnH [156]. Reduction of an a-methoxy ketone and its deoxy analog (1:l ratio)

Achiral B(III) Lewis Acids

119

with B(C6F5)3 (1 equiv.), which was originally believed to be a non-chelating Lewis acid, afforded the a-methoxy alcohol as a major product. Similar results in terms of selectivity were also obtained with Me3A1 in place of B(C6F5)3. These results imply the preferential formation of a chelating pentacoordinate complex rather than a tetracoordinate complex (Eq. 103).

0

0 Ph

+ PhL

1) B(C6F5)3 (1 equiv) toluene

OH

/Go\

2) Bu3SnH * Ph -78-40 "C

+

p

h

L

(lo3)

>20 : 1

Transformations accompanying alkyl or hydride anion abstraction from Group 4 complexes by strong Bronsted or Lewis acids are currently of great interest because they are central to the activation and function of homogeneous single-site ZieglerNatta catalysts based on metallocene and quasimetallocene frameworks. Surprisingly few Lewis acids react cleanly with metallocenes to afford soluble complexes with desirable catalytic activities, and still fewer afford rigorously characterized active species. Effective cocatalysts include Ph3Cf (with appropriate weakly coordinating counter-anions), perfluoroarylboranes [149], and M A 0 (methylalumoxane). Marks and his colleagues reported that sterically encumbered (perfluoroary1)borane-derived cationic complexes are more catalytically active than the MeB(C6F5)3 analogs [157]. Ethylene polymerization activity for eight (Me2Cp)2MCH;CH3B(C6F5)~Ar- complexes measured in toluene solution (25 "C, 1 atm) could be correlated with the metal used (Zr > Hf), and there was substantial correlation with the triarylborane (Ar = C6F5 > 3,5-F2C6H3> Ph - 3,5-Me2C6H3)(Eq. 104).

Despite the interest in B(ChF5)3 as a Lewis acid catalyst for organic reactions or a co-catalyst for olefinic polymerizations, little is known of its reaction with water. There is a report of the compound [NHEt3][HOB(C6F5)3][158] and of the platinum complex, [Pt(HOB(C6F5)3]Me(Bu2bpy)](Buzbpy = 4,4'-di-tert-butyl-2,2'-bipyridine),

120

Ishihara

which is formed by reaction between [PtMe2(Bu2bpy)],B(C6Fs)3 and H20. This latter complex has been structurally characterized and contains the anion [HOB(C6F5)3]- as a ligand coordinated to the platinum center [159]. Finally, it has been reported that isobutylene and p-methylstyrene undergo a carbocationic polymerization initiated by B(C6F5)3in the presence of water. This implies the presence of acidic protons as reactive species [160]. Very recently, Danopoulos et al. have reported that reaction of H20 with B ( C G F ~ ) ~ gives a stable adduct and that this adduct can coexist with its conjugate base although the factors affecting the equilibrium are not yet fully understood (Sch. 1) [161]. Addition of water to B(C6F5)3 gives the neutral compound H20.B(C6Fs)3.2 H 2 0 whereas the reaction between B(C6F5)3 and KOH-H20 in the presence of dibenzo-18-crown-6 which crystallizes together with the gives [K(dibenzo-l8-~rown-6)]+-[HOB(C6F~)~]adduct H20.B(C6Fs)3; the new binuclear borate anion [ ( F S ~ ~ ) ~ B C ~ - O H ) B ( C is ~ F , ) ~ ] ~ formed as a salt with the cation [Ir(y5-C5H5)(C8HI2)H]+by addition of H2O to B ( C G F ~in) ~the presence of [Ir(yS-C5HS)(C8H~2)].

+ [H(solvent)]+

Scheme 1

Fu et al. have developed a boron Lewis acid that bears both an empty a-symmetry orbital and an empty x-symmetry orbital (Fig. 1) [162]. These vacant orbitals can simultaneously accept electron density from an oxygen lone pair and from the n system of a carbonyl group. For instance, an X-ray diffraction study of air- and moisturesensitive [(y6-borabenzene-THF)Cr(C0)3] reveals the THF binds to the boron atom

empty o-symmetry orbiatl

empty x-symmetry orbital

Figure 1

filled x orbital

filled o orbital

\

Achiral B(III) Lewis Acids

121

with a slightly distorted trigonal-planar geometry at oxygen. The B-0 bond in the complex (1.467 A) is markedly shorter than that observed in any other boron-based THF complex (1.51-1.59 A). The structure is consistent with donation from a filled xsymmetry oxygen orbital to an empty x-symmetry borabenzene orbital. [(y6-borabenzene-THF)Cr(C0)3] reacts with 3-(dimethy1amino)acrolein to provide [(y6-borabenzene-3-(dimethylamino)acrolein)Cr(CO)3]. The crystal structure has features typical of Lewis acid/aldehyde complexes: (i) the Lewis-acidic atom lies in the plane of the carbonyl group; (ii) the Lewis acid binds syn to the hydrogen of the aldehyde, rather than syn to the carbon substituent; and (iii) the Lewis acid-oxygencarbon angles is roughly 120". The most noteworthy feature of the crystal structure of the complex is the coplanarity of the borabenzene ring and the a,P-unsaturated aldehyde, a conformation that enables interaction between n-symmetry orbitals of the two fragments.

4.5.2 Diarylborinic Acid Diarylborinic acids bearing electron-withdrawing aromatic groups are effective catalysts for Mukaiyama aldol condensation and the subsequent selective dehydration of P-hydroxy carbonyl compounds [163]. The catalytic activity of diarylborinic acids (C6F5)2BOH and (3,5-(CF3)2C6H3)2BOHin Mukaiyama aldol reactions are much higher than those of the corresponding arylboronic acids. It is worthy of note that small amounts of (E)-isomeric dehydrated product have been isolated in reactions catalyzed by diarylborinic acids ( C G F ~ ) ~ B O and H (3,5-(CF3)2C6H3)2BOH. In contrast, no dehydrated products have been isolated in the presence of (C6F5)3B,despite its extremely high catalytic activity (Eq. 105).

0%

7% 10%

0%

Significant features of these active borinic acid catalysts are that they are strong Lewis acids and have a hydroxy group on the boron atom. Dehydration is strongly favored in THE The reaction usually proceeds smoothly, and aJ-enones are obtained in high yields as ( E ) isomers. In reactions of a-substituted-P-hydroxy carbonyl compounds, a,P-enones are preferentially obtained from anti aldols, whereas most syn aldols are recovered. This dehydration thus represents a useful and convenient method for isolating pure syn aldols from synlanti isomeric mixtures (Eq. 106).

122

Ishihara

\ Ar2BOH

/ A

L

Examples 0 PhA4Ph >99%

0 d P h-

0 d B P uh -

>99%

97%

OH 0 Ph) - y c P h

syn:anti=71:29

OH 0 -Ph+Ph

+

35%

Ph+Ph

65% (>99% S Y ~ )

The mechanism we have proposed to explain borinic acid-catalyzed dehydration is also depicted in Eq. (106). Reaction of the P-hydroxy function with the diarylborinic acid leads to a cyclic intermediate, which should be susceptible to dehydration. Subsequent transformation to a,p-enones occurs via an enolate intermediate resulting from selective abstraction of a pseudo-axial a-proton perpendicular to the carbonyl face. A cyclic intermediate formed from a syn aldol and a diarylborinic acid would be thermodynamically less stable than the cyclic intermediate. Thus, dehydration to (E)-a,Penones occurs selectively for anti aldols. Oppenauer (OPP) oxidation is one of the most useful methods for transforming secondary alcohols into ketones. Functional groups such as carbon-carbon double and triple bonds, aldehydes, amino groups, halogens, or sulfur-containing groups are not affected by this reaction, which is a great advantage over many oxygen-transferring oxidation processes. For the selective oxidation of allylic alcohols in the presence of saturated alcohols, activated M n 0 2 is still one of the most useful reagents, despite the large amount required. We found that (C6F5)2BOH was a suitable OPP catalyst for primary and secondary allylic and benzylic alcohols [164]. Borinic acid (C6F5)2BOH is prepared from the known chloroborane (C6FS)2BC1 with aqueous 2 M HC1 [165]. It is obtained as a white, microcrystalline solid which can be readily handled in air and is soluble in many organic solvents. (C,jFS)2BOH is, furthermore, a stronger Lewis acid than C6F5B(OH)2, although it is weaker than B(C6F5)3 [1661. Several arylboron compounds bearing electron-withdrawing aromatic groups have been examined as catalysts for the OPP oxidation of (S)-perillyl alcohol. Catalysis has been performed with 1 to 2 mol % catalyst in the presence of 6 equiv. pivalaldehyde as hydride acceptor in toluene or benzene solution. Representative results are summarized in Table 1.

Achiral B(II1) Lewis Acids

123

Table 1. The catalytic activity of arylboron compounds in the Oppenauer oxidation of (S)-perillyl alcohol."

.$"

x entry

CHO

cat. Ar,B(OH)3.,,

fBuCHO (6 equiv)

A

toluene or benzene

catalyst (rnol%)

conditions ("C, h)

yield

("/I

a Unless otherwise noted, the oxidation of (S)-perillyl alcohol (1 equiv., 0.25 M) was performed in benzene in the presence of pivalaldehyde and a catalyst. Oxidation of (S)-perillyl alcohol (1 equiv., 0.5 M) in toluene.

The catalytic activity of (C6Fs)zBOH is much higher that those of other diarylborinic acids. In contrast, C6FsB(OH)2 (entry 1) is inert. The catalytic activity of these systems correlates with their Lewis acidity. Surprisingly, B(C6F5)3is also active as a catalyst for these oxidations (entries 4 and 5). The latter result can be explained in terms ) ~ that this is the actual of the in-situ generation of (C6F5)zBOH from B ( C ~ F Sand active catalyst (Eq. 107). We have, in fact, ascertained by I9F NMR analysis that B(C6Fs)3gradually undergoes conversion to (C6FS)2BOHand pentafluorobenzene, and finally to C6F5B(OH)2,under these reaction conditions. In general, triarylboranes and diarylborinic acids bearing electron-withdrawing substituents on their aryl groups are relatively stable in acidic aqueous solutions, but are unstable in neutral and basic aqueous solutions, in which they undergo conversion to arylboronic acids and arenes.

The addition of magnesium sulfate efficiently prevents the inactivation of (C6Fs)2BOHand hence promotes the oxidation. The removal of water by magnesium sulfate might prevent the hydrolysis of (C6F5)zBOH and shift the equilibrium between the mixture of (C6Fs)2BOH and (S)-perillyl alcohol and the mixture of the borinate and water in the direction of the borinate.

124

Ishihara

The generality and scope of the (C6F5)2BOH-catalyzed OPP oxidation has been explored using various primary and secondary alcohols. The results are summarized in Table 2. All the allylic alcohols used are oxidized to or$-enals and a$-enones in high yield (entries 1-5). Unfortunately, however, ( E ) l ( Z )isomerization occurs between Table 2. The OPP oxidation of various alcohols catalyzed by 2. (C6F&BOH (1 or 2 mol%) R'

entry

BuCHO (3 equiv), MgS04 (1 equiv) toluene, rt alcohol

(mol%)

time (h)

yield (Yo)

2

27

85

1

3

95

1

3

98

4

1

3

>99

5

1

2

299

2

42

85

2

5

90

2

5

20

9

2

6

<26

10

2

8.5

P

3

?

7

8d

a

f

O

H

&. Y

6a

(C6F&BOH

S

$OH

O

O

H

H

4 equiv. pivalaldehyde was used. E:Z = 99:l. E Z = 72:28. 2 equiv. MgS04 was used. Other products were included. . cis:trans = 65.51345 51 % of the recovered alcohols (cis:truns = 65.5:34.5).

49 g

125

Achiral B(III) Lewis Acids

geranial and neral (entries 2 and 3). Primary and sterically less-hindered secondary benzylic alcohols are oxidized reasonably efficiently in good yields (entries 6 and 7). The oxidation of propiophenone gives 1-phenylpropanol in somewhat lower yield (entry 8). Saturated alcohols are slowly oxidized to the corresponding carbonyl compounds (entries 9 and 10). In the oxidation of a diastereomeric mixture of carveol (syn:anti = 42:58), the syn alcohol is stereoselectively oxidized and the anti alcohol is recovered in 98 % diastereomeric purity. This shows that the catalytic activity of (C6F5)zBOH is very sensitive to steric hindrance in the alcohols (Eq. 108). In oxidations of equimolar mixtures of geraniol and P-citronellol, geranial is obtained in 96 % yield and most of the p-citronellol is recovered unchanged (Eq. 109). The selective conversion of allylic alcohols in the presence of saturated alcohols is particularly noteworthy. (C6F&BOH (1 mol%)

-

BuCHO (3 equiv)

b

2

MgSO4 (1 equiv) toluene, 9 h

syn:anfi=42:58

0.5 mmol

0

+

48% yield

b

*

O

H

(1 08)

52% yield (98% anti)

0.5 mmol

(C6F&BOH (0.01 mmol)

-

BuCHO (3 mmol) MgS04 (1 mmol) toluene. 1 h

m

C

H

0.48 mmol (96%)

O

+

(109)

O -H

0.034 mmol (7%)

(C6F5)2BH is a highly active hydroboration reagent for a range of simple alkenes and alkynes (Eq. 110). Addition of the olefin or alkyne to a suspension of the borane in benzene leads to rapid dissolution of the solid, and the reaction is complete within 2 min (Eqs 111 and 112). Even sterically demanding olefins are hydroborated very rapidly, and the rates of hydroboration of methylcyclohexene and methylcyclopentene are identical. These observations are in marked contrast with those in reactions using the common hydroboration reagent 9-BBN which, under identical conditions, requires several hours to reach completion bearing these substrates. The only substrates that do not react rapidly with (C6Fs)zBH are those with a B(C6Fs)z substituent, which apparently deactivates the double bond towards subsequent hydroboration. In addition to the convenience of high rates, the regio- and chemoselectivity of ( C ~ F S ) ~ BisH comparable with or better than that of other hydroboration reagents [166a].

126

Ishihara

Hydroboration of aliphatic vinyl silanes with the highly electrophilic HB(C6F5)2 gives predominantly the thermodynamically favored regioisomer with boron and silicon on the same carbon (Eq. 113) [166b]. Thermodynamic product mixtures are obtained because equilibration of isomers by boryl migration is facile in the products of hydroboration with HB(C6Fs)2. The 1,l-substituted isomers are the most stable by virtue of a ground-state /3-silicon effect involving hyperconjugation between the Me3Si group and the electrophilic borane center. More complex thermal rearrangements are observed when aromatic vinyl silanes are hydroborated with HB(C6Fs)2.

kinetic product

thermodynamic product conditions

n=o n=l n=4

kinetic

therm

96:4

13:87 12:88 15:85

1oo:o 1oo:o

4.5.3 Arylboronic Acid There are several different routes to carboxamides. Usually a carboxylic acid is converted to a more reactive intermediate, e.g. an acid chloride, which is then reacted with an amine. For practical reasons it is preferable to form the reactive intermediate in situ. We have found that arylboronic acids bearing electron-withdrawing aromatic groups, e.g. 3,4,5-trifluorophenylboronicacid, 3,4,5-F3C6HzB(OH)2, and 3,5-bis(trifluoromethy1)phenylboronic acid, 3,5-(CF3)2C6H3B(OH)2,act as highly efficient catalysts in the amidation of carboxylic acids with amines [167]. The catalysts are useful in the reaction of primary and secondary amines with a variety of carboxylic acids (Eq. 114).

Achiral B(III) Lewis Acids

3,5-(CF3)&H3BOH (1 mol%) * R'CONHR2R3 R'C02H + R2R3NH toluene, xylene, or mesitylene reflux Examples

127

(114)

I

99%

92%

95%

The catalytic amidation of optically active aliphatic a-hydroxycarboxylic acids with benzylamine proceeds with no measurable loss (< 2 %) of enantiomeric purity under reflux conditions in toluene (Eq. 115). 3,4,5-F3CeH2B(OH)2 (10 mol%)

0 OH

+

298% ee

HZN-Ph

toluene

R$/nph OH

(115)

reflux for 10 h R=Ph: 95% yield, 94% ee R=Bu: 87% yield, >98% ee R=rPr: 96% yield, >98% ee

Other examples

3,4,5-F&H2B(OH)2 (5 mol%) 94%

3,4,5-F&jH2B(OH)2 (1 mol%) 90%

3,4,5F&HzB(OH)z (1 mol%) 93%

Most amino acids are barely soluble in non-aqueous solvents. Nevertheless, their lactams can be prepared by this technique under heterogeneous conditions. For example, when 6-aminocaproic acid and 1 mol % boron catalyst ~ , ~ , ~ - F & H z B ( Oare H)~ suspended in xylene under reflux the solid slowly dissolves and caprolactam is formed in 93 YOyield.

128

Ishihara

The mechanism we have proposed to explain boronic acid-catalyzed amidation is depicted in Sch. 2. Arylboronic acid usually contains different amounts of cyclic trimeric anhydrides (boroxines). The rate-determining step is the generation of ArB (OCOR)(OH).

I

+ RC02H

o-H-o

ArB(OH)2

RKO'

H20

B'Ar

/

HNR'R~

Scheme 2

The hydrolysis of salicylaldehyde imines is catalyzed by boric acid, substituted arylboronic acids, and diphenylborinic acid. The effects of different substituted phenylboronic acids on the rate of hydrolysis at pH 6.0 has been studied by Rao and Philipp [168]. The second-order rate constants, k,,,lK,, are higher for phenylboronic acids bearing electron-withdrawing substituents than for phenylboronic acids bearing electron-donating substituents. The highest value obtained was 2.38 M-' s-l, for 3,5(CF3)2C6H3B(OH)2,and the lowest was 0.09 M-' s-', for 4-MeC6H4B(OH)2.Phenylboronic acids bearing electron-withdrawing substituents bind the imine more tightly than do boronic acids bearing electron-donating substituents. The effects of boronic acid, phenylboronic acid, and diphenylborinic acid on the hydrolysis of the same imine were also studied at pH 6.0. PhB(0H)Z and Ph2B(OH) bind the imine more strongly than boronic acid by factors of almost 25 and 4350, respectively (Sch. 3). 3,5-(CF3)2CsH3B(OH)2is useful for the regioselective protection of amino groups (Sch. 4) [ 1691. For example, verbacine has been synthesized by adding cinnamoyl chloride to a 1:l mixture of 16-phenyl-2,6,11,15-tetraazacycloheptadecan-l-one and 3,5-(CF3)2C6H3B(OH)2in dichloromethane to give verbacine as the major product in 53 % yield, together with recovered starting material, the monocinnamamide acylated at N-11, and the dicinnamamide acylated at both N-6 and N-11. Because the acylation of 16-phenyl-2,6,11,15-tetraazacycloheptadecan-l-one with acyl chloride or acid anhydride in the absence of boronic acid gives only the dicinnamamide, the efficiency of the present regioselective acylation can be attributed to the stability of a 1,3-diaza-2boracyclohexane unit. Thus, the presumed six-membered cyclic intermediate generated by the complexation of 16-phenyl-2,6,11,15-tetraazacycloheptadecan-l-one with 3,5-(CF3)2C6H3B(OH)2at N-11 and N-15 can reasonably be expected to undergo acy-

Achiral B(III) Lewis Acids

ArB(OH)2

129

H-N+

KHo + ArB(OH)2

Scheme 3

lation with the free amino group at N-6. Verbacine is readily transformed in good yield to verbaskine. Moreover, verbacine can be converted to verbacenine in almost quantitative yield by selective acetylation at N-11.

Verbascenine

Scheme 4

130

Ishihara

4.6 Conclusions Arylboron compounds with electron-withdrawing substituents, for example triarylborons, diarylborinic acids, and arylboronic acids, are useful as air-stable Lewis acid catalysts for a variety of organic transformations. In particular, the potential of B(C6F5)3 as a Lewis-acid catalyst has increased strikingly since our initial study [151a]. Despite these impressive recent advances, many unsolved problems remain. These include limitations with regard to scope, and frequent practical problems associated with catalyst preparation and use, especially on a large scale. Nonetheless, continued exploratory research on the application of arylboron compounds to various organic transformations as air-stable and reusable catalysts can be expected to provide powerful and practical methods for Lewis acid-catalyzed organic transformations.

References 1. (a) Barton, D. H. R.; Jaszberenyi, J. Cs.; Theodorakis, E. A. J. Am. Chem. Soc. 1992,114,5904. (b) Matsuda, H.; Nagamatsu, H.; Okuyama, T.; Fueno, T. Bull. Chem. Soc. Jpn. 1984,57,500. 2. (a) Ouazzani, F.; Roumestant, M.-L.; Viallefont, P. Tetrahedron; Asymmetry1991,2,913. (b) Trost, B.; M.; Li, L.; Guile, S. D. J. Am. Chem. Soc. 1992,114,8745. 3. (a) Curran, D. P.J. Am. Chem. Soc. 1983,105,5826. (b) Curran, D. P.; Fenk, C. J. Tetrahedron Lett. 1986,4865. (c) Duclos, 0.;Mondange, M.; DurCault, A,; Depezay, J. C. Tetrahedron Lett. 1992,8061. (d) Calderola, P.; Ciancaglione, M.; De Amici, M.; De Micheli, C. Tetrahedron Lett. 1986,4647. 4. Wehrli, P. A,; Chu, V. J. Org. Chem. 1973,38,3436. 5. (a) Ho, T. L. Synth. Commun.1979,9, 609. (b) Bacos, D.; Celerier, J.-P.; Lhommet, G. Tetrahedron Lett. 1987,2353. 6. Offenhauer, R. D.; Nelsen, S. F. J. Org. Chem. 1968,33,775. 7. Stapp, P. R. J. Org. Chem. 1973,38,1433. 8. Lowrance, W. W., Jr. Tetrahedron Lett. 1971,3453. 9. Tetrashima, M.; Fujioka, M. Heterocycles 1982,19,91. 10. (a) Weiberg, E.; Sutterlin, W. Z. Anorg. Allg. Chem. 1931,202,22. (2) Benton, F.; Dillon, T. J. Am. Chem. Soc. 1942,64,1128. 11. Lansinger, J.; Ronald, R. Synth. Commun.1992,22,1793. 12. Povlock, T. Tetrahedron Lett. 1967,4131. 13. McOmie, J. E W.; Watts, M. L.; West, D. E. Tetrahedron 1968,24,2289. 14. Meyers, A. I.; N o h , R. L.; Collington, E. W.; Narwid, T. A,; Strickland, R. C. J. Org. Chem. 1973, 38,1974. 15. (a) Benton, F. L.; Dillon, T. E. J. Am. Chem. Soc. 1942,64,1128. (b) Manson, D. L.; Musgrave, 0. C. J. Chem. Soc. 1963, 1011. (c) McOmie, J. F. W.; Watts, M. L. Chem. Ind. (London) 1963, 1658. (d) Blatchly, J. M.; Gardner, D. V.; McOmie, J. F. W.; Watts, M. L. J. Chem. Soc. (C) 1968,1545. 16. Schafer, W.; Franck, B. Chem. Ber. 1966,99,160. 17. Youssefyeh, R. D.; Mazur, Y. Chem. lnd. (London) 1963,609. 18. Niwa, H.; Hida, T.; Yamada, K. Tetrahedron Lett. 1981,22,4239. 19. Corey, E. J.; Weinhensker, N. M.; Schaaf, T. K.; Huber, W. J. Am. Chem. Soc. 1969,91,5675. 20. Kabalka, G.; Narayana, C.; Reddy, N. Synth. Commun.1992,22,1793. 21. Narayana, C.; Padmanabhan, S. Kabalka, G. Tetrahedron Lett. 1990,31,6977. 22. Olah, G.; Narang, S.; Field, L.; Karpeles, R. J. Org. Chem. 1981,46,2408. 23. Narayana, C.; Padmanabhan, S.; Kabalka, G. Synlett 1991,125. 24. Atssi, M.; Perlstein, M. Tetrahedron Lett. 1972,1861. 25. Bonner, T. G.; Bourne, E. J.; McNally, S. J. Chem. Soc. 1960,2929. 26. Grieco, P. A,; Hiroi, K.; Reap, J. J.; Noguez, J. A. J. Org. Chem. 1975, 40, 1450. (b) Grieco, P. A.: Reap, J. J.; Noguez, J. A. Synth. Commun.1975,5,155. 27. (a) Boeckman, Jr., R. K.; Potenza, J. C. Tetrahedron Lett. 1985,26,1411. (b) King, P. F.; Stroud, S. G. Tetrahedron Lett. 1985,26,1415. 28. (a) Guindon, Y.; Morton, H. E.; Yoakim, C. Tetrahedron Len. 1983,24,3969. (b) Gauthier, J. Y.; Guindon, Y. Tetrahedron Lett. 1987,28,5985. (c) Guindon, Y.; Yoakim, C.; Morton, H. E. Tetrahedron Lett. 1983,24,2969. (d) Guindon, Y.; Yoakim, C.; Morton, H. E. J. Org. Chem. 1984,49,3912. 29. Corey, E. J.; Hua, D. H.; Seitz, S. P. Tetrahedron Lett. 1984,25, 3.

Achiral B(III) Lewis Acids

131

30. Bhatt, M. V. J. Organomet. Chem. 1978,156,221. 31. Williard, P. G.; Fryhle, C. B. Tetrahedron Lett. 1990,21,3731. 32. Kulkarni, S. U.; Patil, V. D. Heterocycles 1982,18,163. 33. Olah, G. A,; Karpeles, R.; Narang, S. C. Synthesis 1982,963. 34. Yazawa, H.; Tanaka, K.; Kariyone, K. Tetrahedron Lett. 1974,15,3995. 35. (a) Teitel, S.; O’Brien, J.; Brossi, A. J. Org. Chem. 1972, 37, 3368. (b) Teitel, S.; O’Brien, J. P. J. Org. Chem. 1976,41,1657. 36. Williard, P. G.; Fryhle, C. B. Tetrahedron Lett. 1980,21,3731. 37. Manchand, P. S. J. Chem. SOC.,Chem. Commun.1971,667. 38. Toshima, K.; Nagai, H.; Ushiki, Y.; Matsumura, S. Synlett 1998,1007. 39. (a) Nesmeyanov, A. N.; Kocheshkov, K. A. Methods of Elemento-Organic Chemistry; NortliHolland: Amsterdam, 1967; Vol. 1, pp 20-96. (b) Mikhailov, B. M.; Bubnov, Y. N. Organoboron Compounds in Organic Synthesis;Harwood: Amsterdam, 1984. 40. Holliday, A. K.; Jessop, G. N. J. Chem. SOC. (A) 1967,889. 41. Gerrard, W.; Howarth, M.; Monney, E. F.; Pratt, D. E. J. Chem. SOC.1963,1582. 42. (a) Niedenzu. K.; Dawson, J. W. J. Am. Chem. SOC.1960,82,4223. (b) Brinkmas, F. E.; Stone, F. G. A. Chem.Ind. (London)1959.254. 43. Cole, T. E.; Quintanilla,’R.; Rodewald, S. Organometallics 1991,10,3777. 44. (a) Brown, H. C. Organic Synthesis via Boranes; Wiley; New York, 1975; pp 4 5 4 7 . (b) Brown, H. C.; Kulkarni, S. U. J. Organomet. Chem. 1982, 239, 23. (c) Brown, H. C.; Ravindran, N. Inorg. Chem. 1977,16,2938. 45. Soundararajan, R.; Matteson, D. S. J. Org. Chem. 1990,55,2274. 46. Fuji, K.; Ichikawa, K.; Node, M.; Fujita, E. J. Org. Chem. 1979,44, 1661. 47. Danishefsky, S. J.; Pearson, W. H.; Harvey, D. F. J. Am. Chem. Soc. 1984,106,2455. 48. Kawabata, T.; Kimura, Y.; Ito, Y.; Terashima, S.; Sasaki, A.; Sunagawa, M. Tetrahedron 1988, 44, 2149. 49. Sugiyama, S.; Honda, M.; Higuchi, R.; Komori, T. Justus Liebigs Ann. Chem. 1991,349. 50. Sasaki, M.; Murase, T.;Takahashi, T. J. Org. Chem. 1990,55,528. 51. Kamber, B.; Cainelli, G.; Arigoni, D.; Jeger, 0.Helv. Chim.Acta 1960,43. 52. (a) McKenna, J. F.; Sowa, F. J. J. Am. Chem. SOC. 1937, 59, 470. (b) Burwell, R. L.; Archer, S. J. Am. Chem. SOC. 1942, 64, 1032. (c) Hennion, G. F.; Pieronek, V. R. J. Am. Chem. SOC.1942, 64, 2751. (d) Vermillion, G.; Hill, M. A. J. Am. Chem. SOC.1945,67,2209. (e) Hennion, G. F.; Auspos, L. A. J. Am. Chem. Soc. 1943,65,1603. 53. Price, C. C.; Ciskowski, J. M. J. Am. Chem. SOC.1938,60,2499. 54. Olah, G. A,; Kuhn, S.; Olah, J. J. Chem. SOC.1957,2174. 55. Canonne, P.; Regnault, A. Can. J. Chem. 1969,47,2387. 56. Harring, S. R.; Livinghouse, T. J. Chem. SOC.,Chem. Commun.1992,502. 57. Hirschmann, R.; Miller, R.; Wendler, N. L. J. Am. Chem. SOC.1954, 76,4592. 58. Hyatt, J . A.; Raynolds, I? W. J. Org. Chem. 1984,49,384. 59. (a) Fodor, G.; Kiss, J.; Szekerke, M. J. Org. Chem. 1950, 15, 227. (b) Kindler, K.; Oelschlager, H. Chem. Ber. 1954,87,194. 60. Schiemenz, G. P.; Schmidt, U. Liebigs Ann. Chem. 1976,1514. 61. Walker, H. G.; Sanderson, J. J.; Hauser, C. R. J. Am. Chem. SOC.1953, 75,4109. 62. Corey, E. J.; Girotra, N. N.; Mathew, C. T. J. Am. Chem. Soc. 1969,91,1557. 63. Fairlie, J. C.; Hodgson, G. L.; Money, T. J. Chem. SOC.,Perkin Trans. I 1973,2109. 64. Thompson, C. M.; Docter, S. Tetrahedron Lett. 1988,29,5213. 65. Ohta, S.; Kimoto, S. Tetrahedron Lett. 1975,2279. 66. Boeckman, R. K. Jr.; Bruza, K. J.; Heinrich, G. R. J. Am. Chem .Soc. 1978,100,7101. 67. Rigby, J. H. Tetrahedron Lett. 1982,23,1863. 68. Sum, P.-E.; Weiler, L. Can. J. Chem. 1979,57, 1475. 69. Chenard, B. L.; Van Zyl, C. M.; Sanderson, D. R. Tetrahedron Lett. 1986,27,2801. 70. Harding, K. E.; Clement, K. S. J. Org. Chem. 1984,49,3870. 71. Jain, T. C.; McCloskey, J. E. Tetrahedron Lett. 1971,1415. 72. Caine, D.; Graham, S. L. Tetrahedron Lett. 1976,2521. 73. House, H. 0.;Blaker, J. W.; Madden, D. A. J. Am. Chem. SOC.1958,80,6386. 74. Masaki, Y.; Nagata, K.; Serizawa, Y.; Kaji, K. Tetrahedron Lett. 1984,25,95. 75. Noyori, R.; Makino, S.; Takaya, H. Tetrahedron Lett. 1973, 1745. 76. (a) Bosworth, N.; Magnus, l? D. J. Chem. Soc., Perkin Trans. I 1972, 943. (b) Rigby, J. H.; Senanayake, C. J. Or,. Chem. 1988,53,440. 77. Lichtenthler, F. W.; Breunig, J.; Fischer, W. Tetrahedron Lett. 1971,2825. 78. Kikugawa, Y.; Kitamura, T.; Wawase, M. J. Chem. SOC.,Chem. Commun.1989,525. 79. House, H. 0.;Wasson, R. L. J. Am. Chem. SOC.1957,79,1488.

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80. Bird, C. W.; Yeong, Y. C.; Hudec, J. Synthesis 1974,27. 81. Domagala, J. M.; Bach, R. D. J. Am. Chem. Soc. 1978,100,1605. 82. Obuchi, K.; Hayashibe, S.; Asaoka, M.; Takei, H. Bull. Chem. Soc. Jpn. 1992,65,3206. 83. Bach, R. D.; Klix, R. C. J. Org. Chem. 1985, SO, 5438. 84. Hancock, W. S.; Mander, L. N.; Massy-Westropp, R. A. J. Org. Chem. 1973,38,4090. 85. French, L. G.; Fenlon, E. E.; Charlton, T. P. Tetrahedron Lett. 1991,32,851. 86. Loubinoux, B.; Viriot-Villaume, M. L.; Chanot, J. J.; Caubere, F? Tetrahedron Lett. 1975,843. 87. Smith, J. R. L.; Norman, R. 0.C.; Stillings, M. R. J. Chem. Soc. Perkin Trans. I 1975,1200. 88. Conacher, H. B. S.; Gunstone, F. D. J. Chem. Soc., Chem. Commun.1967,984. 89. Durst, T.; Tin, K.-C. Tetrahedron Lett. 1970,2369. 90. Maruoka, K.; Hasegawa, M.; Yamamoto, H.; Suzuki, K.; Shimazakai, M.; Tsuchihashi, G. J. Am. Chem.Soc. 1986,108,3827. 91. Shimazaki, M.; Hara, H.; Suzuki, K.; Tsuchihashi, G. Tetrahedron Lett. 1987,28,5891. 92. Yoshizawa, T.; Toyofuku, H.; Tachibana, K.; Kuroda, T. Chem. Lett. 1982,1131. 93. Davies, J. S. H.; McCrea, P. A,; Norris, W. L.; Ramage, G. R. J. Chem. SOC.1950,3206. 94. Boeckman, R. K. Jr.; Flann, C. J.; Poss, K. M. J. Am. Chem. Soc. 1985,107,4359. 95. Suzuki, H.; Yashima, H.; Hirose, T.; Takahashi, M.; Moro-Oka, Y.; Ikawa, T. Tetrahedron Lett. 1980,21,4927. 96. Takahashi, M.; Suzuki, H.; Moro-Oka, Y.; Ikawa, T. Tetrahedron Lett. 1982,23,4031. 97. Yoshizawa, T.; Toyofuku, H.; Tachibana, K.; Kuroda, T. Chem. Lett. 1982,1131. 98. Tou, J. S.; Reusch, W. J. Org. Chem. 1980,45,5012. 99. Taber, D. F.; Kong, S.; Malcolm, S. C. J. Org. Chem. 1998,63,7953. 100. Marczewski, M. Catalysis by Acids and Bases; Imelik, B., et al., Eds.; Elsevier: Amsterdam, 1985; p 213. 101. Marczewski, M.; Marczewska, H.; Witoslawski, K. Bull. SOC.Chim. Fr. 1991,128,366. 102. Juszczyk, W.; Marczewski, M. J. Chem. Soc., Faraday Trans. 1992,88,3591. 103. McGinnis, M. B.; Vagle, K.; Green, J. F.; Tan, L. C.; Palomer, R.; Siler, J.; Pagni, R. M.; Kabalka, G. W. J. Org. Chem. 1996,61,3496. 104. Danishefsky, S.;Chao, K.-H.; Schulte, G. J. Org. Chem. 1985, SO, 4650. 105. Kotsuki, H.; Asao, K.; Ohnishi, H. Bull. Chem. Soc. Jpn. 1984,57,3339. 106. Gras, J.-L.; Guerin, A. Tetrahedron Lett. 1985,26,1781. 107. Fleming, I.; Paterson, I. Synthesis 1979,446. 108. Fleming, I.; Lewis, J. J. J. Chem. Soc. Perkin Trans. I 1992,3267. 109. Pornet, J.; Damour, D.; Miginiac, L. J. Organomet. Chem. 1987,319,333. 110. Fleming, I.; Patel, S. K. Tetrahedron Lett. 1981,22,2321. 111. (a) Fleming, I.; Henning, R.; Plaut, H. Chem. Commun.1984,29. (b) Crump, R. A. N. C.; Fleming, 1.; Hill, J. H. M.; Parker, D.; Reddy, N. L.; Waterson, D. J. Chem. Soc., Perkin Trans. I 1992,3277. 112. (a) Jansson, K.; Frejd, T.; Kihlberg, J.; Magnusson, G. Tetrahedron Lett. 1986,27,753. (c) Jansson, K.; Ahlfors, S.; Frejd, T.; Kihlberg, J.; Magnusson, G.; DahmCn, J.; Noori, G.; Stenvall, K. J. Org. Chem. 1988,53,5629. 113. (a) Fleming, I.; Urch, C. J. Tetrahedron Lett. 1983,24,4591. (b) Fleming, I.; Urch, C. J. J. Organomet. Chem. 1985,285,173. (c) Coope, J.; Shiner, V. J. J. Org. Chem. 1989,54,4270. 114. Meerwein, H. Chem. Ber. 1933,66,411. 115. Mao, C. L.; Frostick, F. C.; Man, E H.; Manyik, R. M.; Wells, R. L.; Hauser, C. R. J. Org. Chem. 1989,34,1425. 116. Manyik, R. M.; Frostick, F. C.; Sanderson, J. J.; Hauser, C. R. J. Am. Chem. SOC.1953, 75,5030. 117. (a) Hayashi, T.; Kanehira, K.; Hagihara, T.; Kumada, M. J. Org. Chem. 1988, 53, 113. (b) Meyer, W. L.; Brannon, M. J.; Burgos, C. da G.; Goodwin, T. E.; Howard, R. W. J. Org. Chem. 1985, SO, 438. 118. Hauser, C. R.; Hoffenberg, D. S. J. Org. Chem. 1955,20,1448. 119. Yamamoto, Y.; Schmid, M. J. Chem. SOC.,Chem. Commun.1989,1310. 120. Yamamoto, Y.; Maruyama, K. J. Organomet. Chem. 1985,284, C45. 121. (a) Keck, G. E.; Abbott, D. E. Tetrahedron Lett. 1984,25,1883. (b) Keck, G. E.; Boden, E. P. Tetrahedron Lett. 1984,25,265. 122. Keck, G. E.; Enholm, E. J. J. Org. Chem. 1985, SO, 146. 123. Trost, B. M.; Bonk, P. J. J. Am. Chem. Soc. 1985,107, 1778. 124. Marshall, J. A,; DeHoff, B. S.; Crooks, S. L. Tetrahedron Lett. 1987,28, 527. 125. Marton, D.; Tagliavini, G.; Zordan, M.; Wardell, J. L. J. Organomet. Chem. 1990,390,127. 126. Cifolini, M. A.; Spencer, G. 0.J. Org. Chem. 1989,54,4739. 127. Gung, B. W.; Smith, D. T.; Wolf, M. A. Tetrahedron Lett. 1991,32,13. 128 Hosomi, A,; Hashimoto, H.; Sakurai, H. Tetrahedron Lett. 1980,21,951. 129. Smith, A. B. 111;Jerris, P. J. J. Am. Chem. SOC.1981,103, 194.

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130. Erman, W. F.; Stone, L. C. J. Am. Chem. Soc. 1971,93,2821. 131 Wakselman, C.; Tordeux, M. J. Chem. Soc., Chem. Commun.1975,956.

132. Wulf, W. D.; Gilbertson, S. R. J. Am. Chem. Soc. 1985,107,503. 133. Yamago, S.; Machii, D.; Nakamura, E. J. Org. Chem. 1991,56,2098. 134. Nakamura, E.; Kuwajima, I. J. Am. Chem. Soc. 1977,99,961. 135. Sugimura, H.; Shigekawa, Y.; Uematsu, M. Synlett 1991,153. 136. Heathcock, C. H.; Flippin, L. A. J. Am. Chem. Soc. 1983,105,1667. 137. Evans, D. A. Gage, J. R. Tetrahedron Lett. 1990,31,5053. 138. Davis, A. P.; Plunkett, S. J.; Muir, J. E. Chem. Commun.1998, 1797. 139. Duhamel, P.; Hennequin, L.; Poirer, N.; Poirer, J.-M. Tetrahedron Lett. 1985,26,6201. 140. Adlington, M. G.; Orfanopoulos, M.; Fry, J. L. Tetrahedron Lett. 1976,2955. 141. (a) Ibuka, T.; Habashita, H.; Funakoshi, S.; Fuji, N.; Oguchi, Y.; Uyehara, T.; Yamamoto, Y. Angew. Chem., Int. Ed. Engl. 1990,29, 801. (b) Ibuka, T.; Habashita, H.; Okata, A.; Fuji, N.; Oguchi, Y.; Uyehara, T.; Yamamoto, Y. J. Org. Chem. 1991,.56,4370. 142. Fuji, K.; Kawabata, T.; Fujita, E. Chem. Pharm. Bull. 1980,28,3662. 143. SBnchez, I. H.; Soria, J. J.; Lhpez, F. J.; Larraza, M. 1.; Flores, H. J. J. Org. Chem. 1984,49,157. 144. Tani, J.; Oine, T.; Inoue, I. Synthesis 1975,714. 145. Smith, A. B. 111; Branca, S. J.; Toder, B. H. Tetrahedron Lett. 1975,4225. 146. Smith, A. B. IIK J. Chem.SOC.,Chem. Commun.1975,274. 147. Reddy, P. S. N.; Reddy, P.P. Synth. Commun.1988,18,219. 148. Kabalka, G. W.; Tejedor, D.; Li, N.-S.;Reddy, M.; Trotman, S. Tetrahedron Lett. 1998,39,8071. 149. A review of pentafluorophenylboranes: Piers, W. E.; Chivers, T. Chem. Soc.Rev. 1997,26,345. 150. For preparation of 1, see: Massey, A. G.; Park, A. J. J. Organomet. Chem. 1964,2,24.5; Massey, A. G.; Park, A. J. J. Organomet. Chem. 1966,5,218. 151. (a) Ishihara, K.; Hanaki, N.; Yamamoto, H. Synlett 1993, 577. (b) Ishihara, K.; Funahashi, M.; Hanaki, N.; Miyata, M.; Yamamoto, H. Synlett 1994, 963. (c) Ishihara, K.; Hanaki, N.; Funahashi, M.; Miyata, M.; Yamamoto, H. Bull. Chem. Soc. Jpn. 1995,68,1721. 152. (a) Rickbom, B. In ,,Comprehensive Organic Synthesis: “Carbon-Carbon a-Bond Formation”; Pattenden, G., Ed.; Pergamon Press: Oxford, 1991; Vol. 3, Chapter 3.3. (b) Fujimoto, Y.;Kanazawa, Y.; Ikuina, Y.; Kakinuma, K.; Ikekawa, N. J. Chem. SOC.,Chem. Commun.1989,1107. 153. Ishihara, K.; Hanaki, N.; Yamamoto, H. Synlett 1995,721. 154. Parks, D. J.; Piers, W. E. J. Am. Chem. Soc. 1996,118,9440. 155. (a) Gevorgyan, V.; Liu, J.-X.; Yamamoto, Y. J. Org. Chem. 1997,62,2963. (b) Gevorgyan, V.; Liu, J.-X.; Yamamoto, Y. Chem. Commun.1998,37. 156. (a) Ooi, T.; Uraguchi, D.; Kagoshima, N.; Maruoka, K. J. Am. Chem. Soc. 1998,120,5327. (b) Ooi, T.; Uraguchi, D.; Maruoka, K. Tetrahedron Lett. 1998,39,8105. 157. (a) Chen, Y.-X.; Stern, C. L.; Yang, S.; Marks, T. J. J. Am. Chem. Soc. 1996,118,12451. (b) Deck, P. A.; Beswick, C. L.; Marks, T. J. J. Am. Chem. Soc. 1998,120,1772. (c) Chen, Y.-X.; Metz, M. V.; Li, L.; Stern, C. L.; Marks, T. J. J. Am. Chem. Soc. 1998,120,6287. 158. Siedle, A. R.; Newmark, R. A,; Lamanna, W. M.; Huffman, J. C. Organornetallies 1993,12,1491. 159. Hill, G. S.; Manojlovic-Muir, L.; Muir, K. W.; Puddephatt, R. J. Organornetallies 1997,16,525. 160. Shaffer, T. D.; Ashbaugh, J. R. J. Polym. Sci. A 1997,35,329. 161. Danopoulos, A. A,; Galsworthy, J. R.; Green, M. L. H.; Cafferkey, S.; Doerrer, L. H.; Hursthouse, M. B. Chem. Commun. 1998,2529. 162. Amendola, M.; Stockman, K. E.; Hoic, D. A,; Davis, W. M.; Fu, G. C. Angew. Chem., Int. Ed. Engl. 1997,36,267. 163. Ishihara, K.; Kurihara, H.; Yamamoto, H. Synlett 1997,597. 164. Ishihara, K.; Kurihara, H.; Yamamoto, H. J. Org. Chem. 1997,62,5664. 165. (a) Chambers, R. D.; Chivers, T. J. Chem. Soc. 1964, 4782. (b) Chambers, R. D.; Chivers, T. J. Chem. Soc. 1965,3933. 166. (a) Parks, D. J.; Spence, R. E. von H.; Piers, W. E. Angew. Chem., Int. Ed. Engl. 1995,34,809. (b) Parks, D. J.; Piers, W. E. Tetrahedron 1998,15469. 167. Ishihara, K.; Ohara, S.; Yamamoto, H. J. Org. Chem. 1996,61,4196. 168. Rao, G.; Philipp, M. J. Org. Chem. 1991,56,1505. 169. (a) Ishihara, K.; Kuroki, Y.; Hanaki, N.; Ohara, S.; Yamamoto, H. J. Am. Chem. Soc. 1996, 118, 1569. (b) Kuroki, Y.; Ishihara, K.; Hanaki, N.; Ohara, S.; Yamamoto, H. Bull. Chem. Soc. Jpn. 1998, 71,1221.

Lewis Acids in Organic Synthesis Edited bv Hisashi Yamarnoto Copyright 0WILEY-VCH Verlaa GmbH.2000

5 Chiral B(II1) Lewis Acids Kazuaki Ishihara

5.1 Introduction Asymmetric synthesis has recently been the focus of intense interest. Especially noteworthy is the development of homogeneous catalytic asymmetric reactions, in which a small amount of chiral ligand can induce asymmetry in a given reaction. Possible applications depend on the selectivity of the homogeneous catalysts, which are therefore of great interest because they provide simple methods for synthesizing complex molecules in which enantiocontrol is needed. This chapter addresses chirally modified boron Lewis acid complexes, in which there has been increased interest because of their capacity to induce chirality. They have been successfully used for Diels-Alder, aldol, and a variety of other miscellaneous reactions. I will describe and analyze here the different types of catalyst and classify them according to their efficiency, selectivity, and flexibility.

5.2 Enantioselective Carbo Diels-Alder Reactions The enantioselective Diels-Alder reaction is now of great interest because of its usefulness for simultaneous introduction of asymmetric centers during carbon-carbon bond formation.

5.2.1 Chiral Lewis Acids as Stoichiometric Reagents The first example of an enantioselective Diels-Alder reaction using a chiral boron complex was reported by Kelly et al. in 1986 (Eq. 1) [l].The boron complex promotes the reaction of naphthoquinone (juglone) with different dienes. It is prepared from juglone (a peri-hydroxyquinone which is the dienophile for the Diels-Alder reaction) The hydroxy group of the peri-hydroxyquinone and 3,3'-diphenyl-l,lf-bi-2-naphthol. can serve as a ligand for the Lewis acid and reduce the conformational mobility of the complex. The binaphthol derivative serves as the other ligand for the boron. It is also useful because this bidentate ligand has Cz symmetry, which leads to the formation of only one complex, whereas two enantiomers can be formed with other ligands which do not have Cz symmetry. The reaction provides anthraquinone derivatives in good enantiomeric excess (ee). Because this reaction proceeds via coordination of the boron to the dienophile, the use of one equivalent of chiral boron must be used. Chiral borane reagents similar to those described above were independently reported by Yamamoto and co-workers in the same year (Eq. 2) [2]. These reagents promote the reaction of juglone and a variety of dienes in the synthesis of anthracyclinones. The borane reagent used is trimethyl borate. Different tartrate derivatives have been tried and (R,R)-(+)-tartaric acid diamide has proved to be the most efficient. The best results are obtained in the reaction of juglone and (triethylsi1oxy)buta-

136

Ishihara

g:: Ph

1) BH3 (2 equiv) AcOH (2equiv) THF, 20 "C 2) *

Ph (2 equiv)

OH 0 (1 equiv)

70-90% yield -78 "C

(1)

0

H

'H

(1.2 equiv)

(3 equiv) *

0 "C to rt

& OH 0

73% yield

92% ee

OSiEt3

1,3-diene promoted by a combination of trimethyl borate and (R,R)-(+)-tartaric acid diarylamide (CONH(rn-tolyl)) -reaction for 12 h at room temperature gives the chiral adduct in 73 % chemical yield and with 92 % ee. The use of an equimolar amount of chiral boron is necessary and, as a consequence, the regio- and stereoselectivity are good. The alkyl and diamide tartrate derivatives, however, are not so effective. This might be explained by the structure of the intermediate which is formed. The hydrogen-bond between the amide hydrogen and the naphthoquinone carbonyl

Chiral B(III) Lewis Acids

137

makes the diene approach preferentially from the top of the dienophile; this explains the enantioselectivity observed. The use of an arylamide which is electron-withdrawing makes the hydrogen-bond stronger and explains the rate enhancement observed.

5.2.2 Chiral Lewis Acids as Catalytic Reagents The first example of an enantioselective catalytic Diels-Alder reaction is the report in 1976 of cycloaddition between methyl acrylate and cyclopentadiene [3]. The catalyst was BF3 complexed to (-)-methyl menthyl ether. The enantiomeric excess is very small (3 YO), and it seems unlikely that chiral catalysis occurred (e.g., the undissociated complex). About 10 years later the catalytic use of boron derivatives was again investigated by Kaufmann et al. Compounds of the type RBBrz (R = pinanyl) catalyze the DielsAlder reaction at -78 "C with low ee (Eq. 3) [4]. Modified isopinocamphenyl dibromoborane, which has been synthesized since then, gives better results in the reaction of cyclopentadiene and methyl acrylate (Eq. 4) [5].

BBrz.SMe2

A C H O

+

0

(15 mol%) CH2CI2

*

-78 "C to 20 "C 28.5% ee exo, exo:endo=90:10

48% ee endo, exo:endo=0.7:99.3

Kaufmann et al. greatly improved on their results by using a boron compound derived from 1,l-binaphthol (Eq. 5 ) [6]. This compound was unexpectedly obtained from monobromoborane dimethyl sulfide and 1,l'-binaphthol. A diborate structure with a propeller-like shape has been established by X-ray analysis. The reaction between methacrolein and cyclopentadiene is catalyzed at -78 "C in dichloromethane by 3 mol % of the chiral borate, and the ex0 cycloadduct is obtained with high ex0 selectivity (97.4:2.6) and 90 YO ee. The mechanistic details and scope of the reaction are still unclear.

CHO

'LkT

catalyst (3 mol%): 90% ee

Bao and Wulff compared catalysts prepared from vaulted biaryls and from bromoborane dimethylsulfide with those generated from linear biaryls with regard to their capacity to provide enantioselective induction in the Diels-Alder reaction of cyclopentadiene and methacrolein (Eqs 6 and 7) [7]. Because the (S) enantiomers of vaulted biaryls result in induction opposite to that resulting from use of the (S) enantiomer of binaphthol, and because effective catalysts cannot be generated from binaphthol and phenylboron dichloride, suggest that the catalysts obtained from vaulted biaryls do not have the same structure as the C3-symmetrical catalyst produced from binaphthol.

Ph

OH

or PhBCIz

B-X

CHO

Ph Ph

ph

(6)

catalyst (X=Br, 10 mol%): 92% ee catalyst (X=Ph, 10 mol%): 50% ee

H2BBr-SMe2 or PhBCI2 *

Ph

CH2CI2, 25 "C

CHO

catalyst (X=Br, 10 mol%): 68% ee catalyst (X=Ph, 10 mol%): 50% ee

(7)

Chiral B(ll1) Lewis Acids

139

Another promising approach has been devised by Yamamoto and co-workers [8]. They found that the action of a controlled amount of diborane on a carboxylic acid leads to an (acy1oxy)borane RC02BR'2 which behaves as a Lewis acid. The chiral (acy1oxy)borane (CAB) complex 1 formed in situ from monoacyl tartaric acid and diborane is an excellent asymmetric catalyst (Eq. 8) for the Diels-Alder reaction of cyclopentadiene and acrylic acid (78 % ee) (Eq. 9) [8] or of cyclopentadiene and methacrolein (96 % ee) (Eq. 10) [9]. Me0

0

C02H

1

Me0

BH3-THF 0 "C* CHpCI2,

OMe

0

C02H

@Y:H]

(8)

OMe 0

CAB 1

78% ee endo, exo:endo=4:96

1 (10 mol%)

+

CH2C12,-78";

+CHO

(''1

96% ee exo, exo:endo=89:11

The reaction with acrylic acid deserves special attention, because acrylic acid is not usually a good Diels-Alder reagent. That the reaction proceeds catalytically and with high ee indicates the facile exchange of the (acy1oxy)borane of the cycloadduct with the carboxylic group of unreacted acrylic acid, whereas the monoacrylated tartaric acid remains bound to boron (Fig. 1).

Figure 1. The catalytic cycle of the Diels-Alder Reaction.

140

Ishihara

The process is quite general for simple dienes and aldehydes. For example, the reaction of acrolein with cyclopentadiene, cyclohexadiene, or 2,3-dimethyl-1,3-butadiene gives cycloadducts with 80-84 YO ee and exolendo = 12/88-< 1/99. The a-substituent on the dienophile increases the enantioselectivity (acrolein compared with methacrolein). When there is P-substitution in the dienophile, as in crotonaldehyde, the cycloadduct is almost racemic. On the other hand, for a substrate with substituents at both a and /3 positions, high ee is observed, as for 2-methylcrotonaldehyde and cyclopentadiene (90 YO ee, exolendo = 9713). The active boron catalyst is believed to have the structure shown in Eq. (8), with a five-membered ring and a free carboxyl group. The latter seems not to be crucial for the enantioselectivity because comparable results are obtained when the carboxylic group is transformed into an ester. This CAB has also been applied to the enantioselective Diels-Alder reaction of Qbromo-a&enals with dienes [lo]. a-Bromo-a,P-enals are useful dienophiles in the Diels-Alder process because of the exceptional synthetic versatility of the resulting adducts: e.g., an important intermediate for prostaglandin synthesis [17a]. In the presence of 10 mol % 2, R = H, a-bromoacrolein and cyclopentadiene in dichloromethane undergo a smooth Diels-Alder reaction to give the (S)-bromo aldehyde in quantitative yield, 95 YO ee and 94:6 (exolendo CHO) diastereoselectivity (Eq. 11). Similar results are obtained for the catalyst 2, R = o-PhOCsH4, in propionitrile: quantitative yield, 98 % ee ((S) enantiomer major), 94:6 (exolendo CHO) diastereoselectivity (Eq. 11). Other examples are listed below.

2 (10 rnol%)

Br

-78 "C

A C H O

*

I@yzR i-Pro

0

C02H

P !: hOC6H4

4

C

H

O

(11)

Br 95% ee exo, exo:endo=94:6 98% ee exo, exo:endo=94:6

Oi-Pr 0

CAB 2 (R=H or ePhOCsH4)

4cHo Br

D

C BrH

O

98% ee exo 87% ee exo:endo=>99:l Diels-Alder catalyst: 2 (R=H)

D

C BrH

O

95% ee

Yamamoto's catalyst has been applied to the enantioselective intramolecular DielsAlder reaction (Eq. 12) [ll]. The same aldehyde devoid of a methyl group in the a position affords the adduct with 46 % ee (for the endo isomer) and exo:endo = 1:99. An a substituent is essential for high ee, as observed in the intermolecular reaction.

Chiral B(III) Lewis Acids

141

92% ee exo, exo/endo: 1/99

The boron-substituent-dependent enantioselectivity of CAB-catalyzed Diels-Alder reactions has been studied as a first step toward obtaining mechanistic information on the sp2-sp2 conformational preferences in a&enals, where the possibility of s-cis or strans conformers exists in the transition-state assembly of Diels-Alder reaction catalyzed by Lewis acid [12]. a-Substituted a,p-enals (e.g. methacrolein) favors an s-trans conformation in the transition-state assembly irres ective of the steric features of the boron substituent. On the other hand, the sp2-sp conformational preference of aunsubstituted aJ-enals (acrolein and crotonaldehyde) can be reversed by altering the structure of the boron substituent: an s-trans conformation is preferred when the substituent on the boron is small (H, C X B u ) , whereas an s-cis conformation is preferred when the substituent is bulky (o-PhOC6H4). We have also studied the solution conformations of CAB-complexed methacrolein and crotonaldehyde by use of NOE measurements (Table 1) [12]. These results are in agreement with the transition-state preference for the s-trans or s-cis conformation of a$-enals, on the basis of the enantioselectivity of the aldol and Diels-Alder reactions catalyzed by CAB. Finally, it has been established that the effective shielding of the si face of the CAB-coordinated a$-enal arises from n-stacking of the 2,6-diisopropoxybenzene ring and the coordinated aldehyde.

Y

Table 1. The NOE of CAB-methacrolein and CAB-crotonaldehyde complexes.

methacrolein-2 (R=H)

crotonaldehyde-2 (R=H)

NOE (saturate/observe, %)

NOE (saturate/observe, %)

HC/2HmHC/HP Hd/2HmHd/Hp

Hb/2HmHb/Hp HC/2HmHC/HP

-32

-12

-25

-29

-8

-6

2

-32

Helmchen and co-workers [13] and Takasu and Yamamoto [14] have independently found that N-sulfonyl derivatives of a-amino acids react with diborane, giving complexes formulated as CAB 3 (Eq. 13). These CAB complexes catalyze a variety of enantioselective cycloadditions.

142

Ishihara

CAB 3

Takasu and Yamamoto selected CAB 3a from (S)-(+)-2-aminobutyric acid as a catalyst [14]. The best result is indicated in Eq. (14). The catalyst is readily available in both enantiomeric forms; it has broad applicability, although ee is not very high. 3a (1 0 mol%)

A

H

0

+

CHpC12, -78 "C CHO 74% ee

3a

Helmchen and co-workers [13] independently achieved similar results with catalysts of CAB 3 derived from valine (R = i-Pr). When R' is 2,4,6-trimethylphenyl, the cycloaddition of crotonaldehyde and cyclopentadiene occurs with 72 YO ee (exo:endo = 3:97) in the presence of 0.2 equiv. chiral catalyst. More recently, the same authors systematically investigated the influence of different experimental conditions on the enantioselectivity [15]. Improved enantioselectivity was obtained in THF or by addition of THF (ee up to 86 %). A transition-state model is proposed for prediction of the absolute configuration of the adducts (Fig. 2). In this model, the R group directs the R'S02 group to the opposite side of the ring, where the latter group again participates in trans attack on boron. The conformation of the complexed enal has been determined to be s-cis, as has the coordination of carbonyl to boron syn to H. This model correctly predicts the outcome of all the examples studied.

I

R

Figure 2. Helmchen's transition-state model.

Chiral B(III) Lewis Acids

143

Hawkins et al. described a simple and efficient catalyst for the Diels-Alder reaction based on a chiral alkyldichloroborane (Eq. 15) [16]. A molecular complex between methyl crotonate and the chiral catalyst have been isolated for the first time. A study of the crystal structure of the complex enabled the authors to propose a model predicting the approach of the diene on one of the faces of the methyl crotonate, because the other face is protected by x-x donor-acceptor interactions. This secondary attractive substrate-catalyst interaction is the basis of the stereocontrol.

OBC" h

(10 rnol%)

@C02Me+

CH2Cl2, -78 "C* hC02Me

(15)

99.5% ee endo

n

A similar effect was reported a few months later by Corey et al. using CAB 3b catalysts [17]. Especially efficient is the asymmetric catalysis of the cycloaddition between 2-bromoacrolein and different dienes (> 90-95 % ee). The transition state is believed to be as shown below Eq. (16) [17b]. Attractive interactions between the indolyl moi-

R=H 96% ee, exo:endo=97:3 R=Bu 99% ee exo, exo:endo=96:4

BR

i s

3b

144

Ishihara

ety and the n-acidic dienophile protect one face of the dienophile. This effect is well supported by the discovery that replacement of the indole group by a cyclohexyl or an isopropyl group gives the cycloadduct with the opposite configuration (and 70 % ee). CAB 3c derived from N-tosyl (aS,PR)-P-methyltryptophan catalyzes the DielsAlder reaction of 2-bromoacrolein and furan with 96:4 enantioselectivity, enabling efficient synthesis of numerous chiral 7-oxabicyclo[2.2.l]heptene derivatives (Eq. 17) [MI. Interestingly, the analog 3b of catalyst 3c which lacks the ,&methyl group (derived from N-tosyl-(S)-tryptophan) is not as effective at catalyzing the formation of Diels-Alder product, and the reaction rate and yield are considerably lower.

-

V

I

X

X=Br, (>98%), endo : exo=l : 99,92% ee (exo) X=CI, (>98%), endo : exo=1 : 99,90% ee (exo)

Corey et al. have applied the CAB system derived from N-(p-tolylsulfony1)tryptophan to the enantioselective syntheses of cassiol and gibberellic acid (Eqs 18and 19) [19]. ?TIPS

?TIPS

A

H

0

(87%), 97% ee

'OH Cassiol

Chiral B(III) Lewis Acids

II

145

A B r (el%), 99% ee exo exo:endo=99:1

Gibberellic acid

Marshall and Xie have also applied the B-H analog of catalyst 3b to the enantioselective synthesis of the spirotetronate subunit of kijanolide 1201. The optimum conditions required a full equivalent of the (recoverable) Lewis acid at -78 "C to -40 "C. Reaction at -10 "C gives a product with a significantly lower ee (Eq. 20). TBF-

'OBn (82%),72% ee

OMOM

.....

OBn

T

Kijanolide

In a study of enantioselective Diels-Alder reactions catalyzed by CAB 3 derived from N-(arylsulfony1)-L-a-aminoacids, Scheeren et al. [221] varied the position of electron donor functionality in substituent R (Eq. 13), thereby influencing steric repulsion and/or electronic attractive interactions. The experimental results show that enantioselectivity is controlled by the presence of electron donor atoms in positions 2 and 4 (Eq. 21).

A C H O

+

Q

CAB 3d -78 "C

3d (R=PhCH20CH2; R'=pMeC6H4) 3e (R=Ph; R'=pMeC6H4)

56% ee (S)exo, exo:endo=94:6 80% ee (R) exo, exo:endo=98:2

Asymmetric catalysis by bimetallic catalysts is currently a research field of great interest. There have been few studies of the interaction between bidentate Lewis acids and carbonyl groups [22a]. Reilly and Oh [22c] have reported the only example of such an asymmetric Diels-Alder reaction catalyzed by a 1:l complex of N-tosyltryptophan [17-191 with 1,s-naphthalenediylbis(dichloroborane), in which the two Lewisacidic sites work in a cooperative manner (Eq. 22).

Itsuno et al. explored the possibility of using polymer-supported chiral Lewis acids in a model Diels-Alder reaction of methacrolein with cyclopentadiene [23a]. By using an insoluble polymer-supported Lewis acid [23], prepared from borane with crosslinked polymers with a chiral moiety such as an N-sulfonylamino acid, the DielsAlder adduct is obtained in good yield with almost perfect ex0 selectivity and moderate enantioselectivity (Eq. 23).

Chiral B(II1) Lewis Acids

A C H O '

8

Polymeric Catalyst (15 mol%) * 4 C H O

147

(23)

(93%), 65% ee exo, endo:exo=
\ HQoH i-Pr'

0

The chiral tartrate-derived dioxaborolidine has been used to effect the enantioselective Diels-Alder reaction between a-bromoacrolein and cyclopentadiene [24]. In the presence of 20 mol % catalyst, the (2R)-bromoaldehyde is obtained in 96 % yield, 85:15 (R:S)enantioselectivity and 96:4 (exo:endo)diastereoselectivity (Eq. 24).

I

.

0,~,0

(20mol%)

96% exo:endo=96:4 70% ee (R) ex0

The proposed transition state is illustrated in Fig. 3. The two tartrate ester units prefer to occupy the position axial to the dioxaborolidine unit. The stabilized dipoledipole interaction between the carbonyl carbon (6+ a-bromoacrolein) and the proximate ester carbonyl oxygen, together with the attractive interaction of the n-basic benzyl ring and the n-acidic dienophile in the s-cis conformation, locks the dienophile in the s-cis conformation. Approach of the diene from the less sterically hindered side (opposite the aryl ring) gives the cycloadducts in good enantioselectivity.

Figure 3. Loh's transition-state model.

148

Ishihara

An extremely useful enantioselective Diels-Alder reaction which uses a super-reactive cationic oxazaborinane catalyst was recently reported by Corey and co-workers (Eq. 25) [25]. This strong chiral Lewis acid promotes the Diels-Alder reaction between reactive and unreactive dienes and dienophiles. With tetrabromoborate as a counter-ion, good enantioselectivities were achieved in the reaction of cyclopentadiene with several a$-enals. With tetrakis[3,5-bis(trifluoromethyl)phenyl]borate as a counter-ion, the reaction of isoprene and a-bromoacrolein at -94 "C gave the desired cycloadduct in 90 YOyield and 96 % ee.

(1 0 mol%)

The proposed exo transition state (for cyclopentadiene) is illustrated in Fig. 4, and shows that one of the -NCH2Ar groups blocks the lower face of the s-truns-coordinated dienophile [25]. The authors proposed s-trans geometry for the complex a-substituted unsaturated aldehydellewis acid, in contrast with to previous observations that this aldehyde reacts in the s-cis form [17].

Figure 4. Corey's transition-state model.

Mukaiyama and co-workers have reported that prolinol derivatives combined with BBr3 produce promising catalysts for some Diels-Alder reactions [26]. Methacrolein and cyclopentadiene, for example, afford the ex0 adduct (exo:endo > 99:l) in 97 % ee (reaction at -78 "C in dichloromethane with 20 mol % catalyst). The chiral catalyst is believed to be the HBr adduct salt of the amino boron derivative (Eq. 26).

w h p h Me OH

BBr3 *

1

w h p h ] Br' (26) H OBBrz

Me

Chiral B(III) Lewis Acids

149

We have found that chiral boronate complexes with BLA (Bronsted acid-assisted chiral Lewis acids) to give new catalysts for enantioselective synthesis which achieve selectivity by a double effect of intramolecular hydrogen-bonding interaction and attractive x-x donor-acceptor interaction in the transition state by a hydroxy aromatic group [27a]. Reaction of (R)-3,3’-bis(2-hydroxyphenyl)-2,2’-dihydroxy-l,l’-binaphthyl with B(OMe)3 in dichloromethane under reflux and with removal of methanol gives a white precipitate of (R)-4. Extremely high enantioselectivity (> 99 to 92 % ee) and exo selectivity (> 99 to 97 YOe m) are obtained for Diels-Alder additions of a-substituted u,p-enals with dienes in the presence of the catalyst (R)-4 [27a]. The absolute stereo-preference in the Diels-Alder reaction can be easily understood in terms of the most favorable transition-state assembly 5, in which an attractive donor-acceptor interaction favors coordination of the dienophile at the face of boron which is cis to the 2-hydroxyphenyl substituent. At this time, the conformation of a$enal has a strong s-trans preference. We believe that the coordination of a proton of the 2-hydroxyphenyl group with an oxygen of the adjacent B-0 bond in complex 5 plays an important role in asymmetric induction; this hydrogen-bonding interaction via a Bronsted acid would cause the Lewis acidity of boron and the x-basicity of the phenoxy moiety to increase, and the transition-state assembly 5 would be stabilized. The x-basic phenoxy moiety and the x-acidic dienophile could then assume a parallel orientation at the ideal separation ( 3 A) for donor-acceptor interaction. In this conformation, the hydroxyphenyl group blocks the si face of the dienophile, leaving the re face open to approach by diene. BLA 4 (Fig. 5) is one of the best catalysts for the enantio- and em-selective cycloaddition of a-substituted aJ-enals with highly reactive dienes such as cyclopentadiene. The corresponding reactions of a-unsubstituted a&enals such as acrolein and crotonaldehyde are, however, characterized by low enantioselectivity and/or reactivity. The range of dienophiles that can be used with less reactive dienes is quite limited. The use of arylboronic acid with electron-withdrawing substituents such as [3,5bis(trifluoromethyl)phenyl]boronic acid in the preparation of BLA greatly enhances

Br Br >99% ee exo 94% ee exo exo:endo=>99:1 exo:endo=>99:1 4 (10 rnol%) 4 (5 rnol%)

Non-HelicalTransition State (5)

Figure 5. BLA-catalyzed enantioselective Diels-Alder reaction

150

Ishihum

its catalytic activity and asymmetry-inducing capacity. We have developed a more practical BLA 6 which has greater catalytic activity in the enantioselective cycloaddition of both a-substituted and a-unsubstituted a&enals with a variety of dienes (Eq. 27) [27b,d]. Notably, the presence of a BrGnsted acid in BLA catalysts clearly accelerates the cycloaddition. The high enantioselectivity and stereochemical results attained in this reaction can be understood in terms of the model transition state 7.

Ph 1) water THF cF3

2) MS 4A

Ph

(R)-6 Examples

CHO

( 4 - 6 (5 rnol%) >99% yield >99% ee [q

(R)-6 (5 mol%) 84% yield 95% ee [Sl

CHO (R)-6 (20 mol%) 94% yield 95% ee [Sl

CHO (R)-6 (20 mol%) 94% yield 80% ee

CHO 95% yield 99% ee

(R)-6 (10 mol%) >99% yield 96% ee [Sl

(R)-6 (30 mol%) 95% yield 80% ee [q

Transition-state assembly (7)

(27)

Chiral B(III) Lewis Acids

151

BLA 6 is prepared from a chiral triol and monomeric [3,5-bis(trifluoromethyl)phenyllboronic acid in the presence of powdered 4-A molecular sieves in dichloromethaneTHE Although molecular sieves are essential for dehydration, they might also facilitate the aryloxy-ligand exchange reaction. Arylboronic acid usually occurs as a mixture of monomer, trimer, and oligomer. To prevent oligomerization of [3,S-bis(trifluoromethyl)phenyllboronic acid in preparing the catalyst, THFis needed as an additive (Fig. 6) [27d].

+H20

ArB(OH)2

+H20 oligorner

-H20 Ar: 3,5-(CF3)2C6H3

-H20

100

s

k

,"

c

+ 0 0 ._

40

C

7Ar

5

60

40

c 0 ._ c

0 .-c

3

0. - ,o

monomer

c

m 60

5

Ar

a0 monomer

m

0 0 ._

-

7'

I

100

a0

c

AB ,rO ,,

20

e L

2

20

L u)

4-4

v) ._

n

i5 0 1 2 3 4 Additional water (equiv per B atom)

(a) ArB(OH)2 in CD2CI2-THF(20:3)

0 1 2 3 4 Additional water (equiv per B atom) (b) ArB(OH)2 in CD2Cl2

Figure 6. The dependence on additional water of the distribution ratio of boron atoms in a solution of [3,5-bis(trifluoromethyl)phenyl]boronic acid.

The absolute stereo-preference in the Diels-Alder reaction catalyzed by (R)-6 is the opposite of that in the reaction catalyzed by (R)-4. This means that the presence of the 3,5-bis(trifluoromethyl)phenyl group greatly affects the asymmetric induction of BLAs prepared from chiral ligands with the same absolute configuration. In fact, the use of BLAs 4 and 8 prepared from the common chiral tetraol in the Diels-Alder reaction give the opposite enantiomers with high selectivity (Eqs 28 and 29) [27d]. Diarylboronic acids are stronger Lewis acids than the corresponding boronic acids [28]. We have designed BLA 9, prepared from bis[3,5-bis(trifluoromethyl)phenyl]borinic acid and a chiral triol in dichloromethane in the presence of 4-A molecular sieves (activated powder) at room temperature [27d]. The Diels-Alder reaction of cyclopentadiene and a variety of a,p-enals proceeds smoothly in the presence of 5 mol % (R)-9;good enantioselectivity has been observed for the ex0 adducts. The steric bulkiness of the aryl groups in diarylborinic acid is important for a high level of asymmetric induction because BLA formed from diarylborinic acids and chiral ligands have a conformationally flexible structure (Eq. 30). [3,5-Bis(trifluoromethyl)phenyllboronic acid has the advantage of strong Lewis acidity, and forms a bidentate complex with a chiral ligand. Diarylborinic acid, on the other hand, is difficult to use to construct a rigid monodentate complex.

152

Ishihara

414 MS *

CH2C12 rt. 2.5 h

Ph 9

Examples

23% exo 87% ee

77% endo 73% ee [ R j

58% exo 83% ee

42% endo 47% ee [ R j

We have recently reported not only the first examples of enantioselective reactions of dienes, with have prochiral centers, and acetylenic aldehydes catalyzed by CAB 2, BLA 4, and BLA 6, but also an ab initio study which supports the predominance of an ex0 transition structure, thus clarifying the origin of the enantioselectivity observed upon catalysis [27c]. The four possible transition-state structures for the Lewis acid-promoted DielsAlder reaction of cyclopentadiene with propynal are depicted in Fig. 7. In the chiral Lewis acid-promoted reaction, the enantiomeric excess of an adduct originates in the enantiofacial selectivity of cyclopentadiene, which has prochiral reactive centers. The enantioselective pathway presupposes three characteristics: (i) the chiral Lewis acid must sterically shield one enantioface of the coordinated propynal because the open acetylenic n-face in the chiral catalyst-dienophile complex approaches one face of

Chiral B(III) Lewis Acids

153

cyclopentadiene; (ii) the coordination of Lewis acid to propynal in the transition-state assembly must be either syn- or anti-selective, because its selectivity directly influences the enantiomeric excess of the products; and (iii) either the exo or endo transition state must be predominant, for the same reason as in (ii).

0

Q

I

,

1 1

, ,

i\ -0

Q

iy0 /,

I

-

\ MLn

anti-exo-TS

+

+,3

(

Q $ I

,

I

pLn

-0

1 1

\\ I ML, -0

MLn

anti-endo-TS

syn-exo-TS

syn-endo-TS

Figure 7. Four possible transition structures in the Diels-Alder reaction of propynal and cyclopentadiene promoted by Lewis acid. ML,, = Lewis acid.

The results of the enantioselective Diels-Alder reaction of cyclic dienes and acetylenic dienophiles catalyzed by 2 , 4 and 6 are summarized in Table 2. Overall, the reaction catalyzed by BLA 6 proceeded with good enantioselectivity and conversion, although the use of CAB 2 or BLA 4 occasionally gave higher enantioselectivity. The absolute configurations of the adducts with CAB 2 and BLA 4 are the opposite of those with BLA 6 . This inversion of absolute stereochemistry is analogous to the reaction of dienes and a,p-enals [27d]. The optically active norbornadienes 10 and 11 are key intermediates in the synthesis of biologically active analogs of the prostaglandin endoperoxides PGH2 and PGG2 [29] and P-santalol [30]. 3-Iodopropynal is an outstanding dienophile in these catalytic processes not only because of the enantioselectivity and reactivity observed but also because of the synthetic versatility of the resulting adducts. To illustrate, 13 can be smoothly converted into 14 and 15 (Eq. 31), which are synthetic equivalents of adducts prepared by reaction with dienophiles such as propynal and 3-alkylpropynal.

154

Zshihara

Table 2. Enantioselective Diels-Alder reaction of dienes and acetylenic dienophiles catalyzed by 2, 4, and 6." RCSCHO dieneb cat.

product

H

yield

(Yo)

R

CP

2c

&CHO

6d

4

10

<12[-1' 63[37] <28[58] 99

Et02C

CO2Et

Et02C

CH

4d 2csd Ed

Me

CP

&CHO 'C02Et

'

(Yo)

68 (lR,4S)-(-) 88 (lR,4S)-(-) 95 (1S,4R)-(+)

98

78 (1R,4S)-(+) 95 (1R,4S)-(+) 63 (1S,4R)-(-)

18 81 54

86 (-) 84 (4 34 (+)

CP

6

ee

(config)-(rotn)

89 (1R,4S)-(+)

2"d 11

I

CP

4'

&CHO

72g 859

6

85(1S,4R)-(-) 81 (1 R,4S)-(+)

I 12 a Unless otherwise noted, Diels-Alder reaction of a dienophile (1 equiv.) and a diene (4 equiv.) was performed in dichloromethane in the presence of 10 mol % of the catalyst at -78 "Cfor 3-66 h. CP = cyclopentadiene; CH = cyclohexadiene. Propionitrile was used in place of dichloromethane. 20 mol % catalyst was used. Isolated yield. Yield of by-products afforded by Diels-Alder reaction of 10 and CP is indicated in parentheses Not isolated. Overall yield of 13 from the Diels-Alder reaction and subsequent reduction by DIBAH.

'

1. t-BuLi -78°C

-

&OH

(31)

2. H20

14 96%

13

OC

R R=Me: 15 92%

The absolute stereochemical selectivities achieved in these reactions can be explained in terms of the anti-em-transition-state models 16, 17, and 18, which are analogous to those previously proposed for the reaction of dienes and olefinic dienophiles (Fig. 8) [12,27d]. These transition-state models are based on three assumptions: (i) the substituent in the chiral ligand blocks the same enantiofacial side of the carbonyl in the Diels-Alder reactions of acetylenic and olefinic aldehydes; (ii) exo-transition structures predominate; and ( 5 ) anti-coordination of the bulky chiral Lewis acid to carbonyl is preferred in the transition state.

Chiral B(IZZ)Lewis Acids

155

Figure 8. Proposed anfi-exo-transition structures.

To determine the activated face of a carbonyl group in an acetylenic aldehydeCAB 2 complex, an aldol reaction of acetylenic aldehydes with the trimethylsilyl enol ether derived from acetophenone was performed in the presence of 20 mol % 2 under conditions similar to those in the Diels-Alder reaction (Eq. 32). Good enantioselectivity was, with the predominant enantiomer corresponding to attack on the re face, as expected. Although it is essential to stress that the results of an aldol reaction cannot be directly used to explain the transition state in cycloaddition, the effective steric shielding of the si face of the coordinated aldehyde is consistent with cycloaddition via the proposed transition-state model 16.

R-CHO

+

JMS

(201~101%) CAB 2

OH 0

Ph EtCN,-78"C

R=H: 77% ee (88% yield); R=C02Et: 91% ee (91% yield)

Although exo-endu selectivity in the Diels-Alder reaction of olefinic dienophiles has been extensively studied both experimentally and theoretically [31], exo-endo selectivity of the transition structure in the reaction of acetylenic dienophiles has not previously been investigated, because the adducts produced via exo- or endo-transition-state assembly are identical diastereomerically. We used ab initio molecular orbital calculations at the RHF/6-31G* level [32] to identify the transition structures of simple processes of this type, i.e. acid-free and BF3-promoted reactions of cyclopentadiene and propynal (Fig. 9). As expected, our calculations showed that the ex0 transition structures are more stable than the endo structures by 0.8 kcal mol-I for the former reaction and by 2.0 and 2.4 kcal mo1-l for anti and syn pairs, respectively, for the latter. These calculations strongly suggest the predominance of an ex0 transition structure and its enhancement by coordination of the Lewis acid.

156

Ishihara

endo-TS

40.2 I ( 7

exo-TS

:/

/;

39.4 anti-endo-TS

syn-endo-TS

27.1

1;

26.5

-

7

\-

I) 24.1 I ) : ,! syn-exo-TS

23.1 ',

. I

',

anti-exo-TS ',,I\ 'I I 1

I ,

I);

\ ' $ '\

I

4

HCSCHO +CP

/

$1;

t

3.4

++E,.

.- syn-HC=CCHO-BF3 anti-HC=CCHO-BF3 +CP +CP

I

Reaction coordinate

Figure 9. Potential energy profile of Diels-Alder reactions without/with BF3 calculated by the RHFI6311G*//RHF/3-21Gmethod.

The frontier molecular-orbital theory also explains ex0 selectivity in terms of the secondary antibonding interaction between the lobes on C-2 of cyclopentadiene and the carbonyl oxygen of propynal in the endo transition state (Fig. 10).

endo-TS

exo-TS

U

Figure 10. endo and ex0 transition states on the basis of frontier molecular-orbital theory.

According to our calculations, the distances ( d l , d2) between C-2 of cyclopentadiene and the carbonyl moiety in the transition state shorten with the coordination of BF3 (Fig. 11).This proximity is believed to enhance the secondary antibonding interaction and ex0 transition state-selectivity. exo-TS (without BF3)

d,,d~3.628, 4.4468,

endo-TS (without BF3) dl,d~3.626, 4.0238,

: '02'

anti-exo-TS (with BF3) d,,d~3.403, 4.1658, anti-endo-TS (with BF3) dl,d~3.342, 3.511 8,

TS

(&distances shown by dotted lines)

Figure 11. The proximity effect in transition states.

Chiral B(III) Lewis Acids

157

The anti-preference of the BF3-propynal complex in the transition-state assembly, as suggested by our calculations, might be adapted to complexes with bulky chiral Lewis acids such as 2 , 4 and 6. Five months later, Corey and Lee reported the enantioselective Diels-Alder reaction between cyclopentadiene and u,P-acetylenic aldehydes catalyzed by a chiral cationic oxazaborinane catalyst [33].Although initial studies of the Diels-Alder reaction between cyclopentadiene and 2-butyn-1-a1 or 2-octyn-1-a1 with 20 mol % catalyst at -94 "C to -78 "C revealed only 3-5 % conversion to product over a 24-h period, replacement of the P-alkyl substituent on the aldehyde component by R3Si or R3Sn groups resulted in much faster Diels-Alder addition (Eq. 33). The greater yield with 3-tributylstannyl-2-propyn-l-a1, compared with the 3-silyl analogs, results from the rate of reaction with the former. In each instance, good enantioselectivity (80-87 YO ee) was obtained.

(20 rnol%)

R=TMS: 68%, 87% ee (1 R, 45) R=Bu3Sn: 83%, 80% ee (1 R , 4 S )

The chiral Diels-Alder adduct 19 is a versatile intermediate for the synthesis of many chiral bicyclo[2.2.l]heptadienes,because the tri-n-butylstannyl group can be replaced by halogen or a wide variety of carbon appendages, the latter by use of either copper-mediated or palladium-catalyzed cross-coupling reactions. For example, as shown in Eq. (34), reaction of 19 with N-iodosuccinimide produced the iodo aldehyde 12 in 92 YOyield. Coupling of 12 with (E)-P-styryl-tri-n-butylstannane and either 1.5 equiv. copper(1) 2-thiophenecarboxylate (CuTC) or catalytic PdC12(CH3CN)2 afforded the triene aldehyde 20 [34].

Bu3Sn*Ph

NIS (2 equiv) *

&SnBu3CHO

19

THF, 92%rt

CuTC (1.5 equiv) 12

*

NMP, 0 "C 64%

ePh (34)

CHO

20

The absolute stereochemical course of the enantioselective Diels-Alder reactions can be rationalized on the basis of the mechanistic model previously described for the reaction of u,P-enals and cyclopentadiene with a catalyst in which a formyl CH...O hydrogen-bond provides additional organization of the transition state [25,35]. On the basis of that analysis, there are two possible approaches of cyclopentadiene to the

158

Zshihara

chiral Lewis acid-coordinated a$-acetylenic aldehyde: (i) addition of the diene to the u,p-enal x-orbital which is perpendicular to the formyl plane, and (ii) addition of the diene to the a,P-ynal n-orbital which is in the plane of the formyl group; these are represented by transition structures 21 and 22, respectively (Fig. 12). Structures 21 and 22 are both reasonable possibilities for the preferred transition-state assemblies; choosing between them is not possible at this time, although it is clear that 21 should be favored if (as seems likely) the reaction proceeds by an early transition state in which the P-carbon of the a$-ynal is more strongly bonded than the a-carbon to the diene.

21

zz

Figure 12. Corey's transition-state models.

Chiral alkyldihaloboranes are among the most powerful chiral Lewis acids. In general, however, because alkyldihaloboranes readily decompose to alkanes or alkenes as a result of protonolysis or P-hydride elimination, it is difficult to recover them quantitatively as alkylboronic acids. Aryldichloroborane is relatively more stable and can be reused as the corresponding boronic acid. We have developed chiral aryldichloroboranes 23 bearing binaphthyl skeletons with axial chirality as asymmetric catalysts for the Diels-Alder reaction of dienes and a&unsaturated esters (see, e.g., Eq. 37) [36]. (R)-2-Dihydroxyboryl-l,l'-binaphthyl (24) can be synthesized from (R)-binaphthol in several steps [36]. The synthesis of racemic 24a has also been reported by Kaufmann and his colleagues [37].The conversion of (R)-24 to (R)-23 has been achieved by two different methods-via exchange of the methanol boronate with trichloroborane (Method A; Eq. 35) or via exchange of the anhydrides of boronic acids with trichloroborane (Method B; Eq. 36). The latter procedure is simpler and more convenient. Method A 1. MeOH

reflux B(OH)2

24 2. pump on

Method B

benzene

Ar 24

24

1. BC13 hexane-CH2CI2 0 "C to rt * 2. pump on

23

(35)

* 23

(36)

1. BC13, benzene azeotropic reflux

azeotropic reflux 2. pump on

The Diels-Alder reaction of cyclopentadiene and methyl acrylate proceeds smoothly at -78 "C in the presence of 10 mol YOof catalysts (R)-23 to give the endo adduct in high yield with > 99 YOdiastereoselectivity (Eq. 37). Catalyst 23b resulted

Chiral B(III) Lewis Acids

159

in the highest asymmetric induction, but even this is insufficient. The absolute configuration of the major endo adduct is consistent with naphthyl shielding of the re face of the coordinated methyl acrylate, which leads to attack by cyclopentadiene at the si face, as shown in 25. Coordination of the methyl acrylate with the re face exposed as shown in 26 is unfavorable, because of steric interaction of the alkene with the naphthyl. Increased enantioselectivity with the use of 23b can be easily understood in terms of steric repulsion between the alkene and mesityl groups.

eC02Me

+

0

*&

(R)-23 (10 mol%)

CH2C12, -78 "C

(37)

*

C02Me (R)-23a (Ar=H): 91Yoyield, >99% endo, 62% ee ( R ) (R)-23b(Ar=2,4,6-Me3C6H2): 92% yield, >99% endo, 73% ee ( R )

25 (favored)

26 (disfavored)

Reaction of ethylene diacrylate, which is commercially available, and subsequent reduction with lithium aluminum hydride gives endo-5-norbornene-2-methanol with 78 % ee. Although it is not clear why selectivity is increased by the link between dienophiles, similar effects are expected for other asymmetric reactions (Eq. 38).

(R)-23a(Ar=H, 20 mol%)

~

*

CH2C12, -78 "C

dom0fl (8 equiv)

LiAIH4 *

0 84% yield

THF

>99% endo, 78% ee (R)

Ab initio calculations have been performed by Birney and Houk to define the transition state in Diels-Alder reactions catalyzed by boron derivatives [38]. As a model, the authors studied the reaction between butadiene and acrolein complexed with BH3. The preferred route is endo addition of the anti complex of s-cis acrolein.

160

Ishihara

5.3 Enantioselective Hetero Diels-Alder Reactions We have developed a stable CAB 2 (R = aryl) complex that can be prepared in situ by mixing tartaric acid derivative and arylboronic acid at room temperature. In contrast with 2, R = H, which is both air- and moisture-sensitive, the B-alkylated catalyst 2, R = aryl or alkyl, is stable and can be stored in closed containers at room temperature (Eq. 39). A solution of the catalyst (20 mol YO)is effective in catalyzing the hetero Diels-Alder reaction of aldehydes with a Danishefsky diene to produce dihydropyrone derivatives of high optical purity (up to 98 YO ee) (Eq. 40) [39]. The extent of asymmetric induction is largely dependent on the structure of the boronic acid. In general, bulky phenylboronic acid (R = 2,4,6-Me3C6H2,o-MeOC6H4)results in excellent asymmetric induction. i-Pro

0

C02H

@kCozH RB(oH)2 * CAB2 (39) OH EtCN, rt (R=aryl) Oi-Pr

+

R"CH0

TMSO R' R'=H or Me

98% ee, >99% cis (R=o-MeOC6H4)

gR,,

1) 2 (20 rnol%) R, EtCN, -78 "C

2)CF3C02H

(40)

0 R'

97% ee, >99% cis 95% ee (R=eMeOC6H4)(R=2,4,6-Me3C6H2)

Judging from the product configuration, CAB 2 (from natural tartaric acid) should effectively cover the si face of carbonyl when coordinated, and the selective approach of nucleophiles from the re face should agree well with the results of other CAB 2catalyzed asymmetric reactions (Fig. 13). Compared with carbon-carbon bond-forming reactions, catalytic asymmetric reactions involving imines have received little attention. Hattori and Yamamoto recently revealed, however, that chiral boron complex 27 can conveniently be prepared in situ simply by mixing a 1:l molar ratio of optically active binaphthol and triarylborate in dichloromethane at ambient temperature for 1 h (Eq. 41) [40]. The aza-Diels-Alder reaction with a Danishefsky diene is promoted by this catalyst solution in the presence of 4A molecular sieves at -78 "C for several hours, to generate the dihydropyridone compound selectively in 75 YO yield and 82 Yo ee (Eq. 42). The new chiral boron reagent described here has three advantages: (i) both chiral binaphthol and triphenylborate are commercially available and the catalyst can be generated without the need for complex technology; (ii) no difficult isolation procedure is required and the recov-

Chiral B(III) Lewis Acids

161

ery of binaphthol is quantitative; and (iii) either the ( R )or (S) form of the products can be synthesized, because the required reagents are readily accessible in both enantiomeric forms.

Figure 13. Transition state assembly.

Ph"'

Ar=Ph: (75%0),82% ee Ar=3,5-Me2C6H3:(82%), 86% ee

Ar=Ph: (71%0),90% ee

The practical advantage of this method is apparent from the efficient synthesis of anbasine, a piperidine alkaloid. The choice of the solvent is important-use of THF or propionitrile results in low optical yields. This method is of great interest for the synthesis of alkaloids. Hattori and Yamamoto have investigated double stereodifferentiation by the combined use of a chiral mediator and a chiral imine derived from a simple a-methylbenzylamine auxiliary (Eq. 43) [~OC].

162

P N h’

Ishihara

+

OTMS

-

27 (1 equiv) P N h’?

+

P N h’?

(43)

(R)-6 (Ar=Ph), >99 : 1 (61%) (S)-6 (Ar=Ph), 93 : 7 (30%)

Under optimum conditions with our chiral boron reagent, almost complete diastereoselectivity is obtained for a variety of aldimines. The reactions are fast with the better-matching pair and slow with the mismatching pair. The success of the present azaDiels-Alder reaction, in particular, is because of the structural flexibility of the binaphthol ligand. Two-dimensional NOESY has shown that compounds bearing such a sterically hindered chiral auxiliary can form a stable 1:l complex with a chiral ( E ) imine; this effectively covers the si face of the imine and should lead to selective approach of the diene from the re face [44a]. The absolute configuration of the resulting adducts is, therefore, consistent with the experimental findings. The Bronsted acid-assisted chiral Lewis acid (BLA) 28, prepared from a 1:2 molar ratio mixture of a trialkylborate and optically pure binaphthol, is also an excellent chiral promoter for the aza Diels-Alder reaction of imines with Danishefsky dienes (Eqs 44 and 45). Enantioselectivity and double diastereodifferentiation in reactions employing chiral28 are slightly better than those using chiral27 [41].

(44)

BLA (R)-28

R=Bn: 86% ee (78%) R=(S)-PhMeCH: >99% ee (64%)

5.4 Enantioselective Mukaiyama Aldol Reactions The use of CABS prepared from the sulfonamides of amino acids to introduce asymmetry into the Diels-Alder reaction was reported simultaneously by Takasu and Yamamoto [14] and by Helmchen and co-workers [13]. Because of the capacity of boron to complex the carbonyl moiety in this type of catalyst, it is clear they might be effective in promoting the reaction of silyl ketene acetals with various aldehydes.

Chiral B(III) Lewis Acids

163

5.4.1 Chiral Lewis Acids as StoichiometricReagents This reaction of silyl ketene acetals with aldehydes, using 29 as a stoichiometric chiral reagent (Eq. 46), was reported by Reetz et al. [42]. The aldol addition of 1-(trimethylsiloxy)-l-methoxy-2-methyl-l-propene and 3-methylbutanal provides the aldol in only 57 YOyield, but with 90 YOee.

The use of CAB as a chiral reagent seems to be more effective for this reaction, which proceeds faster and with higher yields and enantiomeric excess. Kiyooka et al. first described the use of various chiral oxaborolidines, derived from sulfonamides of a-amino acids and borane, in the course of the selective aldol reaction between silyl ketene acetals and aldehydes (Eq. 47) [43a]. Stereoselectivity and yields were relatively high.

jTsN, -,kO O ,

w

R’CHO

+

&OTMS OEt

3f

(’ equiv’ * R 1 5C02Et (47) CH2C12 -78 “C to rt 7747% yield, 83-93% ee

The role of the trialkylsilyl group is unclear. Changing the trimethylsilyl group not only increases the selectivity but also affects the product of the reaction -,!?-hydroxy acetals are obtained instead of (S)-hydroxy esters. They investigated the course of the reaction with different tert-butyldimethylsilyl ketene acetals and aldehydes with catalyst 3f (Eq. 48). The acetal is probably formed by hydride transfer to an intermediate ester. The tert-butyl group apparently stabilizes the second intermediate and consequently changes the course of the reaction. It should be noted that the first cyclic intermediate is stabilized by coordination of the borane with the oxygen of the carbonyl. The results are outstanding when R2 = Me (92-98 YO), although selectivity and yield (4562 Yo)decrease when R2 = H (Eq. 48). A stoichiometric amount of 3f catalyzed the asymmetric aldol reaction of aldehydes with enol silyl ethers and subsequent asymmetric reduction, in one pot, to afford syn 1,3-diols with high enantioselectivity (Eq. 49) [43b]. With a variety of aldehydes, 1,3diols were obtained in moderate yields (53-70 YO) with high syn diastereoselectivity. The syn 13-diols prepared from aliphatic aldehydes in the reaction (in EtCN as sol-

164

Ishihara

vent) were almost enantiomerically pure (96-99 % ee). Propionitrile was the best solvent for the reaction selectivity. TBDMS substitution of the enol silyl ether reduced the syn selectivity. R2 R'CHO

3f (1 equiv)

+ R2*DMS

*

CH2C12, -78 "C

OEt r

1

i-prwo . O'B

cprFto TsN,

.O-TBDMS

TsN, O ,

OTBDMS

P h q O E t R2 R2

-

OH OTBDMS

R ' V O E t

(48)

R2 R2 R2=H: 77-82% yield, 45-62% ee R2=Me: 79-85% yield, 92-98% ee

i-PrCHO +

OTMS (S)-3f (1 equiv) Aph EtCN -78 "C, 3 h

OH OH

OH 0

i-Pr 65% syn:anti=97:3 99% ee

17% 60% ee (S)

Thus, good to excellent diastereo- and enantioselectivity are achieved simultaneously in the preparation of 1,3-diols whereas enantioselectivity is considerably lower for /3-hydroxyketones. These observations regarding the selectivity of the products suggested that syn-selective reduction of the reaction intermediate takes place after enantioselective aldol addition. On the basis of Kiyooka's working hypothesis for the aldol reaction mechanism, the reduction proceeds via by an intramolecular hydride transfer; this is accelerated by matching between the chirality of the promoter and that of the newly formed aldol (Eq. 50). An alternative mechanism without chelation is also possible, and involves hydride delivery to the preferred 0-silyl oxocarbenium ion conformer (Eq. 51).

Chiral B(III) Lewis Acids

165

A very short asymmetric synthesis of an insect attractant, (lS,3S,5R)-l,3-dimethyl2,9-dioxabicyclo[3.3.l]nonane,has been realized with high enantio- and diastereoselectivity by means of an (S)-3f-mediated aldol reaction strategy (Eq. 52) [43c]. This compound is a host-specific substance for the ambrosia beetle that infests the bark of the Norway spruce.

36%, 94% ee

1

21%, 72% ee

24%, 43% ee

1. TBAF, THF 2. TsOH, CHzCIz

The chiral borane 3f-mediated aldol reaction proceeds with a-chiral aldehydes in a reagent-controlled manner. Both enantiomers are obtained almost optically pure from one racemic aldehyde (Eqs 53 and 54) [43d].

(59-3f (1 equiv) C P 0 2 E h 't

+

(53) OH

I

44%, >99% ee

20%, >99% ee

OTMS PhC ' HO

-t

Y O E t

I

( 4 - 3 f (1 equiv) CH2C12, -78 "C, 3 h

P h G C 0 2 E t OH

C02Et

Ph

+

(54)

OH 41Yo,>99% ee

18%, 299% ee

The reaction of P-chiral aldehydes with ketene silyl acetals gives both syn and anti aldols in similar yields without Cram selectivity (Eq. 55) [43d]. OTMS

+Y

yCHOBn o

OEt

(59-3f (1 equiv) CH2C12, -78 "C, 3 h

*d

C 0 OBn

2

E

OH

t

-+

V3(C02Et . . OBn O H

46%, 98% ee

(55)

42%, 82% ee

In Kiyooka's approach to acetate aldols by use of a stoichiometric amount of 3f, the enantiomeric excess obtained in the reaction with silyl ketene acetals derived from aunsubstituted acetates was much lower (ca 10-20 %) than that obtained in the reaction with l-ethoxy-2-methyl-l-(trimethylsiloxy)-l-propene (> 98 % ee). Introduction of an removable substituent, e.g., a methylthio or bromo substituent, after aldol reaction at the a-position of chiral esters, resolved this problem [43e]. Asymmetric synthesis of dithiolane aldols was achieved in good yield by using the silyl ketene acetal derived from 1,3-dithiolane-2-carboxylatein the 3f-promoted aldol reaction, and desulfurization of the dithiolane aldols resulted in production of the acetate aldols in high enantiomeric purity (Eq. 56).

(S)-3f (1 equiv)

OTMS

CH2C12, -78"C, 3 h

-

OH 0 R V O E t S S

u

R=Ph: 88% yield Ni2B-H2

-

RU

O

E

t

R=Ph: 85% yield, 98% ee ( S )

(56)

Chiral B(III) Lewis Acids

167

A very short asymmetric synthesis of the bryostatin C1-C9 segment was achieved by use of three sequential 3f-promoted aldol reactions under reagent control [43f]. This synthetic methodology is based on the direct asymmetric incorporation of two acetate and one isobutyrate synthones into a framework (Sch. 1).

OH OH OH 0

Me02C B

n

O

w

O

E

t

I

AcO"'

Bryostatin

B n O W C H 0 + c:xOEt

1. TBDMACI

2. DlBAH

TBDMSO

*

1. (R)-3f (1 equiv) OTMS CHzC12, -78 "C, 8 h OH * BnO&C02Et 2.Ni2B-H2 298% ee

OTBDMS &CHO BnO

OH 0

1. TBDMACI

OEt

BnO

(S)-3f (1 equiv) CHZCIZ, -78 "C, 8 h * 2. Ni2B-H2

2. DIBAH

*

TBDMSO A C BnO

OTBDMS H O

-1 00% de

2. Ni2B-H2 -100% de

Scheme 1

The 3f-promoted asymmetric aldol reaction of a variety of aldehydes with a silyl nucleophile derived from phenyl propionate ( E isomer, 98 9'0) resulted in moderate anti-diastereoselectivity with relatively low enantioselectivity. With pivalaldehyde and the silyl nucleophile derived from ethyl propionate (EIZ = 85:15), on the other hand, the syn isomer was obtained as a major product (22:l) with 96 9'0 ee (Eq. 57) [43g].

168

Ishihara

This unexpected switching of diastereoselectivity in the reaction of the bulky aldehyde can be explained by merging Corey's hydrogen-bond model between the aldehyde hydrogen and the catalyst borane-ring oxygen [35e] and Yamamoto's extended transition model 30 [50] as depicted in Fig. 14, where 31 is destabilized by gauche interaction between the methyl and tert-butyl groups. (S)-3f (1 equiv)

OTMS t-BuCHO

+

OEt

PLI

P I

b q u 2

OH 0

OH 0 V

*

-78 "C, 3 h

O

1

E

t

t-Bu-OEt

+

(57)

22:l 96% ee

95% ee

>>

n

n

30

31

Figure 14. Kiyooka's transition-state models.

Important limitations were observed with regard to reagent control in reactions with highly sterically hindered aldehydes involving a chiral hydroxy function at the ,8 position (Eq. 58) [43g]. When (S)-3f was used for 32, diastereo- and enantioselectivity were less satisfactory. When (R)-3f was used, however, the reaction proceeded more smoothly to give the corresponding aldols with moderate syn selectivity in 87 % yield. Each of the isomers obtained was almost enantiomerically pure. The spatial orienta-

T

B

D

M

OTMS 2 CHO S O ~

+

,

3f (1 equiv)

T O T M S OEt

>

CHzC12 -78 "C, 24 h

32

OH 0

TMSO TBDMSOW

O

E

TMSO

1

+

TBDMSOW

33

+

TBDMSOW

O 35

E

t

34

OH 0

TMSO

O

OH 0

E

TMSO 1

'

TBDMSOW

O

OH 0 E

t

36

(S)-3f

33:35=7:5,34:36=5:3 34% yield, syn(33+35):anti(34+36)=2:lI

(R)-3f

87% yield, syn(33+35):anti(34+36)=4:1,33:35=>50:1,34:36=>50:1

(58)

Chiral B(III) Lewis Acids

169

tion of the siloxy group at C-3, which is presumably fixed by the introduction of two methyl groups at C-2, affects the entire conformation of the aldehydes, and when the chiral borane coordinates to the aldehyde, an adequate fit might be needed between the stereocenters of the reagent and the substrate (at C-3) for the stereochemical outcome expected from reagent control. Although the reaction with (S)-3f lost reagent control because of stereochemically mismatching interactions, even in such a complex case the reaction with (R)-3f gave products with stereochemistry at C-3 similar to that expected on the basis of reagent control. Effective approach of the silyl nucleophile might occur via a path similar to 38 in Fig. 15.

T

E: $e

O/"H L B - 0

37

-

Nu

38

Figure 15. Kiyooka's transition-state models.

5.4.2 Chiral Lewis Acids as Catalytic Reagents After the report by Kiyooka et al. in 1991 [43] of the enantioselective aldol reaction by use of CAB 3f under stoichiometric conditions, Masamune and co-workers [44], Kiyooka et al. [45a], and Corey et al. [46] all independently developed CAB-catalyzed systems for enantioselective aldol reactions (Eq. 59). TMSO

(20 mol%) *

R'

X

39

3h

Masamune et al. (for X=OR4 or SR4)

3i Kiyooka et al. (for X=OR4 or SR4)

3b Corey et al. (for X=R4)

0

170

Ishihum

Masamune and co-workers examined several oxazaborolidines derived from a series of simple a-amino acid ligands derivatized as the corresponding N-p-toluenesulfonamides. A dramatic improvement in reaction enantioselectivity was observed when complexes prepared from a,a-disubstituted glycine arylsulfonamides were used. It was suggested that the initial aldol adduct must undergo ring closure, as indicated by the arrow in Fig. 16, to release the final product 40 and to regenerate the catalyst 3 (Fig. 16) [44]. Slow addition of the aldehyde to the reaction mixture was often beneficial (resulting in enough time for 39 to undergo ring closure) in improving the enantioselectivity of the reaction. Kiyooka et al. reported a straightforward improvement of this reaction to a catalytic version by using an N-p-nitrobenzenesulfonyl-derived ligand and nitroethane instead of dichloromethane as a solvent [45a].

R’CHO

+

X

39 Figure 16. The proposed catalytic cycle.

Product enantioselectivity was also optimized as a function of substitution of the arylsulfonamide (Eq. 60) [44]. Thus, for complexes with the general structure 3h, the enantiomeric excess of the benzaldehyde adduct varies along the series: Ar = 3,5-bis

MeO$ *H

,\\.‘

Me0 \

S02Ar

(20 mot%) PhCHO

+

C02Et

(60)

EtCN

52% ee

53% ee

67% ee

78% ee

X=f-Bu: 81% ee X=H: 83%ee X=MeO 86Yoee X=AcNH 86% ee

Chiral B(IZI) Lewis Acids

171

(trifluoromethy1)phenyl (52 YO ee); mesityl (53 YO ee); 1-naphthyl (67 % ee); 2naphthyl (78 Yo ee); 4-tert-butylphenyl (81 YOee); phenyl (83 % ee); 4-methoxyphenyl(86 YOee); 4-acetamidophenyl(86 YOee). An AM1 optimized structure of the chiral borane complex has been used as the centerpiece of a model proposed by Kiyooka et al. to account for the stereochemical outcome of the reaction (Fig. 17) [45a]. It is suggested that the aldehydes coordinate to the boron on the face opposite the isopropyl substituent, thereby minimizing steric interactions. The Kiyooka model places the formyl-H over the five-membered ring chelate subtending an obtuse H-B-0-C dihedral angle. Analogous modes of binding have been proposed for other chiral acid boron compounds used ingeniously for Diels-Alder cycloaddition reactions [17]. The preference for this orientation might result from the presence of a stabilizing anomeric interaction. Alternatively, the bound aldehyde might be locked in the conformation invoked by Kiyooka as a result of a formyl C-H hydrogen bond to the acyloxy donor-in accord with the bonding model proposed by Corey (Fig. 17) [35e,45a].

R 02N The Kiyooka model

02N

The Corey model

Figure 17. The proposed transition-state models.

Kiyooka et al. reported that the 3i-catalyzed aldol reaction of a silyl ketene acetal involving a dithiolane moiety with p-doxy aldehyde resulted in the production of syn and anti 1,3-diols with complete stereoselectivity depending on the stereochemistry of the catalyst used [45b]. This methodology was applied to the enantioselective synthesis of the optically pure lactone involving a syn-1,3-diol unit, known to be a mevinic acid lactone derivative of the HMG-CoA reductase inhibitors mevinolin and compactin (Sch. 2). Corey et al. used 3b in the conversion of aldehydes to 2-substituted 2,3-dihydro4H-pyran-4-ones by reacting them with l-methoxy-3-trimethylsilyloxy-1,3-butadiene in propionitrile at -78 "C for 14 h and then treating them with trifluoroacetic acid (Eq. 61) [46].

R'CHO

OTMS

+

3b (R=Bu, 20 mol%) *

EtCN, -78 "C

OMe

R'y;,'o

TMSO /

CF3C02H

OMe

67-82% ee

172

Ishihara

0

HoTyo

R=H: Mevinolin R=Me: Compactin

P h A C H O

+

OTMS

1.3i (20rnol%) EtN02, -78 "C, 1 h

OEt

2. Ni2B-H2

[)+

OH

P h A C 0 2 E t >98% ee

l. 1. TBDMACI

*

[)=rY

3i (20 mol%) EtN02, -78 "C, 1 h

PhdCH 2. Ni2B-H2 t

2. DlBAH

*

100% de

I

Ph

Scheme 2

CAB 2, R = H, derived from monoacyloxytartaric acid and diborane is also an excellent catalyst (20 mol %) for the Mukaiyama condensation of simple enol silyl ethers of achiral ketones with various aldehydes. The reactivity of aldol-type reactions can, furthermore, be improved, without reducing the enantioselectivity, by use of 1020 mol YOof 2, R = 3,5-(CF3)&H3, prepared from 3,5-bis(trifluoromethyl)phenylboronic acid and a chiral tartaric acid derivative. The enantioselectivity could also be improved, without reducing the chemical yield, by using 20 mol YO 2, R = oPhOC6H4, prepared from o-phenoxyphenylboronic acid and chiral tartaric acid derivative. The CAB 2-catalyzed aldol process enables the formation of adducts in a highly diastereo- and enantioselective manner (up to 99 YOee) under mild reaction conditions [47a,c]. These reactions are catalytic, and the chiral source is recoverable and re-usable (Eq. 62). The relative stereochemistry of the major adducts is assigned to be syn, and the predominant re face-attack of enol ethers at the aldehyde carbonyl carbon has been confirmed when a natural tartaric acid derivative is used as a Lewis acid ligand. The use of an unnatural form of tartaric acid as a chiral source gives the other enantiomer, as expected. Almost perfect asymmetric induction are achieved with the syn adducts,

Chiral B(III) Lewis Acids

1) 2 (10-20 rnol%) EtCN, -78 "C

OTMS

R'CHO

+

R3

p

(99%), 88% ee (2 (10 rnol%), R=3,5-(cF3)&jH3)

H

2

(83%), 97% ee syn syn:anti=>95:5 (2 (20 rnol%), R=3,5-(CF&C6H3)

3

(62)

0

Ph

~

(99%), 96% ee syn (92%), 96% ee syn syn:anti=94:6 syn:anti=99:1 (2 (20 rnol%), R=H) (2 (10 rnol%), R=~,~-(CF~)~CSH~) HO

Ph

HO

d

Ph

R

.

2,

0

HO h

0

HO

'R d

2) 1NHCI

0

HO Phd

~2&

173

Pr

0

aEt

(61%), 88% ee syn syn:anti=80:20 (2 (20 rnol%), R=H)

(95%), 93% ee syn syn:anti=94:6 (2 (20 rnol%), R=3,5-(CF3)2CsH3)

reaching 99 % ee, although a slight reduction in both enantio- and diastereoselectivity is observed in reactions with saturated aldehydes. Irrespective of the stereochemistry of the starting enol silyl ethers generated from ethyl ketone, syn aldols are obtained with high selectivity in these reactions. The high syn selectivity observed in CAB 2catalyzed reactions, and its lack of dependence on the stereoselectivity of the silyl enol ethers, are fully consistent with Noyori's TMSOTf-catalyzed aldol reactions of acetals, and thus might reflect the acyclic extended transition state mechanism postulated in the latter reactions (Fig. 18). Judging from the product configurations, CAB 2 catalyst (from natural tartaric acid) should effectively cover the si face of the carbonyl after its coordination, and the selective approach of nucleophiles from the re face should result. This behavior is totally systematic and in good agreement with the results of previously described CAB 2-catalyzed reactions for all of the aldehydes examined.

anti

sYn

Figure 18. Extended transition-state model.

174

Zshihara

A catalytic enantioselective aldol-type reaction of ketene silyl acetals with achiral aldehydes also proceeds smoothly with 2, R = H; this can furnish erythro P-hydroxy esters in high optical purity (Eq. 63) [47b,c].

+

R'CHO

1) 2 (R=H, 20 rnol%) EtCN, -78 "C *

OTMS

R'

-I

0

HI)

-,nKoi#

(63)

2

HO

HO

Ph

OPh

88% ee syn syn:anti=79:21

Phd

76% ee

0

Pr *OPh:

HO

Pr &OPh

84% ee

HO

0

r

d

P

h

92% ee syn syn:anti=79:21

0

HO P

O:

O

P

97% ee syn syn:anti=96:4

h +OPh 94% ee syn syn:anti=95:5

A remarkable finding is the sensitivity of this reaction to the substituents of the starting silyl ketene acetals. Reactions of silyl ketene acetals derived from more common ethyl esters are totally stereo-random, and give a mixture of erythro and threo isomers in even ratios with improved chemical yields. In sharp contrast, the use of silyl ketene acetals generated from phenyl esters leads to good diastereo- and enantioselectivity and excellent chemical yields. The reason for this is unclear, but certain secondary interaction between electron-rich silyl ketene acetals derived from alkyl esters and Lewis acid might be responsible. By analogy with previous results with enol silyl ethers of ketones, non-substituted silyl ketene acetals result in less stereoregulation. Propionate-derived silyl ketene acetals, on the other hand, result in a high level of asymmetric induction. Reactions with aliphatic aldehydes, however, result in slightly reduced optical yield. With phenyl ester-derived silyl ketene acetals, erythro adducts predominate, but selectivities are usually moderate compared with the reactions of ketone silyl enol ethers. Exceptions are a$-unsaturated aldehydes, for which diastereo- and enantioselectivity are excellent. The observed erythro selectivity and re-face attack of nucleophiles on the carbonyl carbon of aldehydes are consistent with the aforementioned aldol reactions of ketone enol silyl ethers [47]. Harada and his colleagues have reported that arylboron complex 3g derived from Ntosyl-(aS$R)-P-methyltryptophan [17] and (p-chloropheny1)dibromoboraneis an excellent catalyst for enantioselective ring-cleavage reactions of 2-substituted 1,3-dioxolanes with enol silyl ethers [48c]. Interestingly, chiral boron complexes prepared by reacting sulfonamide ligands with BH3-THF do not have appreciable catalytic activity [48a,b]. Success has been achieved in the ring cleavage of 1,3-dioxolanes with aryl and alkenyl groups at the 2-position. The reaction of 2-alkyl derivatives is, however, very sluggish under these conditions. The 2-hydroxyethyl group in the ring-cleavage products can be removed simply by conversion to the iodide then treatment with zinc powder (Eq. 64).

Chiral B(ZZI)Lewis Acids

n 'yo

1.3g (10 mol%) +

CH2C12, -20 "C

R3 R2&0SiMe3

TnAC

Ho-o *

175

0 ~ 1 + ~ 3

R2 R2

1.12, PPh3 * 2. Zn

OH 0

R1+R3

(64)

R2 R2

Examples

0

0

0

Ho-O

Me0 88% yield 86% ee

73% yield 93% ee

80% yield 85% ee

Desymmetrization of meso 1,2-diols has been realized by cliiral Lewis acid 3hmediated enantioselective ring-cleavage of dioxolane derivatives [48d]. Transacetalization of 3,3-diethoxy-l-phenylpropynewith meso-2,3-butanediol stereoselectively gave an 86:14 mixture of syn- and anti-41. Treatment of syn-41 with 3 equiv. Me2C= C(0TMS)OEt and 1.0 equiv. 3h at -78 "C gave the ring-cleavage product 42 (> 20:l diastereoselectivity) in 72 YOyield with 94 YOee (Eq. 65). A separate experiment using pure anti41 showed it to be unreactive under these conditions. Boron complex 3h was also effective in the ring-cleavage of other dioxolanes that could be prepared stereoselectively (syn:anti > 20:l) from the diols under kinetically controlled conditions. The results obtained by use of other catalysts such as 3i and 3j suggest that the structure of N-sulfonyl moiety influences enantioselectivity.

.

.

n

O v 0

-

3h (1 equiv)

:,

Ph

\OAOH

-..

?. +

HOAO,/ph

(65)

/t

li" syn-41

..-

EtOK

I

42 (major)

ent-42 (minor)

(3 equiv)

"?-f0 .B,o 02s-N R'

Ph

3h: R1=tol + 42: 94% ee 3i: R'=Me 4 42: 48% ee 3j: R1=CF3--f 42: 58% ee

Other examples

?C02Et 3h --f 96% ee

?CO*Et 3h

-+ 93% ee

3h --f 85% ee

5.5 Enantioselective Sakurai-Hosomi Allylation Reactions Asymmetric allylation is a valuable method for constructing chiral functionalized structures, and many chiral allylmetal reagents directed toward a high level of asymmetric induction have, therefore, been designed and synthesized. Although for some of these good to excellent enantio- and diastereoselectivity are obtained in reactions with achiral aldehydes, we developed the first novel method for a catalytic process in 1991 [49a]. The CAB 2 catalyst has powerful activity in the Sakurai-Hosomi allylation of aldehydes and gives homoallylic alcohols in excellent enantiomeric excess (Eq. 66) [49a]. Reaction of borane-THF complex with mono(2,6-diisopropyl)benzoyltartaric acid in dry propionitrile at 0 "C affords the catalyst solution. Condensation of achiral aldehydes with allylsilanes is promoted by this catalyst, 2, (20 mol %) at -78 "C to produce homoallylic alcohols with enantio- and diastereoselectivity (Eq. 66). The reactions proceed catalytically to afford homoallylic alcohols in modest to good yield. Alkyl substitution at the olefin moiety of allylsilanes increases the reactivity, enabling the use of a lower reaction temperature with improved asymmetric induction. For y-alkylated allylsilanes diastereo- and enantioselectivity are excellent and erythro homoallylic alcohols of greater optical purity are obtained. Of particular interest is the independence of the erythro selectivity of the reactions on allylsilane stereochemistry. Thus, irrespective of the geometry of the starting allylsilanes, the predominant isomer in this reaction has erythro configuration. The observed preference for the relative and absolute configurations of the adduct alcohols from (2R,3R)-ligandborane reagent is predicted on the basis of an extended transition-state model similar to that for the CAB 2-catalyzed aldol reaction [39].

Chiral B(III) Lewis Acids

3

Ph

:

(64%), 92% ee syn syn:anti=96:4

177

OH Et Bu

(30%), 85% ee syn syn:anti=94:6

Ph (8l%), 96% ee syn syn:anti=97:3

OH Et

(21%), 89% ee syn syn:anti=95:5

(36%), 86% ee syn syn:anti=95:5

(68%), 82% ee

Several arylboronic acids have been examined in place of borane-THF to improve the Lewis acidity of 2 and the stereoselectivity [49b]. The boron substituent of 2 has a large effect on the chemical yield and the enantiomeric excess of the allylation adduct, and 3,5-bistrifluoromethylbenzeneboronicacid results in the greatest reactivitywhen a complex which is easily prepared from a tartaric acid derivative and 3,5-bistrifluoromethylbenzeneboronic acid in propionitrile at room temperature is used, the reactivity is improved without reducing the enantioselectivity. For instance, the reaction of l-trimethylsilyl-2-methyl-2-propene with benzaldehyde in the presence of only 10 mol YO2 proceeds to give 99 YOyield and 88 YOee (Fig. 19).

3

Ph

(82%), 91% ee syn syn:anti=94:6

a

Bu

(70%), 63% ee

22

Ph

(56%), 89% ee syn syn:anti=92:8

Pr \

(88%), 77% ee

Ph \

2

(96%), 84% ee

3

Ph

(99%), 88% ee

Figure 19. Examples of allylation catalyzed by 2 (3,5-(CF3)&H3; 1Q-20 mol %)

Marshall et al. reported that more reactive allyltin analogs can be used instead of allylsilane nucleophiles in our CAB 1 catalyst system, and found that trifluoroacetic anhydride is an efficient promoter that retains stereoselectivity (Eq. 67) [50a].

178

Ishihara

PhCHO

+

E t y S n B u 3

1 * EtCN, -78 "C

1 (20 mol%) : 1 (100 mol%) : 1 (20 mol%) + (CF3)2C0(40 mol%) : 1 (100 rnol%) + (CF3CO)20(200 mol%):

3

Ph

(67)

~

Et

(40%), syn:anti=93:7, 78% ee syn (85%), syn:anti=88:12, 78% ee syn (88%),syn:anti=85:15, 74% ee syn (99Y0), syn:anti=90:10, 85% ee syn

Although several studies on the addition of allylic and allenylstannanes catalyzed by metal complexes of BINOL and BINAP have been described [51] since we reported CAB-catalyzed enantioselective allylation [49], results obtained with crotylstannanes have been given in only one of these reports [52]. In that investigation the addition of cis- or trans-crotyltributyltin to methyl glyoxalate afforded mixtures of syn and anti adducts of modest ee in relatively low yield (38 % and 53 Yo,respectively). Very recently, a limited survey of the CAB and Keck BINOL methodology with crotyltributyltin was conducted by Marshall and Palovich (Table 3) [50b]. A modified CAB, prepared from the 2,6-dimethoxybenzoic ester of (R,R)-tartaric acid, and 1.5 equiv. BH3-THF was used in the addition of crotyltributyltin and allyltributyltin to representative achiral aldehydes in the presence of 2 equiv. (CF3CO)20. Addition to crotyltin proceeded with good to excellent diastereoselectivity and enantioselectivity to give syn adducts in 70-93 YOee as major products (78:22-92:8). The addition of allylstannane to cyclohexanecarboxaldehyde afforded the ( R ) adduct in 55 YOee. In contrast, the use of Keck's BINOL catalyst gave an ally1 adduct in 87 YOee. Addition of crotylstannane to cyclohexanecarboxaldehyde with this catalyst led, however, to a 65:35 mixture of syn and anti adducts 43 (R = Me) and 44 (R = Me) in 95 YO and 49 YOee. Table 3. Comparison of BINOL- and CAB-promoted addition of allylstannanes to cyclohexanecarboxaldehyde. Rq-SnBu3

OH

OH

cat. 43 R

cat.

Me

Ti(Oi-Pr), (10 mol%)+2(R)-BINOL(20 mol%) +TfOH (10 mol%) in CH2C12, MS 4A CAB 1 (50 m0l%)+(CF~C0)~0 (200 mol%) in EtCN Ti(Oi-Pr)4(10 mol%)+2(R)-BINOL(20 mol%) +TfOH (10 mol%) in CH2C12, MS 4A CAB 1 (50 m0l%)+(CF~C0)~0 (200 mol%) in EtCN

Me H H

44 yield, Yo 43(%ee):44(Y0ee) 18

65(95):35(49)

71

93(93):7(80)

53

(87)

42

(55)

Chiral B(III) Lewis Acids

179

The addition of crotylstannane to (R)-and (S)-2-methyl-3-(diphenyl-tert-butylsilyl) oxypropanal ((R)-45 and (S)-45) promoted by a modified CAB Lewis acid gives the s y n j y n and syn,anti products in large predominance (98:2 and 90:lO); this reflects effective complex control in the transition state (Eqs 68 and 69). These results are consistent with the hydrogen-bonded aldehyde transition state proposed by Corey [35c,d]. 0

modified CAB 1

Ph2t-BuSiO"---J'H .

+

A-S~B~3

*

OH

(R)-45

98:2

modified CAB 1 Ph2t-BuSi0G

H

(S)-45

+

A-SnBu3

*

OH

P h 2 1 - B u S i O T

OH +

P h 2 t - B u S i O v

(69)

10:90

5.6 Enantioselective Claisen Rearrangement The Claisen rearrangement has attracted much attention as an attractive tool for the construction of new carbon-carbon bonds. Taguchi et al. reported the enantioselective and regioselective aromatic Claisen rearrangement of catechol mono allylic ether derivatives by means of Corey's chiral boron reagent (Eq. 70) [53a,54]. The mechanism of enantioselectivity is that a rigid five-membered cyclic intermediate is formed by reaction of catechol mono allylic ethers with the chiral boron reagent and this is fol-

180

Zshiharu

lowed by coordination of the allylic oxygen to the boron atom. The re site of the benzene ring of the substrate might be shielded by one tolyl group of the sulfonamide ligand. Therefore, the approach of the allylic moiety should occur on the si face giving rise to the (S) product. The direction of the enantioselectivity observed can be explained satisfactorily by use of this model. This system can be applied to the enantioselective Claisen rearrangement of difluorovinyl ally1 ethers (Eq. 71) [53b].

Phl-7ph O *R '

OH

-

F~

R1=H, R2=TMS: 85% ee

5.7 Enantioselective Hydrocyanation of Aldehydes The hydrocyanation of aldehydes provides access to synthetically important ahydroxy carboxylic acids. This reaction can be catalyzed by acids and bases, but acid catalysis is more suitable because the presence of a base leads to racemization of cyanohydrins. Reetz et al. found that chiral 1-boracyclopentyl chloride or methoxide can be used as a catalyst in the reaction of 3-methylbutanal and trimethylsilyl cyanide (Eq. 72) [42]. Although the asymmetric induction and yield are not good, this is the first example of chiral induction by an organoborane in the hydrocyanation of aldehydes.

PhQ ' I " P h

i-BuCHO

+

X

TMSCN

*

X=OMe, 10 mol%

OH

(72)

i-BuACN

2o mol% (45-55%), 12-16% ee

5.8 Enantioselective Mannich-Type Reactions Yamamoto and co-workers found that 27 is an excellent chiral promoter not only for the aza Diels-Alder reaction of aldimines [40] but also for the stereoselective aldoltype reaction of aldimines with ketene silyl acetals [55].The reaction of (S)-benzylidene . a-methylbenzylamine with trimethylsilyl ketene acetal derived from tert-butyl acetate in the presence of (R)-27 produces the ( R ) adduct in > 92 % diastereomeric excess (de), whereas reaction with (S)-27 gives the adduct in 74 % de. In a similar way, (S)-butylidene . a-methylbenzylamine, an aliphatic imine, can be converted to the (R)-b-amino ester in 94 % de by use of (R)-27 (Eq. 73).

Chiral B(III) Lewis Acids

N

R

Ph

+

OTMS

&Ot-BU R"H

27 (1 equiv) CH2C12, (50-6C

R1=Ph, (R)-27 (Ar=Ph): 92% de R1=Ph, (5)-27 (Ar=Ph): 74% de

-

HN

181

(73) ,C02t-B~

,-,

Ri=Pr, (R)-27 (Ar=Ph): 94% de R1=Pr, (5)-27 (Ar=Ph): 86% de

This method can be effectively applied to the preparation of p-lactam compounds. The ester enolate-imine condensation approach to /3-lactam formation has been developed over the past decade. Thienamycin and related carbapenems have been the focus of particular attention because of their structural uniqueness and potent antibacterial activity. The reaction of an acetylenic imine and silyl ketene acetal with (R)-27 as a Lewis acid catalyst produces the aldol adduct with extremely high anti selectivity (anti: syn = 40:l); it is converted to the p-lactam by use of Ohno's method, which is transformed into the key intermediate for (+)-PS-5(Eq. 74).

t lPh YTBDMS 27 (1 equiv) flH + Et CH2CI2, -78 TMS (70-8OYo) 0;

(R)-27 (Ar=Ph): anti:syn=40:1, 98% de anti (S)-27 (Ar=Ph): anti:syn=2:1, 88% de anti

TMS'

As a dramatic demonstration of our novel reagent system, we have applied it to the stereoselective synthesis of optically pure 3-(l'-hydroxyethyl)-2-azetidinone, a useful synthetic intermediate for thienamycin [56]. Our results are shown in Eqs (75) and (76). In the presence of equimolar boron reagent 27, the reaction of the acetylenic imine and ketene silyl acetal derived from 3-hydroxybutyrate proceeds smoothly at -78 "C for 8 h to afford the ,&amino esters in good yield. The reaction with triphenylborate as the Lewis acid catalyst stereoselectively produces the syn adduct (syn:anti = 9223,diastereomeric ratio of syn adduct = 98:2).In sharp contrast, the use of (S)-27 produces the syn adduct with almost complete diastereoselectivity (syn:anti = 100:0, diastereomeric ratio of the syn adduct = 2:98). These results suggest the high flexibility of our methodology and the unprecedented stereocontrolled synthesis of /?-amino esters. Transformation of ,&amino ester 47 to the desired thienamycin is straightforward. Exposure to phenylmagnesium bromide in ether gives the cis /3lactam 48. This was converted into the trans /3-lactam 49 by treatment with trimethylsilyltriflate in dichloromethane at room temperature, followed by Birth reduction to

182

Ishihuru

give the p-lactam 49. Compound 49 could be transformed into 4-acetoxy-3-[(R)-l(tert-butyldimethylsilyl)ethyl]-2-azetidinone(4-ABA) or 50.4-ABA and 50 are known synthetic intermediates leading to thienamycin and related structures.

N P'h /H TMS

TESO

+

OTES

27(1 equiv)

uOMe

CH2C12,-78

',! q + : :: HN

Ph

P 'h

&H

TMS

C02Me

TMS

(75)

""OTES

46

47

B(0Ph)a: (75%), syn:anti=92:8, 46:47=98:2 (R)-27 (Ar=Ph): (53%), syn:anti=l OO:O, 46:47=67:33 (5)-27 (Ar=Ph): (83%), syn:anti=100:0, 46:47=98:2

45

-

P h z o , ,.,OTBDMS

,,OTES TMS'

Aco%,..OTBDMS

/ / H 49

48

H02C

+..'OTBDMS 4-ABA

50

This methodology also enables stereospecific synthesis of the side-chain of taxol [56]. The N-benzoyl-3-phenylisoserine side chain at C-13 of the taxol molecule is essential for its antitumor activity. The stereoselectivity in this reaction depends on the geometry of the silyl ketene acetal (Eq. 77). The reaction of the (E)-ketene acetal with (R)-27 produces the anti adduct with high stereoselectivity (anti:syn = 98:2,92YO de anti). In contrast, the reaction of the (Z)-silyl ketene acetal with (S)-27 produces the enantiomerically pure syn adduct (syn:anti = > 99:1, > 99 % de syn). Thus, our methodology provides the first practical and efficient route for the preparation of both diastereomers of an a-hydroxy p-amino ester. The syn adduct 52 is transformed to the desired N-benzoyl-(2R,3S)-phenylisoserinemethyl ester by hydrogenolysis over a palladium catalyst then the Schotten-Baumann reaction.

Chiral B(IIZ) Lewis Acids

183

OMe T B D M S(>go% o d O TEB) D M S

Ph-NH

27 (1 equiv)

OH 51 (R)-27 (Ar=Ph): 92% de anti, anti:syn=98:2 (5)-27 (Ar=Ph): 90% de anti, anti:syn=93:7

N-Ph PhKH

OTES

(77)

27 (1 equiv) (90-9570)

OH

52

(R)-27 (Ar=Ph): 94% de syn, anti:syn=6:94 (5)-27 (Ar=Ph): 98% de syn, anti:syn=l:99

BLA 28 is very useful in the double stereodifferentiation of aldol-type reactions of chiral imines [41]. Reaction of (S)-benzylidene-a-methylbenzylaminewith trimethylsilyl ketene acetal derived from tert-butyl acetate in the presence of (R)-28 at -78 "C for 12 h provides the corresponding aldol-type adduct in 94 YOde (Eq. 78). Including phenol in the reaction mixture does not influence the reactivity or the diastereoselectivity. The aldol-type reaction using yellow crystals of (R)-28.(S)-benzylidene-amethylbenzylamine . PhOH proceeds with unprecedented (> 99.S:O.S) diastereoselectivity (Eq. 79). In general, 28 is a more efficient chiral Lewis acid promoter than 27.

(63%), 94% ee

OTMS ph/\/co2f-Bu HNP 'h +(R)-28+PhOH Yellow crystal

(79)

(65%), >99% de

On the basis of these results, we have developed the first method for the enantioselective synthesis of chiral p-amino acid esters from achiral imines and ketene silyl acetals using BLA 28. The enantioselectivity of the aldol-type reaction is dramatically increased by using sterically bulky N-substituents. Condensation of the imine derived from benzhydrylamine occurs with high enantioselectivity (90 % ee) (Eq. 80). Furthermore, the best result (96 YOee) is achieved by use of a 1:l (vIv) mixture of toluene and dichloromethane as solvents. Thus, excellent enantioselectivity (95 % ee or better) has been achieved in reactions of aromatic aldehyde-derived imines

184

Ishihara

(Eq. 81). The N-benzhydryl protecting group can be easily removed from P-aryl-/3amino acid esters by catalytic hydrogenolysis over palladium on carbon; the ease of removal decreases in the order Ph2CH >> PhCH2 > PhMeCH > PhCHCH2C02t-Bu.

R1=l -naphthylmethyl: 46% ee R'=Ph: <5% ee R'=Bn: 29% ee ( R ) R1=Ph2CH:90% ee ( R ) R'=(S)-PhMeCH: 95% ee (17)

(35-58%)

Ar=Ph: 96% ee ( R ) Ar=pMeC6H4:97% ee

Ar=2,4-CI2C6H3:95% ee Ar=pCIC6H4:98% ee Ar=pAcOC6H4:98% ee Ar=2-naphthyl: 96% ee

The absolute configuration of the adducts can be understood in terms of a model involving an intramolecular hydrogen-bonding interaction via a Bronsted acid. Although there is no evidence that the hydrogen-bonded structure exists, this hypothetical interaction would cause the Lewis acidity of boron and the Jt-basicity of the naphthoxy moiety to increase, and the transition state assembly would be stabilized. In complex 53 the 2-hydroxynaphthyl group fixed by the intramolecular hydrogenbond would effectively block the si face of the (E)-imine complexed with (R)-28,and the nucleophile would approach the re face (Fig. 20). The absolute enantioselectivity in the aldol-type reaction of N-benzhydrylimine can be understood by a similar mechanistic model.

nucleophile

a' U

blocked bv fRb28 ,

>

I

The Matched Pair Complex 53

Figure 20. The proposed transition-state assembly.

The enantioselective aldol-type reaction of benzhydrylimines using 28 has been applied as the key step in the total synthesis of the spermidine alkaloid (+)-dihydroperiphylline (54) [55].

Chiral B(III) Lewis Acids

185

0

54

5.9 Other Enantioselective Aza-Reactions The stereoselective Pictet-Spengler reaction has been actively investigated because of its importance in natural product synthesis. Nakagawa and co-workers used BLA 28 in the enantioselective Pictet-Spengler cyclization of nitrones, prepared from Nbhydroxytryptamine with aldehyde, to give chiral l-substituted-2-hydroxytetrahydro-/3carbolines (Eq. 82) [58]. The use of (R)-28 gave the desired products in high yield with good to high enantioselectivity (I 91 % ee, (S)).

(R)-28 (2 equiv) *

CH~CIP,rt, 2 days

/

T

R

O\

H

R

R=H: 81Yo yield, 73% ee (S) R=OMe: 39% yield, 91% ee (S)

The stereochemical outcome can be explained by assuming a model in which the oxygen of the nitrone is coordinated to the boron of BLA, as shown in Fig. 21. The proposed transition state model, which shows re face approach of the indole nucleus to a C=N double bond, would be preferred. Scheeren and co-workers have found that the asymmetric 1,3-dipolar cycloaddition of nitrones with ketene acetals is strongly catalyzed by chiral oxazaborolidines derived from N-tosyl-L-a-amino acids (Eq. 83) [59a]. The 5,5-dialkoxyisoxazolidines are

Figure 21. The proposed transition-state model.

186

Ishihara

obtained regioselectively in high yield with high stereoselectivity and moderate enantioselectivity of up to 62 % ee. Mild hydrogenolysis of the N-0 bond quantitatively yields the corresponding /?-amino ester.

.

Ph ,.

OEt

Yh

P h w N t 0-

+

I

cat. (20 rnol%)

F O E t

CH2C12, -78 "C

The enantioselectivity of the chiral oxaborolidine-catalyzed asymmetric 1,3-dipolar cycloaddition can be controlled by the a-side-chain substituent in this catalyst and the solvent (Tables 4 and 5) [59b]. A remarkable reversal of enantioselectivity is achieved with catalysts with aryl substituents in the a-side-chain and by adding ligand-like solvents. Both enantiomers of a chiral /?-amino ester have been prepared in two catalytic steps. Table 4. Reversal of enantioselectivity in catalytic asymmetric 1,3-dipolar cycloaddition.

BH3-THF

62% ee (-)

4% ee (-)

BH3-SMe2

48% ee (-)

70% ee (+)

0% ee 73% ee (+)

Table 5. Influence of cosolvent on the enantioselectivity of 1,3-dipolar cycloaddition. co-solvent

(S)-3da

co-solvent

(S)-3da

THF t-BuOMe Bu20 PhOMe PhpO Bn20

62% ee (-) 26% ee (+) 14% ee (+) 4% ee (+) 58-79% ee (+) 33-71Yoee (+)

EtCN EtN02 DMSO sulfolan PhN02 Phl

16% ee (+) 43-60% ee (+) 6% ee (+) 15% ee (+) 33% ee (+) 8% ee (+)

"3dwas prepared from 1

M

BH3-SMe2 in dichloromethane.

Chiral B(III) Lewis Acids

187

5.10 Chiral Boron Receptors Nature uses a donor-acceptor combination in molecular recognition. Units with both proton-donor sites and proton-acceptor sites play essential roles in biological functions. Pioneering studies of the use of organoboron compounds as Lewis acids were been reported by Brown and co-workers, who investigated the interaction of various boranes with amines [60]. Bidentate binding of two Lewis acidic boron centers to one methoxide anion was first reported in 1967 by Sheiver and Billas [61]. Bidentate Lewis acids with two boron centers were later developed by Katz [62].Narasaka et al. also reported a bidentate diboronate which recognized the location of two amino groups of diamines [63]. These molecules have Lewis-acidic sites which are electronpair acceptor sites, but do not have any efficiently working electron donor sites (Lewis basic sites). Takaya and co-workers recently reported that a combination of multiple electron donor-acceptor bonds in 2,2'-(1,2-phenylene)bis(4R,5R)-4,5-diphenyl-l,3,2-dioxaborolane) (55) provides more 'sophisticated' functions (Eq. 84) [64a,c]. The exceptionally strong binding of 55 with benzylamine was demonstrated by titration. The ratio of complex formation 55:amine = 1:2 was determined by means of a Job plot. The binding constants, K1 and K2,were determined by non-linear curve-fitting to be K1 << K2. These results can be explained in terms of an allosteric effect. The first amine molecule coordinates with one of the two oxygen atoms in the other dioxaborolane ring to form a hydrogen-bond. As a result, the two dioxaborolane rings are conformationally fixed by two-point binding to provide a preferable binding site for the second amine molecule. Although only weak chiral recognition of 1-phenylethylamine has been obtained with 55, the clear separation of the peaks of the amine suggests that it might be possible to use 55 as an NMR chiral-shift reagent.

i 55

1:l complex (not detected)

Phz' 1:2 complex

Another chiral bimetallic Lewis acid 56 prepared from phenylboronic acid and Ltartaric acid by azeotropic distillation selects 1,6-diaminohexane over 1,2-diaminoethane by using two boron centers and two carbonyl oxygens (Fig. 22) [64b]. In the interaction with 1,2-diamino-1,2-diphenylethane, 56 chooses a different complexation pattern by recognizing the chirality of the amines. In both examples the carbonyl groups in 56 play essential roles as Lewis basic sites.

188

Ishihara

\

stable

Ph

unstable

0-B, Ph

Ph : Phi

NH2

Figure 22.5bdiamine complexes.

References 1. Ross Kelly, T.; Whiting, A,; Chandrakumar, N. S. J. Am. Chem. Soc. 1986,108,3510. 2. Maruoka, K.; Sakurai, M.; Fujiwara, J.; Yamamoto, H. Tetrahedron Lett. 1986,27,4895. 3. Gueseinov, M. M.; Akhmedov, M. L.; Mamedov, E. G. Azer. Khem. Zh. 1976, I , 46 [Chem.Abstr. 1976,85,176295~]. 4. Kaufmann, D.; Bir, G. Tetrahedron Lett. 1987,28,777. 5. Bir, G.; Kauffman, D. J. Orgunomet. Chem. 1990,390,l. 6 . Kaufmann, D.; Boese, R. Angew. Chem., Int. Ed. Engl. 1990,2Y, 545. 7. Bao, J.; Wulff, W. D. Tetrahedron Lett. 1995,36, 3321. 8. Furuta, K.; Miwa, Y.; Iwanaga, K.; Yamamoto, H. J. Am. Chem. Soc. 1988,110,6254. 9. (a) Furuta, K.; Shimizu, S.; Miwa, Y.; Yamamoto, H. J. Org. Chem. 1989,54, 1481. (b) Furuta, K.; Gao, Q.; Yamamoto, H. Org. Synth. 1995, 72,68. 10. Ishihara, K.; Gao, Q.; Yamamoto, H. J. Org. Chem. 1993,58,6917. 11. Furuta, K.; Kanematsu, A,; Yamamoto, H.; Takaoka, S. Tetrahedron Lett. 1989,30,7231. 12. Ishihara, K.; Gao, Q.; Yamamoto, H. J. Am. Chem. Soc. 1993,115,10412. 13. Sartor, D.; Saffrich, J.; Helmchen, G. Synlett,1990, 197. 14. Takasu, M.; Yamamoto, H. Synlett,1990,194. 15. Sartor, D.; Saffrich, J.; Helmchen, G. Richards, C. J.; Lambert, H. Tetrahedron: Asymmetry1991,2, 639. 16. (a) Hawkins, J. M.; Loren, S. J. Am. Chem. Soc. 1991, 113, 7794. (b) Hawkins, J. M.; Loren, S.; Nambu, M. J. Am. Chem. Soc. 1994,116, 1657. 17. (a) Corey, E. J.; Loh, T.-P. J. Am. Chem. Soc. 1991,113,8966. (b) Corey, E. J.; Loh, T.-P.; Roper, T. D.; Azimioara, M. D.; Noe, M. C. J. Am. Chem. Soc. 1992,114,8290. 18. Corey, E. J.; Loh, T.-P. Tetrahedron Lett. 1993,34,3979. 19. Corey, E. J.; Guzman-Perez, A,; Loh, T.-P. J. Am. Chem. Soc. 1994,116,3611. 20. Marshall, J. A.; Xie, S. J. Org. Chem. 1992,57, 2987. 21. Seerden, J.-P. G.; Scheeren, H. W. Tetrahedron Lett. 1993,34,2669. 22. (a) Reilly, M.; Oh, T. Tetrahedron Lett. 1994, 35, 7209. (b) Reilly, M.; Oh, T. Tetrahedron Lett. 1995,36,217. (c) Reilly, M,; Oh, T. Tetrahedron Lett. 1995,36,221.

Chiral B(III) Lewis Acids

189

23. (a) Itsuno, S.; Kamahori, K.; Watanabe, K.; Koizumi, T.; Ito, K. Tetrahedron: Asymmetry 1994, 5, 523. (b) Fraile, J. M.; Garcia, J. 1.; Mayoral, J. A.; Royo, A. J. Tetrahedron: Asymmetry 1996, 7, 2263. 24. Loh, T.-P.; Wang, R.-B.; Sim, K.-Y. Tetrahedron Lett. 1996,37,2989. 25. Hayashi, Y.; Rohde, J. J.; Corey, E. J. J. A m . Chem. Soc. 1996,118,5502. 26. (a) Kobayashi, S.; Murakami, M.; Harada, T.; Mukaiyama, T. Chem. Lett. 1991, 1341. (b) Aggarwal, V. K.; Anderson, E.; Giles, R.; Zaparucha, A. Tetrahedron: Asymmetry 1995,6,1301. 27. (a) Ishihara, K.; Yamamoto, H. J. Am. Chem. Soc. 1994,116, 1561. (b) Ishihara, K.; Kurihara, H.; Yamamoto, H. J. Am. Chem. SOC.1996,118,3049. (c) Ishihara, K.; Kondo, S.; Kurihara, H. Yamamoto, H. J. Org. Chem. 1997,62,3026. (d) Ishihara, K.; Kurihara, H.; Matsumoto, M.; Yamamoto, H. J. Am. Chem. SOC.1998,120,6920. 28. Stereodirpcted Synthesis with Organoboranes; D. S. Matteson, Ed.; Springer: Berlin, Heidelberg, New York, 1995, see also references cited therein. 29. Corey, E. J.; Shibasaki, M.; Nicolaou, K. C.; Malmsten, C. L.; Samuelsson, B. Tetrahedron Lett. 1976,17. 737. 30. (a) Sato, K.; Miyamoto, 0.;Inoue, S.; Honda, K. Chem. Lett. 1981,1183. (b) Monti, H.; Corriol, C.; Bertrand, M. Tetrahedron Lett. 1982,23,947and 5539. 31. For theorctical studies, see: (a) Fleming, I. Frontier Orbitals and Organic Chemical reactions; Wiley: New York, 1976; Chapter 4. (b) Birney, D. M.; Houk, K. N. J. Am. Chem. Soc. 1990,112, 4127. (c) Yamabe, S.; Dai, T.; Minato, T. J. Am. Chem. Soc. 1995,117, 10994 and references cited therein. 32. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Gill, P. M. W.; Johnson, B. G.; Robb, M. A,; Cheeseman, J. R.; Keith, T. A,; Peterson, G. A,; Montgomery, J. A,; Raghavachari, K.; Al-Laham, M. A,; Zakrewsky, V. G.; Ortiz, J. V.; Foresman, J. B.; Cioslowski, J.; Stefanov, B. B.; Nanayakkara, A,; Challacombe, M.; Peng, C. Y.; Ayala, P. Y.; Chen, W.; Wong, M. W.; Andres, J. L.; Replogle, E. S.; Gomperts, R.; Martin, R. L.; Fox, D. J.; Binkley, J. S.; Defrees, D. J.; Baker, J.; Stewart, J. P.; Head-Gordon, M.; Gonzalez, C.; Pople, J. A. Gaussian 94, Gaussian, Inc.: Pittsburgh, PA, 1995. 33. Corey, E. J.; Lee, T. W. Tetrahedron Lett. 1997,38,5755. 34. Allred, G. D.; Liebeskind, L. S. J. Am. Chem. Soc. 1996,118,2748. 35. (a) Goodman, J. M. Tetrahedron Lett. 1992,33,7219. (b) Corey, E. J. Rohde, J. J.; Fischer, A,; Azimioara, M. D. Tetrahedron Lett. 1997, 38, 33. (c) Corey, E. J.; Rohde, J. J. Tetrahedron Lett. 1997, 38, 37. (d) Corey, E. J.; Barnes-Seeman, D.; Lee, T. W. Tetrahedron Lett. 1997,38,1699. (e) Corey, E. J.; Barnes-Seeman, D.; Lee, T. W. Tetrahedron Lett. 1997,38,4351. 36. Ishihara, K.; Inanaga, K.; Kondo, S.; Funahashi, M.; Yamamoto, H. Synlett 1998,1053. 37. (a) Schilling, B.; Kaiser, V.; Kaufmann, D. E. Chem. Beu. 1997, 130, 923. (b) Schilling, B.; Kaufmann, D. E. Eur. J. Org. Chem. 1998,701. 38. Birney, D. M.; Houk, K. N. J. Am. Chem. SOC.1990,112,4127. 39. (a) Gao, Q.; Maruyama, T.; Mouri, M.; Yamamoto, H. J. Org. Chem. 1992,57, 1951. (b) Gao, Q.; Ishihara, K.; Maruyama, T.: Mouri, M.; Yamamoto, H. Tetrahedron 1994,50,979. 40. (a) Hattori, K.; Yamamoto, H. J. Org. Chem. 1992,57,3264. (b) Hattori, K.; Yamamoto, H. Synlett 1993,129. (c) Hattori, K.; Yamamoto, H. Tetrahedron 1993,49,1749. 41. Ishihara, K.; Miyata, M.; Hattori, K.; Yamamoto, H.; Tada, T. J. A m . Chem. SOC.1994,116,10520. 42. Reetz, M.; Kunish, F.; Heitmann, P. Tetrahedron Lett. 1986,27,4721. 43. (a) Kiyooka, S.-I.; Kaneko, Y.; Komura, M.; Matsuo, H.; Nakano, M. J. Org. Chem. 1991,56, 2276. (b) Kaneko, Y.; Matsuo, T.; Kiyooka, S. Tetrahedron Lett. 1994,35, 4107. (c) Kiyooka, S.; Kaneko, Y.; Harada, Y.; Matsuo, T. Tetrahedron Lett. 1995,16,2821. (d) Kiyooka, S.; Kira, H.; Hena, M. A. Tetrahedron Lett. 1996, 37, 2597. (e) Kiyooka, S.; Hena, M. A. Tetrahedron: Asymmetry 1996, 7, 2181. (f) Kiyooka, S.; Maeda, H. Tetrahedron: Asymmetry 1997,8, 3371. (g) Kiyooka, S.; Maeda, H.; Hena, M. A,; Uchida, M.; Kim, C.-S.; Horiike, M. Tetrahedron Lett. 1998,39,8287. 44. (a) Parmee, E. R.; Tempkin, 0.;Masamune, S. .I. Am. Chem. SOC.1991, 113, 9365. (b) Parmee, E. R.; Hong, Y.; Tempkin, 0.;Masamune, S. Tetrahedron Lett. 1992,33,1729. 45. (a) Kiyooka, S.; Kaneko, Y.; Kume, K. Tetrahedron Lett. 1992,33, 4927. (b) Kiyooka, S.; Yamaguchi, T.; Maeda, H.; Kira, H.; Hena, M. A.; Horiike, M. Tetrahedron Lett. 1997,38, 3553. 46. Corey, E. J.; Cywin, C. L.; Roper, T. D. Tetrahedron Lett. 1992,33.6907. 47. (a) Furuta, K.; Maruyama, T.; Yamamoto, H. J. A m . Chem. SOC.1991, 113, 1041. (b) Furuta, K.; Maruyama, T.; Yamamoto, H. Synlett 1991, 439. (c) Ishihara, K.; Maruyama, T.; Mouri, M.; Gao, Q.; Furuta, K.; Yamamoto, H. Bull. Chem. SOC.Jpn. 1993,66,3483. 48. (a) Kinugasa, M.; Harada, T.; Fujita, K.; Oku, A. Synlett 1996, 43. (b) Kinugasa, M.; Harada, T.; Egusa, T.; Fujita, K.; Oku, A. Bull. Chem. SOC.Jpn. 1996, 69, 3639. (c) Kinugasa, M.; Harada, T.; Oku, A. J. Org. Chem. 1996, 61, 6772. (d) Kinugasa, M.; Harada, T.; Oku, A. J. A m . Chem. SOC. 1997,119,9067,

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Ishihara

49. (a) Furuta, K.; Mouri, M.; Yamamoto, H. Synlett 1991, 561. (b) Ishihara, K.; Mouri, M.; Gao, Q; Maruyama, T.; Furuta, K.; Yamamoto, H. J. Am. Chem. SOC.1993,115,11490. 50. (a) Marshall, J. A.; Tang, Y. Synlett 1992, 653. (b) Marshall, J. A,; Palovich, M. R. J. Org. Chem. 1998,63,4381. 51. Marshall, J. A. Chemtracts-Org. Chem. 1996,9,280. 52. Aoki, S.; Mikami, K.; Terada, M.; Nakai, T. Tetrahedron 1993,49,1783. 53. (a)Ito, H.; Sato, A,; Taguchi, T. Tetrahedron Lett. 1997,38, 4815. (b) Ito, H.; Sato, A,; Kobayashi, T.; Taguchi, T. Chem. Commun. 1998,2441. 54. (a) Corey, E. J.; Imwinkelried, R.; Pikul, S.; Xiang, Y. B. J. Am. Chem. SOC.1989, I l l , 5493. (b) Corey, E. J.; Yu, C.-M.; Kim, S. S. J. Am. Chem. SOC.1989,111,5495. 55. (a) Hattori, K.; Miyata, M.; Yamamoto, H. J. Am. Chem. SOC. 1993, 115, 1151. (b) Hattori, K.; Yamamoto, H. Synlett 1993,239. (c) Hattori, K.; Yamamoto, H. Tetrahedron 1994,50,2785. 56. Hattori, K.; Yamamoto, H. Biomed. Chem. Lett. 1993,3,2337. 57. Ishihara, K.; Kuroki, Y.; Yamamoto, H. Synlett 1995,41. 58. Kawate, T.; Yamada, H.; Matsumizu, M.; Nishida, A,; Nakagawa, M. Synlett 1997,761. 59. (a) Seerden, J.-P. G.; Scholte op Reimer, A. W. A,; Scheeren, H. W. Tetrahedron Lett. 1994, 35, 4419. (b) Seerden, J.-I? G.; Kuypers, M. M. M.; Scheeren, H. W. Tetrahedron: Asymmetry 1995, 6 , 1441. 60. (a) Peter, A,; Smith, K.; Brown, H. C. ,,Borane Reagents," Academic Press, London (1988). (b) Pure Appl. Chem. 1991,63,345 and 351. 61. Shriver, D. F.; Biallas, M. J. J. Am. Chem. SOC.1967,89,1078. 62. (a) Katz, H. E. J. Am. Chem. SOC.1985,107, 1420. (b) Katz, H. E. J. Org. Chem. 1985,50, 5027. (c) Katz, H. E. J. Am. Chem. SOC. 1986,108,7640. (d) Katz, H. E. J. Org. Chem. 1989,54,2179. 63. Narasaka, K.; Sakurai, H.; Kato, T.; Iwasawa, N. Chem. Lett. 1990,1271. 64. (a) Nozaki, K.; Yoshida, M.; Takaya, H. Angew. Chem., lnt. Ed. Engl. 1994,33,2452. (b) Nozaki, K.; Tsutsumi, T.; Takaya, H. J. Org. Chem. 1995,60, 6668. (c) Nozaki, K.; Yoshida, M.; Takaya, H. Bull. Chem. SOC.Jpn. 1996,69,2043.

Lewis Acids in Organic Synthesis Edited bv Hisashi Yamarnoto Copyright 0WILEY-VCH Verlaa GmbH.2000

6 Achiral Al(II1) Lewis Acids Takashi Ooi and Keiji Maruoka

6.1 Introduction Because of their availability and low cost, aluminum Lewis acids have been widely used in academia and in industry. Friedel-Crafts-type reactions catalyzed by aluminum halides and organoaluminum chemistry, development of which was triggered by the work of K. Ziegler, are representative, and have been of substantial synthetic and industrial significance. This chapter specifically covers recent advances in achiral aluminum(II1) Lewis acids and their applications. It is arranged in five sections, starting with the most familiar aluminum halides to aluminum alkoxides and then covering the utilization of alkylaluminums including trialkylaluminums, alkylaluminum halides, and heteroatom-substituted alkylaluminums. Finally, modified organoaluminums will be discussed in detail, including the development of designer Lewis acids. Because reduction of unsaturated and carbonyl compounds by aluminum-based reagents obviously occupies an important part of functional transformations and could be the subject of another independent review, discussion of this issue is deliberately excluded here.

6.2 Aluminum Halides Aluminum halides (AlC13, A1Br3) are probably the most widely used commercially available aluminum (111) Lewis acids. They are usually white or slightly colored solids which are very moisture-sensitive and have strong Lewis acidity. AlC13 is the catalyst of choice for Friedel-Crafts type reactions. One might even say that, in general, any organic reaction effected by the catalytic action of AlC13, or related catalysts, can be regarded as a Friedel-Crafts reaction. Many important industrial processes are based on Friedel-Crafts chemistry. The scope of Friedel-Crafts reactions is extremely wide, and forms a large part of the more general field of electrophilic reactions. A very large volume of literature has been published and the reader is referred to monographs [l] and comprehensive reviews [2,3] for more detailed information. AlC13 has also been employed in the chemistry of highly fluorinated carbocations [4]. For example, addition of carbon tetrachloride to tetrafluoroethylene in the presence of AIC13 produced the corresponding halogenated hydrocarbon [5].

AIC13

CC14

+

FzC=CFz

CC13CF2CF2CI

100°C

Although detailed studies of the scope of this type of reaction with AlC13 as catalyst have been reported [6,7], more recent work on the use of halofluoroalkanes as alkylating agents has emphasized the activity and selectivity advantages accruing from the

192

Ooi/Maruoka

use of ACF (A1C1,FY) as catalyst. The catalyst ACF can be prepared separately, or often generated in situ by preliminary C1-F exchange of AlCl3 with halofluoroalkane; the following alkylation reactions are representative [8,9].

ACF

+

CF2C12

CICF2CFC12

F2C=CFp

+

30-40 "C

c2F4

CF3CF2CFCl2

CF3CF2CC12CF2CF3

ACF

F2C=CF2

CICF2CC12CF2CF3

40 "C

Recently, reaction of hexafluoroacetone (HFA) with tetrafluoroethylene (TFA) catalyzed by ACF was reported as producing F-2,2-dimethyloxetane (1) in high yield (Sch. 1) [lo].

1

F3C

+

F2C=CF2

CF3

ACF

60 "C, 16 h

F & T Y F2C-CF2

1

66%

Scheme 1

Polytetrafluoroethylene is the only by-product formed. Trifluoroethylene and 2chloro- and 2-bromo-l,l-difluoroethylene all react with HFA regiospecifically to give monohydrooxetanes 2 in 91-98 % yield. The formation of only one isomer, in sharp contrast to the earlier photochemical process [ll], is consistent with an electrophilic mechanism (Sch. 2).

1

F3C

CFs

ACF

+ CHX=CF2

100 "C, 18 h

XHC-CF2

X=F X=CI X=Br

2

: 98% : 98% : 91%

Scheme 2

ACF is very effective catalyst for other transformations via fluorinated carbocations, e.g. alkenylations [12], rearrangements [13], and isomerizations [14]. The advantage of ACF in this type of chemistry could partially come from the exceedingly high affinity of aluminum for fluorine, which enables the facile generation of a carbocation by C-F bond cleavage in organofluorine compounds. The authors focus on this aspect of aluminum Lewis acids later in the chapter. Schwartz and Carr found that hydrozirconation of olefins or acetylenes using Cp2Zr(H)C1 and subsequent transmetalation by A1C13 resulted in clean formation of the corresponding alkylaluminum dichlorides; these were readily acylated to give ketones in excellent yields as depicted in Sch. 3 [15]. It should be emphasized that because hydrozirconation of internal (or terminal) olefins gives the terminal zirco-

Achiral AZ(III) Lewis Acids

193

nium alkyl exclusively [161, this hydrozirconation-transmetalation sequence effectively provides a simple means of converting a mixture of isomeric olefins to a single ketonic product.

0 "C

0

CH2CIz -30 "C

98%

Scheme 3

3

4

r.t, 12 h 120 "C, 6 h

r

<1% : 100% : 0% <1Yo : 0% 68%

HS-Bu

Scheme 4

On developing easy access to a variety of 6-alkyl salicylic acids, Shirai and co-workers found that the methoxy group of 3-butyl-7-methoxyphthalide (3) was cleanly cleaved during A1C13 (5 equiv.)-promoted displacement with butanethiol at room temperature; the product was the phenol 4 [17]. When the reaction was performed at

194

OdMaruoka

120 "C for 6 h, thiophthalide 5 was obtained in 68 % yield, presumably by means of the reaction mechanism illustrated in Sch. 4. The resulting thiophthalide can be converted to 6-amylsalicylic acid (6), a key intermediate of micacocidin A [18], by alkaline hydrolysis and successive desulfurization by Raney Ni.

6.3 Aluminum Alkoxides The utility of aluminum alkoxides in organic synthesis is probably best documented in the Meenvein-Ponndorf-Verley (MPV) reduction generally promoted by Al(OPrL)3[19-211. In the MPV reduction, reversible hydride transfer from the alcoholate to a carbonyl acceptor via a six-membered transition state [A] is initiated by the activation of the carbonyl upon coordination to Lewis acidic aluminum (Sch. 5 ) [22]. Acetone is formed as a volatile side product, which is removable during reaction. The advantage of the MPV reduction includes its chemoselectivity, mild reaction conditions, operational simplicity, safe handling, and ready adaptation both in the laboratory and on a large scale [23]. Nonetheless, there are several practical problems in the reduction, such as the need for excess alcohol as a source of hydride, low reaction rate, formation of condensation products, and use of higher reaction temperature with concurrent removal of acetone to shift the equilibrated reaction towards the formation of alcohol. Among these, the most important side reactions are the aldol condensation and the Tischenko reaction, which leads to the formation of carboxylic esters, especially with the more reactive aldehyde carbonyls [24]. Accordingly, various modifications of the MPV reduction have been developed to overcome these disadvantages. The more recent improvements of the MPV reduction include the use of catalytic lanthanide alkoxides [25] and microwave irradiation [26].

+ (CH&CHOH

R'-C-R2

8

*

AI(OPrj3

*

r

R'-C-R2 I

+ CH3COCH3

OH

A

Scheme 5

Akamanchi and co-workers reported that aldehydes and ketones can be reduced very rapidly in good yield at room temperature by addition of trifluoroacetic acid (TFA) to A1(OPri)3 as shown in Sch. 6 [27]. CHO

A1(0Prj3 (l eq) CF3C02H (1 eq) benzene, r.t.

* quant

Scheme 6

Achiral Al(III) Lewis Acids

195

This modified reagent can be used in catalytic amounts and very efficiently catalyzes hydride transfer from is0 ropanol. In the MPV reduction of m-nitrobenzaldehyde (7, R' = m-N02-C6H4,R = H), it was revealed that Al(OP& and TFA in as low a ratio as 0.0833 and 0.0032 (equiv.) were sufficient to effect complete reduction within 15 min in the presence of just 1 mol equiv. isopropanol (Table 1, entry 2). Various other carbonyl compounds were subjected to reduction under these conditions; the results are summarized in Table 1.

F

AI(OPrj3 (0.083eq) CFSCOzH(0.0032eq) 7

CPrOH (1 e9) benzene, r.t.

*

RlXi#

Table 1. MPV reduction of carbonyl substrates with catalytic A1(OPr')3-TFA. Entry -

Carbonvl substrate (7)

Time (h)

Conversion (%)

1

Benzaldehyde

0.75

93

2

m-Nitrobenzaldehyde

0.50

97

3

4-Methoxybenzaldehyde

4

61

4

3,4-Dimethoxybenzaldehyde

2

72

5

Acetophenone

22

44

6

Propiophenone

24

20

7

Ethyl 3-benzoyl-2-propenoate

24

45

8

1,3-Diphenyl-2-propen-l-one

24

6

9

Cyclohexanone

6

80

Akamanchi also reported that reaction of A1(OPr')3 with TFA in CH2C12 produced a white solid that is stable when stored under dry conditions. Using this new off-theshelf reducing agent, various aldehydes and ketones were reduced to the corresponding alcohols in moderate to good yields at room temperature in a short time [28]. Maruoka and co-workers reported a conceptually new MPV reduction system based on bidentate Lewis-acid chemistry [29].The initial formation of bidentate aluminum catalyst 9 derived from (2,7-dimethyl-1,8-biphenylenedioxy)bis(dimethylaluminum) (8; prepared from 2,7-dimethyl-1,8-biphenylenediol and 2 equiv. Me3A1) and i-PrOH (4 equiv.), followed by treatment of benzaldehyde with the in situ generated (2,7-dimethyl-l,8-biphenylenedioxy)bis(diisopropoxyaluminum) (9) at room temperature instantaneously produced the reduced benzyl alcohol almost quantitatively (Table 2, entry 2). Even with 5 mol% catalyst 9 the reduction proceeds quite smoothly at room temperature to furnish benzyl alcohol in 81 YOyield after 1 h (Table 2, entry 3). This remarkable efficiency can be ascribed to the double electrophilic activation of carbonyls by the bidentate aluminum catalyst (Sch. 7).

196

Ooi/Maruoka

Table 2. Catalytic MPV reduction of carbonyl substrates with bidentate A1 catalyst.a Entry Substrate

A1 reagent

Hydride source

Conditions Yield ( X )

1

PhCHO

A1(OPr’)3 (1 equiv.)

i-PrOH (1 equiv.)

r.t.’, 2 h

2

PhCHO

8 (1 equiv.)

i-PrOH (1 equiv.)

r.t., 1 min > 99

3

PhCHO

8 (5 molX)

i-PrOH (1equiv.)

r.t., 1h

4

PhCHO

8 (5 mol%)

i-PrOH (3 equiv.)

r.t., 1 h

96

5

PhCH( CH&C=O

Al(OP& (1 equiv.)

i-PrOH (1 equiv.)

r.t., 2 h

tracc

6

PhCH( CHz)ZC=O

8 (5 mol%)

i-PrOH (1equiv.)

r.t., 1 h

91

7

PhCH(CHZ)ZC=O

8 (5 mol%)

i-PrOH (1 equiv.)

r.t., 2 h

99

8

PhC(=O)CHzCI

Al( OP& (1equiv.)

i-PrOH (1equiv.)

r.t., 2 h

N.R.‘

9

PhC(=O)CH2Cl

8 (5 mol%)

i-PrOH (1equiv.)

r.t., 2 h

75

10

PhC(=O)CH2Cl

r.t., 10 h

89

PhC( =O)CH*Cl

8 (5 molX) 9 (5 mol%)

i-PrOH (1 equiv.)

11

PhMeCHOH

r.t., 2 h

> 99

A1(OPr‘)3(1 equiv.)

r.t., 5 h

N.R.

12

10

81

13

CHdCJ%COCH3 C H ~ ( C H ~ ) E C O C H ~8 (5 molX)

i-PrOH (1 equiv.) i-PrOH ( 1 equiv.)

r.t., 5 h

52

14

C H ~ ( C H ~ ) S C O C H ~9 (5 mol%)

PhMeCHOH (1 equiv.)

rS., 5 h

73

15

CH3(CH2)sCOCH3 PhCH=CHCOCH3

9 (5 molX)

PhMeCHOH (3 equiv.)

r.t., 5 h

89

16

8 (5 molX)

i-PrOH (1 equiv.)

r.t., 5 h

3Id

17

PhCH=CHCOCH3

9 (5 mol%)

PhMeCHOH (6 equiv.)

r.t., 5 h

70d

“The MPV reduction of carbonyl substrates was effected with several A1 catalysts under the given reaction conditions. ’Room temperature. “No reaction. dYieldsof 1,2-reduction products. RMeCHOH, 11 bidentate Al H R’-C-R2

R’-C-R2

8

I

room temp

OH RCOMe

Scheme 7

Other selected examples are summarized in Table 2. In addition to aldehydes, both cyclic and acyclic ketones can be reduced equally well. seephenethyl alcohol (11, R = Ph) as hydride source works more effectively than i-PrOH. On the basis of this finding, the asymmetric MPV reduction of unsymmetrical ketones with chiral alcohol in the presence of catalyst 10 was examined [30].Treatment of 2-chloroacetophenone (12)with optically pure (R)-(+)-sec-phenethyl alcohol (1 equiv.) under the influence of catalytic 10 at 0 “C for 10 h afforded (S)-(+)-2-chloro-l-phenylethanol(13) with moderate asymmetric induction (82 %, 54 % enantiomeric excess, ee; Sch. 8). Switch-

Achiral AL(III) Lewis Acids

197

ing chiral alcohols from (R)-(+)-sec-phenethyl alcohol to (R)-(+)-a-methyl-2-naphthalenemethanol and (R)-(+)-sec-o-bromophenethyl alcohol further enhanced the optical yields of 13 to 70 and 82 YOee, respectively.

PhY--CI

II 0 4-

I

chiral bidentate Al catalyst 9 (5 mol%) I C - i - -h /- h P CH2C12,O "C, 10 h

I

I L

P h y

I OH 13 82% (54% ee)

I"kl 0

1

OH 58% (70% ee)

51% (82% ee)

Scheme 8

Maruoka has successfully developed a highly accelerated Oppenauer oxidation [31,32] system using a bidentate aluminum catalyst [29]. This modified, catalytic system effectively oxidizes a variety of secondary alcohols to the corresponding ketones as shown in Sch. 9. For example, reaction of (2,7-dimethyl-1,8-biphenylenedioxy)bis(dimethylaluminum) (8, 5 mol%) with carveol (14) at room temperature in the presence of 4-A molecular sieves, and subsequent treatment with pivalaldehyde (3 equiv.) at room temperature for 5 h yielded carvone (15) in 91 YOyield. Under these oxidation conditions, cholesterol (16) was converted to 4-cholesten-3-one (17) in 75 % yield (91 YOyield with 5 equiv. t-BuCHO).

I

w (h ;t:i

Scheme 9

5 eq of t-BuCHO)

198

Ooi/Maruoka

A simultaneous reduction-oxidation sequence of hydroxy carbonyl substrates in the Meerwein-Ponndorf-Verley reduction can be accomplished by use of a catalytic amount of (2,7-dimethyl-1,8-biphenylenedioxy)bis(dimethylaluminum) (8) [33]. This is an efficient hydride transfer from the sec-alcohol moiety to the remote carbonyl group and, because of its insensitivity to other functionalities, should find vast potential in the synthesis of complex polyfunctional molecules, including natural and unnatural products. Thus, treatment of hydroxy aldehyde 18 with 8 (5 mol%) in CH2Cl2 at 21 "C for 12 h resulted in formation of hydroxy ketone 19 in 78 % yield. As expected, the use of 25 mol% 8 enhanced the rate and the chemical yield was increased to 92 %. A similar tendency was observed with the cyclohexanone derivative. It should be noted that the present reduction-oxidation sequence is highly chemoselective, and can be utilized in the presence of other functionalities such as esters, amides, tert-alcohols, nitriles and nitro compounds, as depicted in Sch. 10.

19 78% with 5 mol% of 1 92% with 25 mol% of 1

18

+

f-BuOH

+ C N J( Al

+

UNO'

Al

CH2CI2,21 "C

OH 70% (cidtrans = 23 : 77)

Scheme 10

Despite such intensive studies on MPV reduction chemistry, the corresponding alkylation, i.e., MPV alkylation had never been realized, mainly because of the inertness of alkyl transfer [C] compared with the facile hydride transfer [B] in the MPV reduction, until Maruoka presented the first example of MPV alkynylations for various aldehydes [34]. This truly represents a non-organometallic way of effecting carbony1 alkylation of aldehydes. The success of the approach relies heavily on the discovery of a ligand-accelerated mode for the MPV alkynylations, which has a beneficial effect on the rate of alkynyl transfer.

Achiral Al(II1) Lewis Acids

199

C

6

When an equimolar mixture of 2,2-dichlorodecanal (20) and the in situ-generated A1(OC(CH3)2C- CPh)3 (22) was stirred at room temperature for 5 h, acetylenic alcohol 21 was obtained in only trace amounts (< 1 YO).The choice of aluminum ligand is crucially important in enhancing the rate of alkynylation. When two phenoxy ligands were introduced to prepare PhC= CC(CH3)20A1(OPh)2 (23: derived from 1 and MeAl(OPh)*) the alcohol 21 was obtainable in higher yield (16 YO)under otherwise identical conditions. Changing the two phenoxy ligands to o-phenylenedioxy (24) and o,o'-biphenylenedioxy (25) ligands, the alkynylation was further accelerated to give 21 in 20 % and 53 YO yields, respectively. In the latter instance, the use of excess propargylic alcohol (3 equiv.) resulted in a synthetically useful chemical yield (70 %; Sch. 11).

20

-

0

CH2C12 r.t., 5 h

-Al

I

21

,OPh

, OPh

23 : 16 Yo 22 : <1 %

H3C(H$+C12C-C-C=C-Ph

+

OH

C=O I

CH3

- A \O I / ' 8 24 : 20 %

/

25 : 53 % Scheme 11

The requisite (propargy1oxy)aluminum reagents 25 are readily accessible from either (i) (o,o'-bipheny1enedioxy)methylaluminum (26a) and the corresponding propargylic alcohols 27; or (ii) (o,o'-biphenylenedioxy)(t-butoxy)aluminum (26b) and 27 by ligand exchange. Thc second preparative method also works well and gives results comparable with those from the first method in the MPV alkynylation of various reactive aldehydes (Sch. 12).

200

OdMaruoka

26a : 7 0 % 26b : 61 Yo

26a : 8 5 % 26b : 7 5 %

26a

26b

Scheme 12

One characteristic feature of the MPV alkynylation is the chemoselective transfer of functionalized alkynyl groups to aldehyde carbonyls. Reaction of chloral with functionalized Al reagent 28 in CH2C12proceeds nicely at room temperature to furnish alcohol 29 in good yield, leaving the keto functionality intact (Sch. 13) [34]. Such transformation is not easily realized by use of ordinary alkynylation procedures because of the difficulty of generating functionalized alkynylmetal reagents.

Scheme 13

The cyanation of aldehydes with commercially available acetone cyanohydrin as cyanide source also appears feasible. For example, treatment of 2,2-dichlorodecanal (20) with acetone cyanohydrin under the influence of aluminum reagent 26a or 26b afforded the corresponding cyanohydrin 30 in high yield (Sch. 14) [34].

Achiral Al(III) Lewis Acids

y

201

3

NC-C-OH I

7

Al reagent, 26a or 26b

CH~(CHZ)~CI~C-C-CN

CH~(CH~)TCI~C-C--H

d

li CH~COCHB

20

30

AH >90%

Scheme 14

Functionalized epoxides are regioselectively opened by use of trimethylsilyl azideAl(0P1-j)~giving 2-trimethylsiloxy azides by attack on the less substituted carbon (Sch. 15); this provides a promising way for the preparation of p-amino alcohols [35]. The functional groups acetoxy, methoxy, phenoxy, tert-butoxy, p-toluenesulfonyloxy, phthalimido, chloro, and bromo were unaffected in this reaction. AI(OPrj3 (0.1 eq)

Rjn("2

H

O

H

Me3SiN3 (1.5 eq)* CH2CI2

"\;("1; Me3Si0

R2

53-93'0

R' = -(CH2)"- (n = 3,4,5), XCH2 (X = CI, Br), f-BuOCH2 CHzOH, CH2=CH(CH2)2,etc., R2 = H Scheme 15

Takai, Oshima, and Nozaki achieved stereoselective epoxidation of allylic alcohols with AI(OBu')3-t-BuOOH (Sch. 16); (E)-allylic alcohols were converted predominantly into threo epoxy alcohols; these are unfavorable products in epoxidations with VO(acac)2-t-BuOOH [36]. AI(OBuq3 (1.5 eq) f-BuOOH (2 eq) benzene 5 "C, 4 h

80% (fhreolerythro = >99.5 : <0.5)

Scheme 16

This system found another application- the oxidation of secondary alcohols into ketones in excellent yield. It is worthy of note that the oxidation procedure tolerates other functional groups including iodide, ester, terminal alkyne, aromatic ether, and 1,3-dioxolane. Certain secondary allylic alcohol such as 2-cyclododecen-1-01 (31) produced the corresponding epoxy ketone 32 in one pot, as exemplified in Sch. 17.

202

Ooi/Maruoka

AI(OBuq3(2.5 eq) t-BuOOH (4eq)

benzene, r.t. 31

32

47%

Scheme 17

Aben and Scheeren discovered that bornyloxyaluminum dichloride, which can be easily prepared from borneol, aluminum chloride, and lithium alanate, acts as an effective catalyst for the hetero Diels-Alder reaction of siloxy dienes and a variety of aldehydes, as illustrated in Sch. 18 [37]. MeM ,e

Scheme 18

6.4 Alkylaluminums 6.4.1 Trialkylaluminums and Alkylaluminum Halides Since Ziegler and co-workers discovered the direct synthesis of trialkylaluminums from aluminum metal, olefin, and hydrogen, and their brilliant application of the reaction to the polymerization of olefins [38,39], organoaluminum compounds have become widely accepted and increasingly important in industry and in the laboratory [40,41]. Most of the chemistry of organoaluminum compounds is readily understood in terms of the Lewis acidity of the organoaluminum monomers, which is directly related to the tendency of the aluminum atom to complete electron octets. Nearly all organoaluminum compounds react vigorously with oxygen or air. Trialkylaluminums and dialkyaluminum halides are particularly reactive and often ignite spontaneously. The strong Lewis acidity of organoaluminum compounds seems to account for their great affinity for various heteroatoms in organic molecules, particularly oxygen. They generate 1:l coordination complexes even with neutral bases such as ethers. These properties (commonly identified with heterogenophilicity including oxygenophilicity) are of great value in the design of selective synthetic reactions. On coordination with a heteroatom-containing substrate the aluminum atom serves primarily as the coordination site for the substrate, while the nucleophilic center attached to the aluminum atom can be activated by the formation of the coordination complex facilitating the nucleophilic attack on the substrate; this was highlighted by the successive Beckmann Rearrangement-Alkylation sequence using trialkylaluminums [42].

Achiral AZ(III) Lewis Acids

203

Treatment of a wide variety of oxime sulfonates with several equivalents of alkylaluminum reagents in CH2C12resulted in formation of the imines, which were directly reduced with excess DIBAH to give the corresponding amines, as shown in Sch. 19. This organoaluminum-promoted Beckmann Rearrangement of oxime sulfonates has been successfully applied to the stereoselective synthesis of naturally occurring alkaloids, pumiliotoxin C, and solenopsin A and B, as illustrated in Sch. 20 [43].

H

Scheme 19

'OTs

Pumiliotoxin C 60% overall yield

4)-

Me3AI

CH3(CH2)n

CH3(CH2)n0

C

H

3

"OMS

. LiAIH4-Me3AI TH F -78-0 "C

CH3(CHdn0 " " C H 3 -95% trans Solenopsin A (n = 10) Solenopsin B (n = 12)

Scheme 20

Combination of silyl enol ethers with the organoaluminum-promoted Beckmann rearrangement of oxime sulfonates resulted in a novel reaction system that leads to the formation of enaminones [44]. Treatment of a mixture of anti-2-methylcyclohexanone oxime sulfonate (33) and 2-(trimethylsiloxy)-l-octene in dry CH2C12 with Et2AlCl at -78 "C for 30 min, and at 20 "C for additional 1 h resulted in formation of the enaminone 34 in 90 % yield (Sch. 21).

204

Ooi/Maruoka

[

dMS Et2AICL

]

33

34

90%

Scheme 21

Kita, Fujioka and co-workers reported that the reaction of a-alkoxycycloalkanone oxime acetates such as 35 with organoaluminum reagents caused Beckmann fragmentation and subsequent carbon-carbon bond formation to give different o-cyano-aalkyl (or alkynyl) ethers of type 36 in high yield, as illustrated in Sch. 22 [45]. R’

-t

CN

36

Scheme 22

It is well documented that direct complexation of 1-alkylindane or 1-alkyltetralin with Cr(C0)6 produces a mixture of two possible diastereomeric chromium complexes, endo and ex0 isomers, and the ratio depends on the steric effect and the nature of the substituents [46]. It might also be possible to synthesize either endo or ex0 isomers stereoselectively, from a common a-tetralone or a-indanone. Alkylation of (a-tetralone)chromiumtricarbonyl37with MeLi and subsequent ionic hydrogenolysis with excess Et3SiH and CF3C02H gave (1-endo-methyltetra1in)chromiumtricarbonyl (39) via stereoselective exo-hydride displacement on 38.On the other hand, the endo-acetate complex 40 was converted into (1-em-methyltetra1in)chromiumtricarbonyl (41) via em-methyl attack to the carbocation by treatment with Me3Al (Sch. 23) [47].

Achiral Al(II1) Lewis Acids

205

II

MeLi

I

37 LiAIH4/Ac20

1 1 Cr(C0).-Q

1

Et3SiH ICF3COzH

1

OAc 40 Me3AI

Me

Me 39

endo

41

ex0

Scheme 23

The course of trialkylaluminum-induced cyclization of unsaturated aldehydes was reported to be profoundly influenced by the solvent and temperature. For instance, unimolecular decomposition of the 1:l complex of citronellal-Me3Al at -78 "C to room temperature afforded the acyclic compound 42 in hexane, whereas isopregol (43)was obtained exclusively in 1,2-dichloroethane. Moreover, the cyclization-methylation product 44 was formed with high selectivity by use of excess Me3A1 in CHZC12 at low temperature (Sch. 24) [48]. An intensive study of R2A1C1-induced cyclization of unsaturated carbonyl substrates was made by Snider and co-workers. Their results show the advantage of alkylaluminum chloride over A1C13 in Lewis acid-catalyzed reactions, because these reagents can act as proton scavengers and Lewis acids. The reaction is interpreted as a Me2A1C1-promoted cyclization of the y,d-unsaturated ketone then sequential hydride and methyl shift, as depicted in Sch. 25 [49]. They also applied this method to the intermolecular ene reactions of aliphatic and aromatic aldehydes with alkenes containing a disubstituted vinylic carbon, a potentially valuable route to homoallylic alcohols [50].Proton-initiated rearrangements do not take place, because the alcohol-Lewis acid complex formed in the ene reaction reacts readily to give methane and a non-acidic aluminum alkoxide. Formaldehyde and excess Me2A1C1gave good yield of ene adducts with all types of alkene, as exemplified in Sch. 26.

206

Ooi/Maruoka

OH 44

t

65% Me3AI

88%

80% CH2C12

48%

34%

Scheme 24

& k Scheme 25

9 : l

k

Achiral Al(ZZZ) Lewis Acids

207

Me2AICI (1.2 eq)

+

+

C5H11

RCHO

*

CH2Cl2 0-25 "C

m

H

R=CH3 R=Ph

R : 91% : 69%

Me2AICI(2 eq) (HCH0)n

CH2CI2 0-25 "C

*

OH C5Hll

80% (cidtrans = 1:9)

Scheme 26

Organoaluminum-catalyzed aldol condensation of aldehydes and silyl enol ethers has been reported [51]. Me2AlCI was found to be most effective and other organoaluminum reagents such as Me3A1, EtAlC12, EtzAlCl, and MzAIC1 led to lower yields of /3-hydroxy ketones (Sch. 27). OSiMe3

8

+

PhCHO

cat MeZAICI CH2CI2 -78 "C

P

P

h

88% ( erythrdthreo = 37 : 63 )

Scheme 27

Lewis acids exert a strong catalytic effect on asymmetric Diels-Alder reactions and induce higher asymmetric induction. As a consequence of faster rates, increased stereoselectivity, and enhanced regioselectivity, Lewis acid-catalyzed [4 + 21 cycloadditions have many attractive synthetic advantages and homogeneous alkylaluminum chlorides have been accepted as the most reliable reagents. Evans and co-workers discovered that chiral c@-unsaturated N-acyl oxazolidones result in high diastereofacial selection in Diels-Alder reactions, particularly those conducted in the presence of Et2AlCl [52]. Reaction of chiral acrylate and crotonate imides with cyclopentadiene furnished endo adducts almost exclusively with diastereoselection of ca 95 %. The exceptional reactivity of these dienophile-Lewis acid complexes enabled the use of less reactive acyclic dienes with high diastereoselectivity (> 95 YO diastereomeric excess, de). The chiral auxiliary is cleaved by transesterification with lithium benzyloxide, forming the corresponding benzyl ester in 85-95 YOyield (Sch. 28).

208

Ooi/Maruoka

85%, 90% de

Scheme 28

They also reported the intramolecular version of this asymmetric Diels-Alder reaction [53]. (E,E)-Trienecarboximides of type 45 derived from chiral oxazolidones undergo Me2A1C1-catalyzed intramolecular Diels-Alder reactions affording bicyclic compounds 46 with high endo and diastereoselectivity (endolexo = -lOO:l). The stereochemistry is controlled by the stereogenic center at C4 of the chiral auxiliary (Xc) (Sch. 29).

45

ende46

X,=

1

0

N'

73%

exo-46

(9515)

%HzPh

Scheme 29

The distinct advantage of homogeneous alkylaluminum chloride over A1C13 was clearly demonstrated by the organoaluminum-catalyzed asymmetric Diels-Alder reaction of (-)-dimenthy1 fumarate with various cyclic and acyclic dienes with remarkably high diastereofacial selectivity [54]. Here a single reaction species might be responsible for the cycloaddition, because when the observed enantioselectivity, In (S,S)I(R,R),was plotted against the reciprocal of the temperature, 1/T(in K) a straight line was obtained at temperatures ranging from 25 to -40 "C (Sch. 30).

Achiral AI(III) Lewis Acids

209

Al reagent

n

COO-(-)-Menthy1

0 i-BuzAICI AIC13

+ -

56%, 95% de 6O%, 66% de

Scheme 30

Murphy and Neville found that dihydrofuran undergoes Me2A1C1-promoted [2 + 21 cycloaddition with benzo- and naphthoquinone [55]. It was proposed that this cycloaddition occurs by initial Lewis acid coordination to the quinone, then Michael addition to dihydrofuran, followed by rapid ring closure of the intermediate dipolar ion, as shown in Sch. 31.

+ + oMe2AICI

0

CHzC12 -78 "C

0

Scheme 31

Interestingly, extension of this reaction with benzoquinone to dihydropyrane resulted in the formation of two diastereomeric products 47 and 48 which have unique tricyclic ring systems. Here, none of the [2 + 21 cycloadduct or the potential benzofurofuran was detected (Sch. 32).

-78 "C

0

R

(R-R

Scheme 32

48

47 = 3

0

)

210

Ooi/Maruoka

The same authors also reported the first example of a Lewis acid-catalyzed [2 + 21 cycloaddition between styrenes and naphthoquinones [56]. The reactions of both methoxy and acetoxynaphthoquinones with styrene proceeded regio- and stereospecifically in CH2C12at -78 "C under the influence of Me2AlC1(Sch. 33).

Me2AICI

R

O

-78 "C

R = H, OMe, OCOMe

Scheme 33

Althouk.. N-methoxy-N-methq- amides (Weinreb amides), very usefL. intermediates in organic synthesis, can be prepared from esters by use of Me3Al-MeONHMe. HC1 [57], Nakata and co-workers found that Me2A1C1-MeONHMe. HC1 reacted smoothly with a variety of esters and lactones to afford the desired N-methoxy-Nmethyl amides in excellent yield [58]. This new method is especially effective for the aminolysis of the sterically hindered lactones as illustrated in Sch. 34. On the basis of 'H NMR data [d 3.02 (3H, s, NMe), 3.83 (3H, s, OMe); in CD2C12] the real species in the aminolysis was proved to be C12A1NMe(OMe). U

Scheme 34

Direct and selective conversion of esters into ketones, a fundamental reaction but difficult to achieve, has been accomplished by Ahn and co-workers [59] by use of organoaluminum-diamine complexes. The reaction of methyl benzoate with Me3Al (3.1 equiv.) and N,N-dimethylethylenediamine (DMEDA) (1.1 equiv.) in toluene under reflux followed by an aqueous work-up produced only acetophenone in almost quantitative yield (98 %). Notably, ketones and even aldehydes survive under the reaction conditions. A mechanistic investigation established that the conversion proceeds through transamidation and subsequent intramolecular nucleophilic attack mediated by organoaluminum complexes; this provides an explanation of the need for 3 equiv. Me3A1for the fast reaction (Sch. 35).

Achiral Al(ZII)Lewis Acids

/

MeN Me3Al (3.1 e9),

A

d

O

M

e

211

\

,NMe / (1.1 e9)

toluene, reflux, 1 h

98%

nNMe

RCOOR'

MeN

Me3AI +

I

HI

H

H30'

*-

toluene, reflux, 1 h

0 RAMe

[MeNpMe Me

I -

n

0

0

-

H30+

AIMe?

Me

Scheme 35

Many of the reactions characteristic of organoaluminums are associated with the availability of the empty p orbital of aluminum, which makes these compounds electrophilic or Lewis acidic. Accordingly, organoaluminums (AlR3) react readily with a variety of neutral or negatively charged Lewis bases (L) to form the corresponding tetracoordinate complexes of type D as clearly observed in this chapter. Recently, several limited examples on neutral pentacoordinate, trigonal-bipyramidal aluminum complexes of type E (R = halogen, hydrogen, alkyl; L = nitrogen or phosphine), where ligands L occupy two axial positions, have been isolated and characterized [60]. Little is, however, known about the existence of another pentacoordinate organoaluminum complex F, and its nature still remains elusive despite its potential mechanistic and synthetic importance. Although pentacoordination of type F (R = Et; L = phosphine) in 1:l Et3Al-diphosphine complexes has been previously claimed for Ph2PPPh2, MeN(PPh&, and EtN(PPh2)z [61], recent evidence obtained for the Me3Al-Ph2PCH2PPh2complex only points to a highly fluxional molecule in solution with tetracoordinate aluminum species of type G, even at -80 "C [62].

D

E

F

G

212

Ooi/Maruoka

In this context, Maruoka and co-workers paved the way by forming a hitherto uncertain pentacoordinate organoaluminum complex F and successfully applying its synthetic potential to chelation-controlled selective reactions of fluoro carbonyl compounds, by taking advantage of the high affinity of aluminum for fluorine, and its inherent oxygenophilicity [63]. The origin of the selectivity depends crucially on the intervention of a previously unknown pentacoordinate trialkylaluminum chelate complex. Treatment of an equimolar mixture of 2-fluorobenzaldehyde and 4-fluorobenzaldehyde in toluene at -78 "C with Me2AIC-CPh (1 equiv.) resulted in formation of two different propargyl alcohols 49 and 50 (X = F, R = Ph; 58 % combined yield) in the ratio 9.2:l. The selectivity is reduced by switching the metals of PhC = C-M to Mg, Ti and Li as shown in Sch. 36. The high affinity of aluminum for fluorine compared with other halogens is evident from experiments on the reaction between chloro analogs and Me2A1C= CPh; for these selectivity is only moderate (2.4:l). X

OH

R

toluene

-78"C, 2 h

50

49

X = F, R = Ph, M

= AIMe2 = MgBr

X = F, R = Bu, M

= AIMe2 = Li

: 62% : 74%

7.1 : 1 ) 1.1 : 1 )

X = CI, R = Ph, M = AIMe2

: 64%

2.4 : 1 )

: 58% ( 9.2: 1 ) : 62% (3.7: 1 ) =TiCI(OPrj2 : 60% ( 2.7 : 1 ) = Li :71% 1.8:l)

Scheme 36

This concept was also applied to a discrimination experiment with 2-fluoro- and 4fluoroisobutyrophenone [64]. Thus, treatment of an equimolar mixture of 2-fluoroand 4-fluoroisobutyrophenone in toluene at -78 "C with Me3AI (1 equiv.) and subsequent addition of tributyltin hydride resulted in formation of two different alcohols 51 and 52 (82 % combined yield) in a ratio of 34:l. Here again, the discrimination capacity is dramatically reduced by using other Lewis acids (Sch. 37).

&;&L:;j!F8":r,& F

-78"C, 2 h Lewis acid:

Scheme 37

OH

51

52

Me$I : 82% ( 34 : 1 ) TiCI2(0Prj2 : 71% ( 1.9: 1 ) : 71% (1.9:1 ) MgBr2 SiCI4 : 12% (2.3:1 ) SnCI4 : 17% (1:1.3) LiC104 no reaction

Achiral Al(III) Lewis Acids

213

The advantage of aluminum reagents over other metal reagents was also seen in the Lewis acid-promoted allylation of fluoro carbonyl compounds. For instance, Me3Al-promoted selective allylation of an equimolar mixture of 2- and 4-fluorobenzaldehydes with allyltributyltin afforded the homoallylic alcohol 53 almost exclusively. Unsatisfactory chemical yield and/or selectivity were obtained with Ti, Mg, Li, Sn, and Si Lewis acids (Sch. 38). F

Lewis acid (2 eq)

F

OH

toluene, -78 "C Lewis acid: Me3AI TiClz(OPrjz MSBb LiC104 SiCI4 SnCI4

54

: 74% ( 3 1 : 56% (9.8 : 18% (7.1 : 17% (4.1 : 30% (3.8 : 84% ( 3.9

1) :1 ) 1) 1)

:1) :1)

Scheme 38

Despite the numerous studies aimed at achieving syn-selective aldol reactions with ordinary aldehydes, the corresponding anti-selectivity has not been easily attainable owing to lack of appropriate methodologies [65,66]. Indeed, the synlanti problem has been one of long-standing concern with regard to 1,2- and 1,3-asymmetric induction in acyclic systems [66]. On the basis of the dramatic metal effect described above, the authors have found that high anti-selectivity is achieved in the aldol reactions of fluoro aldehydes with ketene silyl acetals in the presence of trimethylaluminum. For example, Me3Al-induced reaction of o-fluorobenzaldehyde (55a) with a substituted ketene silyl acetal gave rise to a mixture of fluoro /3-hydroxy esters, 56a and 57a with high diastereoselectivity, because of the effective fixation of carbonyl moiety (56a/ 57a = 16:1), whereas the selectivity was dramatically reduced by use of other common Lewis acids, for example BF3. OEt,, TiC14 and Me3SiOTf. In contrast, however, use of o-anisaldehyde (55b) and benzaldehyde (5%) resulted in moderate selectivity (56b/ 5% = 56c/57c = 5.3:l). In a similar manner, fluoro aldehyde 58a on reaction with a ketene silyl acetal in the presence of trimethylaluminum afforded the fluoro phydroxy ester 59a with good selectivity (59a/60a = 6.1:l) (Sch. 39).

214

Ooi/Maruoka 1) Lewis acid

OSiMe3

-CHO 55a (X = F) 55b (X = OMe) 5 5 (X ~ = H)

% + /

THF r.t., 1 h

OH

2, P O P , (1.2 eq) -78 "C, 1 h

GO

OPh 0

OH

56a (X = F) 56b (X = OMe) 5 6 (X ~ = H)

Lewis acid

BF3*0Et2 TIC14 Me3SiOTf Me3AI

: 70% (56a:57a = 1:1.8) : 74% (2.9:l) : 85% (1:1.5) : 96%(16:1) : 89% (56b:57b = 5.3~1) : 88% ( 5 6 ~ 5 7 C = 5.3:l)

1) Me3AI (1.2 e9) 1 N H C I toluene q

C

H

*-

0

OSiMe3 58a (X = F) 58b (X = H)

2, AOPh (1.2 e9) -78 "C, 1 h

THF r.t., 1 h

/

OPh +

59a (X = F) 59b (X = H)

0

57a (X = F) 57b (X = OMe) 5 7 (X ~ = H)

%

80% (6.1:l) 94% (2.3:l)

OPh

60a (X = F) 60b (X = H)

Scheme 39

The high diastereoselectivity observed is ascribed to effective chelate formation between Me3Al and fluoro carbonyl compounds via pentacoordinate organoaluminum complex H; this was verified by a low-temperature 13C and 19FNMR study. The original signal of the carbonyl carbon in fluoro ketone 61 (model substrate) appeared at 6 208.5. When 61 was complexed with Me3Al in a 1:1 molar ratio in CD2C12 at -50 "C, a significant downfield shift (6 225.0) was observed for the carbonyl carbon by I3C NMR analysis. I9F NMR measurement of the complex H under similar conditions also showed the F signal at 6 -117.4; this originally appeared at 6 -118.02 in 61 [67].

(1-3)

61

61/Me3AI complex, H

This approach is also applicable to selective functionalization of carbonyl substrates with a trifluoromethyl group in an appropriate position, as exemplified by the diastereoselective reduction of 2-trifluoromethylcyclohexanone (62) with Me3A1 and Bu3SnH (Sch. 40) [68]. This selectivity can be interpreted in terms of the formation of the intermediate chelate-like pentacoordinate Me3Al complex [I]. When DIBAH was employed as a reducing agent, total lack of selectivity was observed, and the opposite diastereoselectivity was observed for the reduction with NaBH4 in methanol at 0 "C.

Achiral AC(III) Lewis Acids

&cF3

215

reducing agent

U

to Iuene

Me Me, M ,I e P Ic 0 "'F

62

"I Me3AI/Bu3SnH,-78 "C, 3.5 h

: 69% (81 19)

DIBAH, -78 "C, 1.5 h

: 56% (57 : 43)

NaBH4 (in MeOH), 0 "C, 20 min

: 57% (20 : 80)

Scheme 40

Nozaki and co-workers reported that treatment of the simple ally1 vinyl ether 63 with diethylaluminum phenylacetylide resulted in the [3,3]sigmatropic rearrangement and subsequent alkynylation on the rearranged aldehyde carbonyl, giving the corresponding propargyl alcohol 64 in high yield [69]. Aluminum reagents such as Et,AlSPh and the system Et2A1C1/PPh3were also effective in the rearrangement, providing the normal Claisen products, y,d-unsaturated aldehydes as indicated in Sch. 41. Et2AICECPh

0 63

4

CICH2CH2CI 25 "C, 15 min

25 "C, 15 min

Et2AISPh Et2AICI + PPh3

64 88%

O H C U B U 84% ( E/Z = 39 61 ) 81% ( E/Z = 43 : 57 )

Scheme 41

The same group expanded this organoaluminum-promoted Claisen rearrangement to five-membered ring enol ethers with vinyl substituents [70]. Here reaction proceeded in three different directions: (i) [3,3] sigmatropic rearrangement yielding 7-membered carbocycles, (ii) isomerization to vinylcyclopropane derivatives, and (iii) S&' type displacement with phenylthio anion via oxolane ring opening (Sch. 42).

216

Ooi/Maruoka OH

c,

i-Bu~Al

CH2CI2 25 "C

Me

82%

i-Bu3Al h

CICHZCH~CI reflux

Et2AISPh

&C4H9

h

71%

S

CH2C12 25 "C

P

h 75%

Scheme 42

Overman and Flippin utilized diethylaluminum amides for facile aminolysis of epoxides [71]. The procedure involved treating a primary or secondary amine in CH2C12 with Et3Al (1 equiv.) at room temperature for 30 min, then reaction with epoxide (1 equiv.) overnight. Hydrolysis of the resulting amino aluminate eventually afforded the /3-amino alcohol product in good yield. Aminolysis of cyclopentene oxide with diethylaluminum anilide is shown in Sch. 43 as a typical example.

CH2C12 25-30 "C

"""NH

Ph 86%

Scheme 43

Two research groups independently reported the regioselective alkylation of epoxy alcohols with trialkylaluminums. Nozaki and co-workers reported that introduction of an alkyl or alkynyl group, or hydride takes place regioselectively at the 3 position of the epoxy alcohols with inversion of configuration upon treatment with organoaluminum reagents to produce the corresponding 1,2-diols as shown in Sch. 44 [72]. Roush and co-workers succeeded in synthesizing aldehyde 66 in high enantiomeric purity by treatment of the optically active 2,3-epoxy alcohol 65 with Me3A1, then periodate cleavage. The aldehyde 66 and its enantiomer are well-known intermediates usually prepared from (S)-/3-hydroxyisobutyric acid, and have been used in several recent natural product syntheses (Sch. 44) [73].

Achiral Al(III) Lewis Acids

reagent (3 eq)

H

9% BnO65

OH

HO B~+H

H

R H

Me3AI

: 94% (R = Me)

PhCrCAIEt2 i-Bu2AIH

: 95% (R = PhCGC) : 72%(R=H)

Me3AI (3 eq)

217

OH B

n

CH2C12 0-23 "C

O

-ye v

H

+

B

n

Me

O

v

H

v

H

OH

-ye ___)

+

Me

B

n

O OH

66

69-73%

13-1 4%

Scheme 44

Yamamoto and Maruoka devised an efficient method for the mild and selective synthesis of 3-azidodiols which involves a highly regio- and stereoselective ring-opening of 2,3-epoxy alcohols with Me3SiN3 and Et,AlF (Sch. 45) [74]. OH

+OH

+OH Me3SiN3/Et2AIF NaN3/NH4CI

OH

+

U)S..

84% ( 98 : 2 ) 90% ( 53 : 47 )

Scheme 45

The regioselectivity of epoxide-opening reactions using alkynylaluminum reagents for prostaglandin synthesis has been studied by Matthews and Eickhoff [75].With two different cyclopentane oxide derivatives, they pointed out that simple substitution of an aluminum ate complex for the usual trialkylaluminum can sometimes be useful in achieving the desired regioselectivity, as observed in Sch. 46.

Me2AIC=CCH(OBd)(CH2)&H3 3.3 : 1 L ~ M ~ ~ A I ( C ~ C C H ( O B U ~ ( C H ~ ) & H1~ ):~5 Scheme 46

R=CH(OBd)(CH2)4CH3

218

Ooi/Maruoka

As already discussed in this chapter, aluminum, in addition to its well-known high oxygenophilicity (Al-0 = 511 f 3 kJ mol-l), has exceedingly high affinity toward fluorine; this is evident from the bond strengths in several metal-fluorine diatomic molecules: A1-F, 663.6 f 6.3 kJ mol-'; Li-F, 577 & 21 kJ mol-l; Ti-F, 569 f 34 kJ mol-l; Si-F, 552.7 rt 2.1 kJ mol-l; Sn-F, 466.5 & 13 kJ mol-l; and Mg-F, 461.9 f 5.0 kJ mol-' [76]. Organoaluminum reagents seem, therefore, quite suitable for fluorineassisted selective alkylation of fluoro epoxides, which also represents the experimental demonstration of the intervention of pentacoordinate chelate complexes of trialkylaluminums as plausible intermediates [63].

Alkylation of terminal or 1,2-disubstituted epoxides normally provides a regioisomeric mixture of corresponding ring opening alcohols. For instance, treatment of 3-phenyl-1,2epoxypropane 67 (X = H) with MezAIC- CPh in toluene at -78 to -20 "C gave rise to a mixture of 1,5-dipheny1-4-pentyn-2-01 68 (R = Ph) and 2-benzyl-4-phenyl-3-butyn-1-01 69 (R = Ph) (64 % combined yield) in the ratio of 1.1:l. In marked contrast, however, reaction of its fluoro analog, 3-(2-fluorophenyl)-1,2-epoxypropane67 (X = F) with MezAIC = CPh under similar reaction conditions afforded 1-(2-fluoropheny1)-5-phenyl4-pentyn-2-0170 (R = Ph), exclusively,in 61 % yield (Sch. 47). Me2A'CEC-R

to Iuene -78--20 "C

67 (X = H, F)

m

-

c

f

l

+

E

R

68

O

H

69

R = Ph, SiMe3: 1.1-1.8 : 1 (64-70%) same condition

oT70 C=CR

R = Ph, SiMe3: 61-69%

Ph

72 (X = H, F) ph+CECPh

+ Ph

X = F : >99:<1 (70%) X = H: 1 : 1.2 (42%) Scheme 47

OH

Achiral AZ(III) Lewis Acids

219

The effect of the metal on the regioselectivity of this alkynylation was also examined. Attempted reaction of fluoro epoxide 67 (X = F) with PhCECMgBr or PhC=CTiC1(OPr')2 gave halohydrin 71 (X = C1 or Br) as a sole isolable product. Use of PhC- CLi with substrates 67 significantly retarded the epoxide cleavage irrespective of the presence or absence of a fluoro group. High regioselectivity was also observed for 1,2-truns-disubstituted fluoro epoxide 72 (X = F). Moderate selectivity was even obtained with a 6-fluoro epoxide. Although the hypothetical existence of pentacoordinate trialkylaluminum complexes with fluoro epoxides is strongly implied by the alkynylation experiments described above, more direct evidence was obtained from a low-temperature 13C NMR study of these aluminum complexes (Sch. 48). When 67 (X = F) was complexed with Me3A1in a 1:l.lmolar ratio in CD2C12 at -78 "C, a significant downfield shift of epoxide carbons C-1 and C-2 in structure J was observed with concomitant upfield shift of C-F carbon C-5 at -78 "C; this supported the expected chelate formation of aluminum with fluoro epoxide 67 (X = F). It should be added that the upfield shift of fluorinebearing carbon was also observed in the 13C NMR measurement of fluorobenzene with Me3AI (1.1equiv.) in CD2C12 at -78 "C. A similar tendency was observed in the epoxide 73/Me3A1chelate complex K in CD2C12at -78 "C. Although these I3C NMR data might not rigorously eliminate the possibility of the involvement of a fluxional complex of type G, low-temperature 27AlNMR analysis of several trialkylaluminum complexes further supports the existence of pentacoordinate complexes J and K [77].

I 1 1 I 1 complex J

67 (X = F)

CMR Data

C-1

free 67 (X = F) 6 46.27 complex J

Scheme 48

6 53.60

C-2

2 6 182

C-5

6 50.83 6 161.09

6 59.69 6 160.08

220

Ooi/Maruoka

3,3,3-Trifluoropropene oxide (TFPO) has been afforded much attention by numerous organic chemists and biochemists, because it is quite useful as a starting substrate for liquid crystals and biologically active compounds [78-801. Although several studies have been performed on the cleavage reactions of TFPO, there have been few nucleophilic alkylations of TFPO with reactive organometallics [go]. Recently, Uneyama et al. reported the successful ring-opening reaction of TFPO with a-cyanocarbanions [81]. In conjunction with the discovery of fluorine-assisted selective alkylation of fluorinated carbonyl compounds and epoxides via pentacoordinate trialkylaluminum complexes, a new organoaluminum-promoted selective alkylation of 3,3,3-trifluoropropene oxide (TFPO) (74) with several nucleophiles has been studied. The results are summarized in Sch. 49 [68].

-3

mCH3 53%

/toluene

88% (R=Ph) 80% (R = SiMe3)

64%

59%

51%

62%

Scheme 49

A highly effective catalytic method for alkynylation of epoxides has recently been reported; this involves the chelation-controlled alkylation of hetero-substituted epoxides with Me3A1 and alkynyllithiums via pentacoordinate organoaluminum complexes [82]. For instance, reaction of epoxy ether, (l-benzyloxy)-3-butene oxide (75) in toluene with PhCzCLi under the influence of catalytic Me3Al (10 mol%) proceeded smoothly at 0 "C for S h to furnish the alkynylation product 1-(benzy1oxy)-6phenylhex-5-yn-3-01 (76) in 76 YO yield. The yield of the product was very low (3 YO) without Me3A1as catalyst under similar conditions. This is the first catalytic procedure for amphiphilic alkylation of epoxides. The participation of pentacoordinate Me3A1 complexes of epoxy ethers of type 75 is emphasized by comparing the reactivity with the corresponding simple epoxide, 5-phenyl-1-pentene oxide (77),which was not susceptible to nucleophilic attack of PhC = CLi with catalytic Me3Al under similar conditions (Sch. SO).

221

Achiral AI(III) Lewis Acids

Me3AI (10 rnol%) PhC=CLi (1.1 eq)

BnO

toluene 0 "C, 5 h

75

*

same conditions *

L BnO

C

e

C

P

h 76

76% (3% without Me3AI)

PhA

C

E

C

P

h

Ph 77

<1Yo

Scheme 50

The Me3Al-catalyzed alkynylation of hetero-substituted epoxides can be interpreted in terms of the mechanism shown in Sch. 51. Ligand exchange between the initially formed R C = CA1Me3Li and epoxy ether 75 generates the pentacoordinate Me3Al complex (M). R C s C L i then attacks the epoxide moiety of the complex (M) at the less hindered site to give alkynylation product (N). Further ligand exchange of (N) with alkynyllithium produces the final product 78 with regeneration of alkynylaluminate (L) for further use in the catalytic cycle of the alkynylation.

+

RCECLi

75

OAIMe3Li Me3AI + RCECLi

-----)

RCECAIMe3Li

Ph-0

A

C

E

C

R

(N)

OLi RCECLi

Scheme 51

This new approach has been quite useful in the selective functionalization of bisepoxides of type 79. Reaction of 79 with PhCECLi in toluene can be catalyzed by 10 mol% Me3Al to afford monoalkynylation product 80 in 68 % yield, leaving the remote epoxide moiety intact, as illustrated in Sch. 52.

222

Ooi/Maruoka

OBn

10 mol% Me3AI PhCECLi

*

Ph-CZC

toluene 79

0 "C - r.t.

80

68%

Scheme 52

This catalytic system was successfully applied to the alkynylation of tosyl aziridine with adjacent ether functionality; this should provide a promising method for the synthesis of amino alcohols. Treatment of tosyl aziridine 81 with PhCE CLi in the presence of catalytic Me3A1in toluene at 0 "C for 5 h gave rise to the corresponding alkynylation product 82 in 66 Yoyield (Sch. 53), whereas reaction in the absence of Me3A1 proceeded sluggishly under similar reaction conditions (7 YO yield). The control experiment with simple aziridine 83, in which addition of catalytic Me3Al had almost no influence on the reaction rate, supports the proposed catalytic cycle; its efficacy is based on the formation of the pentacoordinate organoaluminum complex. 10 mol% Me3AI PhCECLi

Ph,OANTs

81

toluene 0 "C, 5 h

NHTs P h - O A C s C - P h 82

66% 7% without Me3AI

P h A N T S

83

PhCECLi toluene 0 "C, 5 h

P h x C E C - P h 4 Yo (with or without Me3AI)

Scheme 53

Yamamoto and Maruoka investigated the reaction of chiral acetals with organoaluminum reagents. Unprecedented regio- and stereochemical control was observed in the addition of trialkylaluminums to chiral a,,!?-unsaturated acetals derived from optically pure tartaric acid diamide [83]. The course of the reaction seemed to be highly influenced by the nature of substrates, solvents, and temperature. These findings provide easy access to optically active a-substituted aldehydes (84), ,!?-substituted aldehydes (SS), a-substituted carboxylic acids (86), or allylic alcohols (87).Because optically pure (R,R)- and (S,S)-tartaric acid diamides are both readily available, this method enables the predictable synthesis of both enantiomers of substituted aldehydes, carboxylic acids, and allylic alcohols from a$-unsaturated aldehydes (Sch. 54).

Achiral Al(III) Lewis Acids

223

,++r

toluene or ClCH2CH2Cl

94-98% ee ( R‘ = Ph )

1

1

ye R’-CHO

f-BuOK

Me

84

R’nCOOH

>95% ee ( R’ = Ph )

86

>95% ee ( R’ = Ph)

R’ 88% ee ( R1 = Pr )

Scheme 54

That this asymmetric reaction has vast potential in natural product synthesis is illustrated by the short synthesis of the side-chain alcohol present in the biologically important vitamins E and K (Sch. 55).

1) Me3AI

2) Ac20-P~ 55%

C O N M 2 ,eO lA c

-0

CONMe2

1) H30+

2)NaBH4

92% (96% ee)

OH Side-chain alcohol of vitamin E and K

Scheme 55

Kinetic resolution of chiral acetals has been effected by use of some organoaluminum reagents [84]. On treating a chiral acetal88, derived from (2R,4R)-(-)-pentanediol,with i-Bu3Al at room temperature, one diastereomer was found to react much faster than the other, and the residual enol ether is transformed into optically pure ketone. The efficiency of this method is demonstrated by a concise synthesis of (S)-(-)-5-hexadecan-1,5-lactone (89),the pheromone of Vespa orientalis, as shown in Sch. 56.

224

Ooi/Maruoka

bMe I \

28% ( >99% d e )

8dOH

34% ( 299% d e )

"'TY

(5%8

0 DIBAH

R--

H30'

&R

?M :

o

~

0 "C, 30 min 86%

37% (

89

= CllH23 )

Scheme 56

This reaction has been further extended to the asymmetrization of the symmetric acetal, and to different modified organoaluminum reagents including i-Bu,Al and bulky organoaluminum amides (Sch. 57) [85].

- ,$ dOH

i-Bu3Al

R

-78-0 "C 99%

+

R

R

R=Me R = t-BU

,$ dOH

90 : 10 89 : 11

Scheme 57

Yamamoto subsequently discovered that ring formation by intramolecular addition of a terminal hydroxy group of 90 to a double bond can be facilitated by Tf20 in the presence of excess i-Pr2NEt at -78 "C to produce, after work-up with aqueous acetic acid, the cyclized hemiacetal 91 in excellent yield (> 95 %) [85]. The resulting hemiacetal was quantitatively transformed to the medium ring iodolactone 92 by the procedure of Suginome [87], Suarez [%], or Nagao [89]. The effectiveness of the method

R

Achiral Al(III) Lewis Acids

225

was, moreover, demonstrated by the facile synthesis of (-)-lardohre [90], the aggregation pheromone of the acarid mite, Lurdoglyphus konoi, in short steps starting with simple ketone 93 as illustrated in Sch. 58.

1

i

90

-& 0

Bu3SnH quant.

:

-

91

92

.+\'

DIBAH

"""

92%

HOu Ho

u

UOH 95%

OCHO

(-)-Lardohre

Scheme 58

On treatment with diethylaluminum trimethylsilylacetylide in the presence of BF,.OEt,, a-acetoxy ether 94 gave the truns-1,3-dioxane 95 in good yield with excellent stereoselectivity, as reported by Rychonovsky and Dahanukar [91]. The trans alkyne adduct has the configuration expected from axial addition to a cyclic oxonium ion (Sch. 59).

moAc

CECSiMe3

BF3*0Et2/CH2C12

*

O Y O C6H13 94

Scheme 59

Me3SiECAIEt2 -78 "C

O Y 0 C6H13 95

77% (>lo

226

Ooi/Maruoka

A direct and satisfactory procedure for tertiary alkyl-alkynyl coupling has been developed by Negishi and Baba, who used trialkynylaluminums readily obtainable from the corresponding alkynyllithiums and anhydrous A1C13 [92]. For instance, tris( 1-hexyny1)aluminum underwent a remarkably clean reaction with 1-adamantyl bromide to produce cross-coupled product 96 in 96 % yield. It is noteworthy that the reaction enables novel geminal alkyl-alkynylation of ketones; this reaction should find a considerable application in natural product synthesis (Sch. 60).

0 "C, 1 h

96

96%

Scheme 60

A highly convenient and versatile cyclopropanation method has been devised which involves treatment of olefins with different organoaluminum compounds and alkylidene iodide under mild conditions [93]. Although Miller found that cyclopropane formation by use of Et3Al-methylene iodide in cyclohexene proceeds in quite disappointing yields [94], Yamamoto and Maruoka reached the conclusion that the intermediate dialkyl(iodomethy1)aluminum species 97 is responsible for the cyclopropanation of olefins and that it readily decomposes in the absence of olefins or in the presence of excess trialkylaluminum. Hence the use of equimolar amounts of trialkylaluminum and methylene iodide in the presence of olefins is essential for the achievement of reproducible results in the cyclopropanation process. In addition, because dialkylaluminum halide can also be used as a cyclopropanation agent, the use of half an equivalent of trialkylaluminum is not detrimental (Sch. 61).

97 R = H and Me ; R' = Me, Et and i-Bu

25 "C, 10-13 h

Scheme 61

85-94%

84-99%

Achiral Al(III) Lewis Acids

227

The organoaluminum-mediated cyclopropanation had unique selectivity not observable in Simmons-Smith type reactions [9S]. Treatment of geraniol with i-Bu3Al (2 equiv.)-methylene iodide (1 equiv.) in CHzClz at room temperature for 5 h produced cyclopropanation products in 75 % combined yields in the ratio 76:1:4. Consequently, methylene transfer by the aluminum method occurs almost exclusively at the C(6)-C(7) olefinic site far from the hydroxy group of geraniol and the C(2) -C(3) olefink bond was left intact. In sharp contrast, the zinc method resulted in the opposite regioselectivity via hydroxy-assisted cyclopropanation, as shown in Sch. 62.

i-Bu3AIICH2I2 Et2Zn/CH212

7 6 : 1 . 4 2 : 7 4 : 3

Scheme 62

Posner and Haines used the strong affinity of aluminum toward fluorine as a new tool for carbon-carbon bond formation by reacting glycosyl fluoride with organoaluminum reagents [96]. Accordingly, various furanosyl and pyranosyl fluorides react rapidly with alkyl, alkenyl, alkynyl and arylaluminum reagents to give C-glycosides in high yields. Effective application of this procedure to a 6-fluoro-1,6-anhydroglucose derivative produced a chain-extended sugar stereospecifically (Sch. 63).

z ' bF ' I b? z b 0

0

toluene Et3AI

Ox'

Et

0 x 0

O"C, 10min 76-79%

Et3AI

toluene 0 "C, 15 min

@

OBn

OBn

84% Scheme 63

( >20 1 )

22%

OdMaruoka

The authors were also intrigued by the possibility of activating fluorine as a leaving group by use of organoaluminums, through the eminent A1-F interaction, and successfully developed the new organoaluminum-catalyzed alkylation of tert-alkyl fluorides with certain nucleophiles illustrated in Sch. 64; this provides a facile route to the construction of quaternary carbon centers in organic synthesis [97]. 10 mol% Me3AI R'R2C=C(OR3)0SiMe3 (99) PhF d

CH2CI2, -78-20 "C

*

Ph+OR3

R'

98

R' = R 2 = R 3 = M e Ri = H, R2 = R3 = Me R' = R 2 = H . R 3 = P h

1

10 mol% Me3AI Me3SiN3,CH2C12 -78-20 "C

Ph2

N

: : :

R2

100

63% 74% 63%

3

10 mol% Me3AI R'R2C =C(OR3)0SiMe3 (99)

"No Reaction"

Ph

CH2C12, -78-20 "C 101

Scheme 64

Treatment of 2-fluoro-2-methyl-4-phenylbutane (98) and ketene silyl acetal 99 (R' = R2 = R3 = Me) in distilled CH2C12 with a catalytic amount of Me3A1 (0.1 equiv.) at -78 to 20 "C for 2 h gave rise to a-tert-alkylated ester 100 (R' = R2 = R3 = Me) in 63 YO yield. The less substituted ketene silyl acetals 99 (R' = H, R2 = R3 = Me and R' = R2 = H, R3 = Ph) were also smoothly alkylated in a similar manner and the introduction of azide functionality seemed to be feasible with trimethylsilyl azide. In marked contrast, attempted reaction of chloro analog 101 with 99 (R' = R2 = R3 = Me) under similar reaction conditions resulted in almost total recovery of the starting chloride 101 (Sch. 64). Attempted use of TiC14 as catalyst in the alkylation of 98 with 99 (R' = R2 = R3 = Me) resulted in significant rate retardation yielding 100 (R' = R2 = R3 = Me) in only 11 YO yield with the predominant formation of chlorination product 101 (39 YO);neither did the reaction proceed with Ti(OP& or SnC14. These results clearly reveal the effectiveness of activation of tertalkyl fluorides by alkylaluminums. One of the characteristic features of this approach is the successful tert-alkyl-alkynyl coupling with dialkylaluminum alkynides which enables the introduction of a quaternary carbon in a position adjacent to an alkynyl group. Such transformation was previously achieved by the cross-coupling of tert-alkyl chlorides with trialkynylaluminums as already described in this section [92]. The reaction of 98 with dimethylaluminum phenylacetylide (1.5 equiv.), readily prepared from lithium phenylacetylide and Me2AICl, in toluene at -78 "C for 30 min resulted in formation of a cross-coupling product in 70 YOyield. This result indicates the efficient and selective transfer of the alkynyl group from the aluminum center in dialkylaluminum alkynides as depicted in Sch. 65.

Achiral Al(III) Lewis Acids

229

Ph-CzC-AIMe2 Ph

-78toluene "C, 30 min*

Ph+

Ph

70%

98 Scheme 65

The new tert-alkylation method was highlighted by the selective functionalization of difluoroalkane with different reactivity profile including tert-alkyllprim-alkyl and tert-alkyllsec-alkyl fluorides. This method provides a facile route to new types of organofluorine compounds which are increasingly important in biochemical/biological, pharmacological, and material science [98]. For instance, reaction of difluoroalkane 102 with ketene silyl acetal 99 (R' = H, R2 = R3 = Me) was catalyzed by 10 mol% Me3A1 to afford alkylation product 103 in 60 % yield, leaving the primary alkyl fluoride moiety intact as shown in Sch. 66.

MeJr:l

10 mol% M e 3 t M e: *F

F4

F

+

CH2C12

-78-20 "C, 2 h

102

60%

Scheme 66

Despite the use of polyhalomethane (CH2C12etc) as a solvent for organoaluminum reagents, explosive reactions have sometimes resulted from mixtures of CC14 with trialkylaluminums, alkylaluminum hydrides, and alkylaluminum halides [40]. The reactions seem to be free-radical chain processes involving the trichloromethyl radical as an initiator. By manipulating the hitherto uncontrolled reactivity of organoaluminum-polyhalomethane systems, a new method for the regioselective addition of polyhalomethane to olefins has been developed by Yamamoto and Maruoka [99]. Although various organoaluminums were surveyed as initiator for the addition reaction, only Me3A1was found to be satisfactory (Sch. 67).

-

Me3AI

/-xi\

C10H21L C C I , 86%

Me3AI C10H21X C C l , BrCC13 hexane

95%

Scheme 67

The organoaluminum-induced addition reaction has been applied to the polyfluoromethylation of olefins as illustrated in Sch. 68.

230

Ooi/Maruoka

Me3AI

+

CF31

CHgC19 -20 "C, 8 h L

I

cat AlBN I C,F3 Phm

Ph\/\/CF3

Bu3SnH

L

---,

(6%

76%

Scheme 68

Negishi and co-workers developed the zirconocene-catalyzed carboalumination of alkynes as a new route to stereo- and regio-defined trisubstituted olefins [loo]. Phenylacetylene and several other alkynes on treatment with CpzZrC12-Me3Al undergo cis addition to afford the corresponding alkenylaluminums almost exclusively. Such alkenylaluminums have already proven to be versatile intermediates in the preparation of a wide variety of trisubstituted olefins. Although the Cp2ZrCl2-catalyzed reaction of alkynes with trialkylaluminum with p hydrogens is complicated by competitive hydrometalation [loll and reduced regioselectivity, the hydrometalation can be avoided by employing dialkylaluminum chloride in place of trialkylaluminum. On the basis of mechanistic investigations, they concluded that the Zr-catalyzed carboalumination reaction probably involves direct Al-C bond addition assisted by Zr (Sch. 69).

PhCECH

1) BuLi

CpzZrCIz

PhCECD

Me3AI

2) Dz0

CpzZrClz

1

Ph Me-iIMez

Me3AI

(96% E)

98% (>98% Z)

Scheme 69

Application of Zr-catalyzed carboalumination to haloalkyl-substituted 1-(trimethylsily1)-1-alkynes provides a new metal-promoted cyclization reaction [102]. The reaction of 4-bromo-3-methyl-l-(trimethylsilyl)-l-butyne(104) and its regioisomer 105 with CpzZrClz-Me3Al furnished the same product, 106. The regiochemical results are in good agreement with the participation of intermediate 107, as indicated in Sch. 70.

CpzZrCI2

Me

Me3AI 104

Me

Me3AI

106

Me SiMe3 Mef i M e0 z B r 107 Scheme 70

Br

Me *SiMe3 105

Achiral Al(III) Lewis Acids

231

The Cp2ZrC12-catalyzed allylalumination and benzylalumination of alkynes was also studied by the same group. These reactions are highly stereoselective but not regioselective (Sch. 71) [103].

100% (3:1)

Scheme 71

Nozaki and Oshima found the bimetallic species, Bu2Mg-2Et3Al to be effective in the carboalumination of silylacetylene [104]. The compound, Bu,Mg-2Et3Al has the bridged structure 108 which is essential for enhancing the reactivity of the C-A1 bond. A similar bimetallic bridged species 109 is also involved in the Cp2ZrC12-catalyzed carboalumination of terminal acetylenes with Me3Al [105]. The new reaction proceeds regiospecifically but not stereoselectively, although substrates bearing unsaturated groups in conjunction with the triple bond result in high or exclusive trans selectivity (Sch. 72).

109

108

80%

-%Me3 C6H13

5 : l

1) Hex2Mg-Et3Al

2) 12 3) B u ~ N F

I

85%

Scheme 72

The allylmetalation of activated alkynes, e.g. alkynyl ketones and alkynols, in both intramolecular and intermolecular versions proceeds smoothly with various allylmetals [106,107]. The allylmetalation of unactivated alkynes, however, is not easy, and only a limited number of allylmetals can serve this purpose [108]. Yamamoto and Asao showed that the addition of allyltrimethylsilane to unactivated alkynes 110 is catalyzed by the EtA1C12-Me3SiC1 catalyst system, affording the corresponding trans silylated 1,4-dienes 111 in good to high yields (Table 3) [109]. The trans-allylsilylation of the enyne and internal acetylene also proceeded smoothly to give the corresponding alkenylsilane in high yield. Although the use of other Lewis acids, for example A1X3 (X = C1, Br) and HfC14 in combination with Me3SiC1, also gave the allylsilylation product, EtAlC12 afforded the best yields of 111.

232

Ooi/Maruoka

~1-~2

+

SiMe3

R'

EtAIC12 e S i M e 3 Me3SiCI 110 a-g

F

a : R' = Ph, R2 = H

d : R' = CH3(CH2)5, R2 = H

R

2 111

f : R' =

, R~ = H

b : R' = pMe-C6H4, R2 = H e : R' = CH3(CH&, R2 = H g : R1 = Ph, R2 = Me

c : R' = PhCH2, R2 = H

Table 3. Allylsilylation of alkynes in the presence of the EtA1C12-Me3SiC1 catalyst system. Entry

110

R1

R2

Product yield (a)

1

a

Ph

H

93

2

b

P-CH&&

H

95

3

C

PhCH2

H

51

4

d

CHdCH2)5

H

90

5 6

e

CHdCHh

H

85

f

1-cyclohexenyl

H

13

1

a

Ph

Me

88

The first example of the vinylsilylation of unactivated alkynes was also reported by the same group [110]. The reaction of the carbon tethered alkynyl vinylsilane 112 in the presence of 0.2 equiv. EtAlC1, in CH2C12at -78 "C gave the trans-carbosilylation product 113 regio- and stereoselectively in 92 % yield (Sch. 73).

51me3 EtAIC12 (0.2 eq) CH2C12, -78 "C 112

92%

Scheme 73

A plausible mechanism for the Lewis acid-catalyzed trans-vinylsilylation is shown in Sch. 74. The coordination of a Lewis acid to the triple bond of 112 would form ncomplex 114 and the a-carbon of the vinylsilane would attack the electron-deficient triple bond from the side opposite to the Lewis acid to produce an aluminum ate complex 115 stereoselectively. The migration of the trimethylsilyl group to the aluminate center would afford 113 and regenerate the Lewis acid catalyst.

Achiral Al(II1) Lewis Acids

233

Scheme 74

Boer and co-workers examined the reaction of sterically hindered a-chloronitroso compounds with Me3A1 [lll].The conspicuous reaction sequence is interpreted in terms of initial ring rupture, methane evolution and chlorine migration from carbon to aluminum; intramolecular reaction of the carbon-carbon double bond with the rather electrophilic carbon atom from the nitrile oxide moiety leads to a seven-membered ring with an exocyclic double bond as shown in Sch. 75. After hydrolysis, the corresponding oxime is obtained.

Scheme 75

The efficiency of Me2A1C1 in a new synthesis of p-lactams from lithium ester enolates and enolizable aldimines was demonstrated by Akiba and co-workers [112]. In the absence of Me2AICI no p-lactam formation was observed, probably because of the proton removal from the enolizable aldimines with lithium ester enolate (Sch. 76).

234

Ooi/Maruoka

k N v P h rr

-78 "C

dnPh

0 95%

Scheme 76

Trost discovered the Lewis acid-initiated alkylation of allylic sulfones such as 116 with organoaluminum reagents [113]. Combination of alkenyl- or alkynylaluminum reagents with A1Cl3 promotes chemo-, regio- and diastereoselective carbon-carbon bond formation in the allylic sulfone substrate with removal of the sulfonyl group. The unique advantage of the sulfone as a leaving group stems from the ease of alkylation a to the sulfone before the substitution, as illustrated in Sch. 77.

reflux

Scheme 77

The capacity of sulfones to be chemical chameleons, i.e. to be nucleophiles in the presence of base and electrophiles in the presence of acid, seems to provide great opportunities for designing new reactions. This is demonstrated by ring expansion of a-phenylthio and a-methoxy ketones [114]. Although the lithium derivative of (pheny1thio)methyl phenyl sulfone 117, generated with BuLi in THF at -78 "C, reacts very poorly with ketones, addition of excess Et2A1C1resulted in smooth alkylation to the carbonyl group. Subsequent rearrangement proceeds cleanly when the adduct is treated with excess Et,AlCl in CH2C12at -78 "C (Sch. 78).

&

S02Ph LiASPh117

S02Ph &SPh

EtzAICI

P

Et2AICI

-20 "C. 4 h

92% (low yield without EtzAICI)

H 79%

Scheme 78

6.4.2 Heteroatom-Substituted Alkylaluminums Kochetkov and co-workers used Me2AlSeMe for direct transformation of esters into selenoesters which proved to be active acyl-transfer reagents in heavy metal-assisted reactions, producing the corresponding ketones as shown in Sch. 79 [115].

'

Achiral AI(III) Lewis Acids

0

0

Me2AlSeMe

C7H15KOMe

BupCuLi

C7H15KSeMe

C7H15

235

BU

96%

r.t.

Scheme 79

A tandem aldol condensation-radical cyclization sequence has been developed for the preparation of functionalized bicyclo[3.3.0]octane systems [116]. Conjugate addition of Me2A1SePh to dimethylcyclopentanone (118) followed by trapping of the resulting enolate with aldehyde gave predominantly the trans, erythro aldol 119; this then underwent radical cyclization with Bu3SnH and catalytic AIBN yielding the bicyclic ketoll20 stereospecifically (Sch. 80).

*

1) Me2AISePh

@

2) CH2=CHC(Me)2CH0

118

+\ Ph

63%

-f$( catAlBN

Bu3SnH Me 120

80%

119

Scheme 80

Oshima and Nozaki generated the aluminum enolate regiospecifically by treatment of a-halo carbonyl compounds with Bu3SnA1Et2;subsequent reaction with aldehydes or ketones under mild conditions gave P-hydroxy carbonyl compounds [117]. This subsequent aldol reaction is accelerated by the addition of catalytic Pd(PPh3)4 (Sch. 81).

.

O

Me B r

Et2AISnBu3

THF 0 "C, 30 min

OAIEt2 Me

PhCHO

55%

Scheme 81

The same group exploited deoxygenation of epoxides with Li[Bu3SnA1Me3] or Et2A1SiPhMe2[118]. The reaction with the A1-Sn or Al-Si reagents proceeded with overall retention of stereochemistry. This stereochemical outcome can be explained by the SN2 type ring opening of epoxides by tributylstannyl anion followed by anti elimination of the Bu3Sn and OAlMe3 groups, as shown in Sch. 82.

Scheme 82

236

Ooi/Maruoka

Nozaki and Yamamoto reported a novel method for regiospecific isomerization of epoxides to allylic alcohols based on diethylaluminum 2,2,6,6-tetramethylpiperidide (DATMP) which can be prepared in situ from Et2AlC1 and lithium 2,2,6,6-tetramethylpiperidide (LiTMP) (molar ratio 1:l) in benzene at 0 "C for 30 min [119]. Reaction of DATMP (4 equiv.) with (E)-cyclododecene oxide in benzene at 0 "C for 3 h produced (E)-2-cyclododecen-l-ol in 90 YOyield. Interestingly, the reaction of diepoxide 121, a useful synthetic intermediate in the preparation of CI8-Cecropia juvenile hormone, with DATMP furnished the trio1 122 in 41 YOyield (Sch. 83).

6

q - A ' E t z(4 e9)

a

O

H

* benzene 0 "C, 3 h 90%

-

121

OH

OH

122

41%

Scheme 83

Yamamoto and Maruoka found that organoaluminum amides are highly effective in the Fischer indole synthesis. In particular, DATMP is the reagent of choice for regioselective Fischer indole synthesis [120]. For instance, treatment of the (E)-Nmethyl-N-phenylhydrazone of 5-methyl-3-heptanone (123) with DATMP affords 3sec-butyl-2-ethyl-1-methylindole(125) as the sole isolable product; its (2) isomer gives 1,3-dimethyl-2-(2-methylbutyl)indole(124) with high regioselectivity under similar reaction conditions, as illustrated in Sch. 84.

123

0-25

"C

Me

124

Z-isomer (€/Z=4:96) €-isomer (€/Z= 96:4)

Scheme 84

Me

: 93% (>99:<1) : 42% (7:93)

125

Achiral Al(II1) Lewis Acids

237

2,3-Epoxy alcohols react with Et2A1N3under mild reaction conditions to afford 3azido-1,2-diols resulting from the regio- and stereoselective attack of the nucleophile at the C-3 carbon of the epoxides [121]. Here the high regioselectivity observed with both cis- and trans-substituted epoxides is not affected by bulky substituents at C-3 (Sch. 85). OH

-78-25 "C

84%

-. .

79%

Scheme 85

Regioselective stannylmetalation of acetylenes in the presence of transition-metal catalysts has been explored [122]. Among various combinations of Bu3SnM-transition metal catalysts, Bu3SnA1Et2-CuCN, (Bu3Sn)2Zn-Pd(PPh3)4, and Bu3SnMgMe-CuCN provide vinylstannanes in high yields (Sch. 86). 5 mol% CuCN PhC=CH

Et2AISnBu3

*

ph

Ph

+

H-:nBu3

Bu3Sn

88% (78 : 21)

Scheme 86

This chemistry has also been extended to the transition metal-catalyzed silylmetalation of allenes as shown in Sch. 87 [1231. Palladium-catalyzed silylalumination resulted in the preferential formation of 3-dimethylphenylsilyI-1-cyclononene(127) whereas copper catalyzed silamagnesation of 1,2-cyclononadiene affords l-dimethylphenylsilyl-1-cyclononene(126) exclusively.

-

D S i P h M e z 126

5 mol% CullMeMgSiPhMe;! 5 mol% PdCI2(P(o-Tolyl)&/Et2AISiPhMe2

Scheme 87

+

c3 127

: 74% (95 : 5 ) : 36% (10 : 90)

SiPhMep

238

Ooi/Maruoka

6.5 Modified Organoaluminums Organoaluminum compounds are highly oxygenophilic, and hence are capable of forming long-lived monomeric 1:l complexes with carbonyl substrates. For example, the reaction of benzophenone with Me3A1 in 1:1 molar ratio gives a yellow, long-lived monomeric 1:1 species which decomposes unimolecularly to dimethylaluminum 1,1diphenylethoxide after some minutes at 80 "C or many hours at 25 "C [124].

PhzC=O

Me3AI 25 "C

[

]

Ph2C=O--*AIMe3 yellow complex

-

Me

I

Ph2C-OAIMe2

80 "C

This unique property can be used for stereoselective activation of the carbonyl group. Among the various organoaluminum derivatives investigated, exceptionally bulky, oxygenophilic organoaluminum reagents such as methylaluminum bis(2,6-di-tertbutyl-4-alkylphenoxide) (MAD and MAT) introduced by Yamamoto and Maruoka in 1985, have resulted in excellent diastereofacial selectivity in carbonyl alkylation [125]. Thus, treatment of 4-tert-butylcyclohexanone with MAD or MAT in toluene produced a 1:1 coordination complex which on subsequent treatment with methyllithium or Grignard reagents in ether at -78 "C afforded the equatorial alcohol almost exclusively (Sch. 88). Methyllithium or Grignard reagents alone undergo preferential equatorial attack yielding axial alcohols as the major product. MAD and MAT have played a crucial role in the stereoselective synthesis of hitherto inaccessible equatorial alcohols from cyclohexanones, as shown in Table 4.

equatorial alcohol R M = MeLi EtMgBr BuMgBr AllylMgBr

MAD: R = M e MAT: R = t-BU

Scheme 88

axial alcohol 84% 91% 67% 90%

(99: 1) (1OO:O) (100 : 0) ( 9 1 : 9)

Achiral AI(III) Lewis Acids

239

Table 4. Stereoselective alkylation of cyclic ketones. Alkylation agent

Chemical yield (%)

Axia1:equatorial ratio

MeLi

75

79:21

MAD-MeLi

84

1:99

MAT-MeLi

92

0.5:99.5

EtMgBr

95

48:52

MAD-EtMgBr

91

0:100

BuMgBr

58

56x44

MAD-BuMgBr

67

0:100

8

MeLi

73

92:s

Entry

9

MAD-MeLi

84

14536

10

MAT-MeLi

80

10:90

11

MeLi

80

83:17

12

MAD-MeLi

69

9:91

13

MAT-MeLi

95

3:97

14

BuMgBr

86

79:21

15

MAD-BuMgBr

I5

1:99

16

MeLi

77

7525

17

MAD-MeLi

82

1:99

This approach has been quite useful in the stereoselective alkylation of steroidal ketones. Reaction of 3-cholestanone (128) with MeLi gave predominantly 3P-methylcholestan-3a-01 (129, axial alcohol), whereas amphiphilic alkylation of the ketone with MAD-MeLi or MAT-MeLi afforded 3a-rnethylcholestan-3~-01(130, equatorial alcohol) exclusively (Sch. 89) [125b].

240

Ooi/Maruoka

Me

OH H 129 MeLi : 97% ( ax/eq= 73 : 27 )

\

128

4 HO : 98% (ax/eq= 2 : 98) : 99% (ax/eq= 1 : 99)

MAD/MeLi MAT/MeLi

Scheme 89

In the course of the synthesis of (+)-3a-acetoxy-l5/3-hydroxy-7,16-secotrinervita7,11-diene, a defense substance isolated from the soldier termite, the need to introduce the methyl group from the hindered a side was achieved for the first time when the amphiphilic alkylation system MAD-MeLi was used (Sch. 90) [126].

toluene, ether

-78“C

AcO”’

H

H

MeLi MAD/MeLi

AcO””

91% (0:lOO) 30% (75:25)

Scheme 90

In the alkylation of a-chiral aldehydes with no ability to chelate with organometallic compounds such as Grignard reagents, erythro alcohols are usually obtained preferentially according to the Cram’s rule [127],and high Cram selectivity can be achieved with alkyltitanium reagents developed by Reetz [128].In contrast, application of amphiphilic alkylation to a-chiral aldehydes enables one to achieve the hitherto difficult anti-Cram selectivity, affording threo alcohols selectively as shown in Sch. 91 [125].

Achiral Al(III) Lewis Acids

Me PhACHO

Meo

+

ph&Me

PhE

OH erythro MeLi, MeMgX MeTi(OPrj3 MeTi(OPh)3 MAD, MeMgl

M

241

e

OH threo

-2:l 88: 12

93:7 3:97

Scheme 91

MAD can be successfully utilized as a highly efficient non-chelating Lewis acid for achieving a high level of stereoselectivity in the alkylation of a- or P-alkoxy cyclic ketones (Sch. 92) [129a]. A similar approach has been elegantly applied to a general diastereoselective synthesis of spiroketals by Ahn and Cohen [129b].

chelation product

MeMgBr MeTi(OPrj3 MAD/MeMgBr

nonchelation product

89% (94 : 6) 72% (67 : 33) 81% (5 : 95)

Scheme 92

Another interesting feature of the amphiphilic alkylation of carbonyl compounds using MAD is its chemoselectivity. For instance, in the alkylation of polyfunctional molecules such as keto-aldehydes 131, the aldehyde carbonyl was selectively methylated with the MAD-MeLi system to give the secondary keto alcohol 132 in 72 % yield (Sch. 93) [130].

CH~-;-(CH~)IOCHO 131

1) MAD

2) MeLi

CH&-(CHz)lo-CHCH3

II

I

132 OH 72%

Scheme 93

In contrast to the facile MAD- or MAT-mediated alkylation of cyclic ketones with primary organolithium or Grignard reagents, reduction takes precedence over alkylation with hindered alkylation agents such as tert-butylmagnesium chloride in the presence of MAD [131]. This amphiphilic reduction system seems to be complementary to existing methodologies which use L-Selectride to obtain axial selectivity (Sch. 94).

242

Ooi/Maruoka OH

Y d 0 =

I

2) t-BuMgCI

equatorial alcohol R=4-t-Bu R=2-Me R=3-Me

axial alcohol 88% ( 9 9 : 1 ) 76% ( 9 0 : 1 0 ) 86% ( 9 5 : 5 )

Scheme 94

Although organolithium reagents normally add to a,P-unsaturated ketones in a 1,2fashion, initial complexation of enones with MAD at low temperatures followed by treatment with organolithiums (i.e. an amphiphilic conjugate alkylation system) resulted in the reversal of regioselectivity, yielding the 1,4 adduct as a major product (Sch. 95) [132]. The stereochemistry in such amphiphilic conjugate alkylations is mostly governed by the size of substituents on the enones, and the trans isomer always predominates over the cis. This trans selectivity is complementary to that in organocopper-mediated conjugate addition reactions [133]. This amphiphilic conjugate alkylation system lacks generality, because its regioselectivity is highly dependent on the structure of substrates and on the steric or electronic nature of the organolithium nucleophiles. The most intriguing aspect of this approach is, however, that the reaction mechanism of conjugate addition is totally different from that of soft organometallics such as organocuprates.

RLi = MeLi BuLi PhLi CH2=C(0Bu')OLi

68% 59% 71% 87%

( 29 : 71 )

(17:83) (33 :67) ( 10 : 90 )

Scheme 95

Stern and co-workers reported that complexation of quinone monoketal and quinol ethers with MAD then addition of organolithium or Grignard reagents gave the corresponding 1,4-addition products in good yields (Sch. 96) [134]. The 4-methoxy moiety present in the quinone monoketals and quinol ethers performs a key function in facilitating 1A-addition reactions through coordination of oxygen lone pairs to organometallic reagents. This interpretation is supported by stereochemical analysis of the lP-addition product from the MAD-mediated reaction of 2-propenyllithium and 4-phenyl-4-methoxy-2,S-cyclohexadienone, which shows the methoxy and 2-propenyl groups to be cis, as also shown in Sch. 96. It should be added that these transformations cannot be achieved by use of conventional organocopper reagents.

Achiral Al(II1) Lewis Acids

243

4 Meh 4

Me Me0

OMe

Me0 OMePh 80%

1) MAD

2) CH2=C(Me)Li

.+. . .hp

OMe

75%

Scheme 96

This amphiphilic conjugate alkylation system has been improved to a synthetically useful level by the development of aluminum tris(2,6-diphenylphenoxide) (ATPH) as a highly efficient carbonyl stabilizer, thereby achieving a practical conjugate addition procedure.

-

W

(ATPH)

The new methodology is particularly effective for the conjugate alkylation to a$unsaturated aldehydes, which, among various conjugate acceptors, are prone to be more susceptible to 1,2 addition with a number of nucleophiles than a,P-unsaturated ketones, esters, and amides, as exemplified in Sch. 97 [135].

Ph-CH=CH-CH=O

1

AlE

Bu

BuMgCl

I Ph-CH=CH-CH-OH

CH&/ether -78 "C 1,Faddition

95% yield

Bu

I

-78 "C

Ph-CH-CHZ-CH=O l14-adduct ATPHlBuLi ATPHiBuMgCl ATPH/BuCal

Scheme 97

Bu I + Ph-CHZCH-CH-OH 1,2-adduct : 92% (49 : 51) : 99% (90: 10) : 88% (98: 2)

244

Ooi/Maruoka

In addition, conjugate addition of lithium alkynides and thermally unstable lithium carbenoids, which is very difficult to achieve in organocopper chemistry, is realized with this amphiphilic conjugate alkylation system (Sch. 98). C=C-Ph L C H O Ph 92%

1) ATPH

2) PhCsCLi

1) ATPH

PhACHo

2) Cl2CHLi

r Ph

1) ATPH 2) CF3CFzLi

C

H

0

91%

CF2CF3 PhL C H O 78%

Scheme 98

This amphiphilic conjugate alkylation has been used successfully for nucleophilic alkylation of electron deficient arenes, on the basis of the unprecedented conjugate addition of organolithiums to aromatic aldehydes and ketones by complexation with ATPH [136]. Thus, initial complexation of benzaldehyde or acetophenone with ATPH and subsequent addition of organolithiums affords 1,6 adducts with high selectivity, as illustrated in Sch. 99.

92-95%

88% (92 : 8)

Scheme 99

The ratio of dearomatization to aromatization products is highly dependent on the choice of solvents and quenching methods, as exemplified by the amphiphilic conjugate alkylation to acetophenone (Sch. 100).

toluene-THFlconc. HCI CHzCI$I N HCI

Scheme 100

: >99 : 99 (39%)

Achiral Al(III) Lewis Acids

245

By applying this system to a,p-unsaturated ketones, even more general and pronounced lA-selectivity (> 99:l) can be achieved, and a variety of alkyllithiums can be used as Michael donors [137]. In addition, this ATPH-alkyllithium system enables the introduction of perfluoroalkyl or perfluoroaryl substituents at the p position of carbony1 functions [138]. An example of cyclohexenone (133) as a Michael acceptor is shown in Sch. 101.

133 RLi = MeLi (83%),PhLi (86%), PhCECLi (99%), CI3CLi (SOY0), CF3CF2Li(75%) Scheme 101

Tandem inter- and intramolecular Michael addition using the enolates of a,/?-unsaturated ketones as Michael donors has also been successfully achieved [139]. For instance, treatment of cyclohexenone (133)-ATPH complex in toluene with a THF solution of the benzalacetone lithium enolate at -78 "C, then reflux for 13 h gave the stereochemically homogeneous annulation product 134 in 50 YO yield (> 84 YO de) as indicated in Sch. 102.

1) ATPHICH~CIZ

*

133 2)Ph

A

/THF

L

i

Scheme 102

The exceedingly bulky aluminum reagent aluminum tris(2,6-di-tert-butyl-4-methylphenoxide) (ATD) [140] was found to be superior to ATPH or MAD as a carbonyl protector in the alkylation of ynones [141]. Initial complexation of 3-octyn-2-one (135) in toluene with ATD and subsequent addition of a hexane solution of BuLi at -78 "C generated 1,4 adduct 136 in 93 % yield together with a small amount of the 1,2 adduct (Sch. 103).

1) ATDItoluene 2) BuLi, -78 "C

Bu

135 Scheme 103

Bu

136

95% (95 5)

246

Ooi/Maruoka

The combination of MAD with some complex aluminum hydride reagents enables the conjugate reduction of a,@-unsaturated ketones [142]. Although selectivity is profoundly affected by the structure of substrates, the 1,4 addition of hydride to quinone monoketals and quinol ethers is successfully mediated by MAD to give reduction products in good yield (Sch. 104) [143]. PhMe2Si0

PhMe2Si0 2) L~BU(CBU)~AIH

83%

1) MAD 2) L-Selectride

OMe

Ph" OMe 66%

Scheme 104

Efficient conjugate reduction of several a,@-unsaturated carbonyl substrates was similarly realized by combining ATPH with diisobutylaluminum hydride-BuLi ate complex (DIBAH-BuLi) as a reducing agent [144]. Diisobutylaluminum hydride-tBuLi was more effective for the 1,4 reduction of a,@-unsaturated aldehydes, as illustrated in Sch. 105.

1) ATPHholuene 2) DIBAH/BuLi THF, -78 "C

CHO Ph?

',,

97% (>99 : 1)

1) ATPHholuene

*

Ph/yCHo

2) reagent, -78 "C

DIBAH/BuLi : 80% DIBAH/f-BuLi : 94%

Scheme 105

Conjugate allylation of a,@-unsaturatedaldehydes is an extremely difficult, hitherto unattainable transformation in organic synthesis, and no useful effective procedure has yet been developed because of the lack of a satisfactory reagent [145,146]. Even organocopper reagents, which are quite powerful in conjugate alkylation to a,@-unsaturated carbonyl compounds [147], gave disappointing results for the conjugate allylation. In fact, attempted reaction of cinnamaldehyde with allylcopper or lithium diallylcuprate gave rise predominantly to the 1,2 adduct, trans-l-phenyl-1,5-hexadien-3-01. The new, amphiphilic conjugate alkylation procedure with ATPH described in this section was also found to be less effective for the conjugate allylation, and only the ATPH-allyllithium system gave modest 1,4 selectivity (Sch. 106).

Achiral Al(III) Lewis Acids

ph/-+c'

247

4or '^

* Phc c H o M 1,4-adduct

ni r

<

CH~=CHCH~CU : (CH2=CHCH2)2CuLi : ATPH/CH2=CHCH2Li : ATPH/CH2=CHCH2MgBr: ATPH/CH2=CHCH2Cal : ATPH/CH~=CHCH~CU:

,

h

x

1,Padducf 98% 98% 80% 96% 92% 70%

(6194) (10:90) (59:41) (1:99) (37:63) (13187)

Scheme 106

This tendency is contradictory to the behavior of the ATPH-Bu-M system for conjugate alkylation to cinnamaldehyde; here 1,4 selectivity is enhanced by changing nucleophiles (Bu-M) from BuLi (1,4-/1,2-ratio = 5050) to BuMgCl(9O:lO) and BuCaI (98:2) [135]. Consideration of the wide availability and versatility of organolithium reagents [148] enabled the development of a new Lewis-acid receptor with appropriate coordination sites for alkyllithium nucleophiles. Among various functionalized aluminum tris(2,6-diphenylphenoxide) (ATPH) derivatives as Lewis-acid receptors, p-F-ATPH was found to be highly effective for this transformation, which clearly demonstrated the synthetic utility of the strong lithium-fluorine participation in selective organic synthesis [149]. coordination site for reagent recognition site for substrate

Lewis acid receptor

The 1,4 selectivity for conjugate alkylation to cinnamaldehyde was examined with the modified ATPH-BuLi system in model experiments (Sch. 107). Selected results are shown in Table 5. p-(Me0)-ATPH and p-(MeS)-ATPH were slightly more selective than ATPH (entries 2 and 3). The 1,4 selectivity was further enhanced by use of p-C1-ATPH and p-F-ATPH (entries 4 and 5). Significant solvent and temperature effects on the 1,4 selectivity were also observed (entries 6-9), and eventually the optimum reaction conditions were achieved by using DME as solvent for BuLi at lower temperature under the influence of p-F-ATPH in toluene, giving the 1,4 adduct with 95 % selectivity (entry 9). Here, the chelation of BuLi with DME is quite appropriate for increasing the steric size of the nucleophile (BuLi) while still maintaining the coordination ability of Li' to fluorine atoms of p-F-ATPH [150]. This molecular recognition system is highlighted by the first successful conjugate addition of allyllithium reagents to u,p-unsaturated aldehydes by complexation with the modified Lewis-acid receptor, p-F-ATPH (entry 13).

248

Ooi/Maruoka

1

1,Padduct

AT' toluene analogue

CH=O*--AI[ p h A x > X]

97%

-

Lo,,

R

L C H O + Ph solvent Ph -78 RLi to -98 "C 1,4-adduct 1,Padduct

W

ATPH (X = H) p(Me0)-ATPH (X = OMe) p(MeS)-ATPH (X = SMe) PCI-ATPH (X = CI) pF-ATPH (X = F)

PF-ATPH

Scheme 107

Table 5. Conjugate addition of RLi to cinnamaldehyde with modified ATPH. Entry

ATPH analog

RLi-solvent

Temp ("C)

Yield (%)

1,4/1,2 ratio

1

ATPH

BuLi-hexane

-78

92

50:50

2

p-(Me0)-ATPH

BuLi-hexane

-78

80

55:45

3

p-(MeS)-ATPH

BuLi-hexane

-78

91

57:43

4

p-Cl-ATPH

BuLi-hexane

-78

92

63~37

5

p-F-ATPH

BuLi-hexane

-78

87

76:24

6

BuLi-e ther

-78

90

79:21

7

BuLi-THF

-78

82

86:14

8

BuLi-DME

-78

75

90:lO

BuLi-DME

-98

83

955

AllylLi-ether

-78

94

77:23

11

AllylLi-THF

-78

89

5050

12

AllylLi-DME

-78

75

9010

13

AllylLi-DME

-98

83

95:5

9 10

p-F-ATPH

Achiral AI(III) Lewis Acids

249

The conjugate addition of prenyllithium to cinnamaldehyde proceeded equally well with excellent selectivity under optimized reaction conditions. The aly ratio of the conjugate adducts was profoundly influenced by the nature of the solvent, as illustrated in Sch. 108.

a-attack Ph

+HO

'

( a / y = 72:28)

( a / y = 10:90)

Scheme 108

In contrast to the smooth conjugate alkylation of a,B-unsaturated aldehydes by organocopper chemistry, little is known about the application of such alkylation to a&y,d-unsaturated aldehydes. Conjugate alkylation of a,/3,y,&unsaturated aldehydes with RzCuLi was usually totally ineffective, and resulted in complex reaction mixtures containing only traces of the desired conjugate adducts. Selective 1,4 or 1,6 alkylation of reactive organometallics to a$,y,d-unsaturated aldehydes can be effected with aluminum tris[2,6-bis(3,4,5-trifluorophenyl)phenoxide](3,4,5-F3-ATPH) as a functionalized Lewis-acid receptor, as summarized in Sch. 109 [151]. Conjugate addition of other organolithium reagents, for example sec-BuLi, PhLi and isopropenyllithium seemed feasible, with excellent selectivities. The unique selectivity observed herein could be ascribed not only to the eminent metal-fluorine interaction but also to the increase in the overall depth of the cavity resulting from the fluorine atoms.

PhL

c

H

o

+ PhL

1,6-adduct

C

H

1,4-adduct

O

+

phd 1,Padduct

RLikolvent sec-BuLi/hexane Lilether 87% (46 48 : 6)

Scheme 109

250

Ooi/Maruokn

It is well known that organoaluminum compounds readily form stable 1:l complexes with ethers [40]. Utilization of the exceptionally bulky MAD as a Lewis-acid receptor makes discrimination between structurally or electronically similar ethers feasible. For example, 13CNMR spectra of a mixture of 1 equiv. each of MAD, methyl 3-phenylpropyl ether, and ethyl 3-phenylpropyl ether in CDC13 revealed virtually complete discrimination between methyl and ethyl ether with MAD giving selectively the 1:l MAD-methyl ether complex [152]. It should be noted that this remarkable selectivity can be achieved only with MAD. Use od conventional Lewis acids dramatically reduced the selectivity, and less bulky organoaluminum reagents did not form coordination complexes with ethers, probably because of their strong self-association through electron-deficient bonds (Sch. 110). The practical separation of some ether substrates is, furthermore, possible by crystallizing a coordination complex with MAD. For instance, treatment of a mixture of diethyl ether and ethyl vinyl ether with MAD resulted in the selective formation of a crystalline complex of the more basic diethyl ether. This is an example of the complete discrimination of two different ethers as a result of their slightly different electronic interactions with a Lewis-acid receptor [152].

-

P h a O M e +

MLn

Ph-OEt

Me

I

Ph-O., "ML,

+

Pha

Et

I

o , , , , "ML,

0

M e G O , A ! , O G M e Me

7(

Ratio = 100 :0

(MAD)

0 No

&oA ,o,l>

withComplexation Ethers

R

Me (R = i-Pr, Me)

i-Bu3Al BF3

0

Ratio=4: 7 Ratio=5:3

Crystallized Scheme 110

80% yield

Achiral AI(III) Lewis Acids

251

Although aliphatic Claisen rearrangements normally requires high temperatures, in the presence of Lewis acidic organoaluminum reagents, the rearrangement has been accomplished under very mild conditions, as discussed in the previous section. The aluminum thiolate, EtzAISPh, or a combination of Et,AlCl and PPh3, was effective for the rearrangement of allyl vinyl ethers, providing the normal Claisen products, y,d-unsaturated aldehydes, although without any stereoselectivity [69]. Accordingly, a new molecular recognition approach for the stereocontrolled Claisen rearrangement of allyl vinyl ethers has been developed on the basis of stereoselective activation of the ether moiety by use of aluminum-type Lewis-acid receptors. Thus, treatment of 1-butyl-2-propenyl vinyl ether with ATPH in CHzClz afforded predominantly ( E ) Claisen products (EIZ ratio 94:6).Use of the sterically more hindered aluminum tris(2-a-naphthyl-6-phenylphenoxide)(ATNP) resulted in better selectivity (EIZ ratio 98:2) [153]. In marked contrast, use of the exceptionally bulky Lewis acidic (MABR) resulted receptor methylaluminum bis(2,6-di-tert-butyl-4-bromophenoxide) in predominant formation of (2)Claisen products (EIZ ratio 9:91),which are very difficult to obtain by conventional methodologies including thermal Claisen rearrangement and its variants (Carroll, the ortho ester, Eschenmoser, and Ireland rearrangements) (Sch. 111) [154].

Al reagent

BuP C H O

P Bu C H O

(€)-isomer

(3-isomer

MABR EtZAISPh Et2AICI + PPh3 ATPH ATN P

41% ( E / z = 9 : 91) 84% (UZ=39 61) 81% (UZ=43 : 57) 87% (€/Z= 94 6 ) 90% (€/Z=98 : 2)

Scheme 111

The exceptional bulkiness of the modified organoaluminum reagent MABR can also be utilized for rearrangement of epoxy substrates under very mild conditions with high efficiency and selectivity. Although BF,.OEtz is regarded as a reliable Lewis acid catalyst for the epoxide rearrangement, attempted rearrangement of the tertbutyldimethylsilyl ether of epoxycitronellol (137) with BF3.0Etz resulted in the formation of several products. In contrast, treatment of this substrate with MABR under mild conditions (-78 to -20 "C) gave the desired aldehyde 138 almost quantitatively. In addition, certain epoxy substrates can be rearranged by use of MABR as catalyst, as shown in Sch. 112 [155].

252

Ooi/Maruoka

MABR uOSiMezBd

*

CH2C12 -78--20 "C

137

Bu'Me2Si 138

98% A Ph

P

h

Ph F C H O Ph

MABR t

CHzCIz -78- - 20 "C

MABR : 200 mol%, 10 mol%,

CHzC12 MABR -78- - 20 "C

*

93% 95%

(m

MABR : 200 mol%, 10 rnol%, 5 rnol%,

98% 96% 91%

Scheme 112

Although the acid-catalyzed rearrangement of epoxides to carbonyl compounds is a well known transformation and several reagents have been developed for this purpose [156], few have been employed successfully for rearrangement of functionalized epoxides with high efficiency and selectivity. With stoichiometric use of MABR, however, a new, stereocontrolled rearrangement of epoxy silyl ethers leading to P-siloxy aldehydes has been developed under mild conditions. Interestingly, when used in combination with the Sharpless asymmetric epoxidation of allylic alcohols this rearrangement is a new approach to the synthesis of a variety of optically active P-hydroxy aldehydes [157] which are quite useful intermediates in natural product synthesis. On the basis of the sign of optical rotation and value of the p-siloxy aldehydes, this organoaluminum-promoted rearrangement proceeds with rigorous transfer of epoxide chirality, and the observed stereoselectivity can be interpreted as arising from the anti migration of the siloxymethyl group to the epoxide moiety (Sch. 113).

Achiral Al(III) Lewis Acids

253

1) Sharpless asymmetric epoxidation 2) Silylation

.. 0 ~

O

S

MABR

i139M

e

2

B

u

*

tCHpCIp, -78 "C U

H

S

M

e

2

B

u

'

99%

CH20SiMe2Bu'

Scheme 113

The exceptional bulkiness of 2,6-di-terf-butyl-4-bromophenoxy ligands in MABR is essential here for the smooth rearrangement of epoxy silyl ethers, and the less bulky methylaluminum bis(4-bromo-2,6-diisopropylphenoxide)(MAIP) was found to be totally ineffective in the rearrangement of the tert-butyldimethylsilyl ether of epoxygeraniol (139). BF3.0Et2 as an ordinary Lewis acid gave fluorohydrin 140 as sole isolable product (Sch. 114).

BF30OEtp uOSiMe2Bu'

.-----CHpClp +

139

I

foH OSiMepBu'

74%

15%

w

O

S

i

M

e

OH Scheme 114

2

B

16%

u

r (MAIP)

OH

140

254

Ooi/Maruoka

The authors found that the successful rearrangement of epoxysilanes to a-silylaldehydes can be accomplished by use of MABR as depicted in Sch. 115 [158]. When epoxysilanes 141a (X = H) was treated with 2 equiv. MABR in CH2C12at 0-25 "C for 12 h, the corresponding a-silylaldehydes 142a (X = H) were obtained in 79 % yield. The rearrangement of a-deuterated epoxysilane 141b (X = D) under the influence of MABR afforded the corresponding a-silylaldehyde 142b (X = D) (79 % yield) with incorporation of a deuterium atom in the aldehyde moiety; this is indicative of initial epoxide cleavage p to the silicon atom then selective migration of the tert-butyldimethylsilyl group. This method has potential for the efficient synthetic conversion of mono-substituted terminal epoxides to aldehydes, which is not attainable by conventional methodologies. SiMezBut

-* MABR

*SiMe2But X

CH2CI2 0-25 "C

141a (X = H) 141b (X = D)

d

c

=

I

o

X 142a(X=H) : 79% 142b(X=D) : 79%

Scheme 115

This epoxysilane rearrangement can also be effected by use of a catalytic amount of MABR. Interestingly, treatment of epoxysilane 143 with 0.2 equiv. MABR facilitated smooth rearrangement at 25 "C to furnish silyl enol ether 144 in 74 YO yield; reaction of 143 with 2 equiv. MABR at -40 "C gave a-silylaldehyde 145 in 93 YOyield (Sch. 116). MABR (0.2 eq) CHzC12 I

143

25 "C, 30 min

MABR (2 eq) CHzCIz -40 "C, 30 min

'fbsiPri3 144 74%

YCHO SiPr\

145

93%

Scheme 116

Because of the high discriminating capacity of MAD for sterically and/or electronically similar ethers, Yamamoto and Maruoka examined the affinity of the compound toward other substrates with oxygen-containing functional groups, for example various carbonyl compounds, including both aliphatic and aromatic aldehydes, amides, esters, ethers, and ketones with similar structural substituents. Binding behavior was monitored by low-temperature I3C NMR spectroscopy of these substrates and their coordination complexes with MAD. As revealed in Sch. 117, coordination of amides to the Lewis acid MAD is stronger than that of aldehydes, esters and ketones; coordination of ether oxygen is rather weak. The order in Sch. 117 implies that even similar

Achiral Al(III) Lewis Acids

255

functional groups have different binding behavior to MAD, depending on the types of substituent (aliphatic or aromatic) and their steric requirements [159]. These results suggest that MAD can also function as an excellent Lewis-acid receptor for carbonyl compounds. 100 : 0

91 :9

I

I

II

u , 64 : 36

100 : 0

88:12

63 :37

u 88 : 12

100 : 0

72 : 28

Scheme 117

In the metal hydride reduction of two different ketones, the sterically less hindered ketone is generally reduced more easily, and modification of hydride reagents by replacement of the hydrides with sterically bulky substituents or electron-withdrawing groups enhances the chemoselectivity. MAD, however, preferentially forms complexes with sterically less hindered or more basic ketone carbonyls, enabling selective reduction of a more hindered, free ketone. Here, MAD behaves as a protector of carbony1 substrates (Sch. 118) [160].

- PhY 'PhY

CBU~AIH KMe PhKBu' 0

Ph 0

+

1

CH2C12 -78 "C

Me OH

OH

99% (2.6 : 1)

MAD

- PhYMephYBu' i-Bu2AIH CH2C12 -78 "C

OH

<

OH

66% (1 10)

protection Scheme 118

Because of this selective Lewis acid-base complex formation, molecular recognition chemistry with MAD as a Lewis-acid receptor for carbonyls enables other types of chemoselectivity. For example, the successful utilization of reactive nucleophiles

256

Ooi/Maruoka

such as Grignard and alkyllithium reagents in the chemoselective alkylation of aldehydes in the presence of ketones can be accomplished by incorporating MAD as an aldehyde activator [130]. In addition, the opposite selectivity can be achieved with organoaluminum amide-alkyllithium systems (Sch. 119).

x

1) MAD

/ 2)MeMgl

*

C8H17

+

Bu

62% (100 : 0) C~HIT-CHO

t

1) Me2AINMePh

2) MeLi

*

C8H17

+

Bu

92% (1 9) Scheme 119

The selective binding behavior of Lewis acidic MAD with two different ester groups also enables the regio- and stereocontrolled Diels-Alder reaction of asymmetric fumarates. Reaction of tert-butyl methyl fumarate (146) with 1.1 equiv. MAD in CHzClz at -78 "C gave rise exclusively to the organoaluminum complex with the methoxycarbonyl group of the fumarate. The Diels-Alder reaction of this selective complex with cyclopentadiene at -78 "C resulted in stereoselective formation of the cycloadduct 147 almost exclusively. In addition, treatment of the complex with 2-trimethylsiloxy-1,3-butadieneafforded the cycloadduct 148 with high regioselectivity (Sch. 120) [161]. Different cycloadducts from tert-butyl methyl fumarate are synthetically useful, because either the tert-butyl or the methyl ester can be selectively cleaved under acidic or basic conditions, respectively.

*cozBu'C02Me 147

Me3si0Y 148 Scheme 120

Achiral AI(IZZ) Lewis Acids

257

The MAD-fumarate complex also reacts with electronically activated olefins to give [2 + 21 cycloadducts smoothly with high regiochemical control, as shown in Sch. 121 [162].

BdO\

+xe-

M

Rco2Bu'+

E

.bS 0 2 B d

MAD

OMe

0 146

SMe toluene -204°C

MeS MeS

C02Me

C02Me

41% (97 : 3)

Scheme 121

Yamamoto and Maruoka demonstrated that ATPH can discriminate between structurally similar aldehydes, thereby facilitating selective functionalization of the lesshindered aldehyde carbonyl [163]. Treatment of an equimolar mixture of valeraldehyde (149) and cyclohexanecarbaldehyde (150) with ATPH (1.1 equiv.) in CH2C12 at -78 "C, then addition of Danishefsky's dime gave hetero-Diels-Alder adduct 151 and 152 in the ratio > 99:l. It is worthy of note that the complexed aldehyde could react with the diene only. The reaction gave relatively low chemoselectivity with other types i ~ cwith l ~ ;Me3A1; 3.7:l with of Lewis acid (ratio of 151/152: 6.2:l with ( P ~ ~ 0 ) ~ T 5:l MAD; 2:l with TiCI4; 1.3:l with BF3.0Et2). This emphasizes that the cavity of ATPH plays an important role in differentiating between the reactivities of the two different aldehydes. In a similar manner, the aldol reaction of a mixture of 149 and 150 was effected with ATPH to furnish 4-hydroxy-2-octanone (153) without formation of 154 (Sch. 122).

Y -78 "C

153

154

75% (>99 : 1)

//

I

-78°C

OMe

To:% 151

87% (>99 : 1)

152

Scheme 122

The selective functionalization of more sterically hindered aldehydes was accomplished by the combined use of methylaluminum bis(2,6-diphenylphenoxide) (MAPH) and alkyllithiums [164]. In this system, MAPH acted as a carbonyl protector of a less hindered aldehyde such as 149, and, therefore, the carbanions react preferentially with uncomplexed, more hindered carbonyl groups (Sch. 123).

258

Ooi/Maruoka

0- MAPH

+

-CHO 149

150

CHO

+ 150

-0lilAIH

CH2C12

-78 "C

reagent

BuTi(OPrj3(1 eq)

BU : 31% (2.5 : 1)

MAPH (1 eq)/BuLi (1 eq)

: 76% (1 : 6.5)

MAPH (2 eq)/BuLi (2 eq)

: 45% (1 : 14)

I

Bu

Scheme 123

Another interesting feature of MAPH is its capacity to stabilize reactive aldehydes by 1:l Lewis acid-base complex formation. Thus, formaldehyde and a-chloro aldehydes can be successfully generated by treatment of readily available trioxane and a-chloro aldehyde trimers, respectively, with MAPH in CH2C12.The resulting complexes can be utilized as a stable source of gaseous formaldehyde and reactive a-chloro aldehydes for the nucleophilic addition of different carbanions, as summarized in Sch. 124 [165].

<07 OVo

4

LiBuCuO

b

MAPH

Bu u B' 63%

61Yo

65%

CH3CICHYOYCHCICH3 1) MAPH

"Yo CHCICH3 Scheme 124

~

2) CH2=C(OLi)Ph

P

h

0

OH 81Yo

dCI

Achiral Al(III) Lewis Acids

259

The authors reported that the Lewis-acid receptor ATPH and its congeners selfassemble with a dicarbonyl guest molecule in organic solvents to form a dimeric capsule; the X-ray crystal structure of such a complex with 1,4-dimethyl-2,5-piperazinedione as a model guest is shown in Fig. 1 [166].

Figure 1

Intermolecular coordination bonding between ATPH and carbonyl moiety hold the two subunits together. Similar capsule formation is observed with ATPH and 1,4cyclohexanedione (155) as shown in Sch. 125. In CDC13 as solvent the equilibrium shifts largely to the complex 157. 13C NMR of 0.5 equiv. monomeric ATPH with 1,4cyclohexanedione (155) in CDC13 at room temperature reveals sharp and well-defined signals of the 1:l ATPH-diketone complex 156 accompanied with the peak of free 155. A considerable downfield shift is observed for the carbonyl resonance complexed with ATPH at 6 234.0 and the uncomplexed carbonyl signal occurs at 6 204.5 which is slightly upfield of the free 1,4-cyclohexanedione (155) carbonyl signal (6 208.6). On addition of another 0.5 equiv. ATPH the carbonyl signal of free 155 disappears completely and addition of a further 1 equiv. ATPH to this solution affords the capsular form 157 further induced by the guest molecule 155, as ascertained by the sharp single peak of coordinated C=O at 6 229.9. The capsule 157 was found to be stable in the presence of another carbonyl substrate. Indeed, attempted addition of 4-tert-butylcyclohexanone (158) (1 equiv.) to the dimeric complex 157 at -78 "C and subsequent treatment with MeLi (1 equiv.) at -78 "C resulted in the predominant formation of 4tert-butyl-1-methylcyclohexanol(159) (86 YO)with 90 % recovery of diketone 155. It should be added that simple addition of MeLi (1 equiv.) to an equimolar mixture of 155 and 158 at -78 "C gave 4-hydroxy-4-methylcyclohexanoneand 159 in 49 YOand 47 % yield, respectively. These results suggest the promising encapsulation of the diketone 155 in the presence of another carbonyl substrate, and 2 equiv. ATPH can be used as an effective protector for the dicarbonyl compound 155 in the alkylation, even with highly reactive organolithium nucleophiles.

260

Ooi/Maruoka

Al

L

156

ATPH

90% recovery

+

12% recovery

+

8%

159 86%

Scheme 125

With this information at hand, the authors further studied the Diels-Alder reaction between 2,5-dimethyl-p-benzoquinone (160) and cyclohexadiene. This cycloaddition proceeds very slowly at room temperature. In CD2C12with molar concentrations of each component, none of cycloadducts are detected by NMR in ca two days.

bMe+ 0CDzCIz

Me

0

160

Me 161

Initial addition of 2,5-dimethyl-p-benzoquinone(160) (1 equiv.) to ATPH (2.2 equiv.) in CH2C12 at -20 "C and subsequent treatment with cyclohexadiene (1.1 equiv.) resulted in only trace amounts of the endo cycloadduct 161, because of virtually complete protection against diene approach by the efficient encapsulation of the quinone substrate (route A in Sch. 126). In marked contrast, however, mixing of cyclohexadiene (1.1 equiv.) and ATPH (2.2 equiv.) in CH2C12 at -20 "C and subsequent addition of 2,5-dimethyl-p-benzoquinone (160) (1 equiv.) under similar reaction conditions afforded the endo cycloadduct 161 in 65 % yield (route B in Sch. 126). It should be noted that this implies the effective inclusion of the diene component by electronic interaction of the diene portion with the concave aromatic interior of the cavity of ATPH (162 in Sch. 126), ensuring smooth cycloaddition on complexation and capsule formation with quinone substrate 160.

Achiral Al(III) Lewis Acids

r o r

2 Al

ATPH

+

261

ATPH

162

A CH2CI2 -20 "C

Scheme 126

A similar tendency is observed in the Diels-Alder reaction between 2,5-dimethylp-benzoquinone (160) and cyclopentadiene, as illustrated in Sch. 127.

/

2-78 : ; :c"C,

15 rnin

\ L

ATPH

Me

161 CH2CI2 -78 "C, 15 min 10%

Scheme 127

One characteristic stereochemical feature of the Diels-Alder reaction is endo selectivity. The origin of the endo preference in Diels-Alder reactions can be ascribed to "secondary orbital interactions" [167]. If the carbonyl functions of dienophilic a& unsaturated carbonyl substrates are effectively shielded by complexation with ATPH, secondary interaction is reduced, thereby disfavoring the hitherto preferred endo transition state (Fig. 2).

262

Ooi/Maruoka

ATPH

Lewis acid (LA)

pi-) I

r

exo transition state

endo transition state

i I

R’

COR

ex0 isomer

endo isomer

Figure 2

Precomplexation of aJ-unsaturated ketone 163 with ATPH in CH2C12 at -78 “C, then cyclization with cyclopentadiene, resulted in the stereochemical reversal to furnish em-164 as a major product, as shown in Sch. 128. Similarly, the Diels-Alder reaction with other dienophiles complexed with ATPH resulted in ex0 selectivity [168].

R

163 (R =Ph, R’ = H)

J+ R1 exo-164

+

&+

R’

COR endel 64 81Yo (73 27)

R = Ph, R’ = Me : 81% (96 : 4) : 87% (87 : 13) R = R1 = Me

Scheme 128

This concept was further extended intramolecularly to 165, producing trans-fused stereoisomer 167, whereas an ordinary aluminum reagent such as Me3A1 gave the cis isomer 166 (Sch. 129).

Achiral Al(III) Lewis Acids

Lewis acid

CH2C12 -78--20 "C

b

263

H

165

cis isomer 166 Lewis acid

H trans isomer 167

Me3AI : 75% (88 : 12) ATPH : 69% (4196)

Scheme 129

The exceptionally bulky Lewis acid MAD has a distinct steric effect on stereoselectivity in the Diels-Alder reaction of cyclic dienes and u,P-unsaturated aldehydes, as exemplified by the MAD-mediated highly em-selective cycloaddition of methacrolein and cyclopentadiene (Sch. 130) [169].

heat Me3AI MAD

(1 : 5 ) 64% (1 : 15) 76% (1 :48)

Scheme 130

The asymmetric Diels-Alder reaction of optically active acrylate and cyclopentadiene is promoted by EtZAlC1 as a Lewis acid giving the endo adduct preferentially with moderate diastereoselectivity; the use of MAD once again enhances diastereoselectivity (Sch. 131) [170].

0-(/)-Menthy1

0

-

Lewis acid CH2C12 heat Et2AICI MAD

C02-(/)-Menthyl

89%, 8% de 99%, 60% de 99%, 80% de

Scheme 131

Interestingly, the Diels-Alder reaction of the acrylate of D-pantolactone and cyclopentadiene in the presence of 2 equiv. MAD results in high diastereoselectivity which is the opposite of that encountered with ordinary Lewis acids. The low-temperature I3C NMR spectrum of the Lewis acid complex of the acrylate of D-pantolactone showed that an ordinary Lewis acid such as SnC14 forms the chelate complex [O] (Sch. 132). In the 1:l acrylate-MAD complex, structure [PI, although predominant, seems to be in equilibrium with the minor complex [Q] with s-cis conformation; this

264

OoiIMaruoka

then reacts with cyclopentadiene to give the cycloadduct. On the other hand, in the 1:2 acrylate-MAD complex, the diastereomeric adduct is produced via complex [R] with s-trans conformation 11711.

ordinary Lewis acids

CO2W

I

MAD (2 eq)

90% de

50-94% de

Scheme 132

Posner and Kinter have demonstrated MAD-promoted highly stereoselective [4 + 21 cycloaddition under mild conditions in the asymmetric total synthesis of an Aring precursor 171 to hormonally active la,25-dihydroxyvitamin D3 [ 1721. Reaction of a pyrone sulfone 168 and an enantiomerically pure vinyl ether 169 under the influence of MAD in toluene-CH2C1z at 4 5 "C for 12 h afforded cycloadduct 170 in 93 % isolated yield as a 98:2 ratio of the endo diastereomers. From 170, the synthesis of 171 required 13 steps and proceeded in 34.6 % overall yield as indicated in Sch. 133.

Achiral AI(III) Lewis Acids

S02T0l

O7$

+

168

cob

MAD

toluene/CH2CI2 * -45 "C, 12 h

169

265

o y sPh v 170 11 13 steps 93%

R10"" &Fi'

R' = SiMe2Bu' R2 = CH2P(0)Ph2

171

34.6% overall

OH j 1a,25-Dihydroxycholecalciferol

Scheme 133

Denmark and Marcin showed that 2,2-disubstituted 1-nitroalkenes undergo facile MAD-promoted [4 + 21 cycloaddition with n-butyl vinyl ether in toluene at 0 "C to give cyclic nitronates as anomeric mixtures in good yield [173]. This method is a promising route to the stereoselective synthesis of disubstituted pyrrolidines and can thus be applied to the synthesis of the biologically active pyrrolidine alkaloid, mesembrine (Sch. 134).

0

O$O .,

OBu anorneric ratio = 1.1 : 1

(6eq)

toluene, 0 "C 30-120 min

OMe OMe 80%

OMe Ts

AcOH (1.05 eq) cat Pt02/H2 (160 psi) MeOH, rt, 24 h

I

OMe

0 "C, 1 h

OMe

OMe

Y Mesernbrine

Scheme 134

266

Ooi/Maruoka

Denmark and co-workers also reported that the [4 + 21 cycloaddition of nitroalkene 172 with enol ether 173, as dienophile, in the presence of MAD proceeded at low temperatures to give the nitronate with two substituents on the C6 carbon (174) in 62 % yield on isolation. Because the cycloadduct 174 undergoes clean intramolecular [3 + 21 cycloaddition in xylene under reflux, in the presence of solid NaHC03. This tandem cyclization strategy is a unique approach to the stereoselective synthesis of polyfunctionalized aminocyclohexane derivatives, as shown in Sch. 135 [174].

OBu

MAD (2 e9)

+ 173

t

e Ph

Ph 172

174 62%

endolexo = 4.611 NaHC03, benzene reflux, 11 h

AcO

'"*..@ ACHN"" Me

i

Ph

1) H$Raney Ni MeOH, r.t.

~

2) AczO, PY r.t., 12 h

$"" p'

Me

Ph

68-83% (overall)

Scheme 135

Yamamoto and Saito reported that the kinetically controlled generation of the more substituted enolate of unsymmetrical dialkyl ketones can be realized by the combined use of ATPH and LDA [175]. Precomplexation of ATPH with 2-methylcyclohexanone (175) at -78 "C in toluene was followed by treatment with LDA in THF, and the mixture was stirred for 1 h. Subsequent treatment with methyl trifluoromethanesulfonate (MeOTf) furnished 2,2-dimethylcyclohexanone (177) and 2,6dimethylcyclohexanone (176) in the ratio 32:1 (53 % isolated yield). Use of tert-butyldimethylsilyl triflate (TBSOTf) in place of alkyl triflates in this alkylation system produced siloxybutylated product 178 as a result of THF ring-opening; alkylation occurred similarly at the more hindered a-carbon of the unsymmetrical ketone 175 (Sch. 136) [176].

Achiral Al(III) Lewis Acids

-

'Me LDA

&Me

MeX

Me&Me

175

1

267

176 alkylation at the less hindered site

ATPH

J

177 alkylation at the more hindered site

Me

175

1) ATPH (1.1 eq)/toluene 2) LDA (1.1 eq)TTHF 3) TBSOTf

*

*OTBS

178

94%

Scheme 136

They also developed a conceptually new strategy for combining two different carbony1 compounds, by use of LDA, in which both substrates are complexed with ATPH. Sequential treatment of a toluene solution of ATPH (2.2 equiv.) with crotonaldehyde (1.0 equiv.) and benzaldehyde (1.0 equiv.) at -78 "C was followed by deprotonation with a THF solution of LDA (1.2 equiv.). The mixture was then stirred for 15 min and quenched with aqueous NH&I to give, after chromatography on silica gel, homoallylic alcohol 179 quantitatively with retention of the olefin configuration. It is worthy of note that deprotonation and subsequent addition occurred exclusively at the y position of crotonaldehyde (Sch. 137) [177].

quant

Scheme 137

J

LDA (1.2 eq) THF, -78 "C

268

Ooi/Maruoka

Control of stereoselectivity in radical reactions has recently attracted much attention from synthetic organic chemists, and extensive research has been conducted on this topic [178]. Among these, the significant effect of Lewis acids and substrate concentration and reaction temperatures on the stereochemical course of reactions has been clearly demonstrated [179]. For instance, Yonemitsu and coworkers have shown elegantly that high levels of /3 diastereoselectivity hitherto difficult to achieve have been achieved in the intramolecular addition of alkenyl radicals to the p position of a@unsaturated esters by use of 8-phenylmenthol as a chiral auxiliary; the presence of Lewis acids was crucial for enhancing selectivity [180]. Upon examining the reaction conditions with a vinyl iodide, from which the alkenyl radical is readily generated even at low temperatures, the diastereoselectivity was found to be improved at the same reaction temperature by increasing the steric bulkiness of the Lewis acid. The greatest selectivity was recorded at -78 "C in the presence of MAD, as indicated in Sch. 138. The origin of this high stereoselectivity is that the acrylate is fixed in the strans conformation in the presence of Lewis acids, and the phenyl group of the chiral auxiliary effectively shields the si face of the ester. thereby enabling the alkenyl radical to attack predominantly from re face (Fig. 3).

COOR*

1) Bu3SnH, Et3B i-Bu3Al, toluene 0 "C, under dry air

-K-

COOR*

2) cat TsOH, benzene

60%, 62% de

COOR*

BuaSnH Lewisacid, Et3B * toluene, -78 "C under dry air

bcOoR* + ..'''\COOR*

(R)-isomer

Lewis acid: none BF3*OEt2 i-Bu3Al MAD

(S)-isomer

67:33 84116 90:lO 96:4

Scheme 138

Renaud and co-workers reported an unusual effect of solvent on diastereoselectivity in the radical deuteration of the sulfinylated benzyl radical with Bu3SnD-AIBN, and exceptional inversion of stereoselectivity was obtained with MAD (Sch. 139) [181].

Achiral Al(III) Lewis Acids

-8

O0

Bu3SnD, AIBN

ph,k%Ph

solvent

/6@ Ph

H SePh

269

O0

Ph

/6@ Ph

+

Ph

D H

H D

87% (66 34) 93% (82 : 18) MAD/CH2C12

85% (2.5 97.5)

Scheme 139

The authors observed a remarkable template effect of ATPH in radical cyclizations [182]. Intramolecular radical cyclization of ,&halo ether, 2-iodoethyl 3-phenylpropynyl ether (180) under standard radical reaction conditions (catalytic AIBN, ) of cyclic ether, 3-benzylidenetetraBu3SnH, benzene, reflux) gave an ( E ) / ( Z mixture hydrofuran (181) in 96 YOyield ( E / Z5050). Reaction of 180 with Bu3SnH and catalytic Et3B as radical initiator at -78 "C yielded 181 in 94 YOyield with better stereoselectivity (EIZ 61:39). In contrast, however, initial complexation of 181 with ATPH (2 equiv.) in toluene and subsequent addition of Bu3SnH (1.5 equiv.) and catalytic Et3B (0.2 equiv.) afforded 181 quantitatively with totally opposite preferred olefin geometry (EIZ 14:86), indicating that Lewis-acid receptor, ATPH, changed the conformation of the transition state in the hydrogen abstraction process [183]. The stereoselectivity was further improved by the use of (Me3Si)3SiH instead of Bu3SnH (Sch. 140). Ph

radical initiator

I

180

Ph

(€)-181

(4-181

cat AIBN/Bu3SnH/benzene, 80 "C, 1h : 96% ( U Z =50 : 50) cat Et3B/Bu3SnH/toluene, -78 "C, 1h : 94% (&Z= 61 : 39) ATPHlcat Et3B/Bu3SnH/toluene, -78 "C, 1h : 99% (&Z= 14 : 86) ATPH/cat Et3B/(Me3Si)3SiH/toluene,-78 "C, 1h : 99% (HZ= <1 : >99) -I

p 1 p%-snBu3

I

Scheme 140

I

(4-181

270

Ooi/Maruoka

On the basis of this observation, intramolecular cyclization of one-carbon elongated halo ether, 3-iodopropyl3-phenylpropynylether (182) was also examined. Surprisingly, radical cyclization of 182 under the influence of ATPH gave the desired cyclic ether 183 quantitatively as the sole isolable product, whereas in the absence of ATPH the yield of 183 was dramatically reduced (16 %) and there was predominant formation of the reduction product 184 (53 YOyield). It is worthy of note that the ( E ) / (2) selectivity of the cyclization products 183 is again different in the presence or absence of ATPH, and nearly perfect (2)selectivity was also obtained with (Me$$SiH, despite the significant rate retardation under similar reaction conditions (30 %! yield of 183; ( E ) / ( Z )< 1:>99 and 70 % recovery of 182) (Sch. 141). The origin of this remarkable template effect might be ascribable to the well-defined reaction environment created in front of the aluminum coordination center; this enables appropriate proximity of the initially generated carbon radical and the triple bond in the transition state for smooth cyclization and hence completely suppresses the undesired intermolecular reduction pathway. Ph

&-'

Ph

:r:t3B/Bu3SnH toluene, -78 "C, 1h*

1a2

( 0 - 183

(4-183

99% ( O Z = 19 : 81)

cat Et3B/Bu3SnH toluene, -78 "C, 1h

1a4

1a3

53%

16% (UZ=54 : 46)

Scheme 141

Tetrahydrofuran 186 can also be obtained with excellent cis selectivity in the radical cyclization of 2-iodoethyl trans-1-methyl-2-hexenyl ether (185) with ATPH as a template, as shown in Sch. 142. This excellent cis selectivity is certainly unattainable under ordinary radical reaction conditions.

185

cis-186

trans-186

95% (3 : 97) 99% (92 : 8) with ATPH

Scheme 142

Achiral AI(III) Lewis Acids

271

Aluminum porphyrin complexes induce living polymerization of MMA under irradiation with visible light giving polymers with controlled molecular weights. Inoue, Aida and coworkers have discovered that polymerization is dramatically accelerated upon addition of certain Lewis acids as monomer activators, affording narrow molecular-weight-distribution (MWD) polyMMAs within seconds under appropriate conditions [184]. Especially important is that when sterically hindered MAD is used undesired attack of the nucleophile on the Lewis acid is suppressed, because of the large steric barrier between the nucleophilic growing species bearing a bulky porphyrin ligand and the sterically crowded Lewis acid center. Accordingly, MAD activates the monomer until reaction is complete, thereby making it possible to obtain polymers with large molecular weights and very narrow MWD with remarkable efficiency (Sch. 143). For example, MMA was added to a CHZC12 solution of (TPP)AlMe and the mixture was irradiated at 35 "C for 2.5 h, during which time the methyl complex was completely converted to the aluminum enolate species whereas conversion of MMA was only 6 %. Upon addition of 3 equiv. MAD, high-speed polymerization with 100 YOconversion was achieved within a few seconds. The polymer thus obtained was of a very narrow MWD (Mw/Mn = 1.07), and the number-average molecular weight was in fair agreement with the value expected, assuming the formation of one polymer molecule from every molecule of (TPP)AlMe.

-

(TPP)AIX (187) (X = Me)

H+

PMMA

hv

C02Me (TPP)AIX (187) (X = Me)

n ==(Me,

. C02Me

MAD

(TPP)AIX (187)

Scheme 143

272

OoUMaruoka

As has been clearly shown, electrophilic activation of carbonyl groups with Lewis acids is a well-established method of enhancing their reactivity and selectivity toward nucleophilic addition. The two principal modes of coordination of carbonyls to metals are x-bonding (S) and o-bonding (T) [185]. The latter mode is generally preferred with main-group metal Lewis acids. In addition, simultaneous coordination to carbonyl groups with two metals of type (U) would alter the reactivity and selectivity of the carbonyl substrates [186,187]. Examples of such double coordination with two maingroup metals are rare, despite its potential importance [188,189], simply because of the high preference for the single coordination mode (T), even in the presence of excess Lewis acids. The nature of such di-o-bonding (U) has, therefore, remained elusive [190,191]. In this context, the authors have developed a modified bis(organoa1uminum) reagent 188 for efficient simultaneous coordination of carbonyls (V), thereby elucidating the characteristics of the double electrophilic activation of carbonyl substrates [192].

The bidentate organoaluminum reagent, (2,7-dimethyl-l,8-biphenylenedioxy)bis(dimethylaluminum) (188) was prepared by treatment of the biphenylenediol 189 with Me3A1 (2 equiv.) in CH2C12 at room temperature for 30 min. Initial complexation of 5-nonanone with the in situ-generated 188 (1.1equiv.) in CHZC12 and subsequent reaction of Bu3SnH (1.2 equiv.) at -78 "C for 20 min gave the corresponding 5-nonano1 in 86 YO yield. In marked contrast, however, reduction of 5-nonanone with Bu3SnH in the presence of monodentate organoaluminum reagent 190 (prepared from 2,6-xylenol and Me3A1; 1:1 molar ratio) under similar reaction conditions afforded 5-nonanol in only 6 YOyield. These results clearly demonstrate that the bidentate Lewis acid 188 strongly enhances the reactivity of ketone carbonyl toward hydride transfer via double electrophilic activation of the carbonyl moiety. A similar tendency is observed in the acetophenone carbonyl reduction (Sch. 144). R

~

0

1) ~ 188 or 190, R 2) Bu3SnH, -78"C R' = R2 = Bu R' = Ph, R2 = Me

Scheme 144

~

OH : 86% with 188 (6% with 190)

: 91% with 188 (9% with 190)

Achiral Al(III) Lewis Acids

273

The Mukaiyama aldol reaction of 1-(trimethylsi1oxy)-1-cyclohexene and benzaldehyde has also been effected with the bidentate 188, giving the aldol products (erythrol threo 1:3) in 87 % yield, though its monodentate counterpart 190 showed no evidence of reaction under similar conditions (Sch. 145).

6

OSiMe3 188 or 190

+ PhCHO

CHzC12 -78 "C, 3.5 h 87% with 188 -0% with190

Scheme 145

Another interesting feature of the bidentate Lewis acid 188 in organic synthesis is the regio- and stereocontrolled Michael addition of silyl ketene acetals to a&unsaturated ketones as acceptors [193]. Reaction of benzalacetone and silyl ketene acetal 191 with dimethylaluminum aryloxides of type 192 gave rise to a mixture of Michael adducts 192 and 194 almost exclusively; ( Z )selectivity decreased with increasing steric size of the phenoxy ligand in 192. Indeed, changing the phenoxy group to 2,6-xylenoxy, 2,6-diisopropylphenoxy, and 2,6-di-tert-butylphenoxy reduced the ( Z )selectivity from 80:20 to 70:30,67:33, and 33:67, respectively. On the basis of these experimental findings, the stereochemical outcome of the (Z)-isomeric Michael adduct 192 is interpreted in terms of the preferred formation of complex (W) between benzalacetone and sterically less hindered 192a or 190. With more hindered 192b or 192c, the coordination complex (Y) is then favored rather than the sterically congested complex (X), thereby increasing the formation of (E)-isomeric Michael adduct 194. Ultimately bidentate 188 can be used to obtain (,!?)-isomeric 194 as a major product via the formation of complex (Z) with s-trans conformation (Sch. 146).

274

Ooi/Maruoka

194 (€-isomer)

192a (R = H), b (R = Pr?, c (R = Bu3 bidentate Lewis acid (188)

28:72 (73%)

Yoyield

'I

W

ph\cH3

A' ,

0'.

'I

X

ph\cH3

+.O

)A1

Y

,,..a, / '''Alz

Scheme 146

The authors applied this new concept to chemoselective functionalization of carbonyls rather than acetals [194], which is usually quite difficult to achieve because of the high reactivity of the acetal counterparts with Lewis acids. Reaction of a mixture of 1 equiv. each of acetophenone and its dimethyl acetal with ketene silyl acetal 191 under the influence of bidentate aluminum Lewis acid 188 in CH2C12at -78 "C for 3 h afforded aldol products 195 exclusively (88 YO yield). It is worth noting that employment of dibutyltin bis(triflate) (DBTT) (10 mol%) as catalyst [195], which is quite useful for activation of aldehyde carbonyls rather than acetals, gave unsatisfactory results, producing the P-methoxy ester preferentially (Sch. 147).

Me0 PhKMe

+

OMe

PhXMe

-Lewis acid

-78 "C, 3 h

OMe 195

Lewis acid : Me3SiOTf

+

Ph

OMe 196

: 81Yo (57 : 43)

Bu2Sn(OTf)2 : 75% (16 : 84) 188

Scheme 147

: 88% (>99 : <1)

Achiral AZ(III) Lewis Acids

275

In the Lewis acid-promoted allylation of aldehydes with allyltributyltin, virtually complete chemoselective functionalization of aldehyde carbonyls is also observable and the opposite chemoselectivity is easily accessible by use of TiCL, as promoter, as shown in Sch. 148 [106]. TiCI4,

eSnBu3

CH2C12 -78 "C, 2 h PhCHO OMe

I

PhAOMe

\

bidentate LA, ( 1 8 8 ) , e S n B u 3 CH2C12 -78 "C. 2 h

*

Ph

<< [

P

h

L

]

86% (<1 : >99)

Scheme 148

The authors used 188 as an efficient system for alkyl-transfer to aldehyde carbonyls which enables facile carbonyl alkylation with otherwise less reactive alkylaluminum species [196]. Treatment of benzaldehyde with 1 equiv. Me3Al in CH2C12 at -78 "C gave a long-lived monomeric 1:l complex which gradually decomposed to a methylation product, phenethyl alcohol, on warming to -20 "C [197]. Derivatization of Me3A1 to dimethylaluminum aryloxide 190 significantly retarded the rate of alkylation under similar reaction conditions, and even use of excess 190 (2 equiv.) gave none of methylation product at -20 "C. In marked contrast, however, the methylation of benzaldehyde proceeded quite smoothly with 1 equiv. bimetallic 188 at -20 "C for 4 h, furnishing phenethyl alcohol in 84 % yield (Sch. 149). The rate acceleration observed is reasonably understood- bimetallic 188 on reaction with aldehyde could result in equilibrium between two 1:l coordination complexes 197 and 198, and 198 is thought to be readily transformed, by way of a cyclic 6membered transition state, to the alkylation product, as also illustrated in Sch. 149.

276

Ooi/Maruoka

* -20 "C, 4 h

OH 84%

AIMe2 Q C H O

CH2C12

Me,&Me

Ph

.Me 198

Scheme 149

This hypothesis has been supported by experiments with a modified bimetallic, two-center system. Initial treatment of bis(dimethyla1uminum) derivative 188 with 1 equiv. MeLi generates a new amphiphilic alkylation system 199 which has both electrophilic and nucleophilic centers in one reagent (Sch. 150). This system is found to be much more effective than symmetric 188, and the carbonyl alkylation of aldehydes proceeds even at -78 to -40 "C. A similar process with monoaluminum derivative 190 and its complex with MeLi, however, gave a trace of methylation product 200 (R1 = Ph) (< 3 % yield), indicating that appropriate internal arrangement of the two metal centers is essential to achieve this remarkable rate enhancement in the new amphiphilic alkylation. nucleophilic site

MeLi (1 eq) 188

toluene or CH2C12 -78 "C, 30 min

Scheme 150

electrophilic site

-3

,Me Me2AI0

Li'

d

AIMe2 \ Me

-

-78--40"C 4-5h

199

OH

200 72% (R' = Ph) 71% (R' = oHex)

Achiral A l ( I I I ) Lewis Acids

277

References 1. (a) Friedel-Crafts and Related Reactions, Olah, G. A,, Ed.; Wiley-Interscience: New York, 196365; Vols 1 4 . (b) Friedel-Crafts Chemistry, Olah, G. A., Ed.; Wiley: New York, 1973. 2. Kranzlein, G. Aluminum Chloride in der Organischen Chemie, 3rd Edn., Verlag Chemie: Berlin, 1939. 3. Thomas, C. A. Anhydrous Aluminum Chloride in Organic Chemistry, Reinhold: New York, 1961. 4. Krespan, C. G.; Petrov, V. A. Chem. Rev. 1996,96,3269. 5. Joyce, R. M. U.S. 2,462,402,1949,to DuPont; Chem. Abstr. l949,43,3834e. 6. Paleta, 0.;Posta, A. Collect. Czech. Chem. Commun. 1967,3,1427. 7. Paleta, 0.;Posta, A,; Jesarik, K. Collect. Czech. Chem. Commun. 1971,36,1867. 8. Sievert, A. C.; Nappa, M. J. PCT WO 95/16655,to DuPont; Chem Abstr. 1995,123,339129. 9. Sievert, A. C.; Nappa, M. J. PCT WO 95/16656,to DuPont; Chem Abstr. 1995,123,339128, 10. Petrov, V. A,; Davidson, F.; Smart, B. E. J. Org. Chem. 1995,60,3419. 11. Harris, J. F.; Coffman, D. D. J. A m . Chem. Soc. 1962,84, 1153. 12. Krespan, C. G.; Dixon, D. A. J. Fluorine Chem. 1996,77,117. 13. Petrov, V. A,; Smart, B. E.; Krespan, C. G. J. Fluorine Chem. 1996,77,. 14. Krespan C. G.; Petrov, V. A,; Smart, B. E. US. 5,416,246, 1995, to DuPont; Chem. Abstr. 1995, 123, i13381. 15. Carr. D. B.: Schwartz. J. J. Am. Chem. SOC.1977.99.638. 16. Hart: D. W.; Schwartz, J. J. Am. Chem. Soc. 1974,96,8115. 17. Nishikawa, A,; Hashimoto, Y.; Shirai, R. Tetrahedron, Lett. 1998,39,7307. 18. Ino, A,; Hasegawa, Y.; Murabayashi, A. Tetrahedron, Lett. 1998,39,3509. 19. Meerwein, H.; Schmidt, R. Liebigs Ann. Chem. 1925,444,221. 20. Verley, A. Bull. Soc. Chim. Fr. 1925,37,537. 21. Ponndorf, W. Angew. Chem. 1926,39,138. 22. Wilds, A. L. Org. React. 1944,2,178. 23. De Graauw, C.; Peters, J.; Van Bekkum, H.; Huskens, J. Synthesis 1994,1007. 24. Tischenko, W. Chem. Zentralbl. 1906,77,1309. 25. (a) Kagan, H.; Namy, J. Tetrahedron 1986, 42, 6573. (b) Huskens, J.; De Graauw, C.; Peters, J.; Van Bekkum, H. Reel. Trav. Chim. Pays-Bas 1994,1007. 26. Barbry, D.; Torchy, S. Tetrahedron Lett. 1997,38,2959. 27. (a) Akamanchi, K.; Varalakshmy, N. R. Tetrahedron Lett. 1995,36,3571. (b) Akamanchi, K.; Varalakshmy, N. R. Tetrahedron Lett. 1995,36,5085. 28. Akamanchi, K.; Varalakshmy, N. R.; Chaudhari, B. A. Synlett 1997,371. 29. Ooi, T.; Miura, T.; Maruoka, K. Angew. Chem. Znt. Ed. Engl. 1998,37,2347. 30. Morrison, J. D.; Mosher, H. S. Asymmetric Organic Reactions; American Chemical Society: Washington, D. C., 1976; p 160. 31. Oppenauer, R. V. Rec. Trav. Chim. 1937,56,137. 32. Recent Modification: Akamanchi, K. G.; Chaudhari, B. A. Tetrahedron Lett. 1997,38,6925. 33. Ooi, T.; Itagaki, Y.; Miura, T.; Maruoka, K. Tetrahedron Lett. 1999,40,2137. 34. Ooi, T.; Miura, T.; Maruoka, K. J. Am. Chem. Soc. 1998, 120,10790. 35. Emziane, M.; Lhoste, P.; Sinou, D. Synthesis 1988,541. 36. Takai, K.; Oshima, K.; Nozaki, H. Tetrahedron Lett. 1980,21,1657. 37. Aben, R. W.; Scheeren, H. W. Synthesis 1982,779. 38. Ziegler, K. Organometallic Chemistry, Zeiss, H. Ed.; Reinhold: New York, 1960; p 194. 39. Wilke, G Coordination Polymerization, Chien, J. C. W. Ed.; Academic Press: New York, 1975. 40. Mole, T.; Jeffery, E. A. Organoaluminum Compounds, Elsevier: Amsterdam, 1972. 41. (a) Reinheckel, H.; Haage, K.; Jahnke, D. Organomet. Chem. Rev. A , 1969,4,47. (b) Lehmkuhl, H.; Ziegler, K.; Gellert, H. G. Houben-Weyl, Methoden der Organischen Chemie, 4th Ed.; Thieme: Stuttgart, 1970; Vol. XIII, Part 4. (c) Bruno, G. The Use of Aluminum Alkyls in Organic Synthesis, Ethyl Corporation: Baton Rouge LA, USA, 1970, 1973 and 1980. (d) Negishi, E. J. Organomet. Chem. Libr. 1976, I , 93. (e) Yamamoto, H.; Nozaki, H. Angew. Chem. Znt. Ed. Engl. 1978, 17, 169. (f) Negishi, E. Organometallics in Organic Synthesis, Wiley: New York, 1980 Vol. 1, p 286. (g) Eisch, J. J. Comprehensive Organometallic Chemistry, Wilkinson, G.; Stone, F. G. A,; Abel, E. W. Eds.; Pergamon Press: Oxford, 1982; Vol. 1, p 555. (h) Zietz, J. R. Jr.; Robinson, G. C.; Lindsay, K. L. Comprehensive Organometallic Chemistry, Wilkinson, G.; Stone, F. G. A,; Abel, E. W. Eds.; Pergamon Press: Oxford, 1982; Vol. 7, p 365. (i) Zweifel, G.; Miller, J. A. Org. React. 1984,32,375. 6)Maruoka, K.; Yamamoto, H. Angew. Chem. Znt. Ed. Engl. 1985,24,668. 42. Maruoka, K.; Miyazaki, T.; Ando, M.; Matsumura, Y.; Sakane, S.; Hattori, K.; Yamamoto, H. J. A m . Chem. Soc. 1983,105,2831. 43. Matsumura, Y.; Maruoka. K.; Yamamoto, H. Tetrahedron Lett. 1982,23,1929.

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Lewis Acids in Organic Synthesis Edited bv Hisashi Yamarnoto Copyright 0WILEY-VCH Verlaa GmbH.2000

7 Chiral Aluminum Lewis Acids in Organic Synthesis WilliamD. Wulff

7.1 Introduction The earliest report of a reaction mediated by a chiral three coordinate aluminum species describes an asymmetric Meerwein-Ponndorf-Verley reduction of ketones with chiral aluminum alkoxides which resulted in low induction in the alcohol products [1]. Subsequent developments in the area were sparse until over a decade later when chiral aluminum Lewis acids began to be explored in polymerization reactions, with the first report describing the polymerization of benzofuran with catalysts prepared from and ethylaluminum dichloride and a variety of chiral compounds including /3phenylalanine [2]. Curiously, these reports did not precipitate further studies at the time because the next development in the field did not occur until nearly two decades later when Hashimoto, Komeshima and Koga reported that a catalyst derived from ethylaluminum dichloride and menthol catalyzed the asymmetric Diels-Alder reaction shown in Sch. 1 [3,4]. This is especially curious because the discovery that a Diels-Alder reaction could be accelerated by aluminum chloride was known at the time the polymerization work appeared [5]. Perhaps it was because of this long delay, that the report of this asymmetric catalytic Diels-Alder reaction was to become the inspiration for the dramatic increase in activity in this field that we have witnessed in the twenty years since its appearance. It is the intent of this review to present the development of the field of asymmetric catalytic synthesis with chiral aluminum Lewis acids that includes those reports that have appeared in the literature up to the end of 1998. This review will not cover polymerization reactions or supported reactions. The latter will appear in a separate chapter in this handbook. 15 rnol % catalyst 4 toluene, -78 OC, 3 h

0

2 1.1 equiv

1

3 69 % yield exo : endo = 98 : 2 72 % ee

EtAlC12 .

A

A

5

4

Scheme 1

OAIC12

7.2 Aldol Reactions The first report of an aldol reaction mediated by a chiral aluminum Lewis acid described catalysts generated from the pinene diol 12 and the bornane amino alcohol 14 [7]. The catalysts were generated by the reaction of each substrate with diethylaluminum chloride and were evaluated in the Muikaiyama aldol reaction of the ketene acetal 7 with iso-valeraldehyde. The most successful of the two was catalyst 13 which gave the aldol adduct 8 in 66 YOenantiomeric excess (ee) but only in 15 YOyield with 20 mol YOcatalyst. Very recently, this reaction has been re-investigated with catalysts generated from type 16 bornane diols [7]. The aldol reaction of ketene acetall0 with dihydrocinnamaldehyde gave the adduct 11 in 58 YO ee and 50 YO yield with 100 mol YOcatalyst (Sch. 2). 20 mol % catalyst toluene

6

-78

7

Hzs

25 O C 10 h

catalyst

8 yield

13

15 %

15

48%

% ee

66 25

100 % mol catalyst 17 -+

0 9

toluene 0 OC, 22 h

10

OH

0

11 50 % yield; 58 % ee

toluene 0 O C , 4.5 h

R 16

R=H

17

Scheme 2

Several catalysts generated from a series of diols of the type 16 were screened [7]. This series of catalysts was evaluated with the reaction of benzaldehyde with the ketene acetal 10 and the optimum catalyst was that with R = H (17), which gave the adduct 19 in 82 YOee. Catalysts generated from 16 in which the substituent R was methyl, ethyl, iso-propyl or phenyl all resulted in lower asymmetric induction. The solution structure of catalyst 17 is not known, but molecular-weight determinations reveal that substantial aggregation is occurring to give an average molecular weight of 8000. Consistent with aggregation of the catalyst is the concentration-dependence and inverse temperature-dependence of induction, with different enantiomers being preferentially produced at 0 "C and -23 "C. The optimum catalyst 17 was found to give 87 YO ee for the reaction of cinnamaldehyde and ketene acetal 10. The same catalyst gave 80:20 anti:syn selectivity from the reaction of benzaldehyde and the ketene acetal

285

Chiral Aluminum Lewis Acids in Organic Synthesis

22 where the major anti isomer was produced with YO YOee. Finally, it was observed that catalyst 17 was ineffective at producing a reaction between aldehydes and ketene acetal25 (Sch. 3). P h y H

s:+;)

+

100 % mol catalyst 17

Ph+ toluene 0 "C, 22 h

0 18

10

OH

19 64 % yield; 82 % ee 100 % mol catalyst 17

20

toluene 0 "C, 22 h

10

OTMS

0 18

0

OEt

Ph+OEt

25 OH

0

21 61 %yield; 87 % ee 100 8 mol catalyst 17

toluene 0 "C, 22 h

22

+OTMS

P h A O E t OH

+

Ph+

0

OH

23 90%ee

0

24

Scheme 3

Although the asymmetric aldol reaction of benzaldehyde and diketene has been reported with a catalyst generated from di-iso-propyl tartrate and iso-propanol, low induction and low yields were observed for the 8-hydroxyl-P-keto ester 27 [8]. Low induction was also observed for aldol reactions mediated by chiral aluminum catalysts generated from a-amino acids [Y]. These types of catalyst have been very successful when employing boron as the Lewis acid, as illustrated in the aldol reaction of ketene acetal 10 with the boron catalyst 31 derived from (S)-valine (Sch. 4) [Y,lO]. Catalysts derived from N-tosyl-(S)-valine and Et2AlCl and i-Bu3Al were relatively ineffective (< 15 YOee) [Y]. 100 % mol catalyst 29

$,,

phYH 0

+

18

CHzClz 0 O C , 24 h

26

phmqoy OH

0

27 22 %yield; 23 % ee i-PrOH Catalysts 29 CH2CIz 25 O C , 1 h

25 O C , 1 h

OH 28 L-(+)-DIPT

w / I

RrrH 0

30 Scheme 4

+

H ( 10

,

Ts'

N,B,o

31

H

I

100 % mol

R,JY/OEt OH

0

32 80 - 87 % yield 83 - 93 % ee

One of the more significant developments in the field of asymmetric catalysis was the report of the aldol reaction of aldehydes with isocyanoacetates promoted by a gold catalyst generated from the ferrocenyl bis-phosphine 41 (Sch. 5) [ll].The product of this reaction is the oxazoline 35 which is produced predominately as the trans isomer in high yield with induction in the range 72-97 % over a range of aldehydes which includes aryl, vinyl, unbranched aliphatic, and branched aliphatic aldehydes. Very recently an asymmetric aldol reaction involving a very different substrate has been developed; this provides predominately cis-substituted oxazolines also with high induction [12]. This reaction is mediated by a chiral aluminum catalyst generated from (R)-BINOL ((R)-bis-1,l’-binaphth-2,2’-01) and trimethylaluminum which effects a formal [3 + 21 cycloaddition of an aldehyde to 2-aryl-5-methoxyoxazoles. All the successful examples in this report involved aryl aldehydes and it was mentioned that cinnamaldehyde and thiophenecarboxyaldehyde gave low yields and induction. % trans = 81 - 100 % o/o yield = 83 - 100 % % ee (trans) = 72 - 97 o/o

1 % mol catalyst 34 0 30

0

CHIC12 25 OC, 20 h

33

O+N

35 % cis = 54 - 97 % % yield = 57 - 91 % % ee (cis) = 75 .90 YO

0

36

31

39

41

40 R-BINOL

Scheme 5

7.3 Carbonyl Additions and Reductions This section reviews the literature on asymmetric carbonyl additions and reductions mediated by chiral aluminum Lewis acids. This does not include aldol reactions, cycloaddition reactions, and ene reactions, each of which will be covered in separate sections. The earliest such carbonyl addition reaction to be reported was, along with the Muikaiyama aldol reaction of ketene acetal7 (Sch. 2), the addition of trimethylsilyl cyanide to iso-valeraldehyde [6]. The catalyst 13 did not result in asymmetric induction as high in this reaction as it did with the Muikaiyama aldol reaction of ketene acetal 7 with iso-valeraldehyde (Sch. 2). The cyanohydrin 45 was isolated in 65 YO yield as a 66:34 mixture of enantiomers only.

Chiral Aluminum Lewis Acids in Organic Synthesis

287

Several years later, more useful catalysts were described; these were prepared from amino acids or dipeptides via their Schiff bases with 2-naphthol-1-carboxaldehyde [13]. The catalyst giving the highest induction for this reaction was prepared from the Schiff base 48 and trimethylaluminum. This catalyst resulted in moderate induction with several aldehydes including the three shown in Sch. 6.

’Tx”

20 mol % catalyst 13

+

Me3SiCN (1 equiv)

6

0

-78

44

+

--

toluene

25 OC 10h

100 mol % catalyst 46

Me3SiCN (3 equiv) 44

30

-

toluene -78 OC 0.5 - 5 h

n

H

catalyst 46

25 O C , 2 h

1 ,:

N

45 65 % yield, 32 % ee

RYCN OH 47 61 - 9 1 %yield R Ph Cy n-Hept

1 ,:

c

% ee

71 56 37

25 OC, 2 h

catalyst 50

Scheme 6

Asymmetric induction was found not to be dependent on catalyst loading. For example, addition to cyclohexane carboxaldehyde occurred with 56 YOee whether 100 or 10 mol YO catalyst was used, although the reaction was slower for the latter, proceeding in 17 h rather than 0.5 h. Several other ligands were evaluated for this reaction and it was found that ligand 48, derived from the cyclohexyl amide of valine was optimal in terms of rate and asymmetric induction. As an example, induction in the addition to benzaldehyde dropped from 71 YOee to 61 YOee when the ligand used in the catalyst was changed from 48 to 49 and the time of reaction increased from 5 to 102 hours. Aluminum catalysts were superior to titanium catalysts for the addition of trimethylsilyl cyanide to aldehydes. For example, a catalyst prepared from ligand 49 and titanium tetra-iso-propoxide resulted in only 19 YOee in the addition to benzaldehyde (compared with 71 YO ee for catalyst 50 under the same conditions) [14]. Interestingly, titanium catalysts were superior to aluminum catalysts for the addition of hydrogen cyanide to aldehydes [14]. As an example, the catalyst prepared from ligand 49 and titanium tetra-iso-propoxide resulted in 78 YOee in the addition of hydrogen cyanide to benzaldehyde. This reaction with titanium catalysts was optimized with other dipeptide derivatives of 2-naphthol-1-carboxaldehyde to give asymmetric induction in the range 62-97 YOee for aryl,. vinyl, and aliphatic aldehydes [14].

A catalyst generated from the PYBOX ligand 52 (Sch. 7) and aluminum chloride has been reported to give greater than 90 YO ee in the formation of mandelonitrile from the reaction of benzaldehyde and trimethylsilyl cyanide [15]. The reaction with 20 mol YOcatalyst is much faster at room temperature (4 h) but induction fell to 44 YO ee. The same reaction at room temperature with a catalyst generated from aluminum chloride and (-)-DIOP occurred in 10 h (92 % yield) and gave the product 47 in 6 YO ee. No reaction was observed with a catalyst generated from eserine and aluminum chloride. The addition of trimethylsilyl cyanide to aliphatic aldehydes was not reported and, although several heteroaromatic aldehydes were found to successfully undergo reaction with catalyst 51, they did not determine the amount of induction in the products from their reaction. On the basis of ‘H NMR studies and quantum chemical calculations, it was proposed that the structure of catalyst 51 involved monodentate coordination of the ligand to the aluminum through one of the oxazolidinones.

+ phYH 0 18

20 mol % catalyst 51 Me3SiCN ( 1.1 equiv) 44

CH2C12 O°C 16 h

H~O+ -

PhYCN OH 47 92 %yield

> 90 % ee

catalyst 51

Scheme 7

There is only one report of asymmetric addition of a Grignard reagent to an aldehyde mediated by a chiral aluminum Lewis acid coordinated to the aldehyde [16]. The catalysts were prepared by reaction of trimethylaluminum with the 2,6-diarylpheno1 61; the reaction stopped after two phenoxide units had been introduced. Attempts to prepare Lewis acids with three phenoxides on the aluminum failed. Of the two catalysts evaluated, 59 was found to be optimum in providing asymmetric induction in aliphatic aldehydes. Three equivalents were needed to give optimum selectivity with aliphatic but not other aldehydes. Additions to conjugated aldehydes were found to be more enantioselective with 60 than with 59, as is indicated by the addition of methyl Grignard to benzaldehyde shown in Sch. 8. The finding that the facial selectivity provided by catalyst 60 for trans-cinnamyl aldehyde was reversed with trans-2-hexenal was not explained and is certainly rather curious. The general observations made with catalysts 59 and 60 are that si face-addition occurs with aliphatic aldehydes and trans-2-hexenal and that re face-addition occurs with benzaldehyde and cinnamyl aldehyde.

289

Chiral Aluminum Lewis Acids in Organic Synthesis CH3MgI (3.0 equiv) S-Lewis acid 59 (3.0 equiv)

+

0

R-CH3

OH S-alcohol 55 90 - 99 8 yield

CH2C12 -78 O C 30 - 120 min

30

RMgX (2.0 equiv) + ph,l(H 0

(Lewisacid I .2 equiv)

30 120 min

RqH

n-BuMgBr (2.0 equiv)

+

0

S-59 PhyR R-60 OH R-60

CHzC12 -78 "C

18

57. -

R = M e 42%ee(R) R = M e 65 %ee(S) R = n-Bu 75 la ee (S)

56 61 - 99 % yield

A

-R

Lewis acid

(1.2 - 2.0 equiv)

R = n-Bu 52 8 ee R=Cy 84%ee R=t-Bu 8 6 % e e

OH S-alcohol

CH2C12 -78 O C 30 - 120 min

R-60 R = P h S-60 R=n-Pr

83%ee 82 % ee

58 86 - 99 % vield

(S) Lewis acid 59

(S) Lewis acid 60

(S) Ligand 61

Scheme 8

A bimetallic catalyst prepared from BINOL and lithium aluminum hydride has been found to result in useful asymmetric induction in the Pudovik reaction [17]. The (R)-ALB catalyst 64 (10 mol Yo) facilitates the addition of dimethyl phosphite to a variety of electron-rich and electron-poor aryl aldehydes in high yield with induction in the range 71-90 YOee. The nature of the solvent is important in this reaction-the induction for addition to benzaldehyde dropped from 85 YO ee to 65 YOee when the solvent was changed from toluene to dichloromethane. Aluminum seems to be a key to the success of this reaction, because reaction with benzaldehyde was not as successful with other bimetallic catalysts. BINOL catalysts with lanthanum and potassium gave only 2 % ee, a catalyst with lanthanum and sodium gave a low 32 Yo ee, and a catalyst with lanthanum and lithium gave only a 28 YOee [18]. Aliphatic aldehydes were not successfully hydrophosphonylated with dimethyl phosphite by catalyst 64 (Sch. 9). Induction was low (3-24 % ee) for unbranched and branched substrates. a&Unsaturated aldehydes were, however, reported to work nearly as well as aryl aldehydes with four examples in the range 55-89 YOee. The failure of aliphatic aldehydes with this catalyst can be overcome by reduction of the product obtained from reactions with u&unsaturated aldehydes. As illustrated by the reduction of 67 with palladium on carbon, this can be done without epimerization of the u-hydroxy phosphonate.

I: ArvH +

H,P(OMe)2

0

10 mol % catalyst 64

Ar

toluene, -40 O C

63

62

I:

H IP(OMel2

{(OMe)2 0

71-90%ee 80 - 95 % yield

65

10 mol % catalyst 64

68 % ee

toluene, -40 ‘C

63

66

x”

67 I0 % PdC, H2 MeOH, 3 h

2BINOL 40

LiAIH4 -

/18”p(oMeh

0THF OC, I h

68

6

68 % ee 98 % yield

(R)-ALB 64

Scheme 9

A mechanism for this reaction has been proposed and is summarized in Sch. 10. The catalyst 64 is thought to be bifunctional with the aluminum center operating as a Lewis acid and the lithium naphthoxide operating as a Lowry-Bronsted base. It was envisaged that the aldehyde coordinates with the aluminum to give the complex 69 and deprotonation of the dimethyl phosphite then gives the aggregate 70 in which the phosphite anion is positioned for P-alkylation of the aldehyde that will occur selectively from the si face when the catalyst is prepared from (R)-BINOL. 0

0

Scheme 10

The first example of an asymmetric Meerwein-Ponndorf-Verley reduction with an aluminum catalyst to appear in the literature was that achieved by Doering and Young in 1950 [l].They reported that cyclohexyl methyl ketone can be reduced with 22 % ee by use of racemic aluminum 3-methyl-2-butoxide 73 (Sch. 11) in the presence of excess optically pure 3-methyl-2-butanol. Woodward proposed the most widely accepted mechanism for this reaction; it involves hydride transfer in a six-membered transition state in a Lewis acid-Lewis base complex between an aluminum alkoxide and a ketone [19]. Doering and Young were able to account for the stereochemistry observed in alcohol 74 by invoking the transition state 75. Although, since this early report, this reaction has been extensively investigated with a variety of chiral aluminum alkoxides and chiral alkyl aluminums, the chemistry involved will not be covered here because other excellent reviews have appeared on this subject [20]. Although moderate selectivity has been achieved with some substrates and certain chiral alumi-

Chiral Aluminum Lewis Acids in Organic Synthesis

291

num alkoxides, high asymmetric induction (2 90 YOee) has never been achieved for any reaction in this class. In a recent study, Kellog and Hu surveyed the asymmetric reduction of acetophenone with iso-propyl alcohol with a variety of chiral aluminum alkoxides prepared from aluminum iso-propoxide and the six diols shown in Sch. 11 [21]. Slightly higher induction was observed with chiral alkoxides derived from erbium iso-propoxide but the reactions were still not synthetically useful. Finally, Krohn and Knauer have reported that a catalyst prepared from a TADDOL ligand and aluminum tert-butoxide failed to give any asymmetric induction in a MeerweinPonndorf-Verley reduction [22].

12

11

--

14 2 2 % e e

8 h, 36 ‘C

15

0.5 Eq Al(OiPr)3 0.5 Eq diol

16 1 E q

11 26 Eq

THF 3 d, 25 ‘C

18 21-86 % ee

19

COOiPr \

OH

COOiPr

OH

80 2 1 % ~

81 7 % e e

82 2 % e e

40 33 % ee

83 21 % ee

84 O%ee

Scheme 11

Asymmetric reduction of carbonyls has also been achieved by Dupas and coworkers by reaction of achiral NADH equivalents mediated by chiral aluminum Lewis acids [23]. They reduced methyl benzoyl formate with the dihydropyrido[2,3-b]indole 86 and chiral aluminum Lewis acids whose structures are drawn and 89 and 90 (Sch. 12). Asymmetric induction was quite low. Details of the reaction, including the conditions used, were not provided; nor were the procedures used for the preparation of the chiral Lewis acids 89 and 90.

Scheme 12

7.4 Claisen Rearrangements The only examples of asymmetric Claisen rearrangements catalyzed by a chiral aluminum catalyst are those published by Yamamoto and coworkers [24-271. The Claisen rearrangement of allyl vinyl ethers of type 91 (Sch. 13) can proceed via either of the two enantiomeric chair transition states 92 or 94. If a chiral Lewis acid is used to activate the process, the transition states become diastereomeric and preferential formation of one enantiomer of the product is possible. This is complicated because coordination of a chiral Lewis acid to the ether oxygen of allyl vinyl ether produces a new chiral center as indicated in 96 and asymmetric induction might occur from a substituent on aluminum to the oxygen and then from the oxygen to the C-3 carbon in the product. In their initial report, Maruoka, Banno, and Yamamoto found that a catalyst prepared from the 3,3’-disilyl-substituted BINOL 97 and trimethylaluminum was effective in this transformation [24]. The catalyst 98 was shown to be monomeric by measurement of freezing point depression.

94

(R)-97

95

(R)-98

(R)-99

Scheme 13

The Claisen rearrangement of trans-cinnamyl vinyl ether (100, X = H) with the chiral catalyst (R)-98 is unsuccessful leading only to carbon-oxygen cleavage products [24,26]. The corresponding iso-propenyl ether (X = Me) does provide a moderate yield of product but only with low asymmetric induction. Excellent induction could be obtained from a-silyl- and a-germyl-substituted vinyl ethers and, as indicated by the data in Table 1, slightly higher induction was observed for the germanium derivatives. Slightly higher induction was also observed for vinyl ethers bearing phenyldimethylsilyl groups compared with those bearing trimethylsilyl groups. The silyl substituents on the 3 and 3‘ positions of the catalyst should also be large if the highest asymmetric induction is required. The t-butyldiphenylsilyl and the triphenylsilyl groups both result in high induction but induction is lower for the t-butyldimethylsilyl group. Curiously, when the three phenyl groups on the silyl group are para-substituted, induction falls off dramatically.

Chiral Aluminum Lewis Acids in Organic Synthesis

Ph

293

1.1 - 2 Eq (R)-98

CH2C12 X 100

101

Table 1. Claisen rearrangement of trans-cinnamyl vinyl ethers 100.

'4r3

X

Two stage reaction conditions ("C, h)

Yield 101 (%) ee 101 (%)

H Me SiMe3 GeMe3 SiMezPh

NP NP 40,O. I ; -20, 8 -78,O.l; -40, 16 -78, 0. I ; 4 0 , 16

0 43 86 73 65

13 80 91

%Me3

-25OC to 25OC

NP

62

%Me3

-25OC to 25OC

NP

48

SiMe3

4 0 , 0.1 ; -20, 8

22

14

SiMe3 SiMezPh GeMe3

40,O.l; -20, 3 -78,O.l; -40, 8 -78,O.l; -40, 8

99 76 68

88 90 93

85

The Claisen rearrangements of several trans-ally1 vinyl ethers with (R)-98 as catalyst were investigated; the results are shown in Table 2 [24,26]. The data show that the catalyst derived from the t-butyldiphenyl-substituted BINOL does not consistently lead to higher asymmetric induction than the catalysts derived from triphenylsilyl-substituted BINOL. The reaction seems to be pericyclic because the dienyl vinyl ethers give only [3,3] sigmatropic rearrangement products. The source of the induction was investigated by use of space-filling models [24,26]. The cavity presented by catalyst (R)-98 seems to enable facile docking with the transition state 92 but not with its enantiomer 94 (Sch. 13), thus accounting for the formation of the (S) enantiomer 103 from the ( R )catalyst 98.

102

103

Table 2. Claisen rearrangement of trans-ally1vinyl ethers 102.

Ar3

R

Ph3

-5IPh -$-Me

t-BuPhz

Two stage reaction conditions ("C, h)

Yield 103 (%) ee 103 (%I

-40,O. 1; -20, 8

86

80

-78,O.l; -40, 8

69

78

-78,O. 1; -40,6

83

72

-40,o. 1; -20,4

79

61

4 0 , o . 1; -20, 10

40

60

-20,O. 1 ; 0,0.7

80

43

-40,O.l; -20,3

99

88

-40,o. 1; -20, 1.5

96

60

-40,O.l; -20,4

84

71

A series of cis-substituted allyl-a-trimethylsilylvinyl ethers was also investigated with the same catalyst (R)-98 [25,26].The data in Table 3 reveal that the enantiomeric purity of the product obtained from asymmetric Claisen rearrangement of the cis-ally1 vinyl ethers 104 is not quite as high as from that of the corresponding trans-ally1 ethers 102. It was, however, surprising to find that the cis and trans isomers both gave the same enantiomer of the product for all the substrates in Table 3.

Chiral AluminumLewis Acids in Organic Synthesis

295

Table 3. Claisen rearrangement of cis-ally1vinyl ethers 104. '4r3

R

Ph3

-m t-BuPh2

5 0

Two stage reaction conditions ("C, h)

Yield 103 (%) ee 103 (%)

4 0 , 3; -15, SO -20,O.l; 0, 3 -20,6; 0 , 3

56 77 81

78 67 65

-20,0.5; 0,22

44

75

-20, 5 ; 0 , 4

70

58

-20,2; 0,20

64

58

-20,6; 0, 3.5

76

50

The change in facial selection at the allyl double-bond in the asymmetric Claisen rearrangement of the cis- and trans-allyl-a-trimethylsilylvinyl ethers can be accounted for by a change in mechanism from one involving a chair transition state for the trans isomer (Sch. 13) to one involving a boat transition state for the cis isomer (Sch. 14) [25,26]. All chair transition states for the catalyzed Claisen rearrangement of the cis-ally1vinyl ether 106 will have 1,3-diaxialinteractions between the substituents R and X. The formation of the boat transition state 108 relieves this interaction in the Claisen rearrangement that gives the product 93, which is the same enantiomer as that produced from the chair transition state of the trans-ally1vinyl ether (Sch. 13) with catalyst (R)-98.Finally, it was shown that racemic catalyst 98 can be used to increase the diastereoselectivity of the Claisen rearrangement of the allyl vinyl ether 110 [24,26]. With this catalyst the rearrangement can be conducted at temperature 220 "C below that of the uncatalyzed reaction, and with increased stereoselectivity (97:3).

109

107

106 93

108

110

111 200 O C -20 O C with (f)-98

112 91 %yield 75 % yield

85 : 15 97 : 3

Scheme 14

An improved ligand design by Maruoka, Saito and Yamamoto has led to a catalyst that is effective for allyl vinyl ethers that are unsubstituted on the vinyl group [27]. This was a serious limitation of the BINOL-derived catalyst 98 which induced only C0 bond cleavage with these substrates (Table 1, entry 1).The ligand (R)-115 was prepared in six steps from (R)-BINOL and was reacted with trimethylaluminum to give C3 symmetrical Lewis acid (R)-116. Five substituted catalysts were prepared and as evaluated with trans-cinnamyl vinyl ether; the catalyst with the para-fluorophenyl group resulted in the highest induction (Table 4). With this catalyst the best asymmetric induction was seen with large substituents, e.g. t-butyl and trimethylsilyl, on the allyl group. Reduced asymmetric induction and reaction rate was observed for catalysts with 3,5-disubstituted phenyl substituents. The optimum solvent for this reaction was toluene; dichloromethane resulted in less asymmetric induction.

Chiral AluminumLewis Acids in Organic Synthesis R

297

R

I

1

1.1 - 2 Eq (R)-116

toluene, -78 O C 10-40h 113

114

Table 4. Claisen rearrangements of ally1 vinyl ethers 113 Ar

R

Yield 114 (%) ee 114 (%)

93

Ph

-$a

61

78

61

63

63

(R)-115 p-FC6H4

-i+ -$Si-/

85

86

70

91

78

92

Me3AI toluene 25 O C , 1 h

(R)-116

"Not reported.

7.5 [2+ 21 and [2 + 11 Cycloadditions The first example of an asymmetric [2 + 21 cycloaddition of a ketene to an aldehyde was reported in 1994 by Miyano and coworkers [28]. They found that chiral aluminum catalysts prepared from different 3,3'-disubstituted BINOL derivatives resulted in low to modest asymmetric induction for a range of aliphatic and aromatic aldehydes. There does not seen to be a correlation between asymmetric induction and the size of the aldehyde. The data in Table 5 show that the optimum ligand for this reaction is triphenylsilyl substituted BINOL. It is curious that the catalyst prepared from this ligand and the catalyst prepared from BINOL result in opposite facial selectivity with

298

Wulff

the same aldehyde than the catalyst prepared from 3,3'-dimethyl substituted BINOL. The optimum bis-trimethylsilyl substituted catalyst results in facial addition to benzaldehyde in a sense opposite to that of addition to aliphatic aldehydes. 0 1.0 Eq (S)-121 117

118

toluene, -78 'C Ih

119

Table 5. [2 + 21 Cycloadditions of ketene with aldehydes. Yield 119 (9%) ee 119 (%)

R2

R'

SiPh3

Me

78

23

Et

67

56

n-Pr

69

45

n-Bu

80

17

i-Pr

59

28

Ph

76

21 a

Me

Et

63

28 a

H

Et

45

36

OH

aEnantiorner of 119 was obtained.

(S)-120

Me3A1 toluene 25 O C , I h

W

O

R2 '

(S)-121

The reaction is thought to involve activated nucleophilic addition of the ketene to the aldehyde which is coordinated to the aluminum. The ketene is added as a gas by bubbling into a solution of the catalyst and aldehyde at -78 "C. Lower induction is observed if the aldehyde is added to a solution of the catalyst and ketene. One of the limitations of this catalyst system is that sub-stoichiometric amounts of the catalyst are not successful. With the 10 mol % of the catalyst less than 5 YO yield of product was obtained. This limitation might be related to the observation that acylated phenols are observed as by-products in this reaction. The yields of the reaction are higher in dichloromethane but asymmetric induction decreases. The reaction in entry 2 of Table 5 was observed to occur in 90 YOyield and in 20 % ee in dichloromethane. The BINOL-aluminum catalyst 121 could only successfully be used in stoichiometric amounts; this limitation was overcome by the same research group in the same year with the introduction of the diazaaluminolidine catalysts 124 (Table 6) [29]. These catalysts are prepared from the bis-sulfonamide 123 and the structure of 124 has been confirmed by X-ray diffraction [30]. The reaction of a variety of aldehydes with catalyst 124c was examined and it was observed that with the exception of benzaldehyde, higher asymmetric induction was associated with increased aldehyde size. Unlike catalyst 121, catalyst 124c gives the same sense of facial selectivity with both aliphatic and aromatic aldehydes. The enantioselectivity of catalyst 124c was also slightly dependent on the nature of the alkyl aluminum used in the preparation of the

Chiral Aluminum Lewis Acids in Organic Synthesis

299

catalyst; this was shown by a screening experiment with propanal. Three different sulfonamide ligands were also screened by use of propanal and catal sts prepared from trimethylaluminum. Catalyst 124a (R2 = Me) and catalyst l24b (R = Me) resulted in 0 YO ee and 10 YOee, respectively, in the reaction of propanal with ketene. This can be compared with 20 YO ee obtained with catalyst l24c for this reaction.

l

0

H,C=C=O 117

1.O Eq 124c

+ 118

toluene, -18 O C

O

lh

Table 6. [2 (R~W

+ 21 Cycloadditions of ketene with catalyst l24c. R'

~

Yield 122 (%) ee 122 (%)

Me

59

30

i-Pr

16

56

CY

15

14

t-Bu

11

65

Ph

11

20

MqAI

Et

55

14

i-Bu3Al

Et

12

23

Et3Al

hR' 122

I

0

~

~

3

Ph

I

I

toluene/DCE 124b 8OoC R3 =

R3 =

124

The number of chiral diazaaluminolidine catalysts has been extended by Dymock, Kocienski and Pons, who introduced the more convenient to handle trimethylsilylketene [31]. The catalysts in this study were prepared from slightly different sulfonamides but asymmetric induction was comparable with that obtained with the ketene and similar aldehydes. With trimethylsilylketene, two diastereomers are possible and in all examples studied the cis isomer 126 was the predominate product. The reactions in Table 7 were performed with 30 mol Y catalyst-with 20 mol YO catalyst the reaction is incomplete. A more active catalyst can be prepared from the bis-trifluoromethylsulfonyl derivative of 128, but asymmetric induction was low. It was reported that ortho substituents on the aryl sulfonamide were necessary for higher induction but data were provided only for the aryl sulfonamide substituents summarized in Table 7. Both symmetrical and unsymmetrical diazaaluminolidines were examined as catalysts in an attempt to optimize asymmetric induction but significant differences were not found. The catalyst prepared from the symmetric bis-sulfonamide 128 with Ar' = 2,4,6-tri-iso-propylphenyl did not give any reaction even at 100 mol YO.

300

WUW

126

127

Table 7. [2 + 21 Cycloadditions of trimethylsilylketene with aldehydes. Ar'

Ar2

R

&/trans

Yield (%) ee 126 (%) 126 + 127 SO2Ar' I

PhCH2

1oo:o

43

40

PhCH2CH2

1oo:o

78

61

CY

95 : 5

63

63

PhCH2

83: 17

56

83

PhCH2CH2

90: 10

80

44

CY

85: 15

32

68

CllH23

94 : 6

67

47

p-OMeC6H4CH2

99 : 1

77

83

PhCH2

79:21

82

62

PhCH2CH2

9 0 : 10

85

30

CY

I1 : 2 3

57

53

PhCH2

75 :25

72

82

PhCH2CH2

94 : 6

82

36

CY

6 9 : 31

43

67

CllH23

8 2 : 18

67

48

p-OMeC6H4CH2

70 : 30

81

75

Ph

128 Me3AI toluene 25 "C, 10 min S02Ar'

A02Ar2

129

The first asymmetric Simmons-Smith reaction with a chiral Lewis acid catalyst was introduced in 1994 by Charette and Juteau and featured a chiral boron Lewis acid prepared from tartaric acid [32]. Although this process resulted in excellent enantioselectivity, it would not turnover, i.e. the yield was less than 10 %. In the same year Imai, Takahashi and Kobayashi introduced a chiral aluminum Lewis acid that would catalyze the cyclopropanation of allylic alcohols with significant turnover numbers but their system did not lead to asymmetric induction as high as that resulting from the dioxaborolane catalyst [33]. The catalyst is prepared from the bis-sulfonamide 132

301

Chiral Aluminum Lewis Acids in Organic Synthesis

and alkyl aluminums upon heating in dichloroethane at 80 "C for 3 h (Sch. 15). The alkyl group on the aluminum is not particularly critical but induction was optimum with iso-butyl. More critical is the nature of the substituent on the sulfur atom. Electron-withdrawing groups on the aryl group are not necessary but the presence of an aryl ring is necessary. A catalyst prepared from the bis-trifluoromethyl sulfonamide of 1,2-diaminocyclohexane and trimethylaluminum gave only 131 in 14 % ee.

The scope of the reaction was examined with a catalyst prepared from the benzene sulfonamide and DIBAL, because it was found that essentially the same induction could be obtained as with those obtained from tri-iso-butyl aluminum. Two years earlier the authors had reported that this Simmons-Smith reaction could also be catalyzed by the aluminum-free sulfonamide 132 (optimum with Ar = p-N02C6H4); the induction obtained is listed in the far right column of Table 8 [34]. It was proposed that a zinc complex of 132 is generated in-situ. Surprisingly, with the exception of the silyl-substituted ally1 alcohol (the last entry in the table) [35],almost identical asymmetric induction obtained by use of the aluminum-containing and aluminum-free catalysts. The main advantage of the diazaaluminolidine catalyst is that it is apparently more soluble than the aluminum-free bis-sulfonamide catalyst, with the result that a tenfold increase in concentration (0.1 M) can be used; this might explain the increased rate observed for the diazaaluminolidine catalyst. Finally, it has recently been reported that a catalyst formed from the C1 symmetrical sulfonamide 135 and DIBAL will induce the formation of 131 from cinnamyl alcohol in 68 % ee [36]. R

~

OEtzZn H

~ +

R2

136

2.0 Eq

+

CH212

3.0 Eq

0.08 Eq catalyst 133 (Ar = Ph) ___

-

CH2C12 / Hexane (9 : 1) - 20 OC

R

I R2

137

V

Table 8. Cyclopropanation of allylic alcohols with the aluminum catalyst 133 (Ar = Ph).

a

R'

R2

Ph H PhCHzCHz TrOCH2 H H MezPhSi

H Ph H H TrOCHz BnOCH2 H

Yield 137 (%)

ee 137 (%)

100 100 100 83

76 73 78 80 56

76 75 82 80

26

13 81

92 91

NR

60

ee 137 (%)"

66

Catalyst is the bis sulfonamide 132 (Ar = p-NOzCsH4). Not reported.

7.6 Diels-Alder Reactions 7.6.1 Aluminum Catalysts from Chiral Alcohols The first examples of an asymmetric Diels-Alder reaction of a non-chiral diene and a dienophile catalyzed by a chiral Lewis acid were reported by Koga and coworkers in 1979 (Sch. 1 and 16) [3]. The catalysts 4,142and 143 were prepared from (-)-menthol, (+)-neomenthol and (+)-borneol. The reaction of methacrolein and cyclopentadiene mediated by catalyst 4 gave a 98:2 mixture of ex0 to endo products and upon separation of these diastereomers by chromatography the ex0 product 3 was obtained in 69 YOyield and 72 YOee. The exo:endo ratios for the other reactions in Sch. 16 were not reported. Low asymmetric induction was observed for acrolein and methyl acrylate with all three catalysts. Moderate induction was observed in the reaction of methacrolein with catalyst 4,and with catalyst 142,but in the latter the enantiomer of 3 was the predominant product. The reaction of methyl acrylate with cyclopentadiene mediated by 10 mol % catalyst 4 was also reported by Kobayashi, Matsumura and Furukawa to give the cycloadduct 141 in 2.9 % ee at 30 "C [37]. These workers also reported that catalyst 4 will give optically active product from the reaction of cyclopentadiene and acrylonitrile, although the optical yield was not determined. In subsequent work, Koga's group surveyed the reaction of methacrolein and cyclopentadiene with several catalysts prepared from a variety of chiral alcohols; the results from these experiments are summarized in Table 9 [38]. The catalysts listed in this table were not isolated but were generated in-situ. This might have an effect on the asymmetric induction observed for many of these catalysts because the induction for 3 was 57 YOee with the in-situ-generated catalyst 4 whereas when catalyst 4 was isolated the induction was 72 % ee (Sch. 16). The cycloadduct 3 was the predominant isomer produced with all the catalysts shown except 147-149 and 152 which gave the enantiomer of 3.The only catalyst that gave higher induction than catalyst 4 derived from menthol was catalyst 144 derived from neomethyl menthol, although the magnitude of the increase (61 % ee compared with 57 % ee) is probably within experimental error.

Chiral Aluminum Lewis Acids in Orgunic Synthesis

3 69-84 % yield exo catalyst 4 72 % ee catalyst 142 66 % ee (ent 3) catalyst 143 25 % ee 11-16 mol% catalyst 0

138

toluene, -78 O C , 3 h CHO 139 40-73 % yield endo

2 1.1 equiv

catalyst 4 0 % ee catalyst 142 3 % ee catalyst 143 27 % ee

q O M e + 0

140

0

4

15-26 mol %catalyst toluene, -78 OC, 3 h

C02Me 141 65-82 % yield endo

2 1.1 equiv

catalyst 4 catalyst 142 catalyst 143

A=

6 % ee 0 % ee 9 % ee (ent 141)

hkL

c12LJkL ClzAlO

c12*lo&

3 4

Scheme 16

142

+*

143

Table 9. Diels-Alder reactions with chiral aluminum catalysts producing adduct 3.

CliAlO

144 80 %yield 61 % e e \

CIiAIO

CIiAIO

147 69 %yield 35 % ee (ent 3)

cWJO% 4

56 %yield 57 70ee

Ph

148 56 %yield 35 % ee (ent 3)

CWO

145 83 %yield 45 % ee

k

tBu

1.50 65 %yield 20 % ee Ph

4

153 70 % yield l6%ee

155 57 5% yield 35 % ee

phz!+ 151 71 %yield 0 % ee

56 %yield 57 % ee

Et

tBuCHzO

149 67 %yield 1 1 % ee (ent 3) 152 75 %yield 7 70 ee (ent 3)

146 83 %yield 45 % ee

c1 145 83 % yield 45 % ee

154 68 % yield 7 % ee

156 67 %yield 23 % ee

303

A few other reactions have been reported with catalysts 4 and 143; these are shown in Sch. 17. Northcott and Valenta investigated the reaction of the exo-cyclic methylenedienophiles 159 and 161 and the benzoquinone 163 with cyclopentadiene [39]. The absolute configurations of the products were not determined for these three reactions but it was determined that catalyst 4 and catalyst ent-143 gave the same major enantiomer of 164 but different major enantiomers of 160. As has been seen in the study of Koga and coworkers [3,38] (Sch. 16), the catalyst derived from menthol was superior to that derived from borneol. Kobayashi and coworkers reported early on that 1.0 equiv. catalyst 4 at 60 "C would effect the cycload-

2 2.0 equiv

159

6-8h

160 48 - 61 % yield catalyst 4 38 % ee exo 13:l exo/endo catalyst ent-143 18 % ee exo 31:l exo/endo

40 mol % catalyst toluene, -78 O C 28 h

2

162 1.1 % yield endo

2.0 equiv

161

catalyst 4

9 163

8: 1 exo/endo

40 mol % catalyst toluene, -78 "C 3-15h

2 2.0 equiv

0

48 % ee exo

0 164 53-80 % yield

catalyst 4 8 % ee catalyst ent-143 6 % ee

ricu

4

0: 100 exo/endo 0: 100 exo/endo

100 mol % catalyst 4 toluene 60 O C 15h

166 (2 eq)

165

2.9 % ee 73 % yield (+)-167

C02Me 100 mol % catalyst CH2C12,23 O C 24h

168

Scheme 17

169 85 - 87 % yield catalyst 4 -1 % e e catalyst ent-143 -1 % ee

ent-143

Chiral Aluminum Lewis Acids in Organic Synthesis

305

dition of butadiene and acrylonitrile to give the cycloadduct 167 in 2.9 % ee [37]. The same level of induction was observed with 10 mol % catalyst. Catalysts generated from EtAICl, and 1-borneol (catalyst ent-143), d-neomenthol (catalyst 142) and l-isoborneol gave levels of asymmetric induction similar to or lower than those observed with catalyst 4. In the only intramolecular study reported for a chiral aluminum catalyst, Roush and coworkers found that both 4 and ent-143 were effective catalysts for the cycloaddition of 168 but cycloadduct 169 was formed almost as a racemate with both catalysts [40]. The structure of the chiral mentholoxyaluminum dienophile complex has not been determined and is difficult to predict because of the large number of degrees of freedom in the menthol ligand, in the dienophile, and in the two associated aluminum oxygen bonds in the complex. In Koga’s original model the si face-selectivity of the catalyst derived from (-)-menthol is explained by structure 170 (Sch. 18) [38]. This model will roughly account for the data shown in Table 9. The result that is least consistent with this model is that from catalyst 145-it would have been expected that the benzhydryl group would have been more effective than the iso-propyl group in shielding the re face of the dienophile. The results from catalysts 4, 155, and 156 have been explained by arguing that replacing one of the chlorides on aluminum with a bulky alkyl group will lead to the preferential orientation of the alkyl group away from the iso-propyl group, as indicated in structure 170. An increase in the size of the alkyl group would then be expected to lead to a decrease in the selectivity for approach to the si face of the dienophile.

c1

170 si-face exposed from front

si-face exposed from front si-face exposed from front

si-face exposed from front

both re and si-faces exposed

Scheme 18

An alternative model proposed by Northcott and Valenta involves an s-cis conformation of the dienophile as indicated in structure 171 [39]. Shielding of the re face by the iso-propyl group requires a change in the coordination of aluminum to the dienophile oxygen such that the aluminum is coordinated by the oxygen on the same side as the carbon substituent of the aldehyde. This model is consistent with the observation of high induction with dienophiles 159 and 161 in which the conformation is locked scis compared with that for dienophile 163 which is locked s-trum (Sch. 17). A combined quantum mechanics-molecular mechanics study has been performed on the

dichloromentholoxyaluminum-mediatedcycloaddition of acrolein and cyclopentadiene [41]. The lowest-energy conformation was predicted to be structure 172, and in accord with the 0 % ee observed experimentally for this reaction (Sch. 16) [3], small energy differences were observed for the transition states resulting from si and re face approaches of the diene. Finally, Corey and Rohde have proposed a model for this reaction that features the form 1 C H 0 hydrogen bond indicated in structure y -. 173 [42]. The presence of an sp -hybridized oxygen participating in the hydrogenbond produces two structures, 173 and 174, the latter of which would be expected to result in no preference. This situation provides an alternative explanation of the effect of substitution at aluminum. The formation of cycloadduct 3 (Sch. 16) is observed to occur with reduced induction when one of the chlorides on aluminum is replaced by bulky alkyl groups in catalysts 4, 155, and 156 (Table 9). This can be attributed to a destabilization of structure 173 relative to 174, because of non-bonded interactions between the alkyl group and the iso-propyl group.

7.6.2 Aluminum Catalysts from Chiral Diols, Sulfonamides, and P-Hydroxysulfonamides The first examples of an asymmetric Diels-Alder reaction with a chiral aluminum catalyst derived from a chiral diol were reported for the reaction of N-crotyloxazolidinone 175 with cyclopentadiene (Sch. 19) [43,44]. The choice of this dienophile was based on the consideration that the geminal dimethyl groups should engender an s-cis conformation in the dienophile and the two carbonyl groups will serve as a bidentate ligand for a Lewis acid thus restricting the number of accessible conformations of the Lewis acid-dienophile complex. There must, however, be other issues important in controlling the stereochemistry of this reaction, as indicated by the low to non-existent asymmetric induction observed for the diols and the sulfonamide indicated in Table 10. Although induction in these reactions was originally reported to be excellent [43], these values were later corrected to those that appear in Table 10 [45]. 0

0

100 mol YO cat 178

CHnC12/-78'C

O

175

k0

0 176 endo

Ligand

Scheme 19

%&

+

CIAIR'R2

+

M

N

'

O

176 exo

Catalyst 178

Chiral Aluminum Lewis Acids in Organic Synthesis

307

Table 10. Diels-Alder reactions with chiral aluminum catalysts 178 producing adduct 3.“

OB n

’

179 EtAlCl? (2 : 1) 89 % yield 1S:ZS endo/exo 3 % ee (S)

180

181

AICli ( I : 1) 55 % yield 88:12 endo/exo 16 % ee (S)

EtAlCl? ( 1 : I ) 76 % yield 95:s endo/exo 28 % ee (S)

183 EtAlC12 (2 : 1) 85 % yield 7030 endo/exo 0 % ee

EtAlCl? (2 : 1) 90 % yield 70:30 endo/exo 3 % ee (S)

Et,AICI (I : 1) 5 9% yield 11:23 endo/exo 3 % ee (S)

T”+msOH

BnO\/\/\OBn OH

OH

182

EtAICl? (2 : 1) 73 % yield 73:27 endo/exo 0 % ee

OH 184 EtAlCl? (2 : 1) 82 % yield 7 1 :29 endo/exo 11 % ee (S)

185

187 EtAIClz ( 2 : I ) 21 %yield 9 1 :9 endo/exo 33 % ee (S)

&NH0

+

OPiv

6H 6

186 EtAlClp (2 : 1) 48 % yield 79:21 endo/exo l3%ee(S)

EtAlCl? (2 : 1) 71 % yield 73:21 endo/exo 2 % ee (S)

Q.G0 OH

Pivo

OH

2

188 EtAlC12 ( I : 1) I S % yield 8 1 :19 endo/exo 3 % ee (S)

”Ratio of aluminum to ligand is given in parentheses after the Lewis acid.

The optimum catalyst for the reaction of 175 and cyclopentadiene was generated in-situ from one equivalent of the diol and two equivalents of ethyl aluminum dichloride. Presumably this generates a Lewis acid with two dichloroalkoxy aluminum groups per molecule of catalyst. The catalyst generated from diol 181 and one equivalent of diethylaluminum chloride is not very active, possibly because here the catalyst is a dialkoxy aluminum chloride. The highest induction was observed for a catalyst generated from the diamino substituted dioll87, which was prepared from tartaric acid. The optimum catalyst for cycloaddition of the N-crotyl dienophile 175 with cyclopentadiene was found to be that generated from diethylaluminum chloride and diol 187. On this basis, the reactions of dienophiles 189 and 181were examined with cyclopentadiene and furan as indicated in Sch. 20. In addition, catalysts derived from two derivatives of dioll87 were also examined, as shown in Table 11 [43-45]. It was found that all three diols resulted in similar asymmetric induction, with the highest induction not exceeding that observed for the N-crotyl dienophile 175. The N-acrolyl dienophile 189 gave an 83:17 mixture of endo and ex0 diastereomers, with 21 % ee for the endo adduct, with a catalyst prepared from diol 187. The same catalyst gave 25 % ee for the cycloadduct of furan with 189 and 2 % ee for the adduct of cyclopentadiene and 191, although in the latter example an increase to 27 YO ee is possible with sub-stoichiometric amounts of catalyst.

50 mol % cat 178 CH2CI21-78OC 12 h

9% +

0

&N O '

L-0 11 0

189

190 exo

190 endo

+ 0

0 2

0

200 mol % cat 178

CH2C12 1-78 OC 12 h

191 192 h

0

4NKo

0 \

I

'

fi

0

50 mol % cat 178

CH2Clp1-78OC 12 h

193 189 194

Scheme 20

A very interesting recent report describes the effect of a catalyst prepared from ethylaluminum dichloride and the diol 199 on the reaction of dienophile 197 with cyclopentadiene [46]. A single catalyst was found to give high asymmetric induction for either enantiomer of the endo adduct 198. The reaction of dienophile 197 with cyclopentadiene gave 82. YOee for 198-endo in dichloromethane and 72 YOee for the enantiomer of 198-endo in tetrahydrofuran. Previously this reaction had been examined in dichloromethane and toluene with a catalyst generated from diol 179 [45]. In the light of the data in Sch. 21, it would be interesting to re-examine the reaction in dichloromethane with the catalyst prepared from dioll79 and one equivalent of ethylaluminum dichloride. An explanation of the effect of solvent on the catalyst generated from 199 was not presented, although it was observed that there was a linear relationship between the optical purity of the diol and the optical purity of the product for the reaction in THE In contrast, a negative non-linear effect was observed in dichloromethane. This suggests a monomeric catalytic species in THF and a catalytic oligomeric species in dichloromethane, in which the heterochiral oligomer is more reactive than the homochiral oligomer.

Chiral Aluminum Lewis Acids in Organic Synthesis

309

Table 11. Diels-Alder reactions with chiral aluminum catalysts 178.a Cycloadditions producing 190

OJPo OH

T

N

187

L OH r

J

?

196

195

EtAIC12 (2 : 1) 80 % yield 83:17 enddexo 21 Wee ( S )

EtAlCl? (2 : 1) 80 % yleld 85: 15 endo/exo I7 9%ee (S)

EtAIClz (2 : I ) 84 % yield 9010 enddexo 19 % ee ( S )

I

Cycloadditions producing 192

187 EtAICI? ( 2 : 1) 94 % yield 5 % ee (S)

EtAICI? (2 : I ) 98 % yield 9 % ee ( S )

Cycloadditions producing 194

QNLN3 OH

187 EtAIC12 (2 : 1) 72 % yield >99: I mdo/exo 25 % ee (S)

a Ratio of aluminum to ligand is given in parentheses after the Lewis acid. The amount of catalyst (mot %) is given in Sch. 20.

-

100 mol % cat 178

+

i

&$2

2

197

+ 0

198 exo

0 198 endo

kH Llgand

.,nH .,~IOH

'

Ph

179 179 99

199 199

EtAICI2 : Ligand

2:l 1:l 1:l 1:l 1:l

Solvent

Temp

%Yield

endo/exo

% ee

CH2C12 toluene CH2C12 toluene

-78OC -78 OC O°C 0 OC 0%

54 98 89 95 87

95 : 5 95 : 5 NR *

23 28 82 14 72 (ent 198)

THF

NR NR *

199

Product reported to be between 65 and 77 % ee endo for all reactions

Scheme 21

The reaction of methyl acrylate and cyclopentadiene has been carefully examined by Ketter, Glahsi, and Herrmann with chiral aluminum catalysts prepared from the seventeen chiral diols and P-hydroxysulfonamides shown in Table 12 [47]. The catalysts were prepared in-situ by reacting the ligand with one equivalent of di-isobutylaluminum chloride in dichloromethane at room temperature for 1 h. The standard conditions for the screening of these reactions were 10 mol % catalyst in dichloromethane and 4 0 to 4 5 “C,as indicated in Sch. 22. Table l2. Diels-Alder reactions with catalyst 200 producing cycloadduct 141.”

Meo2cXoH HO

C02Me

201

202

203

204

205

20 % yield 3.8 endo/exo 2 % ee (S)

10 % yield

15 % yield

10 % yield

10 % yield

2.9 endo/exo 2 % ee ( S )

3.1 endo/exo 2 % ee (S)

3.0 endo/exo 2 % ee (S)

2.1 endo/exo 2 % ee (S)

P h < ’0t o H

OH

H 206 10 % yield 15 endo/exo 33 % ee (S)

\

207 24 % yield >60 endo/exo 65 % ee (S)

208

209

1 I % yield

3 % yield 6.2 endo/exo 8 % ee (S)

3.9 endo/exo I % ee (S)

‘

210 81 % yield >60 endo/exo 3.4 % ee (S)

&: ’S

0 2

211

212

213

214

215

31 % yield 21 endo/exo 12 % ee (S)

91 % yield 40 endo/exo 6 % ee (S)

10 % yield

8 % yield 4.8 endo/exo I % ee (S)

41 % yield 32 endo/exo 40 % ee (S)

6.6 endo/exo 8 % ee (S) P

h v NHTos

216

5 % yield

>60 endo/exo 3 % ee (S)

217 51 % yield >60 endo/exo 2 % ee (S)

Standard conditions are given in Sch. 22.

The molecularity of the catalysts generated from ligands 207, 211 and 212 was examined carefully and thoroughly by measurement of the depression of the freezing point of benzene. A study of the time-dependence of the molecular weight revealed that ligand 207 forms a monomer with di-iso-butylaluminum chloride immediately after reaction which is converted to a dimer after 20 h and further to higher molecular weight aggregates after 120 h. The formation of a dimeric catalyst species from ligand

Chiral AluminumLewis Acids in Organic Synthesis

31 1

211 occurs much more slowly (72 h) and the catalyst shows no sign of oligomerization after 120 h. Methyl acrylate was found to form a complex relatively fast with the monomer of the catalyst from ligand 211 but only very slowly with the dimer of this catalyst. The monomeric catalysts were found to afford better asymmetric induction than the dimeric catalysts. It is probable that monomeric catalysts were formed under the catalyst-formation conditions used to collect the data in Table 12. 10 mol % cat 200

140

CH2C12 -40 to -45 OC

2

21 - 187 h

+

Ligand

141 exo

141 endo

CHpC12 Al(iBu)&I

Catalyst 200 1 h, 25 OC

Scheme 22

Most of the catalysts for the reactions indicated in Table 12 do not turnover, i.e., the yield is less than 10 %. A few of the ligands give catalysts which provide high endolexo selectivity, but only the catalyst from ligand 207 gives asymmetric induction higher than 50 % ee. Three of the catalysts have inverse temperature-dependence, giving higher induction above the standard temperature of 4 5 "C. Specifically, the catalyst from ligand 207 gives 70 '30ee at -10 "C (49 YO yield after 161 h), that from ligand 206 gives 43 YOee at -5 "C and that from 211 gives 33 % ee at -10 "C. The reaction of several different acrylate esters with cyclopentadiene was examined for the optimum catalyst derived from ligand 207 and under optimum conditions (-10 "C; Sch. 23). Asymmetric induction was found to increase with the size of the substituent of the ester to the extent that 81 YOee could be obtained with the 1-butyl ester, although the reaction was quite slow (15 YO yield after 164 h). This is one of very few examples of investigation of the effect of the size of an ester substituent on asymmetric induction.

dOR 140

+

0 2

10 mol Yocat 200 (from ligand 207) CH~CIZ -10 OC, 130-164 h

%OR 141 endo

R

Yield

endolexo

Yoee

Me Et t-Bu

49% 46% 15%

>60: 1 >60: 1 >60:1

70 73 81

Scheme 23

Diels-Alder reactions of aldehydes are typically much faster than those of esters and thus reasonable rates were observed by Rebiere, Riant, and Kagan with chiral aluminum catalysts derived from chiral diols for the reaction of unsaturated aldehydes with cyclopentadiene [48]. A series of chiral diols was screened for the reaction of methacrolein with cyclopentadiene. The catalyst was prepared in-situ from a chiral diol and 1 equiv. ethylaluminum dichloride at room temperature for 3 h. This was

expected to lead to the loss of 1 equiv. ethane and, thereby, an aluminum catalyst which can internally chelate the second oxygen to give a more rigid platform for the chiral centers of the ligand (i.e. structure 220; Sch 24).

qH0 +

2

1

10mol%cat219

+

QH

CH&2 -78 OC,20 h

,p2

0 (9-3 ex0

H 3 endo

218

Y

220

221

222

223

90 % yield 95:5 exo/endo 20 % ee (+)

90 % yield 95:5 exo/endo 20 % ee (+)

90 % yield 92:8 exo/endo 0 Yoee

224

95 O h yield 95:5 exo/endo 0 % ee (2 eq AICI2Et)

Scheme 24

It was found that catalyst aging time was crucial. The optimum procedure under which all of the diols in Table 13 were screened involved aging of the catalyst for 3 h at room temperature. The highest asymmetric induction was observed for diol 225 which gave 73 % ee for the exo isomer of 3 under optimum conditions. If, however, the catalyst from 225 was aged for 20 h at room temperature, induction dropped to 17 YOee. In contrast, if the catalyst was not aged at all but rather generated and used directly at -78 "C induction was only 6 YOee. Solvent was not important; both dichloromethane and toluene resulted in the same induction (73 and 72 YOee, respectively) for the catalyst from 225 and induction rose from 73 to 86 YO ee for the same catalyst when the temperature was lowered from -78 to -100 "C. Reactions with catalysts derived from the diols 237-239 (Table 13) were reported by Jones and Guzel and were screened with catalyst generated from both ethyl aluminum dichloride and diethyl aluminum chloride although the conditions used for catalyst generation were not reported for either [49]. All these catalysts gave the (+) enantiomer of the 3-exo cycloadduct with the chromium tricarbonyl group leading to increased induction as a result of coordination to either face of the aromatic ring in ligand 237. The optimum catalyst for the reaction of methacrolein and cyclopentadiene was investigated for the reactions of acrolein and methyl acrylate (Sch. 25). The induction for both was substantially less than that observed for methacrolein and, as expected, the reaction with methyl acrylate was much slower and was performed at -20 "C. The absolute configurations of 139 and 140 were not determined.

313

Chiral AluminumLewis Acids in Organic Synthesis Table 13. Diels-Alder reactions with catalyst 219 to give cycloadduct 3." M e a h

M e D - N p

HO' 'OH 225

HO OH 226

90 % yield 98:2 exo/endo 73 % ee (-)

OH 228

227

231 90 % yield 92:8 exo/endo 18 % ee (-)

90 % yield 95:5 exo/endo 0 % ee

HO

OH

HO

90 % yield 98:2 exo/endo 55 % ee (-)

230

P

80 % yield 98:2 exo/endo 44 % ee (-)

30 % yield 96:4 exo/endo 0 % ee

232

234

90 % yield 90: 10 exo/endo 0 % ee

90 % yield 90:lO exo/endo 0 % ee

HO

h

p

OH 224

40 % yield 93:7 exo/endo 6%ee(-)

P h R e HO

OH 229

90 % yield 96:4 exo/endo O%ee

235

236

80 % yield 98:2 exolendo 18 % ee (+)

90 % yield 98:2 exo/endo 20 % ee (+)

OH

F

Me0

O

H

With EtAlC12 67 Yo yield 85: 15 exo/endo 29 % ee (+)

Me0

238

237 With EtaAICl 98 % yield 66:34 exo/endo 21 % ee (+)

With EtAIC12 92 % yield 96:4 exolendo 53 % ee (+)

With Et2AICI 82 % yield 99:l exolendo 31 % ee (+)

With EtAIC12 99 % yield 9 5 5 exo/endo 61 % ee (+)

239 With Et2AICI 83 % yield 98:2 exo/endo 41 % ee (+)

"The catalysts were prepared from EtAIClz unless otherwise specified. Reactions with catalysts from ligands 237-239 performed with 20 mol % catalyst.

+ Q 138

10 mot % cat 219 (from ligand 225) +

-78 OC,18 h

2 .SQkf&

CH2CI, toluene

70% 70%

10 mot %cat 219

0

(from CHZCIZ ligand 225) 140

2

-20 'C,18 h

&H

0 H .. 139 endo

Sndolexo 70:30 84: 16

139 exo Xeeendo 29%ee 25%ee

9 0

+

OMe

141 endo

%eeexp 2 3 % ~

----

&me 141 exo

40 YOyield; 8 4 3 6 endo:exo; 36 % ee endo

Scheme 25

Rebiere, Riant, and Kagan made the interesting observation that reaction of methacrolein and cyclopentadiene with the catalyst prepared from ligand 225 occurs with asymmetric auto-induction [48]. The optical purity of 3-ex0 at 4 % conversion is 38 % ee and this increases to 73 % ee at the end of the reaction (Fig. 1).This is the first time asymmetric auto-induction has been seen for a Diels-Alder reaction or for a chiral aluminum catalyst. It is clear that the catalyst changes when exposed to the reactants and -78 “Cand that this change continues during the course of the reaction. The catalyst during the early part of the reaction is not very enantioselective and the catalyst in the final turnovers of the reaction must be highly selective (in excess of 75 % ee). The catalyst does not have a non-linear effect, because ligand of 50 % optical purity gave product that was exactly half the optical purity with optically pure ligand and thus the catalyst should be monomeric in aluminum. The authors suggest that the catalyst at the beginning of the reaction could involve a pentacoordinate or hexacoordinate aluminum with that is coordinated to at least two molecules of methacrolein.

ai

100

:;l-----80

50

% ee 40 30

20 10 0

I

I

I

I

1

7.6.3 Aluminum Catalysts from Axially Chiral Bis-Phenols Atropisomers of conformationally restricted bis-phenols have been popular ligands in several applications (Sch. 5, 8, 9, 11-13; Tables 4 and 5). Aluminum compounds prepared from bis-1,l’-binaphth-2,T-01(BINOL) 40 and the derivatives 97 were examined as chiral catalysts in the reaction of methyl acrylate and cyclopentadiene by Maruoka, Concepcion and Yamamoto [50] and by Ketter, Glahsl and Hermann [47]. Four catalysts prepared from four derivatives of the 3,3’-bi~-triarylsilylderivatives of 97 and trimethylaluminum were examined in both toluene and dichloromethane; the results are summarized in Sch. 26 [SO]. Slightly higher asymmetric induction was observed in toluene and for the t-butyldiphenysilyl derivative 97b. The catalyst prepared

315

Chiral Aluminum Lewis Acids in Organic Synthesis

from ligand 97d gave similar asymmetric induction, and that from ligand 97c was lower. Asymmetric induction in the 75 % ee range could be obtained in toluene at lower temperatures but the reaction times were longer. Ethyl and t-butyl acrylates were found to lead to reduced asymmetric induction with catalyst 98a, in contrast to the trend seen for this substitution with the catalyst prepared from diol207 (Sch. 23). Catalyst 98a was also found to give 55 % ee in the formation of the cycloadduct 241. This is the first reported example of asymmetric induction by a chiral catalyst in the Diels-Alder reaction of an acetylenic dienophile. Aluminum catalysts derived from the three BINOL derivatives outlined in Table 14 have been used in the asymmetric cycloaddition of the N-crotyloxazolidinone 175 and cyclopentadiene. These reactions are slower and require the use of stoichiometric amounts of catalyst. Although the dienophiles 175 are bidentate and should lead to a more conformationally restrained dienophile-Lewis acid complex, asymmetric induction is quite low. 0 40Me

+

140

0

4

10 mol % catalyst -__-

M

+

// P O

e

141 exo

141 endo

0

M

oAOMe

2

Catalyst 98a 98a 98a 98b 98b 242

O

Solvent CH2C12 CH2C12 toluene CH2CIz toluene CH2C12

Temp (OC) 0 -78 to 0 0 0 0 -45

YOyield endo/exo

Time (h) 9 17 9 11 11 130

83 82 81 68 62 44

97:3 96:4 95:5 97:3 97:3 97:3

% ee 58 67 64 64 69 16

10 mol % catalyst 98a

M e

240

+

2

CH2Ch -40 OC, 3 h; 0 OC, 11 h

%OM.

0 241 22 Yoyield; 55 % ee

Catalyst 98

(R)-97a (R)-97b (R)-97c (R)-97d

Scheme 26

Ar Ar, Ar Ar

=Ph = tBuPh2 = 3,5-Et2C6H3 = 4-tBuC6H4

P

O

H

(R)-40 BINOL

~(il3~)~CI Catalvst 242

.

Table 14. Diels-Alder reactions with catalyst 178 t o give cycloadduct 176 (Sch. 19)."

/

(R)-99 With EtpAlCl (1 : 1) 92 % yield 68:32 endo/exo 11 % ee (-)

(R)-243

(rn-40

With EtAICI2 (2 : 1) 92 % yield 76124 endo/exo 14 % ee (-)

/

With AICI3 (1 : 1) 59 % yield 82:18 endo/exo 5 % ee (+)

With EtpAICI (4 : 1) 46 % yield 83117 endo/exo 3 % ee (-)

aRatio of aluminum to ligand i s given in parentheses after the Lewis acid.

The vaulted biaryl ligands 245 and 246 (Sch. 27) were examined as ligands for aluminum Lewis acids for the Diels-Alder reaction. The bis-phenanthrol ligand 246 (VAPOL) proved more effective than either the vaulted biaryl ligand 245 (VANOL) or the linear biaryl ligands 40 or 97a in asymmetric cycloaddition of methacrolein and cyclopentadiene [50,51]. The four catalysts were generated from diethylaluminum chloride and the ligand in dichloromethane at room temperature for 30 min. The catalyst prepared from the VAPOL ligand gave the ex0 adduct (-)-3 in 98 % ee with a 98:2 exo:endo selectivity with 200 turnovers in 4 h at - 78 "C. As was observed with the catalysts prepared from diol 225 (Sch. 25) and menthol (Sch. 16), the catalyst generated from VAPOL did not result in high asymmetric induction for the reaction of acrolein and cyclopentadiene (28 % ee, 9223 endo:exo). CHpCIp -79 to -82 OC \

1

slow addition

2 1.2 equiv.

Ligand

4

C

H

O

t

0.005 equiv catalyst 224

CHO 3 endo

(9-3 exo

4 hours EtpAICI(1 eq)

4

catalyst 244

CHpClp 25OC. 30 min

8 phqH 8:; phG m S i A r 3 \

\

OH

Ph

' OH

Ph

OH

/

/

/

&OH

SiAr3

-

\

(R)-40 BINOL 5 % yield 95 : 5 exo:endo 41 % ee (+)

Scheme 27

(R)-97a

100 % yield 93 : 7 exo:endo 17 % ee (-)

(R)-245 VANOL

100 % yield 96 : 4 exo:endo 29 % ee (+)

\

\

(S)-246 VAPOL

100 % yield 98 : 2 exo:endo 98 % ee (-)

Chirul Aluminum Lewis Acids in Organic Synthesis

317

Obtaining optimum asymmetric induction in the cycloaddition of methacrolein with the catalyst prepared from the VAPOL ligand involved the slow addition of the dienophile. Initially 10 YOof the dienophile was added, the remainder being added over 3 h with a syringe pump (Table 15). If the dienophile was added in one portion asymmetric induction in the cycloadduct 3 at the end of the reaction was only 87.7 YO ee (Table 15, entry 3). The amount of asymmetric induction was also found to be a function of concentration, and increased from 91.4 to 97.8 YOee when the concentration of dienophile was reduced from 1.0 to 0.05 M (Table 15, entries 1 and 2). The amount of induction was also found to be function of the substrate-to-catalyst ratioselectivity was lower at higher ratios (Table 15, entries 1 and 3 ) . Finally, it was observed that asymmetric induction was less at the early stages of the reaction that at the end. When the reaction was stopped after 30 YOcompletion the induction was 81.1 YOee whereas at 100 YOcompletion it was 87.7 YOee (Table 15, entries 3 and 5). Table 15.Diels-Alder reactions with catalyst 244 from VAPOL to give cycloadduct 3.

Amount catalyst (mol Yo)

a

[ 1]

10 10

1.o 0.05

0.5 0.5 0.5 (slow) a

1.o 1.o 1.O

Time (h) 16 24 3 0.25 4

Yield (YO)

em :endo

ee (%)

100 100

98 : 2 98:2

91.4 97.8

98 30 100

97 : 3 92:8 97 : 3

87.7 81.O 97.7

10 % of dienophile added followed by slow addition of the rest over 3 h by syring pump.

The observations made for the VAPOL-aluminum catalyst in Table 15 are suggestive of asymmetric auto-induction similar to that for catalysis of the same reaction by a chiral aluminum catalyst prepared from the diol 225 (Sch. 24; Fig. 1) [48]. Because the Diels-Alder reaction between methacrolein and cyclopentadiene was too fast, monitoring of the time course of asymmetric induction, thus this was done for the reaction between methyl acrylate and cyclopentadiene [53].The VAPOL-aluminum catalyst catalyzes the reaction of methyl acrylate and cyclopentadiene with asymmetric auto-induction as indicated in Fig. 2. The first data point that was collected was after 20 YOconversion, at which point the cycloadduct 141 was 47 'YO ee; when the last data point was collected at the end of the reaction it was found that 141 was 82 'YO ee. It was proposed that auto-induction was a consequence of the coordination of two carbonyl compounds to the aluminum. The aluminum could have two molecules of dienophile, two molecules of product or one of each; these are illustrated by structures 249, 251, and 250, respectively (Sch. 28). If these complexes are in equilibrium, it would be expected that 249 would predominate at the beginning of the reaction and that 251 would be the major species at the end of the reaction. The auto-induction could thus be explained if the Diels-Alder reaction of the Lewis acid complex 249 occurred with lower asymmetric induction than the Diels-Alder reaction of complex 250. Consistent with this model is the finding that if the reaction is initiated in the presence of 0.5 equiv. optically pure product 141, the optical activity of the newly formed product in the reaction was found to be 96 YOee, substantially above the 82 Yo ee observed for this reaction.

0

dOMe 0 (fromVAPOL 246)

10 mol % catalyst 244

+

CHzC12. -78O C 140

*

4... 141 endo

2

100

90

60

50 40 0

20

40

60

80

100

% Conversion

Figure 2. Dependence of induction of 141 on added aldehyde 252 and malonate 258.

Scheme 28

The model in Sch. 28 would lead to the expectation that other carbonyl compounds should be able to coordinate to the aluminum and effect asymmetric induction of the reaction. The data in Sch. 29 demonstrate that this is true both for carbonyl and dicar-

Chiral AluminumLewis Acids in Organic Synthesis

319

bony1 compounds. Aldehydes are more effective than esters and this might be because of the greater ease with which aldehydes coordinate aluminum. Amides kill the reaction and this might be because of the inability of the dienophile to compete for coordination of the amide. More sterically bulky carbonyl compounds are more effective, as is illustrated by pivaldehyde and 1-adamantyl carboxaldehyde. When 0.5 equiv. of each are added to the reaction at -78 "C, pivaldehyde increases the amount of induction in the reaction from 82 to 96 YO ee, whereas, 1-adamantyl carboxaldehyde increases the amount of induction to 98.5 YOee.

0

+

JOMe

10 mol % catalyst 244 (from VAPOL 246)

1.2 equiv. 140

CH$&

h O M e 0 141 endo : ex0 = 94 - 99 : I

Additive (0.5 equiv)

,? none

-78 OC (24 h)

M e:* 253

252

87 % yield 82 % ee

80 % yield 96 % ee

255

256

70 % yield 87 % ee

0 % yield

254 (0.5 equiv) 60 % yield 98.5 % ee

65 % yield 90 % ee

(0.1 equiv) (0.05 equiv) 75 % yield 73 % yield 87 % ee 82 % ee

257

258

49 % yield 98 % ee

76 % yield > 99 % ee

Additive (0.5 equiv)

-40 OC (24 h)

none 76 % yield 47 % ee

w: 254 80 % yield 88 % ee

M e O q O M e

& o q o +

257 80 % yield 90 % ee

258 100 % yield 92 % ee

Additive (0.5 equiv)

84 % yield 37 % ee

Scheme 29

258 67 % yield 69 % ee

(0.5 equiv) 90 % yield 85 % ee

259

(1 .O equiv) 80 % yield 92 % ee

The model predicts that the effect of the added carbonyl compound will be a function of its concentration. This was found for 1-adamantyl carboxaldehyde, for which induction was only 87 YOee with 0.1 equiv. and 82 YOee with 0.05 equiv. Malonates are the most effective additives reported and of these the most effective were those derived from the more bulky alcohols. This is dramatically illustrated by the effect of added diadamantyl malonate 259. On addition of 1.0 equiv. 259, asymmetric induction in the reaction is increased from 82 to 92 YOee at the same time as the reaction temperature is raised by 80 "C.The effect of malonate is even more dramatically illustrated by the graph in Fig. 2 for addition of 0.5 equiv. di-t-butyl malonate 258 to the reaction at -78 "C. The first data point taken in this reaction, at 25 5% completion, reveals that the product 141 is more than 99 % optically pure and it remains so throughout the course of the reaction. A model to account for the high stereoselection of cycloaddition occurring at the re face of the dienophile in the presence of added malonate is depicted in Sch. 30 [54]. The assumption is made that the chloride is not lost and that the malonate is coordinated as a bidentate ligand. This thus requires that the aluminum be six-coordinate. Analysis of model 260 by CPK models reveals that for steric reasons it is not possible to have the VAPOL ligand and a hindered malonate ester in a facial arrangement around the aluminum atom. The four oxygens of these two ligands are thus expected to be meridinal with apical chloride and acrylate ligands. There are two low-energy conformers about the aluminum-acrylate bond which are indicated in Sch. 30 as incleft and out of cleft. The space-filling models with di-adamantyl malonate reveal that the olefin of the acrylate is nearly hidden by one of the malonate esters in the in-cleft conformation, whereas, the olefin is much more exposed in the out of cleft conformation which would lead to re face attack, as is seen for the ( S ) enantiomer of VAPOL.

0 260

--- lineof sight

in cleft

Me- 0

\

s, face

OWA'\

0 260 out of clen

\

260

in cleft

R = 1- adamantyl

260 out of cleft

R = I-adamantyl

'

Re face

line of sight

Scheme 30

7.6.4 Aluminum Catalysts from Bis-Sulfonamides An effective chiral aluminum catalyst prepared from the bis-sulfonamide 263 was reported by Corey, Imwinkelried, Ikul, and Xiang for the Diels-Alder reaction of Nacyloxazolidinones [55]. They found that 10 mol YOcatalyst 266 would effect the reaction of N-acrylyl derivative 261 in 10 min at -78 "C to give the endo adduct 262 in 92 YOyield and 91 YOee. The reaction of the N-crotyl derivative 197 was slower but

Chiral Aluminum Lewis Acids in Organic Synthesis

321

five turnovers were observed at -78 "C in 16 h to give 96:4 selectivity for the endo adduct in 94 Yoee. The rates of these reactions are quite remarkable given that analogous reactions with catalysts generated from chiral diols are considerably slower (Sch. 19-21). The procedure for preparation of the catalysts has been described in detail [56] and the structures of the catalysts in these reactions have been confirmed as those indicated in Sch. 31 by X-ray analysis [30]. The solid-state structure of catalyst 266 reveals that the molecule occurs as a colorless dimer in which an aluminum on each monomer is bridged to an oxygen of the sulfonamide on the adjacent monomer.

2

261

262 ex0 92 % yield; endo/exo >50:1 91 % ee endo

262 endo

no1 Yo266

0

198 endo

F ~ C O ~ S H N 'NHSO~CF~ 263

88 % yield; endo/exo = 96:4 94 % ee endo

CICHzCHzC 80 OC, 3 h

A

A

264 R = M e 265 R = i-Bu

266 R = M e 267 R = i - B u

Scheme 31

These diazaaluminolidine catalysts are not as effective with acrylate esters; this is illustrated by the reaction of methyl acrylate with cyclopentadiene with catalyst 267, which gives only 50 YO enantiomeric excess of the cycloadduct 141. Menthol esters can, however, be used to achieve high stereoselectivity if a proper chirality match is observed. The acrylate ester of (-)-menthol reacts with cyclopentadiene in the presence of the (S,S) catalyst 267 to give 52 % de whereas in the presence of the (R,R) catalyst 265 97 % de was observed. The structure of the Lewis-acid-dienophile complex was shown to be that indicated in structure 271 (Sch. 32) by 'H and 13C NMR experiments [30]. The catalyst itself was shown by X-ray analysis to be dimeric with bridging aluminum-oxygen bonds; this structure was disrupted upon addition of the dienophile to give structure 271. The nitrogens are sp2 and the facial selectivity at the dienophile is controlled by the phenyl groups in the diamine fragment.

50 rnol % 267 -78 OC. 24 h

1.2 equiv

q

O0 M

e

,g-

141 50 % ee

0

50 rnol % 267

1.2 equiv.

-78 OC, 24 h

i-Pr

o 269 5 2 % d e

Me

271

Q

50 rnol % 265

1-Pr

-78 OC, 24 h

1.2 equiv.

270 9 7 % d e M~ 85 % yield (85 % de with 264)

An application of these diazaaluminolidine catalysts to the synthesis of prostaglandins is shown in Sch. 33 [57].The Corey lactone 275 is a key intermediate in an elegant route to prostaglandins; in its original form 275 was prepared from the racemic bicycloheptanone 274 and obtained optically active by intermediate resolution [58]. A direct preparation of optically pure ketone 274 was achieved by cycloaddition of the substituted cyclopentadiene 272 and dienophile 261 with catalyst 266, which gave the adduct 273 in 95 YOee and 94 YOyield. OBn

dNlo + i

10mol%266

~____-

272

261

94 % yield,

CHzClz, -78O C 10 h

,

2’3 64%

0~.

j

0 5steps

3 steps 83 Yo

I& L O B n OH

275

0 274

Scheme 33

The first example of an asymmetric Diels-Alder reaction of a maleimide was reported by Corey, Sarshar, and Lee, who used the same catalyst system [59]. The catalyst and maleimide were optimized for the cycloaddition with 2-methoxybutadiene as shown in Sch. 34. For high asymmetric induction it was found that that 3,s-dimethyl substituents

Chirul Aluminum Lewis Acids in Organic Synthesis

323

on the phenyl group of the catalyst and an ortho substituent on the phenyl group are required. An increase in size of the ortho substituent leads to an increase in induction for the 3,5-dimethylphenyl-substitutedcatalyst 279 but not for the phenyl-substituted catalyst 266, for which a slight decrease is observed. The presence of electron-withdrawing groups in the para position results in slight enhancement of induction.

2o

i// Me0A 276

Catalyst

Ar

rnol %

+

'd0

8N-R

h,NTf

TfN

\AI Me

Me0

toluene, -78 OC 278

277

R in 277

% yield 278

% ee 278

30 58 48 52

___ 96 97

62 93 93 95 >97 >95

Scheme 34

Changing the dienophile from a maleimide to maleic anhydride results in the loss of all asymmetric induction. Changing the diene from 2-methoxybutadiene to isoprene results in a drop in induction from > 95 to 67 % ee. The loss of induction for the reaction of maleic anhydride was attributed to coordination of the aluminum to lone pair b rather than lone pair a (structure 283;Sch. 35). For a maleimide with a bulky group on the nitrogen, coordination to lone pair b is sterically inhibited. It was proposed that the structure of the Lewis acid-dienophile complex was that indicated in structure 284; this was supported by NMR experiments. NOE studies reveal that the dienophile is located over the top of the molecule and that the ortho substituent of the maleimide is oriented toward the substituted phenyl group on the catalyst. This is suggestive of a van der Waals attraction between the t-butyl and methyl groups. The high asymmetric induction thus seems to result from the combined shielding of one face of the dienophile by the 3,5-dimethylphenyl group of the catalyst and the t-butyl group of the maleimide.

324

WuZff

10 mol % 266 CH2C12, -78 OC

Me0

0 276

281

280

0 % ee

dp I I

20 mol % 279 +

/I

Me

toluene. -78 OC 36 h

\\

0 Me/

282

277

-

A

.N+\ Me'

0

~NOp

u

\

0 Me

278 74 O h yield 67 Yoee

A

283 Me'

284

Scheme 35

The newly developed catalytic asymmetric Diels-Alder reactions of maleimides was cleverly applied to the first total synthesis of gracilin B and C by Corey and Letavic [60]. The Diels-Alder reaction of 2-trimethylsilylmethylbutadiene285 proceeds in high enantioselectivity with the o-t-butyl substituted maleimide 277 to give the cycloadduct 286 in 89 YO yield and 95 YO ee (Sch. 36). The Diels-Alder adduct 286 contains the six carbon chain of the tricyclic backbone of the targets. The oxidation state of the acetal carbons in the product are adjusted by first reduction to the diol 287 and then reoxidation to a dialdehyde which is trapped as the acetal anhydride 288. An oxidative allylic transposition and carbon-carbon bond cleavage provides differentially oxidized carbons of the ends of the six carbon backbone in the form of the seco acid 290. An acid catalyzed rearrangement leads to the desired tricyclic system. After installation of the double-bond in the five-membered ring, an aldol reaction provides the two diastereomeric aldol adducts 293 and 294. A stereospecific dehydration with DCC provides the ( E ) - and (2)-dienyl esters 295 and 297. Finally, epoxidation, solvolysis and acetylation complete the synthesis of gracilin B and C.

325

Chiral Aluminum Lewis Acids in Organic Synthesis

WQ

Vle3Si

Me3Si

y

20 mol % 279 +

toluene;78oc 12 h

J$N{

"

0

dsteps 81 %

yp I

H

OH

o,, LC""

H

n I

0 t-Bu 277

285

Me&i

H/?

I

286

287

89 % yield

70 %

95 O h ee

1

3steps

i

100 %

HO

87 %

vo ?A$%&&{ OMe

290

289

288

OH0

H

I100 step %

H

H

co

292

1 step 90 %

@yY@:

1

1

78 % AcO

21 : 79

0

I step

293

1

73 %

H

H

H

H

AcO

0

\ O

0

AcQ Gracilin C 296

294

295

297

ACO Gracilin B 298

Scheme 36

7.7 Ene Reactions The first asymmetric ene reaction catalyzed by a chiral Lewis acid appeared in a report by Maruoka, Hoshino, Shirasaka, and Yamamoto in 1988 and utilized the aluminum complex 98 [61]. The presence of the triphenylsilyl groups on the 3 and 3' positions of the catalyst was crucial-it was found that the diphenyl analog 302 gave racemic product 301 from the reaction of chloral with 2-thiophenylpropene whereas catalyst 98 gave 301 in 57 % ee (Sch. 37). The asymmetric ene reaction with catalyst 98 is restricted to activated aldehydes as is indicated by the data in Table 16. The rates of the reaction are such that it is not applicable to internal olefins. A variety of 1,l-disubstituted alkenes can be used to give good asymmetric induction with the fastest rates observed with phenyl vinyl thioethers. Turnover can be realized with the more reactive aldehydes andlor alkenes but only in the presence of molecular sieves. The reaction of chloral with a-methylstyrene shows that higher induction can be achieved with lower temperatures although the reaction is slower. The nature of the solvent affects the rate of the reaction. The reaction is much slower in toluene than in dichloromethane.

110 mol % catalyst

c13c

c13c

CHzC12, -78 OC,1-2 h

301

300

299

catalyst 98 catalyst 302

(R)-98

(R)-97

69 % yield; 57 % ee low yield; 0 % ee

(R)-99

Scheme 37

Table 16. Ene reactions with catalyst 98. Aldehyde C~FSCHO

Olefin

rnol % 98

CHz=C(Me)z CHz=C(CH& CH2=C(CH2)6 CH*=C(Me)t*u CHz=C(Me)Ph

110 110 110 110 110 20 a 110

CH2=C(Me)SPh

1 1 1-2 1 1

-70 -70 -70 -20 -78

ee ("A)

1.5 I -2 1.5 1-2

20 a 10a 110 20 a 110 110 20 a 110 20 a

-70 -70 -70 -20 -70 -20 -70 -70 -70 -70

1 1-2 1-2 1-2 1 1-2 1 1-2 1-2 1-2 1-2

60 70 79 27 99 30 07 40 43 69 50

30 74 70 56 64 61 54 76 73 57 53

110 20 a

-70

1-2 1-2

96 36

65 49

110

110

CHz=C(Me)SPh

-20 -20 -70 -20 -20

Yield (%)

04 06 00 92 71 70

10a

CHZ=C(Me),

Time (h)

56 42 40 42 05 35 90 00 67

20 a

C13CCHO

Temp (OC)

00 00 70

the presence of 4-A molecular sieves.

A Lewis acid prepared from (-)-menthol and ethyl aluminum dichloride has also been examined as a catalyst for the ene reaction [62]. As would be expected, this catalyst is apparently faster than the dialkoxy methyl aluminum catalyst 98 and results in 75 % yield of the homoallylic alcohol 305 with 10 mol % catalyst at -78 "C.It is sur-

327

C h i d Aluminum Lewis Acids in Organic Synthesis

prising that the menthol catalyst 4 results in nearly the same level of asymmetric induction (66 compared with 78 YOee) as the substituted BINOL catalyst 98 for the reaction of chloral with 2-methylpropene. The catalyst 4 was employed in the ene reaction of 2-methylpropene with the racemic a&dichloropropanal306. Apparently, one chlorine in the a-position is sufficient to activate the aldehyde, because 307 was produced in 70 YOyield after reaction at -78 "C for 4 h with only 10 Yo catalyst. In this example, the activating chlorine was later employed as a functional group in the formation of the epoxide in chlorohydrins 308 and 309 (Sch. 38).

10 mol Yo catalyst 4

c13c

c13c

toluene, -78 OC, 4 h

303

305 75 Yoyield; 66 Yoee

304

10 mol % catalyst 4 CI

toluene, -78 OC, 4 h

306

CI

304

307

KOH

70 % yield; 60 % ee 76 : 24 mixture of diastereomers

n

n

5

4

(-)-menthol

CI

308

309

95 % yield; 50 Yoee

Scheme 38

7.8 Epoxide-Opening Reactions Chiral aluminate complexes of the type 312 and 314 (Sch. 38) have been shown to effect ring-opening of meso epoxides giving optically active /3-chloroalcohols [63]. The ate complex 312 was derived from (-)-menthol and was found to give a 34 % yield of the alcohol 311 in 40 % ee. The same ring opening with dichloromenthyloxy aluminum 4 was much faster giving 37 YOof 311 but in 10 YO ee only. Other bases were screened including primary and tertiary alkyllithiums, but optimum induction was observed with the ate complex derived from s-butyllithium. Several bases were examined for the preparation of the most effective ate complex from BINOL for this reaction and optimum asymmetric induction was observed for the lithium n-butoxide adduct of the aluminum BINOL derivative 313. It has recently been reported that aluminum derivatives of chiral salen ligands do not lead to induction in the ring opening of epoxide 310 with benzoic acid [64].

110 mol O h ate complex

atecomplex 312 314

"'GI

CH2C12

310

311

s-BuLi

EtAIC12

Temp Yield -20% 40%

% ee

40% 26%

34 40

x

&OH

A

n

20 mol % ate complex 314

K

CH2C12,O OC, 16 h

315

315

0:

100 mol O h 314

21 O h recovery 52 % ee

0:

317

2 mol %

o+-

CH2C12 317 15 % recovery 27 % ee

O

316 50 % yield

318

BlNOL + Al(OiPr), 319 95 % ee

Scheme 39

The same ate catalyst will effect the kinetic resolution of racemic epoxides although not with great selectivity [63]. Reaction of the epoxide 315 with ate complex 314 gives a 52 YOee after 21 YV recovery. The product of this reaction is the rearranged aldehyde 316 in which the optical activity is lost during the process and thus cannot be determined. In a similar manner the epoxide 317 is reacted with 314 to give a 15 YO recovery of epoxide with 27 Yoee. The ring opening of the meso epoxide 318 was reported in a review [65] to give the alcohol 319 in 95 YOee. The catalyst was prepared from BINOL and aluminum iso-propoxide and used at 2 mol % but no other details were given. The kinetic resolution of keto epoxide 320 has been reported with the same ate complexes [63] and the resolved epoxide has been used in the synthesis of juvenile hormone [66]. In addition to the ate complexes 312 and 314, the complex 322 was also examined but it was found that complex 314 was the most effective for this reaction. Complex 314 provided the keto epoxide 320 in optically pure form after reaction had gone to 80 YOcompletion.

329

Chiral Aluminum Lewis Acids in Organic Synthesis

-d;--.---"-

75 mol % catalyst CH2C12

/

0.2 - 5 h

320 racemic

321

320

Catalyst

312 314 322

Temp ("C)

-20 -30 -40

% Recovery 320

% ee 320

6 20 10

322 Scheme 40

7.9 Free-Radical Reactions Most organic free radicals are nucleophilic and will react with electrophilic centers. Lewis acids have been used to activate a$-unsaturated carbonyl compounds towards addition of free radicals and also to stabilize a-keto radicals [67]. The first report of the use of a chiral Lewis acid to effect an asymmetric free-radical reaction was that of Urabe, Yamashita, Suzuki, Kobayashi, and Sat0 in 1995 [68]. They found that if the BINOL aluminum catalyst 313 is stoichiometrically complexed with lactone 323 and then treated with butyl iodide and tributylstannane in the presence of triethylborane the alkylated lactone 324 can be isolated in 47 YOyield with 23 % ee (Sch. 40). Shortly after this first report, Nishida, Hayashi, Nishida and Kawahara reported the radical cyclization of vinyl halides on to unsaturated esters and amides mediated by the chiral Lewis acids 98 and 326 [69]. The optimum procedure involved pre-complexation of the ester with 4 equiv. Lewis acid 98 then reaction with tributylstannane in the presence of triethylborane at -78 "C to give 327 in 36 YOee. The radical cyclization of vinyl iodide 328 was conducted in the same manner except the reaction temperature was 0 "C, because radical cyclizations forming six-membered rings are much slower. Even this higher temperature could not prevent the formation of some of the reduced product 330 but the cyclized product was formed in good yield in 48 YOee. Interestingly, the cyclization of the amide 331, corresponding to the ester 325, undergoes ring closure with the opposite facial selectivity on the olefin. This is probably because esters exist preferentially in an s-trans conformation whereas amides prefer an s-cis conformation. Fhal and Renaud have examined the alkylation of a radical generated from the aiodoimide 333 with a variety of Lewis acids, as shown in Sch. 42 [70]. The stereogenic step in this process would be hydrogen atom transfer from tin to a Lewis acid-complexed radical generated from 333. Initial screening was performed for the reaction of allyltributylstannane and imide 333, which was conducted by precomplexation of the imide with the Lewis acid and then addition of the stannane in the presence of AIBN under irradiation at 10 "C. The Lewis acid prepared from BINOL was ineffective whereas that prepared from the bis-sulfonamide 337 was slightly superior to that from the TADDOL ligand 339.

0

nBul Bu3SnH

323

313

Et3B,air toluene -78to 20 OC

O q n B U

324 47 % yield; 23 % ee 1.15Eq Et3B 1.5Eq Bu3SnH CHpClp, -78OC 20 rnin

98 326

325

R=SiPh3 R=H Catalyst

98 326 326

328

327 Eq Catalyst

%Yield 327

1 .o 1 .o 4.0

89 75 72

329 63 % yield; 48 % ee Me N-OMe

Scheme 41

2 12 36

330 21 % yield

0

4.0Eq

326 331

% ee 327

1 .IEq 5 Eq Et3B 1.5 Bu3SnH

,kN,OMe I

CHpCI2, -78'C 20 rnin

,

73

Me

332

83 Yo yield 26 % ee

331

Chiral Aluminum Lewis Acids in Organic Synthesis

1.7 Eq Bu3SnCH2CH=CH2 Lewis acid 335 AIBN, hu CH2C12, 10 OC

1.1 Equiv

M

CH2C12

+

336 337 339

Lewis acid 335

phxph

TfHN

NHTf

O ''"% ',

N

a

O

\

I

-

334 Yoyield 334 YOee 334 90 0

Ligand

Ligand

4

4

20 min

333

e

20 6)

89 88

Ar

338 A r = P h 339 A r = 1-Np 340 Ar=2-Np

'OH OH

x

Ar/ 'Ar

337 (S)-BINOL 336

Scheme 42

A more extensive study was conducted with methallyltributylstannane; the results are shown in Sch. 43. Here the promise shown by the catalyst prepared from the bissulfonamide was not fulfilled. This screening involved all the ligands shown in Sch. 42 and reaction temperatures of 10 and -78 "C.Here both the BINOL and bis-sulfonamide ligands were found to be ineffectual and the best ligand was TADDOL with 1naphthyl substituents, although poor induction was achieved with the catalyst prepared from this ligand.

Lewis 1.1 Equiv acid 335 AlBN 1.7or EqEt3B

a

R

Ligand

Me Me Me Me Me Me Me H Me Me

336 336 337 337 338 339 339 339 340 340

Temp ("c) 10 -78 10 -78 10 10 -78 -78 -78 -78

N

I

CH2CI2

333

Scheme 43

Y

YoYield 334 92 93 93 80 80 95 93 90 93 90

O

334

R a

A

o/o

ee 334 4 8 8 8 0 24 34 32 0 10

Conf R

R S

S

_R

R R

__ R

Reactions at 10 OC initiated with AlBN and hu; those at -78 OC initiated with Et3B.

The formation of a quaternary carbon center by the radical-mediated allylation of an a-iodolactone was examined for substrate 341 by Murakata, Jono, and Hoshino [71]. Lewis acids for this reaction were prepared from a bis-sulfonamide and trimethylaluminum in dichloromethane. Other aluminum compounds were employed in the preparation of the catalyst but all resulted in similar or lower asymmetric induction. The Lewis acid was complexed with the lactone and then the allylation procedure in Sch. 44 was performed. It was found that superior asymmetric induction could be achieved if the Lewis acid was prepared from the ligand with two equivalents of trimethylaluminurn. It was also interesting that some turnover could be achieved, as indicated by the data obtained from use of 50 mol YOcatalyst.

m: I

+

1 Eq

Lewisacid346

1 Eq Et3B toluene, -78 OC

341a R = CH20Me 341b R = CH70Bn Ligand

ph2ph ‘NHSO~R

RO~SHN’ 343 344 345

R=CF3 R=CeFs R=CH2CF3

+

Me3AI X Equiv

342

CH2C12

Lewis acid 346

25 OC, 1 h

substrate

Ligand

Eq 346

X Eq Me3AI

341a 341 b 341 b 341 b 341 b

343 343 344 345 344

1 1 1 1 0.5

1 1 2 1 2

% Yield 342

50 75 76 76 72

% ee 342

5R 25 R 51 R 13 S 54 R

Scheme 44

The same reaction was investigated with the substituted BINOL catalyst 98 and initially it was found to be inferior to catalysts prepared from the bis-sulfonamides. Surprisingly, it was found that in the presence of 1 equiv. diethyl ether high asymmetric induction could be achieved as summarized in Table 17 [72]. The reactions are also greatly accelerated by the presence of ether. It was suggested that a pentacoordinate aluminum species is involved in this reaction. The effect of ether was observed for all reactions whether or not an ether linkage was present in the substrate. The effect falls off with more hindered ethers and with amines. Another remarkable aspect of this reaction is that the catalyst to substrate ratio can be reduced to 10 mol YO although the induction does fall off to some extent.

Chiral Aluminum Lewis Acids in Organic Synthesis

333

m: a I

f

341a R = CH20Me 341b R = CH20Bn 3 4 1 ~R = CH20Et 341d R = M e

toluene R -98

Table 17. Effects of additives on the radical allylation of lactone 341. Substrate 341d 341d 341a 341a 341a 341a 341a 341c 341c 341b 341b 341a 341a 341a

Equiv. 98 1.o

1.o 1.o 1.o 1.o 1.o 1.o 1.o 1.o 1.o 1.o 0.5 0.2 0.1

Additive (1 equiv.) none Et20 none Et20 i-Pr20 THF MeN(CH2)4 none Et20 none Et20 Et2O Et20

Et20

Yield 342 (%) 72 84 75 85 83 71 59 77 85 72 76 81 78 76

ee 342 ("h) Config 27 81 10 82 43 33 3 6 85 3 91 81 80 74

R R S R R R R S R S R R R R

7.10 Friedel-Crafts Reaction It is known that ortho-substituted phenols can be prepared by reaction of metal phenolates with electrophilic reagents; the regio-control is thought to be provided by chelation of the incoming electrophile to the metal. The first chiral examples of this reaction involved the aluminum-mediated reactions of phenols with chloral, as shown in Sch. 45 [73,74]. The chiral aluminum Lewis acid is prepared in-situ by the reaction of a chiral alcohol with 1 equiv. diethylaluminum dichloride. One equivalent of this Lewis acid is then reacted with the phenol and the resulting aluminum phenolate is reacted with chloral in toluene at room temperature for 24 h. The most effective chiral catalyst was that prepared from (-)-menthol, as was judged by screening the reaction of 4-methylphenol. Induction fell from 54 % to 29 % ee for this catalyst if the temperature was reduced to 0 "C. Asymmetric induction falls off rapidly with catalyst-to-substrate ratio but turnover does occur. A survey of ten different phenols was reported and the results are presented in Sch. 45. It is apparent that good asymmetric induction can be realized with some ortho-substituted phenols.

334

Wulff

0

OH

+

/

R'O-AI

Et

C13CCUH

'Cl

toluene, 24 h

Me

349

348 347

(-)-menthol

350

alcohol

Eq 348

350 351 352 353 354 355 350 350 350

1 .o 1 .o 1 .o 1 .o 1 .o 1 .o 1 .o 0.5 0.2

(+)-neomenthol

351

Temp ("C)

% Yield 349

25 25 25 25 25 25 0 25 25

97 85 79 75 65 80 82 85 51

Ph (-)-borne01

352 OH

c13cc*

OH /

356 96 % yield 34 % ee

(+)-sec-butanol

(-)-8-phenylmenthol

353

(+)-2,2,2-trifluoro-1-(anthryl)ethanol

354

355

OH OH

c13cc*

/

357 t - h 97 % yield 41 % ee

359 65 % yield 76 % ee

94 % yield 33 % ee

360 78 Yoyield 54 % ee

Me

361 53 YOyield 36 % ee

362 55 YOyield 80 % ee

363 51 70yield 8 % ee

52 % yield 6 % ee

Scheme 45

7.11 Heteroatom Diels-Alder Reactions The first report of a chiral aluminum Lewis acid employed in a heteroatom DielsAlder reaction utilized Koga's mentholoxy dichloroaluminum catalyst 4 [75]. trunsPiperylene and 1-methoxybutadiene were reacted with n-butyl glyoxalate and diethyl mesoxalate; the results are summarized in Sch. 46. The asymmetric induction and chemical yield in these reactions are quite poor but the authors did find that moderate asymmetric induction could be obtained from reactions catalyzed by Eu(hfc)3.

Chiral AluminumLewis Acids in Organic Synthesis

cI

335

catalyst 4

+

R

365

367 R = OMe 30 % yield, 9 % ee R = Me 15 % yield, 4 % ee

c

pcoZBu+ Po

catalyst 4

,,COzBU

HKCozBu 0 -78

+

I

4

O C

368

R

R

R

365

369

370

R = OMe 17 % yield, 16 % ee 9 % yield, 3 Yo ee 6 % yield, 5 % ee R = Me 6 % yield, 5 % ee

Scheme 46

The 3,3'-bi~-triarylsilyl BINOL ligands 98 were first introduced by Maruoka, Itoh, Shirasaka, and Yamamoto for the heteroatom Diels-Alder reaction of electron-rich dienes with unactivated aldehydes [76,77]. The catalyst was prepared by treating the BINOL 97 with trimethylaluminum in dichloromethane at room temperature for 1.5 h. The catalyst is pink to wine red and was found, by freezing point depression, to be a monomer. A typical procedure for the Diels-Alder reaction is illustrated for the reaction of the trisubstituted diene 371 and cyclohexylcarboxaldehyde. The reaction is complete with 10 mol % catalyst at -20 "C in 2 h in toluene and, after treatment with TFA to effect elimination of the methoxyl group, the product of the reaction is predominately the cis-pyrone 373. The triphenylsilyl substituted catalyst gives the product in 93 % ee (Sch. 47).

Me3siot Hb Me

10 mol % 98

+

(SiR, = SiPh,) toluene -20 OC, 2 h

OMe 371

CH2Cl2 0 OC, 1 h

372

(R)-97

Scheme 47

TFA

(R)-98

0

Me 373 cis

373 trans

76 % yield 93 % ee

9 70yield

(R)-99

The reaction is remarkably general for several different aldehydes, as illustrated by the data in Sch. 48 obtained with the triphenylsilyl catalyst derivative. Toluene is the optimum solvent for this reaction-it was found that more polar solvents lead to lower selectivity and ethereal solvents greatly retarded the rate of the reaction. For example, in dichloromethane the asymmetric induction for the reaction of 374 with benzaldehyde drops from 95 to 82 YOee. Me

M

e Me 3

7

0 +

OMe 374

10 rnol % 98 (SiR3 = SiPh3)

TFA

toluene

CHzCIz

-20 OC, 2 h

0 OC, 1 h

+

0 Me 376 cis

375

Aldehyde PhCHO (E)-PhCH=CHCHO (E)-PhCHSHCHO * C-CCHI jCHO CH3(CH&CHO

% yield cis 376

Oh

77 89 93 65 62

ee cis 376 95 90 96 91 86

M;n Me

R'

376 trans % yield trans 376

7 10 2 -

18

* Catalyst 98 with SiR3 = Si(3,5-~ylyI)~

Scheme 48

The data in Table 18 summarize observations made for the reaction of a series of different oxygenated dienes with benzaldehyde in the presence of several different catalysts. Danishefsky's diene is only a moderate substrate for this reaction giving the pyrone 378 in 56 YO ee. High induction for this substitution pattern can be obtained with the diene 379 and the trixylylsilyl substituted catalyst. An in-depth analysis of the effect of the nature of the silicon substituents on the catalyst were made for the reaction of diene 374. Larger substituents not only increase the amount of asymmetric induction, but also increase the yield, and the diastereoselectivity in favor of the cis product. Other BINOL ligands of type 99 (Sch. 47, R = H, Me, Ph) were examined; they would only function stoichiometrically and gave less satisfactory results.

Chiral Aluminum Lewis Acids in Organic Synthesis

337

Table 18. Asymmetric catalytic heteroatom Diels-Alder reactions of alkoxydienes. Diene

SiR3

Yield cis pyrone (%) ee pyrone (%)

Yield trans pyrone (“A)

MesSiO

Y/ 0nPh OMe

377

378

56

SiPh3

Me3si0Y

P

O

I

I

0&Ph Me3Si0

378

SiPh3 Si(3,5-~ylyI)~

379

71 81

Me3si07

86

0

381

OMe

Si(3,5-~ylyI)~

0 0

AconP0 h

AcO

380

67 81

83

F? O Me3si0<e

Si(Ph),

374

h

5

M0 e Me q P h

OMe

SiMe3 SiMeetBu SiPh3 Si(3,5-~ylyI)~

95

91

Me3si04e Me

P Me

382

OMe

371

v

376

38 63 77 90

64 84 95 97

34 28 7 3

An extraordinary observation was made for the reaction of diene 374 and benzaldehyde (Sch. 49) [78]. A sample of the catalyst 98, which was prepared in racemic form, was treated with 1 equiv. (+)-3-bromocamphor and the resulting mixture was used as catalyst to provide the pyrone 376 in 82 % ee. If (-)-3-bromocamphor was used, the

enantiomer of 376 was obtained in 82 YO ee. It was suggested by the authors that this was the result of selective complexation of one of the enantiomers of the catalyst by the ketone. Only half of an equivalent of ketone gave rise to slightly lower induction, and thus decomplexation of one of the enantiomers of the catalyst by benzaldehyde was much easier than it was for the other. Whereas the reaction with optically pure catalyst in toluene gives 95 % ee for 376 (Table 18), reaction in dichloromethane gives 82 YO ee, the same as for the racemic catalyst with added ketone. Seven other chiral ketones were also examined but all gave inferior results.

0

10 mol % 383

TFA

376

374

78 % vield 82 % ee

V

Catalyst 383

(+)-3-bromocamphor (1 equiv)

(+98

Scheme 49

Aluminum catalysts prepared from BINOL derivatives have also been investigated for the reaction of unactivated dienes with activated carbonyl compounds [79,80]. The reactions of isoprene and 2,3-dimethylbutadiene were investigated with ethyl glyoxylate and a catalyst generated from BINOL and trimethylaluminum. This catalyst gave results superior to those generated from catalysts prepared from either of the BINOL derivatives 98 or 99 (Sch. 50). The catalyst 388 gives moderate to good selectivity for formation of the cycloaddition product over the ene product. High induction is observed for the cycloaddition products from both dienes but higher chemical yields were realized with 2,3-dimethylbutadiene. Reaction of methyl glyoxylate with both dienes was also examined, but similar or less useful results were obtained. A heteroatom Diels-Alder reaction with imines has been reported with the same catalyst 388 but this substrate proved quite poor in comparison with aldehydes [81].

339

Chiral Aluminum Lewis Acids in Organic Synthesis

x+

10 mol % 388

*OEt

H&OEt CHzC12 -78 to 25 OC

0

18 h

c+

385

9 % yield, 88 % ee

10 mol % 388

H&OEt

/

I/

0 384 73 % yield, 97 % ee

CHzCl2 -78 to 25 OC

0

18 h

a

O

E II

t

+

e

E

0

387

386 29 % yield, 97 % ee

14 YOyield, 88 % ee

mH

Me3AI 388 CH2Clz 25OC, 1 h

SiAr3

Ph

(R)-98

(R)-99

(S)-BINOL 336

10 mol % 388 N-Ph Me3Si0Y Phi '

t

-d

15 %yield 12 % ee

(from R-BINOL)

+

OMe

CHzC12 -78 OC

Ph

'Ph

Scheme 50

7.12 Michael Addition Reactions The first chiral aluminum catalyst for effecting asymmetric Michael addition reactions was reported by Shibasaki and coworkers in 1986 [82]. The catalyst was prepared by addition of two equivalents of (R)-BINOL to lithium aluminum hydride which gave the heterobimetallic complex 394. The structure of 394 was supported by X-ray structure analysis of its complex with cyclohexenone in which it was found that the carbonyl oxygen of the enone is coordinated to the lithium. This catalyst was found to result in excellent induction in the Michael addition of malonic esters to cyclic enones, as indicated in Sch. 51. It had previously been reported that a heterobimetallic catalyst prepared from (R)-BINOL and sodium and lanthanum was also effective in similar Michael additions [83-851. Although the LaNaBINOL catalyst was faster, the LiAlBINOL catalyst 394 (ALB) led to higher asymmetric induction. A variety of heterobimetallic catalysts with aluminum were also investigated; the results are summarized in Sch. 52 [82]. These catalysts were prepared by reaction of 2 equiv. BINOL with DIBAL and then with a metal-containing base. Notice that the catalyst prepared from n-butyllithium resulted in the same induction as catalyst 394 prepared from lithium aluminum hydride (Sch. 51). The sodium catalyst was as effective as

that containing lithium, but the potassium catalyst led to substantially less asymmetric induction. This was also true of the barium containing catalyst, although this catalyst was remarkable faster, requiring only 6 h for completion whereas the others all required 72 h. 0

0 10 mol Yocatalyst 394 THF, 25 OC, 60 - 72 h

390a R1 = Et, R2 = Me 390b R1 = Bn. R2 = H

389

I”,

C02R‘ R2 ‘C02R’ 391a 84 Yoyield, 91 Yoee 391b 93 Yoyield, 91 YOee

10 mol Yocatalyst 394

+

R‘O

THF, 25 OC, 72 h \

C02R’ 393b 88 Yoyield, 99 % ee 393c 90 Yoyield, 93 % ee 393d 87 Yoyield, 95 % ee

390b R 1 = B n 390c R ’ = M e 390d R1 = E t

392

8:; /

+

/

THF

LiAIH4

0 ’

OOC, 1 h

/

(R)-BINOL 40 2 Equiv

\ /

394

Scheme 51

10 mol O A catalyst 395

uOBn

THF, 25 ‘C, 6 - 72 h

390b 392

M(Wn nBuLi NaOtBu KN(SiMe& Ba(0tBu)Z

(R)-BINOL 40 2 Eq

Scheme 52

1 Eq (iBu)2AIH THF, 0 OC, 0.5 h

1 Eq M(Wn

YoYield 393b 46 50 43 100

Catalyst 395

% ee 393b 98 98 87 84

Chiral AluminumLewis Acids in Organic Synthesis

341

One particular advantage of aluminum bimetallic catalysts is that they enable the tandem Michael-aldol sequence shown in Sch. 53 [82]. The reaction of cyclopentenone with malonate 390a and dihydrocinnamyl aldehyde 396 in the presence of catalyst 394 gave the Michael adduct 391a in 7 % yield and the tandem Michael-aldol adduct 397 in 64 YO yield. The LaLiBINOL catalyst gave 397 in 30 % yield and 391a in 46 YO yield (3 % ee). The LaNaBINOL and LaBINOL catalysts gave only 391a in 73 YO yield (86 YO ee) and 57 YO yield (83 YOee), respectively. The tandem Michaelaldol adduct 397 obtained with dihydrocinnamyl aldehyde was obtained as a single diastereomer, whereas, the adduct 399 obtained with benzaldehyde was obtained as a mixture of diastereomers. The asymmetric induction in 399 was determined to be 89 YOee after oxidation to the diketone 400.

0

0 +

389 1.0 Eq

10 mol % 394

0

E t O v O E t Me 390a 1.0 Eq

+

p

h

J

H

-GF>&~ 36 h

396 1.2 Eq

T

P

$z.Et

Me

C02Et

COZEt

~~~

397 64 % yield 91 % e e

0

E t O q O E t

+

C02Et

Me

+

PhKH

Me

PCC -

389

390a

398

1.0 Eq

1.2 Eq

Ph

THF, 25 "C,

C02Et

Me

72 h

1.0 Eq

391a 7 Yo yield 90 % ee

OH

0 +

h

399

82 % yield

COZEt

400 100 % yield 89 % ee

Scheme 53

The mechanism proposed for the tandem Michael-aldol sequence is presented in Sch. 54. It is suggested that the ALB catalyst 394 reacts with cyclopentenone 389 and malonate 390a to give the bimetallic complex 401 in which the aluminum is coordinated to the enone and the lithium enolate of the malonate is coordinated to an oxygen of one of the aluminum BINOL ligands. An intramolecular Michael addition would then yield the Michael adduct 402. Internal protonation of the enolate in 402 would lead to the Michael adduct 391a whereas reaction with the aldehyde would result in carbon-carbon bond formation and the generation of the bimetallic complex 403 which upon protonation would give the aldol adduct 397 and return of the ALB catalyst 394. There is, apparently, a delicate balance between internal protonation and aldehyde addition to intermediate 402, because replacement of aluminum with lanthanum gives predominately internal protonation and the formation of the Michael adduct rather than aldehyde addition. Furthermore, the tandem Michael-aldol sequence fails with malonates that are not substituted in the 2-position. Support for coordination numbers higher than four for aluminum in this mechanism comes from 27AlNMR studies. The X-ray structure of 394 with 1 equiv. cyclohexenone reveals a tetrahedral aluminum with the enone coordinated to lithium. The 27AlNMR of 394 in the presence of 3 equiv. cyclohexenone was interpreted as indicative of the presence of a hexacoordinate aluminum coordinated to two molecules of enone.

H

I

Me

/

\

H

397

H

401

//

403

396 402

Scheme 54

The lithium aluminum bimetallic catalyst with BINOL (ALB) that was developed by Shibasaki for the Michael addition of malonates to enones as described above was subsequently investigated by Feringa and coworkers for the Michael addition of anitroesters to enones [86]. The optimum conditions for this reaction are shown in Sch. 5.5 and involve the generation of the catalyst from lithium aluminum hydride and 2.45 equiv. BINOL and then performing the reaction in THF at - 30 "C. The reaction of enone 404 with the nitroester 405 was also investigated with a catalyst generated from the 3,3'-dimethylBINOL 408 and it was found that although the yield of 406 was high (86 YO) the induction was quite low (< 5 YOee). The catalyst generated from 408 was not completely soluble and the reaction was thus performed with the heterogeneous catalyst. The effect of temperature on the reaction in THF was quite dramatic dropping from 74 YOee to 7 YOee as the temperature was increased from -30 "C to 2.5 "C.Nearly identical results were obtained with the nitroester 409 which is derived from (-)-menthol; this indicates that the chiral auxiliary plays no role in the induction.

343

Chirul Aluminum Lewis Acids in Organic Synthesis

NO2

10 mot % catalyst 407

qMe 0 + No2$OBn Me 404

3

OH

Bno*Me0

/

solvent THF THF toluene ether CI(CH&CI CH2C12 CH2Cl2 CHZCI;!

catalyst 407 THF 0 'C, 0.5 h

(R)-BINOL 40 2.45 Equiv

10 mol % catalyst 407

qMe 0 + No2$OMen* Me 404

0

406 81 - 86 %yield

LiAIH4

OH

/

72 h

405

THF, 72 h

NO2

74 7 7 19 4 6 20 25

Me 408

ye 0

'Meno*Me 0

409

Yo ee 406

Temp ("C) -30 25 -30 -30 -30 -20 25 40

410 7 % de at 25 OC 70 % de at -25 OC

Scheme 55

The results from four other reactions with catalyst 407 are summarized in Sch. 56. Induction ranged from 5 to 49 % ee, below the value obtained (74 % ee) from the reaction of enone 404 and malonate 405. The reaction of malonate 405 with the unsaturated carbonyl compounds 413,392 and 414 all failed to produce product. The reaction of 405 with acrolein led to polymerization. The stoichiometry of catalyst formation is crucial for optimization of the Michael adduct. The reaction between enone 404 and nitroester 411 with catalyst 394 generated with 2.0 equiv. BINOL gave the double Michael adduct 416 as the major product. When the amount of BINOL is increased to 2.45 equiv. the Michael adduct 415 constitutes a minimum of 80 % of the product mixture. Larger amounts of BINOL resulted in an insoluble catalyst. 0

10 mol % catalyst 407

NO2

THF, -21 to -24 O C , 72 h

0

0

41 1

409

6 qoEt Et

Me

0

414

392

Et Ph

R2 Me Et Et Me

0 10 mol % catalyst 394

0 404

0 412

R'

413

3'

THF

41 1

%Yield 412 %ee412 84 49 86 47 84 86

33 5

NOp

3'

0

+ 0

415 < 40 %

Scheme 56

417

BnO 0

0 416 > 60 %

344

Wulff

The dramatic effect of temperature on the reaction of enone 404 with malonate 405 in THF suggests competing reactions from different aluminum species. Crystallization of the catalyst 407 prepared from 2.45 equiv. BINOL surprisingly gave the bimetallic complex 417 comprising three BINOL ligands, one aluminum and three lithiums as determined by X-ray diffraction. An aluminum NMR study of the solution of catalyst 407 revealed the presence of three aluminum species one of which was assigned as the hexacoordinate species 417. Catalysis of the reaction of enone 404 with malonate 405 with 10 mol % 417 gave the Michael adduct 406 in 65 YOee at 20 "C. This shows that although the aluminum species 417 can result in significant asymmetry in this reaction, it cannot be the only aluminum species responsible for the induction observed in reactions summarized in Sch. 55. Inspired by the bimetallic catalyst developed by Shibasaki and coworkers with 2:l complexes of BINOL with aluminum, Manickam and Sundararajan prepared 2:l complexes of the aminodiol420 with aluminum [87,88]. Reaction of malonate esters with cyclopentenone or cyclohexenone results in asymmetric induction of at least 90 % ee with dibutyl malonate, as detailed in Sch. 57. A catalyst prepared by the reaction of 2 equiv. diol 419 with lithium aluminum hydride was found to result in asymmetric induction for the reaction of cyclohexenone with malonate 390d similar to that observed with the catalyst derived from 420 and from BINOL, although the rate was slightly slower.

33 mol % catalyst 418

THF, 0

ROuOR

+ 25 OC,5-8 h

390d R = Et 390b R = B n 390e R = t B u

389

b+

C02R 391d 86 Yo yield 86 % ee 391b 78 Yoyield 83 % ee 391e 83 %yield 90 % ee 33 mol % catalyst 418

ROuOR THF, 0

25 O C , 5-8 h

390d R = E t 390b R = B n 390e R = t B u

392

-

4 C 0 2 R C02R

393d 87 % yield 80 % ee 393b 83 %yield 92 % ee 393e 80 Yoyield 94 % ee

/Ph P h Y - N T OH >APh OH 419

4 C O z R

LAH, THF

catalyst 418

0 O C , 30 min

420 2 Equiv

Scheme 57

The catalyst prepared from aminodiol 420 was also examined for its capacity to effect asymmetric Michael addition of a malonate to an acyclic enone. The single example reported is shown in Sch. 58 and occurs with significantly lower asymmetric

345

Chiral AluminumLewis Acids in Organic Synthesis

induction than with either cyclopentenone or cyclohexenone [87]. Finally, catalyst 418 was shown to be extremely effective in promoting the rapid Michael addition of thiophenols to cyclic enones, although the asymmetric induction was not useful.

P 33 mol % catalyst 418

EtOU

+

O

E

t

THF, 0 a 25 O C , 4 h

0

I

C02Et

390d 421

A+ 389

95 % yield 62 % ee

0 30 mol % catalyst 418 X

G

S

H

THF, 0 OC, 30 sec

422a X = H 422b X = M e

4s*

423a 423b

97 % yield, 32 YOee 96 % yield, 26 % ee

0 30 mol % catalyst 418

THF, 0 392

OC,30

sec

422a X = H 422b X = M e

424a 97 % yield, 45 % ee 42413 97 % yield, 40 % ee

Scheme 58

Surprisingly, the Horner-Wadsworth-Emmons reaction of 425 with cyclohexenone in the presence of simple bases such as sodium t-butoxide does not give significant yields (- 10 %) of the alkene product 429 (1,2 adduct) nor does it give detectable amounts of the 1,4 adduct 425 (Sch. 59) [89]. Shibasaki and coworkers found that although the ALB catalyst 394 (Sch. 51) does not promote any reaction between cyclohexenone and the phosphonate 425, catalyst 428, prepared by reaction of 394 with 1 equiv. sodium t-butoxide, will catalyze the exclusive formation of the 1,4 adduct 426 in 64 YO yield and 99 % ee [89]. The reaction of ALB 394 with 1 equivalent of other bases can also produce active catalysts-nBuLi and KOtBu give 426 in 98 and 89 YOee, respectively. The reaction with cyclopentenone with 425 in the presence of catalyst 428 gives the 1,4 adduct 427 in 95 Yo yield and 95 YOee. The synthetic advantage of the Michael addition of phosphonates of type 425 is that the Michael products can be used in a subsequent Horner-Wadsworth-Emmons reaction. For example, the Michael adduct 427 was reacted with a base (after protection of ketone) in the presence of benzaldehyde to give the alkene 430. The asymmetric induction of the Michael addition of 425 to 389 (and that of 425 to 392) was determined on the alkene product 430, because the Michael adduct 427 was formed as mixture of diastereomers.

6

0 +

10 mol % 428

(MeO),

392

OMe

THF, 50 OC, 140 h

425 426 64 % yield, 99 % ee

+

(MeO)2p& 0

389

0 OMe

+

/

4-

THF, 10 mol 25 % OC,428 72 h

C02Me

H

425

3:; /

(R)-BINOL 40 2 Equiv

LiAIH4

429

+C02Me

PO(OMe)2

Ph

427 95 YOyield, 95 % ee

OOC, THF1 h

NaOtBu Eq

3

; /

:

A /

I

:

F

N",

430

g /

/

OtBu

428

Scheme 59

The structure of catalyst 428 was proposed as a result of the several experiments shown in Sch. 60 and discussed below [89]. Firstly, it was observed that treatment of ALB catalyst 394 (Sch. 51) with methyllithium produced a solution from which the hexacoordinate aluminum species 434 (M = Li) could be crystallized in 43 % yield. The same compound could also be obtained from solutions prepared from 394 and nBuLi, and the sodium enolate of 425. Solid-state X-ray analysis of this compound revealed that it has the same structure as the species 417 (Sch. 56) isolated by Feringa and coworkers during the preparation of ALB with excess BINOL (Sch. 55) [86]. The tris-BINOL(tris-lithium) aluminum complex 434 is not the active catalyst in the Michael addition of phosphonate 425 to cyclohexenone because the use of this material as catalyst gave the Michael adduct 426 in 28 YOyield and 57 YOee which is dramatically lower than obtained by use of catalyst 428 (Sch. 59). In addition, the use of catalyst 434 (M = Li) gave the alkene product 429 in 13 YOyield, a product that was not seen with catalyst 428. Additional evidence comes from the reaction between 425 and cyclopentenone with catalyst 434 (M = Li) which gives the adduct 427 in 78 % yield and 12 YOee. A mechanism for the formation of the hexacoordinate species 434 is presented in Sch. 60 [89]. Association of metal bases with the ALB catalyst 394 gives species 431 which can undergo disproportionation to give tricoordinate aluminum species 432 and the bis-alkoxide of BINOL (433). Addition of this bis-alkoxide of BINOL to ALB would then produce the hexacoordinate aluminum species 434. If this scheme is correct, it is certainly possible that the three-coordinate aluminum species 432 is the active catalyst. To test for this possibility, this species was prepared by the reaction of BINOL with trimethylaluminum and was crystallized to give crystals which were characterized by X-ray diffraction as the dimeric pentacoordinate THF adduct 435. This aluminum compound has been used previously for Mukaiyama type aldol reactions

Chiral Aluminum Lewis Acids in Organic Synthesis

h,

Li I 394 (ALB)

Ili

432

Nu

347

433

431

L uo.:i Li

433

394 (ALE)

6 392

0 +

(Meoh

IJ

434

10 mol % 434 (M = Li) OMe

THF, 50

OC,

92 h

425 429 1 3 %

426 28 % yield, 57 % ee

fi

436

Scheme 60

(Sch. 5) [12], free radical cyclizations (Sch. 41) [69], [2 + 21 cycloadditions (Table 5) [28], and heteroatom Diels-Alder reactions (Sch. 50) [79,80] but no X-ray structure had ever been reported for it or for the 3,3'-disubstituted derivatives which were first introduced as an asymmetric Claisen catalyst [2427]. Although compound 435 was found not to induce any reaction between cyclohexenone and phosphonate 425 under the standard conditions for catalyst 428, consistent with the proposed equilibrium of species 394, 431, 432, 433, and 434 is the finding that catalysis of the reactions between cyclohexenone or cyclopentenone and phosphonate 425 with a 2:l mixture of 434 (M = Li) and 435 gave only the Michael adducts 426 and 427 in 96 % ee and 92 % ee, respectively. Because 394 and 432 are inactive catalysts and 434 results in much lower induction and some 1,2-adduct, it was proposed that the active catalyst in the Michael addition of phosphonate 425 to cyclohexenone was the species 431 resulting from association of ALB catalyst with a metal alkoxide. It was proposed that the stereochemical determining step involved intramolecular transfer of the enolate of 425 to the coordinated cyclohexenone in species 436. The application of the Michael addition of phosphonate esters in the synthesis of coronafacic acid was reported by Shibasaki and coworkers and is outlined in Sch. 61 [89]. The Michael adduct ent-427 was prepared in 94 % ee in the same fashion as its enantiomer 427 (Sch. 59) by employing a catalyst prepared from (S)-BINOL.

348

Wulff

All the carbons of the target were introduced by a Horner-Wadsworth-Emmons reaction of ent-427 with a-ethylacrolein, which gave a mixture of ( E ) and ( Z )olefins 437. The synthesis of the ( E ) isomer of 437 constitutes a formal synthesis of coronafacic acid because its conversion to the natural product has been reported by Nara, Toshima, and Ichihara [YO]. They reported that 437-E could be cyclized with base to hydrindenones 438 and 439 in 71 YOyield. After purification, the major diastereomer 438 could be hydrolyzed to coronafacic acid in 95 YOyield.

4

.,,,IH CO2Et

H

PO(OMe)2

ent-427b 91 %yield, 94 Yo ee

0

TsOH NaOtBu,

?rCHO 0

A 1 TsOH

Et02C 437-2

43 %

437-E 27 Yo

EtONa I EtOH 25 'C, 24 h

440 95%

438 53%

439 18 Yo

coronafacic acid

Scheme 61

The catalytic asymmetric Michael addition of malonate esters to cyclic enones with the ALB catalyst 394 (Sch. 51) has been applied by Shibasaki and coworkers to the synthesis of 2-deethyltubifolidine 444 and tubifolidine 449, syntheses which are outlined in Sch. 62 [Yl]. Improved conditions for the asymmetric Michael reaction were included in this report and involve the use of molecular sieves to accelerate the reaction-enabling the use of only 1 mol Y catalyst and the use of potassium t-butoxide as an additive which increases asymmetric induction for the reaction of 392 with 390c from 93 % ee (Sch. 51) to 99 YOee. This synthesis of Michael adduct 393c was conducted on a 100-g scale. The next key step in the synthesis is the conversion of 393c to the known tricyclic intermediate 441 via a highly regioselective Fischer indole synthesis [Y2,93]. The synthesis of deethyltubifolidine begins from 441 via the installation of the amine in the side-chain to give intermediate 442. The piperidine ring is closed oxidatively with DDQ [94] with subsequent reduction of the iminium to give the tertiary amine 443. This is the first time that the DDQ oxidative closing and the reduction step have been performed concurrently. The final conversion of 443 to the target 444 was achieved by a procedure developed by Bosch and coworkers [!XI. The conversion of intermediate 441 to tubifolidine 449 was conducted in a similar manner as that to the nor-ethyl derivative with the exception that the two-carbon ethyl side-chain

Chiral Aluminum Lewis Acids in Organic Synthesis

349

was introduced via an aldol reaction of ester 441 with acetaldehyde and then converted to the proper stereochemistry by hydrogenation, which gave a 7.3:1 mixture in favor of the required stereochemistry.

6

1) PhNHNH2.HCI AcOH, 80 'C

1 rnol % catalyst 394

+

uoMe

Meo

390c

392

0.9 mol % KOtBu THF, 25 OC, 72 h 4 MS

A 393c 96 %yield, 99 % ee

441 9 2 %

1) HP.(Ph3P)3RhCI

2) EtSH, BF3.OEt2

THF, 0

EtS,

448 6 6 %

+ 9 % epimer

OC

MeO,

449 35 % tubifolidine

444 44 %

443 77 OO/

20-deethyltubifolidine

Scheme 62

The asymmetric catalytic tandem Michael-aldol sequence that Shibasaki's group developed with the ALB catalyst 394 (Sch. 53) has been showcased in a prostaglandin synthesis. The synthesis of 11-deoxy-PGF1 457 is outlined in Sch. 63 and begins with reaction of cyclopentenone, malonate 390f and 450 mediated by the (S) enantiomer of catalyst 394. The improved protocol was employed in this reaction and thus with 5 mol YO catalyst and 4.5 mol 740 NaOtBu in the presence of molecular sieves the tandem Michael aldol adduct 451 was isolated in 84 % yield. This compound was isolated as a mixture of diastereomers and to simplify the measurement of asymmetric induction it was dehydrated to the conjugated enone 452; asymmetric induction was determined to be 92 YO ee. After stereoselective reduction of the enone system, the remaining challenge in the synthesis is the installation of the C8 side-chain. Both ester carbons of the malonate unit were sacrificed to give the methyl ketone 454. This particular strategy seems wasteful, but is necessary because unsubstituted malonate esters are not useful in the tandem Michael-aldol sequence although they work well for Michael additions alone. The reaction of dibenzyl malonate 390b with cyclopentenone and aldehyde 450 with the ALB catalyst (9-394 gives only a 9 YO yield of the adduct corresponding to 451. The final six carbons are introduced into intermediate 454 by an aldol addition and elimination to give the enone 455. Upon reduction of the ketone to the alcohol and protection as an acetate, the allylic acetate is equilibrated with a palladium catalyst to give predominately the C-15 acetate and, after hydrolysis, the alcohol 456 in 40 YO isolated yield. Final deprotection provides 11-deoxy-PGF1, in 17 steps and 7 YO overall yield from the aldehyde 450.

5 mol % (5)-394

+ + B n O q a O B n

HMe0

4.5mol% NaOtBu THF, 25 OC, 90 h

Me

390f

450

1.0Eq

1.2 Eq

1.5 Eq

1) HP. Pd/C 2) Pb(0Ac)d

C02Bn

4 MS

389

84 % yield 6 : 1 to 17 : 1 mixture of diastereorners

OTBS 4 steps

--

3) K$03 / MeOH

COnBn

453

63 % yield

452

87 % yield, 92 % ee

OTBS 3 steps

40 %

0 454

0 75 %yield

455

85 % yield

61 %

c

OH

456 R' = TBS. R2 = Me 457 R', R'= H 11-Deoxy-PGF1,

Scheme 63

The most impressive result of the catalytic Michael-aldol cascade is the kinetic resolution of the racemic cyclopentenone 458 shown in Sch. 64. The reaction is performed with 10 mol YO(S)-ALB to give the tandem Michael-aldol adduct 459 in 97 YOee and 75 YOyield based on malonate 390f. Asymmetric induction in 459 was measured after dehydration of the hydroxyl group, as was done for 451. Clearly, this demonstrates the viability of this new asymmetric strategy for the synthesis of a variety of fully functionalized prostaglandins. 0 II

I

H -

Me

TBSO

1o mol % (s)-394 9 mol % NaOtBu THF, 25 O C , 40 h

4 MS 458

2.0Eq racemic

390f 1.2Eq

450 1.5 Eq

W

O

+ . s C 0 2 B n TBSo Me C02Bn

M

e

459

75 % yield, 97 % ee 12 : 1 mixture of diastereomers

Scheme 64

7.13 Strecker Reaction The only known metal catalyst for the asymmetric catalytic Strecker reaction is the aluminum salen catalyst 465 (Sch. 65) recently reported by Sigman and Jacobsen [97]. They prepared 11 different chiral salen complexes from different transition and main group metals and screened these complexes for the addition of trimethylsilyl cyanide to imine 460 at room temperature. The aluminum catalyst 465 was optimum in terms both of asymmetric induction and rate. This constitutes the first aluminum salen complex successfully developed for an asymmetric catalytic reaction.

Chiral Aluminum LewisAcids in Organic Synthesis

351

0 N-

+

PhAH

5 mol Yo catalyst 465 Me3SiCN

461

TFAA

Toluene, 23 OC, 15 h PhACN

460

462 100 % conv, 45 % ee

0 N-

PhA

+ H

5 mol % catalyst 465

HCN

463 1.2Equiv

460

TFAA

CF3AN-

Toluene, -70 O C , 15 h PhACN

462 91 % yield, 95 % ee

Et2AICI CHpCI2, 25 OC, 2 h

‘‘Bu 464

“Bu

465 95 YOyield

Scheme 65

The reaction with trimethylsilyl cyanide failed if strictly anhydrous conditions were used. Thus, it was suspected that hydrogen cyanide was the actual substrate of the reaction. In a control experiment, it was found that the background reaction of HCN with imine 460 was quite rapid at room temperature, but was completely suppressed at -70 “C. Optimum conditions were thus identified as those indicated for the reaction of imine 460 with HCN in Sch. 65. Although the reaction works well for a variety of aryl imines, as summarized in Sch. 66, asymmetric induction decreases substantially for imines derived from aliphatic aldehydes. Several optimization studies were performed in an effort to improve the induction resulting from alkyl substituted imines. Although several other sterically and electronically modified chiral salen ligands were examined, no improvement in asymmetric induction was observed. The imine nitrogen substituent was also varied for the imine derived from pivaldehyde; optimum induction was observed for the benzyl derivative (474,49 % ee). Finally, the utility of this asymmetric catalytic Strecker reaction was demonstrated in the synthesis of the a-amino ester 478. In this example the cyanohydrin was isolated after conversion to the methyl ester 477 by methanolysis. This ester was obtained in 78 YOyield and in 92 ‘70ee. Cleavage to the free amine was achieved by palladium(0) and, after crystallization, the amino ester 478 was isolated in 60 % yield and in 2 99 YOee.

Me0 462 91 myo y,eld, 95

ee

Me

466 93 O h yield, 91 yo ee

467 99 % yield, 94 70ee

0

CF/’Ne

C

N

471 472 77 %yield, 57 % ee 69 % yield, 37 % ee

5 rnol %catalyst 465

MeOH

Toluene, -70 OC, 15 h

HCI

476

468 93 % yield, 79 % e e

469 95 Yoyleld, 93 % ee

0

C F 3 A N e e

‘-.

468 92 %yield, 81 % ee

0

C F i B \ N e

C &( 470 93 %yield, 93 % ee

Br

Me

ChANe

C

CN

N

473 88 % yield, 49 % e e

474 67 %yield. 44 % e e

475 74 %yield, 40 % ee

HN-

NH2 HCI

5 mol % Pd(PPh&

477 78 %yield, 92 % ee

CHPCI~, 25 ‘C. 3 h RC02H

478 recrvstallized 60 %yield, $99 % ee

Scheme 66

Acknowledgment The author would like to thank Jianming Bao, Douglas Heller, Daniel Eugene Grant, Eliza Yeung and Hongqiao Wu who have developed chiral catalysts in our laboratories. We also like to thank the National Institutes who supported their work. The author is grateful to Hongqiao Wu and Loncarre for proofreading the manuscript.

Goldberg, aluminum of Health Catherine

References 1. 2. 3. 4.

5. 6. 7. 8. 9. 10.

11. 12. 13. 14.

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65. Noyori, R., Asymmetric Catalysis in Organic Synthesis, John Wiley & Sons, New York, New York, 1994, p 234. 66. Naruse, Y.; Esaki, T.; Yamamoto, H., Tetrahedron Lett., 1988,29,1417. 67. Renaud, P.; Gerster, M., Angew. Chem. lnt. Ed. Engl., 1998,37,2563. 68. Urabe, H.; Yamashita, K.; Suzuki, K.; Kobayashi, K.; Sato, E, J. Org. Chem.,1995,60,3576. 69. Nishida, M.; Hayashi, H.; Nishida, A,; Kawahara, N.;J. Chem. Soc., Chem. Commun.,1996,579. 70. Fhal, A.-R.; Renaud, P., Tetrahedron Lett., 1997,38,2661. 71. Murakata, M.; Jono, T.; Hoshino, O., Tetrahedron Asymm.,1998,9,2087. 72. Murakata, M.; Jono, T.; Mizuno, Y.; Hoshino, O., J. Am. Chem. Soc., 1997,119,11713. 73. Bigi, F.; Casiraghi, G.; Casnati, G.; Sartori, G.; Zetta, L., J. Chem.SOC.,Chem. Commun.,1983,1210. 74. Bigi, F.; Casiraghi, G.; Casnati, G.; Sartori, G.; Fava, G. G.; Belicchi, M. F.,J. Org. Chrm.,1985,SO, 5018. 75. Quimpere, M.; Jankowski, K., J. Chem. Soc., Chem. Commun.,1987,676. 76. Maruoka, K.; Itoh, T.; Shirasaka, T.; Yamamoto, H., J. Am. Chem. Soc., 1988,110,310. 77. Maruoka, K.; Nonoshita, K.; Yamamoto, H., Syn. Comm.,1988,18,1453. 78. Maruoka, K.; Yamamoto, H., J. Am. Chem. SOC.,1989,111,789. 79. Graven, A.; Johannsen, M.; Jorgensen, K. A., J. Chem. Soc., Chem. Commun.,1996,2373. 80. Johannsen, M.; Yao, S.; Graven, A,; Jorgensen, K. A,; Pure & Appl. Chem.,1998,70,1117. 81. Hattori, K.; Yamamoto, H., Tetrahedron, 1993,49,1749. 82. Arai, T.; Sasai, H.; Aoe, K.-I.; Okamura, K.; Date, T.; Shibasaki, M., Angew. Chem. lnt. Ed. Engl., 1996,3.5,104. 83. Sasai, H.; Arai, T.; Shibasaki, M.; J. Am. Chem. Soc., 1994,116,1571. 84. Sasai, H.; Arai, T.; Satow, Y.; Houk, K. N.; Shibasaki, M., J. Am. Chem. Soc., 1995,117,6194. 85. Sasai, H.; Emori, E.; Arai, T.; Shibasaki, M., Tetrahedron Lett., 1996,37,5561. 86. Keller, E.; Veldman, N.; Spek, A. L.; Feringa, B. L., Tetrahedron Asym.,1997,8,3403. 87. Manickam, G.; Sundararajan, G., Tetrahedron Asym.,1997,8,2271. 88. Manickam, G.; Sundararajan, G., Ind. J. Chem.,1997,36A & B, 516. 89. Arai, T.; Sasai, H.; Yamaguchi, K.; Shibasaki, M., J. Am. Chem. Soc., 1998,120,441. 90. Nara, S.; Toshima, H.; Ichihara, A,, Tetrahedron, 1997,53,9509. 91. Shimizu, S.; Ohori, K.; Arai, T.; Sasai, H.; Shibasaki, M., J. Org. Chem.,1998,63,7547. 92. Magnus, P.; Sear, N. L.; Kim, C. S.; Vicker, N., J. Org. Chem.,1992,57,70. 93. Berger, L.; Corraz, A. J., U. S. Patent 4,009,181,1977. 94. Oikawa, Y.; Yonemitsu, 0.;J. Org. Chem.. 1977,42,1213. 95. Amat, M.; Linares, A,; Bosch, J. J. Org. Chem., 1990,55,6299. 96. Yamada, K.-I.; Arai, T.; Sasai, H.; Shibasaki, M., J. Org. Chem.,1998,63,3666. 97. Sigman, M. S.; Jacobsen, E. N.,J. Am. Chem. Soc., 1998,120,5315.

Lewis Acids in Organic Synthesis Edited bv Hisashi Yamarnoto Copyright 0WILEY-VCH Verlaa GmbH.2000

8 Silicon(1V) Lewis Acids Masataka Oishi

8.1 Introduction In contrast with more traditional Lewis acids, the application of organosilicon compounds as Lewis acids in selective organic synthesis has a relatively brief history. Early studies of organosilicon compounds sought to develop protective methods for various protic functional groups. Because synthesis of the complex organic molecules requires operationally convenient and stereoselective transformations, demands for efficient reagents and catalysts in Lewis acid-promoted reactions and anionic reactions heightened accordingly. In particular, a wide range of silicon nucleophiles and their commercial availability brought serious attention to the development of Lewis acids. Among these organosilicon Lewis acids perform well as homogeneous catalysts in common organic solvents. Such silicon-based reagents contrast sharply with conventional Lewis acids such as metal halides, frequently undergoing aggregation and disproportionation or ligand exchange. It must be mentioned that the most versatile and representative organosilicon Lewis acid is undoubtedly trimethylsilyl triflate (la), the structure of which reflects the inertness of tetraalkylsilanes for Lewis basic substrates and the requirement of a counter-anion to increase the electrophilicity of the silicon center. Noyori’s pioneering studies on the reactions of trimethylsilyl triflate not only provided a general outline for stoichiometric transformations, but also inspired an extraordinary number of subsequent studies of the catalytic use of Lewis acids in selective organic synthesis. One of the most successful current topics is the chemistry based on hypervalent silicates that enables simultaneous bond making and bond breaking by coordination of a substrate and a Lewis base. The synthetic utility and broad applicability of electrophilic organosilanes are perhaps best demonstrated by the publication of excellent review articles [1,2].Numerous surveys on synthetic and structural aspects of silylium ions have also appeared [3]. This chapter concentrates on applications of Lewis acidic organosilanes in stereoselective organic synthesis, although the development of organosilicon compounds as protecting and deprotecting agents are not included [4]. This chapter is organized according to the type of reactions employed, and topics covered here include, firstly, carbon-carbon bond formation by aldol-type reactions, allylation and related reactions; intramolecular aldol reaction and allylation; ring construction; isomerization and rearrangement; glycosidation; oxidation and reduction; and finally a spotlight on reactions via hypervalent silicon species. Literature on these topics up to 1998has been surveyed.

8.2 Preparation of Organosilicon Lewis acids Simple organosilicon Lewis acids, for example trimethylsilyl triflate (la) [5], trimethylsilyl nonaflate (2) [6], iodotrimethylsilane [7], tert-butyldimethylsilyl triflate (lc) [8], triisopropylsilyl triflate (la) [8], etc., are commercially available, but because of their easy hydrolysis and the appearance of traces of a protic acid during storage,

356

Oishi

occasionally they are freshly prepared before use. The most direct method for their preparation involves reaction of trialkylsilyl chloride with the corresponding acid or silver salt, the latter being more promising (Eqs 1 and 2). R3SiCI

+

X-H

R3SiCI

+

Ag-X

- HCI

*

R3SiX

*

R3SiX

- AgCl

Protodesilylation of allyl- or aryl-substituted trialkylsilanes with an acid partner is a cleaner method, producing propene or an aromatic hydrocarbon as a volatile inert byproduct. Although some methods of isolation have been reported, they can usually be prepared in situ in aprotic media and employed without further purification. Methods of preparation of representative organosilicon Lewis acids, la, trimethylsilyl bis(trifluoromethanesu1fone)imide (7) [9], trimethylsilyl perchlorate (6a) [lo], iodotrimethylsilane, and trimethylsilyl tetrakis(trifluoromethanesulfony1)borate [111are described below. In principle, these analogs are also accessible in a similar manner (Table 1) [2d]. Table 1. Preparation of organosilicon Lewis acids." Organosilicon Lewis acid

Representative method of preparationb

Ref.

Main purpose

Me3Si0SO2CF3(la)

A; 20 "C, 1 h (85 Yo)

5

Protection, Lewis acid

Et3SiOSOZCF3(lb)

B; 20 "C, 15 h (90 %)

12

Protection, Lewis acid

tBuMeZSiOSOzCF3(lc)

B; 60 "C, 10 h (80 Yo)

2b, 8

Protection, Lewis acid

iPrSiOS02CF3 (Id)

B; 22 "C, 16 h (97 Yo)

2b, 8

Protection, Lewis acid

tBuPhzSiOS02CF3 (le)

A; 70 "C, 0.5 h (73 %)

13

Protection

Me3SiOSOZC4Fg (2)

A; 0 "C, 15 min (89 Y )

6

Lewis acid

Me3SiOS02C8F17 (3)

A; 0 "C, 15 min (77 %)

5b

(Me3Si0)2S02(4)

B; reflux, 12 h (76 %)

14

Sulfonylation

Me3SiOSOZF (5)

A; -78 "C (ca 50 Y )

15

Lewis acid

Me3SiC104(6a)

C

10

Protection, deprotection, Lewis acid

Et3SiC10, (6b)

D; 0 "C to room temp. (92 YO)

10

Protection, Lewis acid

Ph3SiC104(6c)

C; (66 %)

16

Lewis acid

Me3SiN(SOzCF3)2 (7)

A; -196 to 22 "C (92 Yo)

9

Lewis acid

Me3SiN(S02F)2 (8)

C; 0 "C, 1 h (quant.)

17

Lewis acid

MesSiI

E

7,18

Protection, deprotection, Lewis acid

tBuMezSiI

F; (53 Yo)

18

Lewis acid

MesSiBr

F; (75

18,19

Protection, deprotection, Lewis acid

Oh)

See Ref. 2d. Method A, protodesilylation wth acid; Method B, reaction of silylchloride and acid; Method C, reaction of silylchloride and silver salt; Method D, reaction of silane and trytyl salt; Method E, reaction of disilane and halogen; Method F, reaction of selenosilane and halogen. a

Silicon (W)Lewis Acids

357

8.2.1 Trirnethylsilyl Triflate (la) [5c] To a solution of trifluoromethanesulfonic acid (1.5 g, 10 mmol) in dry dichloromethane (8 mL), allyltrimethylsilane (1.6 g, 14 mmol) is added dropwise with stirring. The reaction temperature is maintained between 15 and 20 "C for 1 h. The resulting mixture is transferred directly to a distillation apparatus and distillation under reduced pressure gives trimethylsilyl triflate as a colorless liquid (1.9 g, 85 YO),bp 5253 "C/31 Torr; 'H NMR (CDC13) 6 0.50 ppm.

8.2.2 Trimethylsilyl bis(Trifluoromethanesulfony1)imide (7) [9a] In an FEP reactor, HNTf2 (0.85 g) is reacted with a 3:l molar excess of Me3SiH. When the mixture is left to warm from -196 "C, an initial rapid reaction occurs near 22 "C. After 4 h and occasional agitation, the homogeneous mixture is cooled slowly to -196 "C. A quantitative amount of hydrogen is recovered, and the excess silane is pumped away at 10 "C, giving Me3SiNTf2(0.98 g, 92 YO)as a colorless liquid of low volatility. 19FNMR (CFC13) -77.47 (s) ppm; 'H NMR 0.57 (s) ppm; major m/e [Cl] 163 (Me3SiOH+), 147 (Tf"), 77 (?),73 (Me3Si+)with weak ions at 282 (TfiNHi) and 354 (M+).

8.2.3 Trimethylsilyl Perchlorate (6a) [lob] This is not commercially available is readily prepared by a silver perchlorate-chlorotrimethylsilane anion exchange. A solution of AgC104 is added to a solution of chlorotrimethylsilane in benzene under argon. Quantitative precipitation of AgCl is observed. The filtered pale yellow solution turns into a dark brown to black solution upon evaporation. Vacuum distillation of 1-2 mL portions of the remaining liquid yields trimethylsilylperchlorate as a colorless liquid. Caution, the title compound fumes on exposure to air, and decomposes explosively on ignition or upon heating!

8.2.4 Iodotrirnethylsilane [70] Several preparative methods have been described for iodotrimethylsilane. Of these the reaction of hexamethyldisilane with iodine looks cleanest. A mixture of hexamethyldisilane (0.3 g, 2 mmol) and iodine (0.5 g, 2 mmol) is heated at ca 65 "C in a 20-mL flask fitted with a reflux condenser; an exothermic reaction occurs and a homogeneous solution is formed. The mixture is then heated under reflux for 1.5 h. At this stage, hexamethyldisilane is converted quantitatively to iodotrimethylsilane (confirmed by NMR).

8.2.5 Trimethylsilyl tetrakis(Trifluoromethanesulfony1)borate [ll] Trifluoromethanesulfonic acid (531 pL, 6 mmol) is added to boron tribromide (distilled from A1 powder; 190 pL, 2 mmol) at 0 "C. After evolution of HBr has ceased the flask is evacuated for 1 h to give B(OTf)3 as a viscous yellow liquid. In a separate flask, a solution of l a is prepared by addition of trifluoromethanesulfonic acid (177 pL, 2 mmol) to a solution of allyltrimethylsilane (320 pL, 2 mmol) in dichloro-

358

Oishi

methane ( 5 mL), and the resulting mixture is left to stand for 10 min. Addition of this solution to the B(OTf)3 at 0 "C results in evolution of heat and formation of a pale yellow solution of Me3SiB(OTf)4 (0.4 M).

8.3 Reactions Promoted or Catalyzed by Silicon-Based Lewis Acids 8.3.1 Aldol-Type Reactions, Allylation and Related Reactions The Mukaiyama aldol reaction of carbonyl substrates with silyl enol ethers is the most widely accepted of Lewis acid-promoted reactions. Many Lewis acids for the reaction have been developed and used enantioselectively and diastereoselectively. In 1980, catalytic amounts of l a were found by Noyori et al. to effect aldol-type condensation between acetals and a variety of silyl enol ethers with high stereoselectivity [2c,20]. Unfortunately, l a has poor Lewis acidity for activation of aldehydes in Mukaiyama's original aldol reaction [21]. Hanaoka et al. showed the scope and limitation of ll-catalyzed Mukaiyama aldol reaction, by varying the alkyl groups on the silicon atom of silyl enol ethers [22]. Several efforts have been since been made to increase the reactivity and/or the Lewis acidity of silicon. One way to enhance the catalyst activity is to use an additional Lewis acid. Davis et al. described elegant work on a rate enhancing effect in aldol and allylation reactions [23]. Trialkylsilyl triflate or chloride was combined with B(OTf)3 to form complex 9 in situ and the "B NMR spectrum suggested a silylium ion-like species with a spherically symmetrical anion B(0Tf); (Sch. 1).Stereoselective construction of acyclic carbon skeletons is of central importance in this field; outstanding studies have been performed by Heathcock and collaborators [24]. In addition, high stereoselectivity in the catalytic aldol reaction of aldehyde 10 with silyl enol ether 11was also achieved by increasing the steric hindrance of alkyl groups on the silicon atoms. 'Pr3Si was chosen rather than other trialkylsilyl groups in the following aldol reactions. R3SiX

+

B(OTf)3

-

R3Si+[BX(OTf)3]-

X = OTf, CI

9

R3SiB(OTf)4 (5 mol%)

phycHo + APh OSiR3

10

11

CHzCIz -80 "C

R3Si0

*

0

Ph+Ph

R3SiO +

p

syn-12

R3Si= Me3Si Et3Si 'BuMe2Si 'Pr3Si

h

e

0 P

h

anti-12

44% ( 8 : 1 ) 60% ( 1 8 : 1 )

82% ( 25 : 1 ) 71% ( 9 7 1 )

Scheme 1

Yamamoto et al. recently reported that the exceptionally bulky organoaluminum reagents MAD and MABR, which had been developed for selective transformations and as Lewis acid-type receptors with molecular recognition capacity, seemed to have

Silicon (IV)Lewis Acids

359

a similar effect [25]. The feebly Lewis acidic Me3SiOS02Me and l a can be used as a super Lewis acid catalyst with an organoaluminum cocatalyst. This new system also enables cross aldol reactions between simple ketones. For instance, exposure of isopropyl methyl ketone 13 and silyl enol ether 14 to a catalytic amount of 1:l l a and MABR in dichloromethane then acidic work-up afforded the corresponding aldol 15 in high yield, whereas only a trace of the adduct was obtained without the use of any cocatalyst (Sch. 2).

13

14

-78 "C, 1.5h

catalyst:

15

la 1alMAD 1alMABR

1% 77% 91%

MAD (R=Me) MABR (R=Br) Scheme 2

Aldol-type condensation of silyl enol ethers with acetals under the influence of l a is rather familiar. Unlike the Mukaiyama aldol reaction, 1-5 mol o/' loading of l a is enough to complete the coupling reaction under mild conditions [20]. This transformation is applicable to the synthesis of a wide variety of P-alkoxy carbonyl substrates and has three characteristic features: (i)

condensation products are obtained in high yields with several different substrates; (ii) in reactions creating new chiral centers, high to moderate erythro selectivity is obtained irrespective of the double bond geometry of a silyl enol ether; and (iii) solely an acetal condensation adduct is obtained chemospecifically leaving an aldehyde intact when a 1:1 mixture of acetal and aldehyde is employed as the aldol acceptor. As expected from the extreme downfield shift of the silicon signal of 8 compared with that of l a in 29SiNMR, the trimethylsilyl imide analog has greater catalyst activity (Sch. 3) [16]. Significantly different yields were obtained after 1 min of the following reaction at -78 "C.

360

Oishi

c

OSiMe3

C&3CH(OMe)2

+

My.4

catalyst (5 rnol%) *

C6H13

CHzC12 -78 "C, 1 rnin catalyst:

la

27%

8

73%

Scheme 3

The silyl ketene acetals and silyl thioketene acetals are known to be much more nucleophilic than the silyl enol ethers of the ketones. 2-Trimethylsiloxyfuran is one of the unique, commercially available silicon nucleophiles which reacts readily with aldehydes regioselectively in the presence of Lewis acid leading to the formation of 8-hydroxy butenolides. These adducts have an attractive structure which is often encountered in natural products and they could become useful building blocks for the introduction of two contiguous stereogenic centers. Investigation of the Lewis acidpromoted reaction of the furan derivative with some aldehydes demonstrated how useful diastereoselectivity could be used to furnish either the threo or erythro adduct predominantly (Sch. 4) [26a]. Threo stereoselectivity can be exploited in the synthesis of muricatacin, a natural metabolite of the bioactive annonaceous acetogenins [26b]. Among Lewis acids tested in the reactions, other trialkylsilyl triflates and l a work well, giving rise to the highest diastereoselectivity and good chemical yields; the catalytic use of tetraammonium fluoride in THF results in the opposite, erythro, selectivity. Lewis acid

R-CHO

+

Q o s , ~ ~ ~o*.-

+

HO

HO threo

erythro

HO

(+)-muricatacin

Scheme 4

It is interesting to note recent mechanistic aspects of the catalytic Mukaiyama aldol reaction, although there might be few direct advantages in organic synthesis. Two groups attempted to determine the nature of the Lewis acidic species during the course of the reaction effected by catalytic use of some metal triflates (Sch. 5). Bosnich et al. came to two conclusions [27]: (i)

TrOTf employed as a catalyst is actually neither an initiator for the production of la nor a catalyst. TrOTf is, in fact, readily hydrolyzed by trace amounts of water in the system to leading of the formation of TfOH. Then, the acid reacts with the silyl enol ether to generate la, a true Lewis acid in the catalytic cycle.

361

Silicon (IV) Lewis Acids

(ii) With Cp2Ti(OTf)2l a is formed in the initial step of aldol addition. Subsequently, the catalytic cycle is performed by la. Labeling experiments performed by Carreira et at. showed that other metal triflates and the related Lewis acids, Yb(OTf)3, Sn(OTf)*, Zn(OTf)*, and LiC104 induced silicon group-transfer processes rather than not metal-catalyzed processes [28]. These observations confirm that 1 is a true Lewis acid catalyst, although the situation would be more complicated when Lewis bases trapping trialkylsilyl groups are contained in the system. TrOTf

+

H20

-

TrOH

0

Q+

OSiMe3

TrOH

+

HOTf

+

la

Metal-Catalyzed

-

-

MX,

R'CHO

XnM.O

+O,MXn

RiAH

+

x : i 2 [

+0,SiR3

R3Si0 MXn

Ri dOR2

+

t

R : u 0 R 2

0

X,.iMO R3SiX

+

R ' u O R 2

Silicon-Catalyzed R3Si,0 xRiuOR2

Scheme 5

+0,SiR3

I

-

R3SiO R3SiX +

0

RiuOR2

Aldol-type condensation of silyl ketene acetals with imines constitutes an efficient route to synthesis of p-lactams, which are of pharmaceutical importance because these components are seen in many naturally occurring antibiotics, for example penicillins, cephalosporins, monobactams, and thienamycin, etc. In 1987, the catalytic use of l a for this reaction was first reported by Guanti although there was one report by Pilli on the reaction of silyl enol ethers of ketones with imines (Sch. 6) [29,30], although only non-enolizable aromatic and conjugate imines bearing an N-aryl group were studied in the paper. In subsequent studies l a was compared with newly developed Lewis acid catalysts and was found to catalyze the aldol-type reaction of diverse substrates with good productivity [31]. Because diastereoselectivity in favor of the anti configuration is heavily dependent on the reactants and conditions employed, it is not easy to elucidate factors determining the stereochemical outcome.

362

Oishi

OSiMe3 Ph,fPh

+

P h a O M e

l a (1 Omol%)

P h - ~o ~

H20

CH2C12 *-65 "C, 15h

Ph,

NH 0

P h v O M e + Ph-OMe Ph Ph 85% (14 : 86)

EIZ = 36164 Scheme 6

Reaction of silyl enol ethers with alkyl N,N-dialkylaminomethyl ethers was investigated by Sakurai's group [32]. Iodotrimethylsilane, which was cleanly generated from hexamethyldisilane and iodine by their own method, is a most efficacious Lewis acid. The reaction is strongly affected by solvent and the structure of alkyl N,N-dialkylaminomethyl ether. Best results are obtained when n-butyl dimethylaminomethyl ether is used in acetonitrile. la, which can also be used as a Lewis acid in dichloromethane, gives less satisfactory results. The aminomethylation was further modified by Sekiya et al. to liberate a free amine (Sch. 7) [33]. Instead of the alkyl aminomethyl ethers, N,N-bis(trimethylsily1) methoxymethylamine was used. According to their observation, the N,N-disilyliminium salt is formed in the initial stage of the reaction by the cleavage of the methoxymethylamine with la, generating trimethylsilyl methyl ether. The salt then reacts with silyl ketene acetals to afford the N,N-bis(trimethylsily1)-Paminocarboxylic acid esters in high yield. Successive desilylation of the adduct is performed simply by heating under reflux in methanol to give the corresponding p-amino esters. The method was applied to the synthesis of a precursor of monobactam antibiotics.

R,gri;

l a (lmol%)

(Me3Si)2N,0Me

+

R2

.

MeOH *

CH~CI~ r.t.

H2N4

reflux 24h

0 M R' R2

e

Scheme 7

Reaction of allylic silanes and aldehydes or ketones in the presence of Lewis acids furnishes homoallylic alcohols that can be prepared enantioselectively and diastereoselectively; the reaction was first developed by Sakurai et al. [34]. Because, like the Mukaiyama aldolization, 1 is insufficient to catalyze the Sakurai allylation, a highly reactive catalyst system of Me3SiB(OTf)4 was again described by Davis's group [ll]. As can be seen from the following results, in the presence of very small amounts of the super Lewis acid, aromatic, aliphatic and sterically somewhat hindered aldehydes undergo the Sakurai reaction under the given reaction conditions (Sch. 8). After a brief reaction then the usual work-up, homoallylic alcohols are obtained in high yields, although occasionally accompanied by an unidentified byproduct.

Silicon (IV)Lewis Acids

Me$3B(OTf)4 (0.2-1 mOl%) 3e MiS, +. . .p RCHO

HCI *-

CHzCI2 r.t., 5-25 min R=

Ph CHzCH2Ph n-C4H9 C-C6H11

363

MeOH

R

80% 93% 80% 84%

Scheme 8

Although allylation of acetals can be effected by catalytic l a or iodotrimethylsilane [35], the reaction time can be substantially and consistently reduced for a range of condensations by replacement of triflate by the N(S02F)2or NTf2 anion (Sch. 9) [16,36].

catalyst: l a (1 mol%) 7 (5 mol%) 8 (5 mol%)

-60 - -45 OC, 18 h 81 Yo -78 "C, 45 min 91% -78 "C, 45 min 91%

Scheme 9

The corresponding allylated ethers are also readily obtainable in one step from parent aldehydes or ketones by the silyl modified Sakurai (SMS) reaction; the key step is formation of the heteroacetal by l a [37]. la-induced allylations of a-heteroatom-substituted acetals such as a-sulfenyl acetals and a-halo mixed acetals were examined [38]. The stereochemistry and mechanism of the reaction were also discussed. Unlike the titanium-mediated stereoselective reactions introduced by Reetz (chelation or non-chelation) [39], the high anti selectivities were explained in terms of an S N 2 reaction path via an acetal complex with l a coordinating to the alkoxy group antiperiplanar to the C-S bond (for the reaction of a-sulfenyl acetals), or by the Felkin-Anh model of the oxocarbenium ion (for the allylation of a-halo mixed acetals) (Sch. lo). Asymmetric allylation of carbonyl substrates and their derivatives is currently of particular interest in the synthesis of a wide range of optically active compounds, owing to the easy derivatization of the carbon-carbon double bond to a desired functional group. The strategy for reaching this goal can be classified into three approaches: (i) enantioselective allylation using chiral Lewis acid catalysis; (ii) diastereoselective addition to chiral acetals followed by removal of the chiral auxiliaries; and (iii) allylations of chiral allylic silanes.

364

Oishi

OMe g i RS

M

e +

la

e S i M e 3

*

OMe

+\+\

CH&N

RS

RS

R = Me

57% (75 : 25)

35% (97: 3)

But

Me0 Rs+:e i H

l a (20rnol%)

OSiBu'Mep n-C8Ht7+0Me

+

I M+

/mSiMe3

+

OMe

CH&Iz -78 "C

X

OMe

+ n-CaH17+\

n-CeH17-\

X

X

0 X = Br I

41% (70:30) 89% (96:4)

Nu

Scheme 10

So far, the first approach, i.e. the enantioselective Sakurai reaction using chiral Lewis acid catalysts has been accomplished by Yamamoto's chiral (acy1oxy)borane (CAB) catalysis [40] and others that are not included in this chapter. Progress in developing chiral silicon Lewis acids for the reaction is now awaited but a recent publication by Jorgensen and Helmchen on a chiral silylium ion appears in a later section on ring construction [41]. Thus, other two approaches are shown herein. Although the second type using other traditional Lewis acids, for example BF3. OEt, and TiC14, has been described by several groups [42], there are few examples employing l a and other silicon Lewis acids. Mark6 and coworker extended their SMS reaction to the diastereoselective version [37]. According to one scheme illustrated in that paper, trimethylsilyl ethers of chiral 1-arylethanol were examined to afford diastereoselectivity in an allylation of allyltrimethylsilane and cyclohexanecarboaldehyde (Sch. 11). A diastereomeric ratio of up to 1O:l was achieved at lower temperatures.

Ar=

C6H5 2,6-CI&H3

68% ( 2 : 1 ) 67% ( 8 I )

54% ( 1 0 : 1 ) [ o o c ]

Scheme 11

Silicon (IV) Lewis Acids

365

Tietze et al. emphasized the usefulness of chiral trimethylsilyl ethers of readily accessible amino alcohol derivatives in allylation of aldehydes and ketones [43]. As a consequence, careful design of the norpseudoephedrine derivatives and proper choice of silicon Lewis acids have led to the convergent preparation of enantiomerically enriched secondary and tertiary homoallylic alcohols in high yields (Sch. 12) [43a]. It should be noted that the configuration of the newly formed stereogenic center of the secondary homoallylic alcohols is the opposite of that in the allylation of ketones [43c]. They also described in detail mechanistic studies of the above allylation reaction by use of 13C and 19FNMR.

82%, ds = 89 : 11

Scheme 12

The final approach was elegantly presented by Panek [44]. Several optically active (E)-crotylsilanes are available via stereoselective Ireland-Claisen rearrangement of enantiomerically pure vinylsilanes. Addition of the chiral crotylsilanes to acetals or to mixtures of aldehyde and trimethylsilyl methyl ether is effected by l a to afford homoallylic ethers in exceedingly high diastereo- and enantioselectivity (Sch. 13). Occasionally a stoichiometric amount of l a is required for allylation of aliphatic acetals, preserving the excellent level of asymmetric induction. The synthesis of (+)-macbecin I involving triple use of the strategy underscores the utility of the la-catalyzed asymmetric allylation [44c]. Solid-supported synthesis has rapidly emerged as an important strategy in synthetic organic chemistry. Solid-phase methodology is aimed at the direct synthesis of libraries of molecularly diverse compounds for biological evaluation in lead discovery. The asymmetric addition of polymer-supported chiral crotylsilanes to acetals and allylation of polymer-bound acetals linked through an ester with the chiral crotylsilanes has been investigated [44d]; l a can be employed in these crotylation reactions and results in the formation of polymer-supported homoallylic esters with diastereoselectivity similar to that of solution-phase reactions.

366

Oishi

l a (0.4-2 equiv)

OMe RAOMe

-4:O2M SiMe2Ph e

+

CHzCl2, -78 "C *

OMe

OMe

R+4C02Me

synlanti >30 : 1, >94%de

0

(+)-macbecin I

Scheme 13

8.3.2 Intramolecular Aldol-Type Reaction and Allylation Intramolecular carbon-carbon bond formation is an effective means of creating a variety of functionalized carbocyclic and heterocyclic ring systems. Apparently, proper choice of Lewis acid promoters and conditions enables stereoselective ring construction by use of l a and other Lewis acids. Bis(trimethylsily1) enol ethers react with a variety of 1,4-dicarbonyl substrates in the presence of a Lewis acid promoter to afford [3 + 41 annulation products [45]. The use of Tic&, employed in the initial studies, poses difficulties and complete regiocontrol in the cyclization is often lacking. Among many Lewis acids tested, surprisingly, l a promotes the [3 + 41 annulation with high regio- and diastereoselectivity (Sch. 14).

0

Me

0

76% (1 : >35) Scheme 14

Silicon (ZV) Lewis Acids

367

Other intramolecular aldol reactions have been reported. In the first total synthesis Shibasaki et al. of A9('2)-capnellene-8P,10a-dioland A9(12)-capnellene-3~,8~,10a-triol reported that excess l a with Et3N effects the cyclization of intermediate 16 giving 17 in 42 % yield (Sch. 15), although a wide variety of different acidic and basic reagents meet with failure [46].

O2Et

1a (3 equiv) Et3N (2 equiv) *

benzene reflux 42%

16

17

Scheme 15

la-induced selective cyclizations involving an intramolecular ene-type reaction or the Sakurai reaction have been intensively studied by Tietze and coworkers [47]. Alkenyl imines undergo ene-type cyclization in the presence of various Lewis acids; l a affords high yields and selectivity (Sch. 16).

1a / 'BuOMe FeCI3/ AI2O3/ CH2ClB FeCI3/ A1203 / toluene

96% (1911) 71% (1 1 : 1) 78% (7.1 : 1)

Scheme 16

Fluoride- or Lewis acid-induced cyclization of alkylidene 1,3-dioxo compounds with an allylic silane moiety has also been studied. When l a was used very high trans preference was observed. A stereoselective tandem Sakurai-carbonyl-ene reaction for the synthesis of steroid derivatives has been reported [48]. When EtAlC12 and l a were employed in this cyclization, stereochemical control was different. The cyclization product obtained with l a is only 19 (Sch. 17), even though the starting material contained all four geometrical isomers; use of EtAlC12 resulted in a mixture of two different stereoisomers in lower yield.

l a (1.1 equiv) 0' SiMe3

18 Scheme 17

CH2C12 -78 "C,2h -30 "C, 2h 52%

19

368

Oishi

Another example of a similar intramolecular ene-reaction was reported by Wartski et al. [49]. They chose lactones bearing a trans vicinal 3-aroyl, 2-ally1 moiety and examined the cyclization with a variety of Lewis acids. One equivalent of l a gives the corresponding bicyclic product 21 with endo olefin selectively in high yield (Sch. 18). Metal chlorides such as A1C13, TiC14 and SnC14,however, afford the chlorinated cyclohexanol22 only.

80-85%

22

21

20

90% ( 9 : 1)

Scheme 18

As mentioned above, acetals are much more reactive acceptors in la-catalyzed allylation than aldehydes or ketones. Intramolecular allylation has been examined for the synthesis of highly functionalized piperidine derivatives [50]. Catalytic use of l a effects cyclization of nitrogen-containing acetal 23 bearing an allylic silane to give piperidine 24 with moderate selectivity (Sch. 19).

+

l a (lOmol%) *

Et02C

OMe

CH~C~Z -20 "C, 12h

23

Me

N C02Et 24

&Me Me

N C02Et

76% (85 : 15)

Scheme 19

8.3.3 Ring Construction Among many Lewis acid-promoted cycloadditions Diels-Alder reactions have been most widely investigated to date. Simple silicon Lewis acids such as l a do not, unfortunately, catalyze the standard Diels-Alder reaction of acrylate and cyclopentadiene. Accordingly, silicon Lewis acids are generally not very suitable for the related cycloaddition reaction. Few reports on silicon Lewis acid-promoted cycloaddition reactions are thus shown herein. In 1988, Gassman et al. described ionic Diels-Alder addition of vinyl ortho ethyl ester 25 to a series of 1,3-dienes in the presence of l a (Sch. 20) [51]. This concept came from their previous report that allylic cations are powerful Diels-Alder dienophiles toward 13-dienes. When an attempt was made to clarify the nature of the intermediate 27 by trapping with trimethylsilyl cyanide, 24 % 28 was accompanied by 25 % adduct 26.

Silicon (W)Lewis Acids

la *

CH2C12 0 "C, 0.3h

+

&COzEt

C02Et 26 62% ( 6 : 1)

25

+

4

369

C(OEt)2 28

27

Y(W2 CN

Scheme 20

lc-catalyzed Diels-Alder reaction between N,N-dimethylacrylamide and activated cyclic dienes was reported by Ghosez. Non-catalyzed thermal reaction or use of Eu(fod)3 resulted in exo-preference, whereas complete stereochemical divergence was observed with l c under mild conditions (Sch. 21). Lewisacid

'BuMeZSiO

H200r

0

benzene

I

OSiBu'Me2

'BuMe2SiO

none / 170 "C, 6 days Eu(fod), (IOmol%) / reflux, 6 days l c (IOmol%) / 20 "C, 0.5h

OSiBu'Mez

73% (30 170) 82% (4 : 96) 87% (92 : 8)

Scheme 21

Compound 7 was evaluated as a Diels-Alder catalyst instead of silyl triflate (Sch. 22). As expected from 29Si NMR measurement, substantial rate acceleration was observed in the Diels-Alder reaction of methyl acrylate with a variety of dienes.

0

Lewis acid (1Omol%)

+

IfozMe

toluene r.t., 1h

C02Me

la 7

0% 92% (49 : 1)

Scheme 22

Diels-Alder reaction of l c with cationic species formed from chromones or pyrones was reported by Akiba et al. (Sch. 23) [53]. The cationic intermediates react with a range of 1,3-dienes to furnish the corresponding cycloadducts in moderate to good yields.

370

Oishi

$uMePSiO

lc

*

80”C, l h

chromone

-6 H ?

Ph

lc 2,6-lutidine CH2C12,reflux

0, TfO -

H

OSiBu’Me2

96%

?SiBu’Me2 OSiBu’Me2

pyrone 60%

Scheme 23

Asymmetric Diels-Alder reaction of acryloyl oxazolidinone and 1,3-cyclohexadiene using the chiral silyl cationic catalyst (S)-29 (Sch. 24, TPFPB = tetrakis(pentafluoropheny1)borate) was recently reported by JGrgensen and Helmchen [41]. This work was based on two concepts: (i)

to synthesize a chiral organosilicon compound anchored in C2-symmetric binaphthyl backbone by creating an asymmetric environment around a silicon center; and (ii) to adapt the chemistry of silylium ion to Lewis acid-catalyzed reaction. Although enantioselectivity was low, this catalyst system might have profound potential.

c+

dNiO

(S)-29 (1 Omol%)

u

CD&N -40 “C, 1h

*

3

N

X

Lo 95% (>95% endo, 1O%ee)

%@ \

Si-Me

0

TPFPB \

(S)-29

Scheme 24

l a or l c was found by several groups to promote hetero Diels-Alder reactions. In the reaction of 4-ethoxy-1,2-dioxo-3-butenyl oxazolidinone 30 with (2)-1-acetoxy-2ethoxyethene 31 endo- and em-selective formation of the adduct are observed, depending on the Lewis acid used (Sch. 25). la, which gives endo adduct 32 as the major product, is slightly less effective than MezAlCl [54].

371

Silicon (IV)Lewis Acids 0

0

OEt l a (1.5 equiv) t

OAc

AcO

CHzC12

OEt

-78 "C, 24h 30

AcO"' OEt

endo 32

31

0 ex0 33

77% (7.1 : 1)

Scheme 25

The la-promoted imino Diels-Alder reaction is highly susceptible to the Lewis acid employed and to the structure of substrates. N-Phenyl aromatic aldimine 34 readily cyclizes with the silyl enol ether of 35 under the influence of 10 mol % l c to give ex0 adduct 36 exclusively (Sch. 26), whereas up to 98 % endo selectivity is observed when A1Cl3 is used at 20 "C [55a].

lc

A

(1Omol%)

?' r H

p

+

7'

A r , , H , , p

t

CH2C12 20 "C, 1.5h

Ar

35

34

OSiMe3

OSiMe3

ex0 36

endo 37

84% (>98: 2)

Ar = C6H4(pOMe)

Scheme 26

N-Benzyl aliphatic aldimines are much less reactive to 2-siloxy-1,3-dienes even when an equimolar amount of l c is used (Sch. 27). Diastereoselectivity at 2,6-substituents of piperidine is increased by the bulkiness of the aldimine [55b]. l a (1 equiv) ~

'P r

'

I'

~

~

2

+

' P r yH2Ph y ,

' P r yH2Ph y h

OSiMe3 ' ~ *

+

A

P

h

CH2C12 0 "C-r.t., 2 days

OSiMe3

OSiMe3

65% (98:2) Scheme 27

N-(2,3-epoxypropyliden)cyclohexylamine-N-oxide reacts with 1 equiv. l c at low temperatures to form a nitrosonium ion which undergoes a new type of cyclization reaction on treatment with olefins then KCN, leading to cis-fused cycloadducts in moderate to high yield (Sch. 28) [56]. Further basic and acidic treatment furnishes amethylidene-y -1actones.

372

Oishi

1

L

\OSiBu’Mep

1

n

\OSiBu’Me2 88%

Scheme 28

Me3SiI and l a can be used as Lewis acids in the Nazarov cyclization (Sch. 29) [57]. The success of the reaction depends on the substrates and on the reaction conditions.

C O ~ E ~Me3Sil (2 equiv) CCI4, r.t., 24h 48%

Scheme 29

As an example of a rare cyclization, exposure of the sulfenic acid trimethylsilyl ester 38 to l a in dichloromethane yields the diacetoxycephalosporin 39 in 58 % yield with elimination of a silanol group (Sch. 30) [2a]. 0

0

H

?SiMe3

l a (1.5 equiv) CH2C12 15”C, 12h

38

58%

*

0 0 C02Me

39

Scheme 30

Ring contraction and ring expansion are important in the construction of new ring systems. 3-Trimethylstannylcyclohexanonescause ring contraction in the presence of a Lewis acid leading to 2-methylcyclopentanones [58]. The best results are obtained with la; other Lewis acids give a mixture of the desired product and destannylated cyclohexanone (Sch. 31). The key step in the proposed mechanism is Lewis acid-promoted intramolecular cyclopropyl ring formation. This transformation was applied to the synthesis of (+)-@uparenone [58b].

Silicon (IV)Lewis Acids

373

Lewis acid \/

&SnMe3 49% (41 : 59) 40% (32 : 68) 52% (0 : 100)

TiCI4 (-78 "C, 3h) BF3 .0Et2 (r.t., 12h) l a (-78 "C, 3h) -

Scheme 31

Cyclopropyl groups play a crucial role in ring expansion because of the strain present. Cyclopropanated sugar 40 undergoes ring opening with catalytic la, providing ring expanded product 41 (Sch. 32) [59].

P

'BuMe2Si0

-

l a (10rnol%)

AcO'"' AcO

CH3CN

ACO'"'

78%

40

41

Scheme 32

Cyclization of silylated vinylcyclopropanol 42 upon treatment of la at -78 "C afforded bicyclo[4.4.0]decane 43 (Sch. 33) [60]. This cyclization protocol provides a new route to six-, seven- and eight-membered ring systems attached to a spirobutanone.

OSiMe3

1a (1Omol%)

CH2C12 -78 42

Scheme 33

oc

& OMe +

H

OMe 43

H 91% ( 7 : 1)

374

Oishi

8.3.4 Isomerization and rearrangement In addition to the formation of silyl enol ethers, isomerization of epoxides to allylic alcohols is another highly typical transformation performed by combination of a silicon Lewis acid with a tertiary amine. Reaction with l a was examined, and its scope and limitation reported, by Noyori [61]. Epoxide 44 can be successfully converted into the corresponding ally1 silyl ether 45 (Sch. 34). l a (1 equiv) DBU *

44

benzene 22 "C, 20h

OSiMe3

45

Scheme 34

Oxiranes of terminal monosubstituted and internal disubstituted olefins do not undergo the isomerization under standard conditions, but give aldehydes at elevated temperature. For the special substrates described in Sch. 35, different modes of reaction originated from intermediary carbocationic species, involve neighboring functional group participation, oxidation, etc. An improvement employing other silicon Lewis acids, for example Me3SiI and Me3SiBr, was developed by Kraus, Detty, and Sakurai [17,19f,62].

OSiMe3

Scheme 35

Acetals are also isomerized by a similar Lewis acid-base system [63]. Interestingly, according to Rychnovsky's work, selective protection of secondary alcohols is feasible by isomerization of asymmetric cyclic acetal 46 then cyclopropanation (47) (Sch. 36) [64].

Silicon (IV) Lewis Acids

46

47

375

72%

Scheme 36

Silicon Lewis acid-induced isomerization of a functionalized cyclopropane ring has been reported; transicis ratios >98:2 were obtained (Sch. 37) [65].

&

Me3Si0

C02Me

H R

cidtrans

-

10 190 35 165

cat. 2 or Me3Sil *

r.t. R = H, D, Me, n-Bu, allyl, benzyl

Me3Si0 H C02Me 67-94% ( ~ 9 8 % trans)

Scheme 37

Since introduction of the Ireland-Claisen rearrangement in 1972, the Ireland variant has become increasingly popular in organic synthesis [66]. Although excess l c with appropriate base is often employed as selective silylating agent, the role of residual trialkylsilyl triflate and base has not been detailed. Illustrated here are some examples of silyl triflate-mediated rearrangement which can be conducted under milder conditions. Nakai et al. described silyl triflate-mediated Claisen rearrangement of geometrically defined allylic esters (Sch. 38) [67]. With increasing steric hindrance of both silyl groups and tertiary amine, the syn-major rearrangement product (49) is obtained from (E)-48 whereas (2)-48 results in anti selectivity. NMR monitoring indicated the occurrence of silyl triflate-promoted (Z)-enolate formation from the C-silylated ester produced early in the reaction. This selective enolate formation is in good agreement with the stereochemistry of the products. When, moreover, enantiomerically enriched allylic ester 51 (90 %ee) was treated with l c and dicyclohexylmethylamine the acid 52, in 86 % enantiomeric excess (ee) was obtained, implying relatively higher asymmetric transmission than the anionic Ireland variant.

376

Oishi

lc (c-Hex)2NMe

+ & \CO2H

H."c+\ ether, 25 "C

OT48

49

50 69% (92 : 8) 62% (4 : 96)

(q-48 (4-48

lc

O

P 0

ether, 25 "C

51

52

66%, >9O%E, 86Yoee

90%ee

Scheme 38

[2,3] Wittig rearrangement by means of a la/Et,N system was also studied by this group (Sch. 39) [68]. The rearrangement of preformed silyl ketene acetal with ( E ) allylic ether can be effected by catalytic l a to give erythro selectivity. The silyl triflatemediated amino-[2,3] Wittig rearrangement also proceeds under similar conditions, whereas the corresponding lithium amino-enolate does not undergo the sigmatropic rearrangement [68b]. l a (1.2 equiv) Et3N (1.1 equiv) *

0

'1C02Pr'.

4

CH2CI2,25%

CO2Pri + &CO*Pr' \

OH

OH

86% (95 5)

l a (5 equiv) Et3N (4 equiv)

+ &C02Me

*M e, , ,+

MeN)

C02Me

CH2C12, 25 "C

NHMe

NHMe

69% (81 : 19)

Scheme 39

The non-aldol aldol process is an attractive strategy for obtaining each enantio- and diastereoisomeric aldol, because of the facile availability of the starting epoxide enantiomers by Sharpless asymmetric epoxidation of allylic alcohols. Some Lewis acids, and BF3.Et20, are effective [69]. Silicon-based catalysts (ca 5 mol %) catalyze the transformation affording high yields [70]. Rearrangement product 54, obtained from 53, is a key intermediate in the chiral total synthesis of isoaveanaciolide (Sch. 40) [69c].

Silicon (W)Lewis Acids

3

Lewis acid

e ,

Me3Si

pH 7 buffer

C8H17

BnO

*

OSiMe3

377

BnO*C8H17 OH 0

CHZC~Z

54

53 Ti& (3 equiv) l a (0.05 equiv) Me3Sil (0.05 equiv) Me3Sil (0.02 equiv) MeaSiBr (0.05 equiv)

90% 92% 100% 98% 93%

L

9-~ . .

OQJ''.C8H17 isoaveanaciolide

Scheme 40

A similar type of rearrangement was reported by Jung [71]. The rearrangement proceeds via in situ silylation and Lewis acid-catalyzed selective hydride migration. The aldehyde function was further elongated in three sequential steps: Horner-Wadsworth-Emmons olefination and ester reduction followed by Sharpless epoxidation to furnish 5-siloxy 2,3-epoxy-l-alkanol 57,which was again treated with lb-DBMP, giving rise not to the expected terminal aldehyde but to cyclization product 58 in a high yield; the tetrahydrofuranose structure of 58 is useful in the synthesis of many natural products (Sch. 41). l c (1.3 equiv) 'PrzNEt (1.35 equiv) t

55

95%ee

molecular sieves -42 "C

'BuMe2Si0 Pr q

56

78%

lb

Et3Si0

DBMP Pr w O S i E t 3

OSiEt3 t

91% 57

Scheme 41

H

58

378

Oishi

8.3.5 Glycosidation The increasing demand for synthesis of precisely designed oligosaccharides and natural and unnatural nucleosides, and their analogs, has resulted in increasing interest in glycoside synthesis. Lewis acids have become attractive tools for constructing glycosyl bonds with high selectivity and in high yield. In general, the Lewis acid-promoted glycosidation reaction is profoundly affected by the structures of glycosyl donor and acceptor, the nature of the Lewis acid, and the reaction conditions. Silicon Lewis acids have also been examined as Lewis acid promoters. Some representative examples are summarized herein. N-Glycosidation of protected sugars and silylated bases, known as the Hilber-Johnson reaction, occurs in the presence of Friedel-Crafts Lewis acid catalysts such as SnCI4, but work-up is often complicated by the formation of emulsions and colloids. The organosilicon promoters la, 6a and 2 introduced by Vorbiiggen et al. for nucleoside synthesis often result in simple and clean reactions and high yields [72]. Although effective glycosidation can often be achieved by use of catalytic amounts of 1 or 6a, because of o-complexation of a Lewis acidic silicon center and a heteroatom of the base, a small excess of the silicon Lewis acid is usually employed to reduce reaction times. In contrast, Me3SiC1 and 4 do not behave as activators. In the glycosidation of more basic silylated pyrimidine bases, e.g. 60a and 60b, tuning of Lewis acidity is very important (Sch. 42). Likewise, pyranose 62 when exposed to 1 or 2, reacts with 63 to give a high yield of nucleoside 64 (Sch. 43). To furnish /3-2-deoxyribonucleosideswith high selectivity, glycosyl donors modified with 0-2-(methylsulfinyl)ethyl group at C-3 were examined [73].

24 "C

59

60a R = O M e 60b R = N n O

la

u

SnCI4

BzO

OBz

61a

61b

89% 53%

95% 39%

~~

Scheme 42

L

CICH~CHPCI 62

Scheme 43

63

reflux, 2.5h 92%

OAc 64

Silicon (IV)Lewis Acids

379

Except for silylated pyrimidine and purine bases, silylated imidazoles and trimethylsilylazide undergo similar glycosidation in the presence of la, leading to a variety of nucleoside precursors or analogs [74]. As first reported by Isono, l a and 6a are also effective Lewis acids in the transglycosidation of pyrimidine 65 to afford adenine nucleoside 67 (Sch. 44) [75]. NHAc

NHBz

6a CH3CN-

65

67

66

Scheme 44

P-Glycosidation of 1-siloxy glycolyl donors and aldehyde acetals in the presence of l a was achieved by Tietze in 1981 [76]. The use of glycosyl donor 68 of stereochemically defined starting silyl ethers and extremely mild conditions provided the corresponding P-glycoside 70 in high yield (Sch. 45). The procedure has been applied to the stereoselective synthesis of iridoid glycosides [76c]. OAc

-

OAc

cat.1a

AcO&OSiMe3

+

BnCH(OMe)2

OAc

AcO&O OAc

CH2C12

68

69

-78oc

70

YBn OMe

Scheme 45

Ogawa et al. found that a range of glycosyl acceptors, for example alcohols and stannyl ethers, can be used for 0-glycosidation with protected pyranoses [77]. This method, employing l a as Lewis acid in the presence of acid captors, e.g. powdered 4-A molecular sieves or 1,1,3,3-tetramethylurea,has been shown to overcome a drawback of classical Konigs-Knorr glycosidation- the occasional need to use explosive or toxic reagents and sometimes very drastic reaction conditions (Sch. 46). Anthracycline synthesis by this method was reported by Terashima et al. [78]. AcO O , Ac &O-OAc OAc AcO AcO

O , Ac

la MS 4a OAc

*

CICH2CH2CI 20 "C, 3h

Scheme 46

380

Oishi

0-glycosidation between 0-silylated glycosyl acceptors and several 1-substituted sugars, glycopyranosyl or furanosyl silyl ethers [79a], fluorides [SO], phosphates [Sl], and trichloroacetimidates [82a] has been examined to develop other efficient and stereoselective procedures catalyzed by silicon Lewis acids. The trichloroacetimidate glycosyl donors are fairly reliable and were used for the synthesis of ganglioside GD3 by Ogawa (Fig. 1)[82b].

H@

C02H I

OH

AcHN OH

ganglioside CD3 Figure 1

Many biologically active C-glycosides, for example aryl C-glycoside antibiotics, have been found in nature [83]. Toshima et al. examined silicon Lewis acids and combined use of l a and AgC104 in C-glycosidation of unprotected sugars with phenol and naphthol derivatives [84]. Their strategy for finding practical and highly stereoselective C-glycosidation methods involved suppressing self-coupling of the glycosyl donor and deactivation of promoters and was based on creating a reaction system in which cleavage of the 0-glycoside bond is followed by formation of the C-glycoside bond. As an example, a mixture of unprotected 2-deoxy sugar 71 and naphthol 72 when treated with 20 mol YO la-AgC104 under given reaction conditions, produces aryl C-glycoside 73 in high yield and with complete 0-selectivity (Sch. 47).

la-AgC104 (20mol%)

+ HHOO

k 71

O

H

*

\

HO

CHzC12

72

25 "C,1 h

OH

73 92?'0,a/P=I :>99

Scheme 47

8.3.6 Reduction and Oxidation la-catalyzed reduction of acetals and the Baeyer-Villiger type oxidation were both developed by Noyori et al. [85a,S6]. Under standard conditions ketones are reduced by trialkylsilanes in the presence of l a (1 mol YO). Because acetal formation by reac-

Silicon (ZV)Lewis Acids

381

tion of the ketone with the silylated alcohol produced occurs before hydride transfer from the silane to the ketone carbonyl, giving rise to dimeric ethers, a mixture of acetal and trialkylsilane treated with l a under mild conditions produces the reduction product in high yield (Sch. 48).

4

Me3SiH

+

caf'la

O'OQ 86%

28 "C, 13h

Scheme 48

An improved procedure via in situ preparation of acetals was used for stcreoselective synthesis of a C/D ring synthon for 20-epi-22-oxavitamin D3 (Sch. 49) [85b]. l a (1 equiv) Et3SiH (1 equiv) CH2C12 -78--25 "C

'BuMe2Si0

'BuMe2Si0

Scheme 49

The Baeyer-Villiger oxidation of ketones with bis(trimethylsily1)peroxide 74 is effected by use of catalytic amounts of l a [86]. In particular, cyclic ketones are readily converted to the corresponding lactones in good yields although the attempted oxidation of alkyl phenyl ketones failed. This present reaction is also chemo- and regio75 upon exposure to 74 selectively useful. For instance, bicyclo[3.2.0]hept-2-en-6-one and 10 mol % of l a leads exclusively to prostaglandin intermediate 76 in 75 % yield (Sch. 50). l a (10rnol%) Me3SiOOSiMe3 74

+

7s

CH2C12 -40--35 "C, 4.5h

76

75%

Scheme 50

This indicates that under these reaction conditions the carbon-carbon double bond is not affected and oxygen transfer occurs at a more substituted carbon-carbonyl bond.

382

Oishi

8.4 Reactions via Hypervalent Silicon Species The first observation of penta- and hexacoordinate silicon compounds was reported at the beginning of the 19th century by Gay-Lussac [87] and Davy [88]. Subsequent investigation of hypercoordination in silicon compounds stimulated widespread use of nucleophilic activation and catalysis in the application of organosilicon compounds as reactive species in organic synthesis. Synthetic application for silicon-fluorine bond formation can be found in several reviews over the last two decades, and this section focuses on recent advances in the use of hypervalent organosilicon compounds in selective organic synthesis, in particular, selective carbon-carbon bond formation [89]. The Lewis acidic character of reactive pentacoordinate silicon compounds has been unequivocally confirmed by Corriu, Sakurai and Hosomi [90]. Allylsilicates prepared from allylsilanes and catechol can undergo allylation reaction with aldehydes in the absence of Lewis acid promoter (Sch. 51).

Scheme 51

The silicon-carbon bonds within the anionic species are activated by KF, NaOMe, CsF or by heating. The reaction between geometrically defined crotylsilicates and benzaldehyde is completely stereoselective (Sch. 52).

solvent PhCHO

+

.

reflux threo

X = Et3NH or Li

(HZ=9 : 1 ) (€/Z= 2 :8 )

erythro

82-88% (9 : 1) 91% (2 18)

Scheme 52

The role of the catecholate group and fluoride is to delocalize negative charge and increase the Lewis acidity of the silicon center, which coordinates a carbonyl oxygen to form a hexacoordinate silicate. The six-membered cyclic transition state in the chair conformation is consistent with high threo and erythro selectivity similar to that of ally1 boronates [91]. It is interesting to see the structure-reactivity and structureselectivity correlation shown in Sch. 53 [92].

Silicon (W)Lewis Acids

Lewis acidity Steric hindrance Reactivity Selectivity

high small high low

383

*

low large no reaction no reaction

*

* *

low high

Scheme 53

There might also be a critical borderline between allyltrifluorosilicate selectivity and lack of selectivity, i.e. CsF-mediated reaction of allyltrifluorosilane [93] proceeds stereoselectively whereas no selectivity is observed with tetrabutylammonium fluoride because of the generation of the allylic anion-like species [94]. Reaction of functionalized ketones such as a-hydroxy ketones or 1,3-ketones with allyltrifluorosilane in the presence of Et3N has also been investigated [95]. Although catecholate does not play a key role in the pentacoordination of silicon, chelating hexacoordinate intermediates are formed to give allylation products with high yields and selectivity (Sch. 54).

-4

OH

Et3N

L

O

H

v e S i F 3

r.t., 15h

EIZ=97:3

83% syn /anti = 97 : 3

-

+

Et3NH

Scheme 54

Asymmetric allylation using optically active allylic siliconates has been reported [96]. The allylic siliconates were prepared by asymmetric hydrosilylation of 1,3-dienes and’HSiC13catalyzed by a chiral palladium catalyst followed by ethanolysis. Complete asymmetric induction of allylic siliconates to homoallylalcohols was accomplished (Sch. 55).

384

Oishi

PhCHO Ph\(V/-ph

aoH

+

Ph&ph

OH

50%ee

OH

OSi(OEt)3 *P -h

11%ee

Et3N

OH

51%ee

50%ee 27% (90 : 10)

+

, >hP

PhCHO

aoH

P & h -

Ph

-

Et3N

OH

OH

OH

11%ee

11%ee 77% (86 : 14)

Scheme 55

Pentacoordinate silicon, in the form of allyltrichlorosilane, in the presence of DMF or HMPA, also undergoes allylation with aldehyde [97,98]. The Lewis base-promoted approach has the merit of operational convenience. Stereoselective formation of allylic trichlorosilanes is achieved by copper-catalyzed coupling of allylic chloride and trichlorosilane or by palladium-catalyzed hydrosilylation of 1,3-dienes (Sch. 56) [99]. DMF or HMPA

/45sic13

+

PhCHO

0 "C-r.t.

v b c l

Ph

cat. CuCl

+ HSiCI3

\/bSic'3

Et3N

76% ( E / Z= 99 : 1)

84% ( E / Z = l ~ 9 9 ) Scheme 56

The latter reaction was applied to asymmetric allylation with optically active allylic siliconates (Sch. 57) [loo]. Regioselective preparation of both propargylic and allenic alcohols was achieved by Kobayashi [loll. The high regioselectivities are ascribed to the selective formation of propargylic and allenic trichlorosilanes (77 and 78) by means of CuC1-'Pr2NEt and Ni[CH3C(0)CHC(O)OEt]2-pmp systems (Sch. 58).

385

Silicon (IV)Lewis Acids

Pd-(R)-MOP-phen (0.1rnol%) HSiC13 20 "C, 5days

PhCHo

fisic13

w

~

d

P

h

DMF, 0 "C

99%

92%, 8O%ee

(4-MOP-phen PPh3

Scheme 57

\.LPh \

aorb

*

+

79

DMF, 0 "C

//

.@sici3 78

80 77 I 78

a: cat CuCl I iPraNEtpI 2 3 "C b: cat. NiL2/ prnp 166 "C

15 : 1 <1 : >30

79 I 8 0

71% (>30 : 4) 80% (cl : 230)

(LH = CH3C(O)CHzC(O)OEt) prnp = 1,2,2,6,6-pentarnethyIpiperidine

Scheme 58

Chiral Lewis bases, 81,82, and 83 modified from HMPA and biquinoline dioxide were developed by several groups for a new type of enantioselective allylation (Sch. 59) [102]. Aromatic and conjugate aldehydes react with allyltrichlorosilane with moderate to good ee values under mild conditions but for aliphatic aldehydes reactivity and selectivity are poor.

386

Oishi

chiral Lewis base PhCHO

+

cl3siCH2C12 -78 "C,6h

81 (1 equiv)

Ph

(S)-83(0.1 equiv)

82 (1 equiv)

'Pr2NEt (5 equiv) Denmark 81Yo,6O%ee (R)

lseki 84%, 85%ee (S)

Nakajima 85%, 88%ee (R)

Scheme 59

Denmark further applied this concept of chiral diamine-derived phosphoramide bases to catalytic diastereo- and enantioselective aldol reactions (Sch. 60) [lo31 and enantioselective ring opening of epoxides (Sch. 61) [104]. For instance, catalytic 84 effectively promotes aldol coupling of aldehydes and enoxytrichlorosilane at -78 "C with predominant formation of anti or syn aldols from ( E ) - or (2)-enolates, respectively.

-78 "C Ph.,,

Me NO ,.

'$0

Ph

Me

94% anti/syn = >49 : 1 95%ee (ant4

(S,S)-84

Scheme 60

The opposite diastereoselectivity is observed in the absence of Lewis bases. This clear switch of diastereoselectivity is rationalized by invoking a chair-like transition state in the hexacoordinate siliconate and a boat-like transition structure in the pentacoordinate siliconate.

Silicon (ZV)Lewis Acids

(R)-85 (1 Omol%)

GI *

Ph

CHpCl2 -78 "C, 3h

387

Ph+Ph OH 94%, 87%ee

Scheme 61

Non-catalyzed aldol reactions via hypervalent silicon species have also been studied. An aldol reaction between aldehydes and silyl enol ethers of amides was reported by Myers [105]. The reaction can be conducted under mild conditions to produce anti aldol without Lewis acid or base catalysts (Sch. 62). Asymmetric induction was particularly high when the (2)-silyl ketene N,O-acetal derived from prolinol was used.

80% (1.8: 1)

77% (39 : 1)

Scheme 62

A subsequent paper from this group indicated that the aldol reaction mechanism involves face-centered attack of benzaldehyde on 86 followed by pseudorotation of the resulting trigonal bipyramidal structure of 87, containing apically-bound aldehyde, into 88 (Sch. 63).

388

Oishi

' Y

Scheme 63

During the course of further mechanistic studies of this reaction, the reaction rate was found to be dramatically accelerated by incorporation of the silicon atom within a four-membered ring (Sch. 64) [106a]. The reaction of trimethylsilyl ketene acetal 89a with 90 requires heating at 150 "C, and less than 25 % 91a is formed after 24 h. In marked contrast, the silacyclobutane counterpart 89b reacts completely and clearly with 90 within 24 h at 27 "C to furnish 91b quantitatively. This implies that reaction proceeds by way of a pentavalent organosilicon species in which a boat-like transition state is preferred. OSiR2Me Me0

+

0

C6D6

PhCHO

I

-

OSiRpMe

MeOJK'Ph I

90

89

\

91

a R=Me b R=(CH2)3

t 1 ~>2days, 150 "C t1/2

30min, 27 "C

Scheme 64

The ring-strain-released aldol reaction was described in detail by Denmark and was subjected to asymmetric reaction by use of enoxysilacyclobutanes attached to chiral auxiliaries (Sch. 65) [106].

i\ PhCHO +

Os';0R* 6 0 M e

1. toluene, -60 "C 2. HFITHFIH20, 1 h *

0

OH

M e O v P h anti (>99 : 1)

* ROH : (-)-menthol

7%ee (-)-8-phenylmenthol 95%ee (-)-trans-2-cumylcyclohexanol 97%ee

Scheme 65

389

Silicon (IVj Lewis Acids

Allylation of allylsilacyclobutane with carbonyl substrates also proceeds bimolecularly (Sch. 66) [107]. In contrast with the aldol reaction, a mechanism with pentacoordinate silicon intermediates in chair-like transition states resulted in high stereoselectivity. 1) 130 "C, 24h

PhCHO

+

"PrdASi,

Ph

2) HCI aq

*

L\

Ph

-

+

p h h \ "Pr

nir

€-isomer Z-isomer

68% (95:5) 66% (5:95)

Scheme 66

8.5 Conclusions Exploration of the chemistry of organosilicon Lewis acids has led to the discovery of a new dimension in Lewis acid-base interaction, and selection of the most effective reagents from a variety of classical Lewis acids. The usefulness of such homogeneous silicon Lewis acid catalysts in modern organic synthesis has been well demonstrated by a number of successful applications to organic transformations, in particular carbon-carbon bond-forming strategies. Fundamental investigation of the synthetic and coordination behavior of silicon-based chiral Lewis acids is now in progress. This seems to be directly linked to progress in silylium ion chemistry, i.e., low-valent silicon species. Design of cationic silicon compounds with specific structure and reactivity will require further experimental and theoretical information. Over the last two decades remarkable progress has been made in the chemistry of hypervalent silicon species as a result of the enormous number of basic studies. This concept might affect the future use of other Lewis acidic main group elements.

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35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53.

54. 55. 56. 57.

58. 59. 60. 61. 62. 63. 64. 65.

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76. 77. 78 7Y.

80. 81. 82. 83. 84.

(a) Tietze, L. F.; Fischer, R. Angew. Chem. Inr. Ed. Engl. 1981,20, 969. (b) Tietze, L. F.; Fischer, R. Tetrahedron Lett. 1981,22,3239. (c)Tietze, L. F.; Beller, M. Angew. Chem. Int. Ed. Engl. 1991, 30,868. (c) Tietze, L. F.; Fischer, R. Angew. Chem. Inf.Ed. Engl. 1983,22,888. Ogawa, T.; Beppu, K.; Nakabayashi, S. Carbohydr. Res. 1981,93, C6. Kimura, Y.; Suzuki, M.; Matsumoto, T.; Abe, R.; Terashima, S. Chem. Left.1984,501. (a) Tietze, L. F.; Fischer, R.; Guder, H.-J. Tetrahedron Left. 1982, 23, 4661. (b) Nashed, E. M.; Glaudemans, C. P. J. J. Org. Chem. 1989,54, 6116. (c) Combination of catalytic amounts of 1 with Ph*S=S or catecholate oxotitanium activates the reaction system and gives high selectivities: Mukaiyama, T.; Matsubara, K. Chem. Lett. 1992,1041; Mukaiya, T.; Yamada, M.; Suda, S.; Yokomizo, Y.; Kobayashi, S. Chem. Lett. 1992,1401. Hashimoto, S.; Hayashi, M.; Noyori, R. Tetrahedron Lett. 1984,25,1379. Hashimoto, S.; Honda, T.; Ikegami, S. J. Chem. SOC.,Chem. Commun.1989,685. (a) Schmidt, R. R.; Grundler, G. Angew. Chem. Znt. Ed. Engl. 1982,21, 781. (b) Ito, Y.; Numata, M.; Sugimoto, M.; Ogawa, T. J. Am. Chem. SOC.1989, I l l , 8508. For recent reviews of C-glycosidation, see: (a) Postema, M. H. D. Tetrahedron 1992,40,8545. (b) Levy, D. E.; Tang, C. The Chemistry of C-glycosides; Pergamon Press: Oxford, 1995. Toshima, K.; Matsuo, G.; Ishizuka, T.; Ushiki, Y.; Nakata, M.; Matsumura, S. J. Org. Chem. 1998, 63,2307.

(a) Tsunoda, T.; Suzuki, M. Noyori, R. Tetrahedron Left.1979, 4679. (b) Hatakeyama, S.; Ikeda, T.; Irie, H.; Izumi, C.; Mori, H.; Uenoyama, K.; Yamada, H.; Nishizawa, M. J. Chem. Soc., Chem. Commun.1995,1959. 86. Suzuki, M.; Takada, H.; Noyori, R. J. Org. Chem. 1982,47,902. 87. Gay-Lussac, J. L.; Thenard, L. J. Mimoires de Physique et de Chimie de la Socilti d’Arcueill809, 85.

2,317.

88 89.

90. 91. 92. 93. 94. 95.

Davy, J. Phil. Trans. Roy. Soc. London 1812,102,352. For recent reviews (a) Furin, G. G.; Vyazankina, 0.A.; Gostevsky, B. A.; Vyazankin, N. S. Tetrahedron 1988, 44, 2675. (b) Sakurai, H. Synlett 1989, 1. (c) Corriu, R. J. P. J. Organomet. Chem. 1990,400,81. (d) Chuit, C.; Corriu, R. J. P.; Reye, C.; Young, J. C. Chem. Rev. 1993,93,1371. ( e ) Fensterbank, L.; Malacria, M.; Sieburth, S. M. Synthesis1997,813. (a) Cerveau, G.; Chuit, C.; Corriu, R. J. P; Reye, C. J. Organomet. Chem. 1987,328, C17. (b) Hosomi, A,; Kohra, S.; Tominaga, Y. J. Chem. Soc., Chem. Commun. 1987, 1517. (c) Kira, M.; Sato, K.; Sakurai, H. J. Am. Chem. SOC.1988,110,4599. Hoffman, R. W.; Zeiss, H. J. J. Org. Chem. 1981,46,13OY. Kira, M.; Sato, K.; Sakurai, H. J. Am. Chem. Soc. 1990,112,257. Kira, M.; Kobayashi, M.; Sakurai, H. Tetrahedron Lett. 1987,28,4081. Kira, M.; Hino, T.; Sakurai, H. Tetrahedron Lett. 1989,30,1099. (a) Sato, K.; Kira, M; Sakurai, H. J. Am. Chem. SOC. 1989,111,6429. (b) Kira, M.; Sato, K.; Sekimoto, K.; Gewand, R.; Sakurai, H. Chem. Lett. 1995,281.

Silicon (IV)Lewis Acids

393

96. Hayashi, T.; Matsumoto, Y.; Kiyoi, T.; Ito, Y. Tetrahedron Lett. 1988,29,5667. 97. (a) Kobayashi, S.; Nishio, K. Tetrahedron Lett. 1993,34,3453.(b) Kobayashi, S.; Nishio, K. J. Org. Chem. 1994,59,6620. 98 Denmark S. E.; Coe, D. M.; Pratt, N. E.; Griedel, B. D. J. Org. Chem. 1994,59,6161. 99. (a) Furuya, N.; Sukawa, T. J. Organomet. Chem. 1975, 96, C1. (b) Kira, M.; Hino, T. Sakurai, H. Tetruhedron Lett. 1989,30, 1099. 100. Kitayama, K.; Tsuji, H.; Uozumi, Y.; Hayashi, T. Tetrahedron Lett. 1996,37,4169. 101. Kobayashi, S.; Nishio, K. J. Am. Chem. Soc. 1995,117,6392, 102. (a) Denmark, S. E. (b) Iseki, K.; Kuroki, Y.; Takahashi, M.; Kobayashi, Y. Tetrahedron Lett. 1996, 37, 5149. (c) Iseki, K.; Kuroki, Y.; Takahashi, M.; Kishimoto, S.; Kobayashi, Y. Tetrahedron 1997, 53, 3513. (d) Nakajima, M.; Saito, M.; Shiro, M.; Hashimoto, S.-i. J. Am. Chem. Soc. 1998, 120, 6419. 103. (a) Denmark, S. E.; Winter, S. B. D.; Su, X.; Wong, K.-T. J. Am. Chem. Soc. 1996,118,7404. (b) Denmark, S. E.; Wong, K.-T.; Stavenger, R. A. J. Am. Chem. Soc. 1997,119,2333. (c) Denmark, S. E.; Winter, S. B. D. Synlett 1997,1087. 104. Denmark, S. E.; Stavenger, R. A,;Wong, K.-T. J. Org. Chem. 1998,63,918. 105. (a) Myers, A. G.; Widdowson, K. L. J. Am. Chem. Soc. 1990,112,9672. (b) Myers, A. G.; Widdowson, K. L.; Kukkola, P. J. J. Am. Chem. Soc. 1992,114,2765. 106. (a) Myers, A. G.; Kephart, S. E.; Chen. H. J. Am. Chem. Soc. 1992,114,7922. (b) Denmark, S. E.; Griedel, B. D.; Coe, D. M. J. Org. Chem.1993,58,988. (c) Denmark, S. E.; Griedel, B. D.; Coe, D. M.; Schnute, M. E. J. Am. Chem.Soc. 1994,116,7026. 107. Matsumoto, K.; Oshima, K.; Utimoto, K. J. Org. Chem. 1994,59,7152.

Lewis Acids in Organic Synthesis Edited bv Hisashi Yamarnoto Copyright 0WILEY-VCH Verlaa GmbH.2000

9 Sn(I1) and Sn(1V) Lewis Acids Kazuaki Ishihara

9.1 Introduction The element tin has played an increasingly important role in organic and organometallic chemistry, serving as a source of Lewis acids for selective transformations [l]. The main activity in these fields has been focused on Sn(1V) compounds, and Sn(I1) compounds have been used primarily as reductants of aromatic nitro compounds to aromatic amines [2]. During the last decade, however, asymmetric synthesis has developed increasingly, and in this field both Sn(I1) and Sn(IV) reagents have played major roles. The electronegativity of Sn(1I) and Sn(IV) is shown in Table 1 [3,4]. Sn(I1) is more electropositive and hence cationic than Sn(IV), and is expected to coordinate with nucleophilic ligands. The covalent and ionic radii of Sn(I1) are, on the other hand, larger than those of Sn(IV) (Tables 1 and 2) [3-111. This is because electronic repulsion of the unpaired electrons of Sn(l1) weakens the 8-bond because Sn(I1) uses the p-orbital for bonding. This chapter focuses on the synthetic applications of Sn(I1) and Sn(1V) Lewis acids. Table 1. Comparison of ionic radii and electronegativity. Oxidation state

Ionic radii

Electronegativity (Pauling)

(A)

Electronegativity (Sanderson)

Sn(I1)

1.02

1.80

1.58

Sn(IV)

0.71

1.96

2.02

Table 2. Sn-X bond distances

(A) in the gas-phase.

SnXz

Sn-X

SnX4

SnR2

2.28

SnR4

2.17

2

SnClz

2.42-2.43

SnC14

2.28-2.31

3-6

SnBr2

2.55

SnBr,,

2.44

3/47

Sn12

2.13-2.18

Sn14

2.64

3,4,7

Sn-X

Refs

396

Ishihara

9.2 SnX2-CatalyzedReactions 9.2.1 Sn(I1) Halide-Catalyzed Reactions 9.2.1.1 (3

+ n] Annulation

Cyclopentanoids are prepared by stereocontrolled synthesis with a 1,2-dicarbonyl component and 12-dianion synthon derived from the treatment of 3-halo-2-[(trimethylsilyl)methyllpropenes (X = Br, I) with SnF2 in THF at 25 "C (Eq. 1) [12]. Several 12-diketones (R, R' = Me, Et, Ph, Pr, C1(CH2)4,-(CHZ)~-;0 "C for R = R1 = Ph) afford the cisdiols.

K X

SiMe3

Y=Rr I

6

H

25"C,THF

40-80%

O

R R

~

I

SnF, seems unique for this annulation. After generation of the allylstannane, the Sn4+ serves as a Lewis acid catalyst and provides internal chelation. The fluoride counter ion is an ideal nucleophile for the activation of the allylsilane. The high stereoselectivity (25:l to 75:l) is attributed to chelation (Eq. 2) [12]. ,Sn4'

R 0'

pP

r_x"bH H30+

HO R'

(2)

F-7 (+

Me3Si

Cyclohexanediols are prepared in approximately 20-60 % yields (diastereomeric ratios from 4:1 to 50:1) by a [3 + 31 annulation using a,@-epoxyaldehydes (R = alkyl, H) as the dielectrophilic partner (Eq. 3) [13]. The high stereoselectivity and the lack of appreciable [3 + 21 annulation are attributed to internal chelation and internal trans-diaxial epoxide opening (Eq. 4) [13].

Sn(II) and Sn(IV) Lewis Acids

397

9.2.1.2 P-Diketo Ester Synthesis Aldehydes are efficiently converted to P-diketo esters in 50-90 YOyield by addition of ethyl diazoacetate in the presence of SnC12 (Eq. 5). Although the reaction can be effected by a variety of Lewis acids, SnCI2,BF3, and GeC12 are the most effective [14]. 13-Diketones can be prepared in 42-90 YOyield by SKI2-catalyzed reaction of adiazo ketones with aldehydes (Eq. 6) [15]. 0 BnAH + NZ=CHCOzEt

SnC12 71%

0 BnAH + N2ZCHCOPh

*

SnC12 90%

uOEt

uFh' Bn

(5)

(6)

9.2.1.3 Aldol and Michael Additions Aldehydes, acetals, orthoesters, and u,P-unsaturated ketones are sufficiently activated by a combination of SnC12 and chlorotrimethylsilane [16a] or SnC12 and trityl chloride [16b] to react with silyl enol ethers to give the corresponding addition products in 79-97 YOyield (Eq. 7). These reagents are also effective in facilitating the reaction of activated alkenes such as 3,4-dihydro-2H-pyran, vinyl ethers, and styrene, with acetals to afford the corresponding adducts in 55-85 % yield under extremely mild condi'tions [16c]. SnC12 facilitates the work-up in the TiC&-catalyzed reaction of aldehydes with silyl enol ethers by inhibiting p-elimination and the formation of polymers (Eq. 8) ~ 7 1 . Silyl enol ethers react with bromomethyl methyl ether in the presence of a catalytic amount of SnBr2 to yield a-bromomethyl ketones (Eq. 9) [lS]. Other tin halides such as SnF2 and SnC12 can be used successfully in the reaction.

398

Ishihara

OTMS

RaH+

A

H

+

Br-OMe

R=Pr

-

OH 0

H RU TiCI4: 68% TiCI4 + SnCI2: 81%

(8)

SnBr2 CHzC12, rt

9.2.1.4 Glycosidations Combined use of SnC12 and AgC104 effectively promotes the stereoselective glycosylation of glucosyl fluorides with hydroxy compounds. a-Glucopyranosides are predominantly prepared by the reaction of 2,3,4,6-tetra-O-benzyl-~-~-glucopyranosyl fluoride with a variety of hydroxy compounds, including sterically hindered (Eq. 10) [19]. Under the same conditions, a P-ribofuranoside is obtained as a major product from 2,3,5-tri-O-benzyl-~-~-ribofuranosyl fluoride. a-Ribofuranosides are prepared when SnC12is combined with trityl perchlorate (TrC104) instead of AgC104 (Eq. 11) [20].Although the precise structure of an active species generated from SnClz and AgC104 is not clear, formation of SnC1(C104)or Sn(C104)2is postulated.

+ ROH

Bzo-~ BnO

SnCl2-AgCI04 B Et20, MS 4A

-15 "C 76-96%

Z

O q BnoOR c~:p=80:20-92:8

(10)

Sn(II) and Sn(W)Lewis Acids

+

ROH

BnO OBn

BnobR

SnC12-TrCIO 4 * Et20, MS 4A -15 "C

399

(11)

BnO OBn

a:P=81:19-88:12

8a-96%

Although more than stoichiometric amounts of promoters are required in the above examples, catalytic reactions are realized by use of SnCI4-AgC104. In the presence of a catalytic amount of SnC14-AgC104, 1-0-2,3,4,6-tetra-0-benzyl-~-glucopyranose reacts with alcohol trimethylsilyl ethers to afford the corresponding a-glucopyranosides in high yields (Eq. 12) [21]. Other examples of the preparation of P-glucosi[21d] have also been reported. des [21c] and a - and P-2-amino-2-deoxyglycosides 10 mol% ROSiMe3 SnCI4-AgC1O4*

+ BnO

OAc

Et20, MS 4A 0 "C

B

z

0

q

(12)

BnoOR

~~:P=90:10-97:3

86-95%

9.2.1.5 Deprotection p-Methoxybenzyl (PMB) ethers can be cleaved selectively in the presence of benzyl ethers by employing Me3SiC1-anisole and a catalytic amount of SnC12 (Eq. 13) [22].

-

3.0equiv MeaSiCl 1.5equiv anisole

' & O q

(13)

0.1equiv SnC12 87%

BnoOMe

9.2.1.6 Allylations Aromatic acetals can be converted in 63-87 % yield to a-allylbenzylbromides by use of allyltrimethylsilane and a catalytic amount of SnBr2 in combination with excess acetyl bromide (Eq. 14) [23]. This reaction works equally well with SnC12 and acetyl chloride to yield the corresponding a-allylbenzyl chlorides. The Friedel-Crafts allylation of anisole with allylic bromides catalyzed by SnBr2 has also been reported (Eq. 15) [24]. OMe

SnBr2, AcBr *

+ -SiMe3

PhAOMe

CH2CI2, rt

87%

Ph

400

Ishihara

Ph

OMe

3.0

THF, SnBr2 reflux * Ph

(15)

OMe para:orthu=>99:1

74%

9.2.2 Sn(0Tf)Z-Catalyzed Reactions 9.2.2.1 Rearrangement Coordination of a Lewis acid to the amide nitrogen of acylaziridines catalyzes a rearrangement to the oxazoline, whereas coordination to the carbonyl oxygen is better at activating the substrate toward external nucleophilic attack. More azaphilic salts, Zr1(0Tf)~,Cu(OTf)2, and SII(OT~)~, do not catalyze the addition of nucleophiles to acylaziridines, but instead promote the rearrangement of acylaziridines to 2-aryloxazolines (Eq. 16) [25]. Ar

Zn(OTf)*, Cu(OTf)2, or Sn(OTf),

Nho

9.2.2.2 Aldol Reactions Mukaiyama and Kobayashi et al. have developed the use of Sr1(0Tf)~in diastereoselective and enantioselective aldol-type reactions [26,27]. Initially, the stereoselective aldol reactions were performed with a stoichiometric amount of Sn(OTf), [28]. The reaction between 3-acylthiazolidine-2-thione and 3-phenylpropionaldehyde is a representative example of a diastereoselective syn-aldol synthesis (Eq. 17). Sn(OTf)2

95%, syn:anti=>97:3

R'=Bn, R2=BnCH2

Enantioselective aldol-type reactions were achieved by addition of chiral diamines, readily prepared from (S)-proline, to the reaction mixture [29]. Sn(I1) has three vacant orbitals, and after coordination of two nitrogen atoms one vacant orbital still

Sn(II) and Sn(IV)Lewis Acids

401

remains [30]. Chiral diamino-coordinated Sn(I1) thus has a rigid bicyclo[3.3.0]octanelike structure consisting of two fused five-membered rings, and can activate an aldehyde by use of the vacant orbital without changing the rigid structure [31]. Addition of (S)-l-methyl-2-[(piperidin-1-ylmethyl]pyrrolidineto the reaction of 3acylthiazolidine-2-thione and 3-phenylpropionaldehyde provides the syn aldol with greater than YO % enantiomeric excess (ee) (Eq. IS) [2Y].

In the presence of a stoichiometric amount of Sn(OTf)*,chiral diamine, and Bu3SnF,1S-ethyl-1-trimethylsiloxyetheneor 1-S-t-butyl-1-trimethylsiloxyethene reacts with aldehydes to afford the corresponding adducts in high yields with high enantioselectivity (Eq. 19) [32].No chiral induction is observed if Bu3SnFis not used. Although the precise function of Bu3SnF is not yet clarified, it is believed that the fluoride connects the chiral Sn(I1) Lewis acid with the nucleophile, the silyl enol ether [33,34]. Sn(OTf)3-chiral diamine

CHzCIz, -78 "C

n

&..~\\\!% 50-90%, 81->98% ee

Me

chiral diamine:

O.'''\\Na or

\

In the reactions with the propionate derivatives, which provide synthetically useful a-methyl-P-hydroxy ester derivatives, a combination of Sn(OTf)2, (S)-l-methyl-2-[(N1-naphthylamino)methyl]pyrrolidine,and B U ~ S ~ ( O Agives C ) ~ better results (Eq. 20) [33,35]. The asymmetric aldol reactions proceed with higher enantioselectivity and, in addition, the reactions proceed faster with B u ~ S ~ ( O A as C )an ~ additive than with Bu3SnF. A wide variety of aldehydes including aliphatic, aromatic, and a,p-unsaturated aldehydes can be used in this reaction, and the aldol adducts are always obtained in high yields with perfect syn selectivity; the enantiomeric excesses of these syn adducts are > 98 %.

402

lshihuru

OSiMe3

R'CHO +

Sn(OTf)2-chiral diamine Bu2Sn(OAc)2 (20)

F S E t

CH2CI2, -78 "C

chiral diamine:

In the presence of Sn(OTf)2, (S)-l-pentyl-2-[(piperidin-l-yl)methyl]pyrrolidine, and Bu3SnF, 1-(S)-ethyl-1-trimethylsiloxyethenereacts with methyl pyruvate to give the desired adduct in 92 YOee (Eq. 21). Methyl isopropylglyoxylate and methyl phenylglyoxylate also react with 1-(S)-ethyl-1-trimethylsiloxyetheneto give the corresponding 2-substituted malates in good yields and excellent enantioselectivity [36]. Sn(OTf)z-chiral diamine Bu3SnF * CH2C12, -78 "C

0 RIKCO2Me

R'

When (Z)-1-(S)-ethyl-1-trimethylsiloxypropene is treated with alkyl pyruvate in the presence of Sn(OTf)2, (S)-l-penty1-2-[(piperidin-l-yl]pyrrolidine, and BqSnF, the reaction proceeds smoothly to give the syn isomer in high yield with high diastereoand enantioselectivity (Eq. 22) [37]. Successive asymmetric centers including quaternary carbons are constructed efficiently with high selectivity by use of this methodology [37b]. (E)-1-(S)-ethyl-1-trimethylsiloxypropene, on the other hand, reacts with methyl phenylglyoxylate or methyl pyruvate very slowly under the same conditions.

0 R1KC02Me

e,,, OSiMe3

+

Rlyc,,t

Sn(OTf)2-chiral diamine Bu3SnF MeO& * CH2C12, -78 "C

(22)

o.""'y> Pent

chiral diamine:

OH0

v

R'=Me: 87% 94% syn, 82% ee R2=Ph: 85% 96% syn, 96% ee

Asymmetric synthesis of 1,2-diol derivatives based on asymmetric aldol reactions of a-alkoxy silyl enol ethers with aldehydes has been developed. The reaction of (2)2-benzyloxy-1-(S)-ethyl-1-trimethylsiloxyethene with benzaldehyde was conducted in dichloromethane at -78 "C with a chiral promoter consisting of Sn(OTf);?, (S)-1-ethyl2-[(piperidin-1-yl)methyl]pyrrolidine, and Bu2Sn(OAc)2, to afford the corresponding aldol adduct in 83 YOyield with 99 YOanti preference. The enantiomeric excess of anti aldol is 96 YO[38a]. In the aldol reaction of several kinds of aldehydes, e.g. aromatic,

Sn(II) and Sn(IV)Lewis Acids

403

aliphatic, u&unsaturated aldehydes and a dienal, under the same conditions as above, anti-u,P-dihydroxy thioesters are obtained in high yields with excellent diastereo- and enantioselectivity (Eq. 23).

R’CHo+

OSiMe3 &SEt

Sn(OTf)2xhiral diarnine Bu2Sn(OAc)2

OH 0 (23)

CH2C12, -78 “C * R’-SEt OBn 72-88% 91-99% anti 95-98% ee

OBn Et chiral diarnine:

The Sn(I1)-mediated reaction of a-alkoxythiolketene acetals with u,P-unsaturated aldehydes results in enhanced reactivity and high anti selectivity in the glycolate product when an a-benzyloxy substituent is present in the aldehyde, a finding which was applied to the synthesis of a segment (C26-C33) of the immunosuppressant rapamycin (Eq. 24) [38b].

OR

Sn(OTf)2-chiral diarnine Bu2Sn(OAc)2 * CH2C12, -78 “C

0 Pent

@‘D chiral diamine

E

OH t OR

OSiMe2Bu’ S

W

(24)

R=Me: 7% yield, syn:anti=25:75 R=3,4-(Me0)2C6H3CH2:80% yield, syn:anti=8:92

Raparnycin

In contrast with the syn preference of aldol reactions of the silyl enol ether derived from (S)-ethyl propanethioate with aldehydes using the above chiral promoter, anti selectivity has been achieved in reactions of (Z)-2-benzyloxy-l-(S)-ethyl-l-trimethylsiloxyethene with aldehydes. Studies of the transition states of these aldol reactions have led to the assumption that:

coordination of the oxygen atom of the a-benzyloxy group of silyl enol ether to the Sn(OTf)2 is essential in the anti selective transition state, leading to a different course in diastereofacial selectivity compared with that of the syn selective reaction of (2)-1-(S)-ethyl-1-trimethylsiloxypropene,and (ii) syn a,B-dihydroxy thioesters would be formed when this coordination is restrained.

(i)

In accordance with this hypothesis, the t-butyldimethylsilyl group was chosen as a sterically hindered functional group; this would forbid coordination of the oxygen atom to the Sn(I1) atom. As expected, in the presence of Sn(OTf)2, chiral diamine (S)-l-propyl-2-[(piperidin-l -yl)methyl]pyrrolidine, and B U ~ S ~ ( O A C the ) ~reaction , of (Z)-2-benzyloxy-l-(S)-ethyl-l-trimethylsiloxyethene with benzaldehyde proceeds smoothly to give the corresponding aldol adduct in high yield and with high syn selectivity (Eq. 25) [39]. SnfOTfL-chiral diamine Bu2Sn(OAc)2 I

OSiMe3

R'CHo+

&,,

OTBS

I L

6~"NG Pr

chiral diamine:

(25)

CHzC12, -78 "C OTBS 4693% 88-97% syn 82-94% ee

It is also possible to synthesize both enantiomers, including 1,2-diol units, with perfect stereochemical control by use of similar chiral sources (Fig. 1) [40]. In the presence of and B u ~ S ~ ( O A C(2)-2)~, Sn(OTf)2, (S)-1-methyl-2-[(isoindolin-l-yl)methyl]pyrrolidine, (t-butyldimethylsiloxy)-l-ethylthio-l-trimethylsiloxyethenereacts with aldehydes to afford the desired aldol adducts with 2S,3R configuration. When, on the other hand, (S)-l-methyl-2-[(indolin-l-yl)methyl]pyrrolidine is used, the reaction also proceeds smoothly, but the absolute configuration of the adducts is the reverse, 2R,3S. In both reactions, the syn selectivity is very high; almost perfect selectivity and > 98 % ee are obtained. Me

Me

Figure 1. Chiral diamine ligands for Sn(OTf),.

On the basis of investigations to characterize the above promoter system and to clarify the mechanism of these reactions toward a truly catalytic aldol process [41], the following catalytic cycle is postulated (Sch. 1).

~ j~vre3 :~i Sn(II) and Sn(IV)Lewis Acids

RCHO A M

e

405

n N

l

N.

E t S 5

0

OTf

ESJY-,

+

N

N

Me3SiOTf

=

&\&

Scheme 1. The catalytic cycle of the asymmetric aldol reaction.

When metal exchange between Sn(I1) and silicon of the above product occurs smoothly, the corresponding aldol adduct can be obtained as its trimethylsilyl ether together with regeneration of the catalyst. If the metal-exchange step is slow, undesirable Me3SiOTf-promoted reaction [42] (to afford the achiral aldol adduct) proceeds and results in reduced selectivity. To accelerate this metal exchange step, various polar solvents with low melting points (below -78 "C) have been carefully examined, and finally propionitrile has been found to be an excellent solvent [43]. Sn(OTf), is more soluble in propionitrile than in dichloromethane, indicating that coordination of the nitrile group to Sn(I1) is rather strong, but that ligand exchange of the nitrile for the diamine takes place smoothly to form the desired chiral Lewis acid when the chiral diamine is added to this propionitrile solution of Sn(OTf)2. Several aldehydes, including aromatic, aliphatic, and a$-unsaturated aldehydes, can be used in this reaction, and the desired products are obtained in good yields or selectivities (> 90 YOee) even when 10 mol YOcatalyst is used [44]. Efficient enantioselective synthesis of antifungal sphingofungins has been demonstrated by use of this Sn(I1)-catalyzed asymmetric aldol reaction (Fig. 2) [45]. OH OH .

-

OH

Figure 2. Sphingofungin B

Recently Mukaiyama et al. also reported the catalytic asymmetric aldol reaction using Me3SiOTf, a chiral diamine, and SnO [46]. In this reaction, the lone pair electrons of SnO interact with Me,SiOTf to weaken the Lewis acidity of Me3SiOTf, with resulting high selectivity. On the basis of this idea, it has been found that in the presence of a novel chiral catalyst system consisting of Sn(OTf),, a chiral diamine, and SnO, highly enantioselective aldol reactions of the silyl enol ether of S-ethyl ethanethioate or S-ethyl propanethioate with aldehydes proceed smoothly to afford the aldol adducts in high yields (Eq. 26).

406

Ishihara

Sn(OTf)2(20 mol%) chiral diamine (24 mol%) OSiMe3 SnO (20-40 molyo)

(26)

EtCN, -78 "C

50-85% 95-1 00% syn 84->98% ee

R2=H, Me

L

v

slow addition 4-6 h

chiral diamine:

Evans et al. recently reported the use of structurally well-defined Sn(I1) Lewis acids for the enantioselective aldol addition reactions of a-heterosubstituted substrates [47]. These complexes are readily assembled from Sn(OTf)2 and C2-symmetric bis(oxazo1ine) ligands. The facile synthesis of these ligands commences with optically active 1,2-diamino alcohols, which are themselves readily available from the corresponding a-amino acids. The Sn(I1)-bis(oxazo1ine) complexes were shown to function optimally as catalysts for enantioselective aldol addition reactions with aldehydes and ketone substrates that are suited to putatively chelate the Lewis acid. For example, use of 10 mol % Sn(I1) catalyst, thioacetate, and thiopropionate derived silyl ketene acetals added at -78 "C in dichloromethane to glyoxaldehyde to give hydroxy diesters in superb yields, enantioselectivity, and diastereoselectivity (Eq. 27). The process represents an unusual example wherein 2,3-anti-aldol adducts are obtained stereoselectively.

OSiMe3 Et0)(tH

0

+ R'

(10 mol%)

*

(27)

-78 "C, CHpCI;! R'=H, 98% ee R'=Me, 95% ee, anti/syn=90:10

Aldol additions to methyl pyruvate by silyl ketene thioacetals have been shown to proceed in high yield and with excellent asymmetric induction (Eq. 28). This process is an uncommon example of catalytic, asymmetric aldol additions to ketones, providing access to synthetically useful compounds. The remarkable ability of the catalyst to differentiate between subtle steric differences of substituents flanking a 1,2-diketone has been elegantly demonstrated in highly enantioselective additions to 2,3-pentanedione (Eq. 29). The aldol adduct of S-tert-butyl thiopropionate derived silyl ketene acetal afforded 2,3-anti-aldol adduct (>99:1 antilsyn) in 98 % ee and 97:3 chemoselectivity for the methyl ketone.

Sn(II) and Sn(IV)Lewis Acids

(10 mol%)

Meup 0

M

+ fSR

e

0

-78 "C, CH2C12

O

407

h R'

R=But, R'=Me, 99% ee, anti/syn=99:1

I

-78 "C, CH2C12 98% ee, anti/syn=99:1, regioselection 97:3

An important feature of the Evans system is the insight provided into catalyst struccomplex displays the ture. The X-ray crystal structure of the [Sn(Ph-pybo~)](OTf)~ central Sn(I1) atom in square pyramidal geometry. The three amino donors occupy a meridional position with the triflate counter ions trans-diaxially bound. These are slightly distorted away from the stereochemically relevant, Sn-centered lone pair that resides in the meridional plane. Electrospray ionization studies reveal that the cationic complex is readily generated by dissociation of the triflate counter ions, underscoring the kinetic lability of [Sn(Bn-box)](OTf)z and [Sn(Ph-pybo~)](OTf)~ towards ligand exchange, the sine qua non of a catalytic process.

9.2.2.3 Allylation Mukaiyama et al. have designed a chiral allylating reagent consisting of an allyldialkylaluminum and a chiral diamine chelated to Sn(OTf)2. The reaction of this agent with various aldehydes gives corresponding homoallylic alcohols with good to excellent enantioselectivity (Eq. 30). Other Sn(I1) compounds (SnC12, SnBrz, SnF2, Sn(OAc)$ react in this system to give the homoallylic alcohols in good yield but with almost no enantioselectivity [48]. Sn(OTf)z,chiral diamine

(30)

*

CHzC12, -78 "C Me chiral diamine:

R1

52-84% ee 65-93% yield

408

Ishihara

9.2.2.4 Cyanation Asymmetric cyanation of aldehydes is important in organic synthesis. Mukaiyama and Minowa have developed a new chiral Lewis acid catalyst which is readily prepared from 1,l'-dimethylstannocene, triflic acid, and (+)-cinchonine [49]. In the presence of this Lewis acid reaction of TMSCN with aldehydes proceed smoothly at -78 "C in dichloromethane to give the corresponding cyanohydrin trimethylsilyl ether in high yield with good to excellent ee. In this reaction the products are isolated as trimethylsilyl ethers and the reaction proceeds smoothly in the presence of 30 mol % tin(I1) Lewis acid (Eq. 31). The catalyst, Sn(I1) monoalkoxymonotriflate, is assumed to be regenerated from the initially produced Sn(I1) alkoxide and trimethylsilyl triflate.

Catalyst C)-CHO

+ Me3SiCN

CN

(31)

CH2C12, -78 "C

catalyst:

+

90% ee

9.3 SnX4-CatalyzedReactions 9.3.1 SnC14-CatalyzedReactions 9.3.1.I Introduction SnC14 is used extensively in organic synthesis as a Lewis acid for enhancing a variety of reactions. SnC14is classified as a strong Lewis acid according to HSAI3 theory, and therefore interacts preferentially with hard oxygen and nitrogen bases. Six-coordinate 1:2 species and 1:l chelates are the most stable coordination complexes, although 1:lfive-coordinate species are also possible [50].SnC14can be used in stoichiometric amounts, when it is regarded as a 'promoter', or in substoichiometric amounts, as a catalyst, depending upon the nature of the reaction. SnC14is attractive to boron, aluminum, and titanium Lewis acids because it is monomeric, highly soluble in organic solvents, and relatively easy to handle. SnC14and TiC14are among the most common Lewis acids employed in 'chelation control' strategies for asymmetric induction. SnC14,however, is not often the Lewis acid of choice for optimum selectivitiesand yields. SnC14is also the principal source of alkyltin chlorides, R,SnC14, [51]. Allyltrialkyltin reagents react with SnC14 to produce allyltrichlorotin species through an SETpathway (Eq. 32) [52-561. Allyltrimethylsilanes react with SnC14 to produce the corresponding allyltrichlorotin (Eq. 33) [57].Silyl enol ethers react with SnC14to give a-trichlorotin ketones (Eq. 34) [58].Transmetalation or metathesis reactions of this type

Sn(II) and Sn(IV)Lewis Acids

409

compete with nucleophilic addition reactions where SnC14 is present as an external Lewis acid. As a consequence, four important experimental variables must be considered when using SnC14as a promoter: (i) (ii) (iii) (iv)

the stoichiometry between the substrate and the Lewis acid; the reaction temperature; the nature of the Lewis base site(s) in the substrate; and the order of addition.

These variables influence the reaction pathway and product distribution [59].

Me3s -f l &

Ph+ SnC14

CIS Sn. nPh + Me3SiCI (33)

9.3.1.2 Allylation Reactions SnC14 is effective in promoting the addition of nucleophiles to simple aldehydes. Among the most synthetically useful additions are allylstannane and -silane additions. The product distribution in the stannane reactions can be' influenced by the order of addition, stoichiometry, and reaction temperature. The anti geometry of the tin-aldehyde complex is favored because of steric interactions. Furthermore, the six-coordinate 2:l complex is most probably the reactive intermediate in these systems. The use of crotylstannanes provides evidence for competing transmetalation pathways (Eq. 35) [60]. TiC14 results in superior selectivity.

,xH +

R=c-Hex

22.8 21.8 90.5 4.4

Lewis acid *SnBu3

*

normal addition inverse addition normal addition inverse addition

26.0 74.9 7.0 90.8

1.3 equiv SnCI4: 1.3 equiv SnCI4: 1.05 equiv TiCI4: 2.1 equiv TiCI4:

36.4 1.2 2.1

-

14.8 2.2 0.5 4.9

410

Ishihara

The Lewis acid-mediated desymmetric intramolecular cyclization of prochiral allylstannyl diketone gives a mixture of two diastereomers, and highly diastereoselective synthesis of each diastereomer has been accomplished by proper choice of the Lewis acid. The use of TiC14 and TiC12(Oi-Pr)2affords the cis-trans diastereomer with high diastereoselectivity, whereas use of SnC14,InC13, and Yb(Oi-Pr)3 gives cis-cis diastereomer exclusively or predominantly (Eq. 36) [61]. When Tic14 is used as a Lewis acid, the transmetalation takes place very rapidly and the resulting allyltitanium compound undergoes cyclization via a cyclic transition state. On the other hand, transmetalation between allylstannane and SnC14would be slower, and thus the cyclization would take place via an acyclic transition state, in which the Lewis acid would coordinate to carbony1 oxygen and facilitate the cyclization.

TiCI4: 92 : 8 (83% yield) SnCI4: 1 : >99 (62% yield)

Alkoxy-substituted allylstannanes are transmetalated on treatment with Sn(1V) halides to give allyltin trihalides which react with aldehydes with effective remote asymmetric induction [62]. For example, the 5-benzyloxy-4-methylpent-2-enylstannane gives predominantly the 1,5-anti products with useful stereoselectivity (Eq. 37) [62b]. Allylstannanes and 5-benzyloxy-4-methylpent-2-enylsilanes also react with aldehydes with modest levels of 1,5-induction after treatment with SnC14. Transmetallation to give intermediate allyltin trihalides might be involved (Eq. 38) [63]. 1. SnCI4 -78 "C,5 rnin

OH

-

B n O F S n B u S

B

n

O

y

R

2) RCHO -78 "C, 0.5-1 h

SnC14 B n O y S i M e 3

+

B

BnO-SnCI3

- Y

e

R (37)

*

-78 "C, 0.75 h

OH n

O

PhCHO

%,/

B

n

295 : 5

-78 "C, 2 h Zisorner: E isomer:

OH

O

T

P

OH h

+

BnO+

ph

(38)

86 : 14 73 : 27

The presence of additional Lewis base sites within the molecule can result in the formation of chelates with SnC14 or TiC14, which can lead to 1,2- or 1,3-asymmetric induction with the appropriate substitution at the C-2 or C-3 center. NMR studies have provided a basis for explaining the levels of diastereofacial selectivity observed

Sn(II) and Sn(IV)Lewis Acids

411

in nucleophilic additions to Lewis acid chelates of P-alkoxy aldehydes with substitution at C-2 or C-3 [64]. These studies reveal that SnC14 chelates are dynamically unstable when substrates are sterically crowded at the alkoxy center, thus enhancing the formation of 2:l complexes and/or competing metathesis pathways. Furthermore, for P-siloxy aldehydes, the 2:l SnC14 complex is formed in preference to the corresponding chelate [65]. Three modes of reaction of aldehydes with allylsilane bearing sterically demanding silyl substituents are mediated by the proper choice of Lewis acid (Eq. 39) [66a]. Thus, influenced by SnC14,allyl-t-butyldimethylsilane reacts with aldehyde in 2:l stoichiometry to afford a ketone derivative. In contrast, use of BF3.OEtz leads to the formation of a 1,3-dioxane derivative, which is a 1:2 adduct. Furthermore, ZrC14-promoted [2 + 21 cycloaddition of allylsilane and aldehyde furnishes oxetanes in good yields [66b].

c

Sit-BuMe2

Sit-BuMe2

,i,

BF3*Et20

+ -Sit-BuMe2

*

s

oi\o

(39)

,U+,,,,Sit-BuMe2 ZrCl RehSit-BuMe2

Lewis acids such as SnBr4 promote the coupling of 4-acetoxy-1,3-dioxanes with crotyl-metal species to generate propionate motifs (Eq. 40) [67]. The reactions show a marked dependence on Lewis acid, crotyl metal species, and the presence and stereochemical disposition of a C5 methyl group. A 1,3-syn methyl relationship is favored in these additions.

Bn-OAC

.

0-0 t-Bu

SnBrd

.

+ *SiMe2Ph

* CHpC12, -78 "C

t-Bu

t-Bu

82% yield, anti:syn=10.8:1

412

Ishihara

9.3.1.3 Aldol Reactions Lewis acid-promoted Mukaiyama aldol additions of a chiral aldehyde to a silyl enol ether or silyl ketene acetal occur with good diastereofacial stereoselectivity [68]. The reaction has been investigated with non-heterosubstituted aldehydes [69], and thiosubstituted aldehydes [70]. High diastereoselectivity is observed in the SnC14- or TiCI4-promoted aldol addition of silyl enol ethers to a - and @-alkoxyaldehydes. Chelation of the aldehyde before addition of the enol silane is important because certain enol silanes interact with SnC14 to produce a-trichlorostannyl ketones, which lead to lower selectivity [71]. Simple diastereoselectivity is dependent on the geometry of the enol silane, and the reaction does not proceed through prior Si-Ti or Si-Sn exchange. Good anti selectivity (up to 98:2) are obtained in SnC14-promoted reactions of chiral a-thio-substituted aldehydes only with a-phenylthio-substituted aldehydes (Eq. 41). Stereorandom results are obtained with SnC14 when other alkylthio-substituted aldehydes, such as a-isopropylthio-substituted aldehydes, are used. Boron trifluoride etherate catalysis results in better anti selectivity than SnCI4 for aldehydes with smaller alkylthio substituents. Excellent syn selectivity is obtained for a-thio-substituted aldehydes with TiC14.

SR'

+

-u"

Lewis acid

, ' OTMS

OH

*

OH

9.3.1.4 Michael Reactions The mechanism of Mukaiyama-Michael reaction of ketene silyl acetal has been discussed by Otera et al. [72]. The competition reaction employing various types of ketene silyl acetals reveals that those bearing more substituents at the @-positionreact preferentially over less substituted acetals (Eq. 42). When, however, ketene silyl acetals carry bulky siloxy and/or alkoxy group(s), less substituted compounds react preferentially (Eq. 43). The Lewis acids play an important role in these reactions. Enhanced preference for the more sterically demanding Michael adducts is obtained with Bu2Sn(OTf)2, SnC14, and Et3SiCIO4 in the former reaction whereas TiC14 results in the highest selectivity for the less sterically demanding products in the latter case.

SnC14

1oo:o

Sn(II) and Sn(IV)Lewis Acids

413

These results are interpreted in terms of alternative reaction mechanisms. The reaction of less bulky ketene silyl acetals is initiated by electron transfer from these compounds to a Lewis acid (Sch. 2). Bulkier ketene silyl acetals, on the other hand, undergo a ubiquitous nucleophilic reaction. Such a mechanistic change is discussed on the basis of a variety of experimental results and on semi-empirical PM3 MO calculations. OEt

a-

*AotSiEt3

+

I

SnCI3

OEt

L

SnCla

b

t-Bu

k

Scheme 2. One-electron transfer mechanism.

I

SnC13

414

Ishihara

Michael reaction of macrocyclic ketene silyl acetals or a-enones occurs smoothly under electron-transfer conditions whereas the reaction of 6-membered analogs is more sluggish, indicating the importance of ring flexibility to enable the a$-carboncarbon bonds of both reaction components to rotate when the radical species are generated [72c]. The complexation of a-enones [(E)-MeCH=CHCOR] with SnC14 has been studied by NMR spectroscopy and by semi-empirical and ab initio SCF-MO methods, which indicate a preference for linear coordination of Lewis acids with a-enones because of the steric effect of R groups in the s-cis conformation (Table 3) [73]. Table 3. Bond angle (L Sn-0-C) of the 2:lcomplexes between a-enones and SnC14.

'R

d

H Et

136 (138) 163 (164) 170 (172) 175 (172)

But Ph

aCalculated by the PM3 method. 'Average of two values. 'The values in parentheses show the bond angles for the 1:l complexes.

9.3.1.5 Additions to Nitriles SnCI4-promoted addition of malonates and bromomalonates to simple nitriles (not electron-deficient) gives a,P-dehydro-P-amino acid derivatives (Eq. 44) [74]. SnC14 is the Lewis acid of choice for the condensation of aroyl chlorides with sodium isocyanate, affording aroyl isocyanates in 70-85 % yields [75]. Non-aromatic acyl chlorides react under more variable reaction conditions. 0 ROuOR

0

+

EtCN

1. SnCI4 * RoZc< 2.Na2CO3 ROzC 55%

(44) NH2

Sn(II) and Sn(IV)Lewis Acids

415

9.3.1.6 Glycosylutions The reaction of glycofuranosides with a free hydroxy group at C-2 with functionalized organosilanes, in the presence of SnC14, provides C-glycosyl compounds with high stereoselectivity (Eq. 45) [76]. Organosilanes such as 4-(chlorodimethylsilyl)toluene, chlorodimethylvinylsilane, allyltrimethylsilane, and allylchlorodimethylsilane are effective reagents. The presence of a leaving group on the silane is essential for good selectivity, because the reaction proceeds intramolecularly through a 2-0-organosilyl glycoside. The availability of furanosides in the ribo, xylo, and arubino series make this reaction valuable for the stereoselective synthesis of C-furanosides. Regioselective glycosylation of nitrogen-containing heterocycles is also effectively promoted by SnC14 [77]. SiMe2CI

%

RO SnC'4

+

(45)

OH

9.3.1.7 De-0-benzylation Regioselective de-0-benzylation of polyols and perbenzylated sugars has been achieved with organotin or other Lewis acids [78,79]. The equatorial 0-benzyl group of 1,6-anhydro-2,3,4-tri-O-benzyl-~-~-mannopyranose is selectively cleaved by SnC14 or TiCI4 (Eq. 46) [51]. The equatorial 0-benzyl group is also selectively cleaved when one of the axial 0-benzyl groups is replaced by an 0-methyl group. The 2-0-benzyl group of 1,2,3-tris(benzyloxy)propaneis selectively cleaved (Eq. 47), but no debenzylation is observed with 1,2-bis(benzyloxy)ethane.

SnC14

92%

5%

TiCI4

77%

19%

9.3.1.8 Rearrangements Lewis acid-promoted (SnCI4or Et2A1C1)rearrangements of allylic acetals provide substituted tetrahydrofurans [80]. Upon addition of SnC14,4,5-dimethyl-2-phenyl-4-vinyl-1,3dioxolane rearranges to the all-cis furan (Eq. 48). No racemization is observed with opti-

cally active acetals; addition of KOH, however, completely epimerizes the furan-carbonyl bond, as does quenching at room temperature. Acetals successfully undergo similar rearrangement provided the alkene is substituted. This reaction is related to the acid-catalyzed rearrangements of 5-methyl-5-vinyloxazolidines to 3-acetylpyrrolidines, which involves an aza-Cope rearrangement and Mannich cyclization [81].

(48)

t

q o ) -0 P h -10 "C, 2 h

Ph

58%

The rearrangement is also useful for furan annulation, through enlargement of the starting carbocycle [82]. Thus addition of SnC14to either diastereomer of the allylic acetal produces the cis-fused cycloheptatetrahydrofuran in 4&76 % yield (Eq. 49). Acetals derived from trans-diols rearrange to the same cis-fused bicyclics in higher yield.

48-76%

An efficient pinacol rearrangement mediated by trialkyl orthoformate has been developed [83]. The reactions of various types of 1,2-diol with a catalytic amount of SnC14 in the presence of trimethyl orthoformate afford the rearranged product in good yields via a cyclic ortho ester intermediate (Eq. 50). This combined system is applicable not only to cyclic and acyclic tri- and tetrasubstituted diols but also to diols forming acid-sensitive acetals.

Ho OH R1*R4 R' R3

SnCI4 (0.2-0.4 equiv) HC(OMe)3(1 equiv) CH2CI2,0 "C-rt 66-97% yield

Bridged ethers incorporating stereocontrolled placement of functionality can be prepared by SnC14-induced cyclization of 3,4-epoxy alcohols. A reaction sequence with a ring contraction and tandem cyclization enables the construction, from unfunctionalized alkenes or arenes, of the 8-oxabicyclo[3.2.l]octanesystem with one or two additional fused rings (Eq. 51) [84].

Sn(II) and Sn(IV)Lewis Acids

417

S ~ C I ~

9.3.1.9 Ene Reactions The Lewis acid-catalyzed ene reaction is synthetically useful methodology for forming new carbonxarbon bonds [85]. Ene reactions utilizing reactive enophiles such as formaldehyde and chloral can be promoted by SnC14. SnC14 also enhances intramolecular ene reactions (Eq. 52) [86,87]. Proton scavenging aluminum Lewis acids such as RAIClz are most often used in ene reactions to eliminate proton-induced side reactions.

with aldehydes is proThe reaction of 6-ethylthio-3,4-dihydro-2-methoxy-2H-pyran moted by SnC14, and has been used in the diastereoselective synthesis of highly functionalized tetrahydropyrans (Eq. 53) [@a] whereas the reaction of 2,2-diethoxy-6(ethylthio)-3,4-dihydro-2H-pyran with aldehydes in the presence of SnC14 gives aldol adducts of glutarates (Eq. 54) [88b].

osit

SnC14(10 mol%)

+

Me0

*

WHO

toluene

MeO"' 4242% yield

418

Ishihara

Et0

0 SEt

-

+ RCHO SnCI4 (10 mol%) R O (54) T S E CH2C12

EtO

71-93% yield

Cationic cyclization of polyenes containing groups such as cyclic acetals are promoted by SnC14 and have been used in the synthesis of cis- and trans-decalins, cis- and trans-octalins, and tri- and tetracyclic terpenoids and steroids [89]. In most instances, all-trans-alkenes yield products with trans, anti, trans stereochemistry (Eq. 55) whereas cis-alkenes lead to syn stereochemistry at the newly formed ring junctions. The stereoselectivity of polyene cyclizations is often greatly diminished when the terminating alkene is a vinyl group rather than an isopropenyl group. Acyclic compounds which contain terminal acyclic acetals and alkenes or vinylsilanes can be cyclized in a similar manner to yield eight- and nine-membered cyclic ethers (Eq. 56) [90].

I H ‘#OH

U

R=H

OMe

The analogous cyclization of chiral imines occurs in high yield (75-85 YO)with good asymmetric induction (36-65 YOee) [Sl]. For example, the cyclization of the aldimine derived from methyl citronellal, using SnC14,affords only the trans-substituted aminocyclohexane in high yield (Eq. 57). ex0 Products are formed exclusively or preferentially over the thermodynamically favored endo products.

Sn(II) and Sn(IV)Lewis Acids

419

Asymmetric azo-ene reactions of di-(-)-(1R,2S)-2-phenyl-l-cyclohexyl diazenedicarboxylate with alkenes are promoted by SnC14.Use of cyclohexene affords the ene adduct in 80 % yield with a diastereomeric excess of > 97:3 (Eq. 58) [92].

80%, >94% de

SnC14-inducedcyclizations between alkenes and enol acetates result in cycloalkanes or bicycloalkanes in high yield (Eq. 59). It is interesting to note that the Me,SiOTfcatalyzed reaction can yield fused rather than bicyclo products. Alkenic carboxylic esters, allylic alcohols, sulfones, and sulfonate esters are also cyclized in the presence of SnC1,; alkenic oxiranes, however, often cyclize in poor yield [89a].

I

SnC14 is also effective in the opening of cyclopropane rings to produce cationic intermediates useful in cyclization reactions. For example, the cyclization of aryl cyclopropyl ketones to form aryl tetralones, precursors of lignan lactones and aryl naphthalene lignans, is mediated by SnC14 (Eq. 60) [93]. The reaction is successful in nitromethane, but not in benzene or dichloromethane. Analogous cyclizations with epoxides result in very low yields (2-5 %).

420

Ishihara

SnC14-promoted intramolecular additions of allylsilanes to a-lactones proceed smoothly to give differently substituted cyclopentanes (Eq. 61) [94]. When the u-benzyloxy-a-lactone is subjected to standard cyclization conditions, the expected cyclopentane product is only obtained as a minor product; the major product, isochroman, is derived from a Friedel-Crafts alkylation (Eq. 62). 1) SnCI4 (2 equiv) -78 "C to 25 "C

SiMe3

(61)

0

CHzCIz, 16 h

80% yield trans:cis=lO:l

35% yield

The synthesis of calixresorc[4]arenes from aldehydes and resorcinol is catalyzed by mineral acids and by Lewis acids. The presence of an alkyl or aryl substituent coming from the aldehyde results in formation of four conformers labeled rccc (all-cis, the crown conformer), rcct (the diamond conformer), rctt, and rtct. SnC14, when used in the condensation of isovaleraldehyde with 1,3-dimethoxybenzene, catalyzes selective formation of the rccc conformer in high yield (Eq. 63) [95].

j:Z-l.

MeovoMe \

+A

C H O

CHC13 SnCI4

(63)

rt, 24 h 85% yield

Cationic polymerizations are catalyzed by SnC14 and other Lewis acids. Propagation is based upon the formation of a cationic species upon complexation with SnC14 (Eq. 64) [96]. Radical pathways are also possible for polymer propagation [97].

R=i-Bu, etc HB (Brernsted acid)=CF&O2H, etc

Sn(II) and Sn(IV)Lewis Acids

421

9.3.1.10 Aziridinations

Reaction of N-benzylidine-o-anisidine with ethyl diazoacetate as the carbene-donor fragment in the presence of SnC14 as the catalyst ( 5 mol %) gives the cis-aziridine selectively as the catalyst in reasonable yields (Eq. 65) [98]. In the presence of SnCI4 no reaction occurs. This imine-SnC14 intermediate gives important information about the reaction course for the Lewis acid-catalyzed aziridination of imines.

C02Et SnCI4 (5 mol%)* JCO2Et

0 " HI

H

i

SnC14 Me

(65)

--N2

Me

X-ray structure

Aziridine-2-carboxylates are also prepared in high yield by reaction of hexahydro1,3,5-triazines or N-methoxymethylanilines with alkyl diazoacetates in the presence of SnC14 or BF3.E t 2 0 (Eq. 66) [99].

R1\Y-YN2+ LA C02R2 LA=Lewis acid

R1

9.3.1.11 [m + n] Cycloadditions

Diels-Alder reactions are enhanced by the complexation of dienophiles or dienes by Lewis acids [loo]. Lewis acids have, furthermore, been successfully employed in asymmetric Diels-Alder additions [loll. Although SnC14 is a useful Lewis acid in Diels-

422

lshihara

Alder reactions, in most instances titanium or aluminum Lewis acids afford greater yields andlor selectivity. The stereoselectivity in Lewis acid-promoted Diels-Alder reactions between chiral @-unsaturated N-acyloxazolidinones results in unexpected selectivity as a function of the nature of the Lewis acid (Table 4) [102]. Optimum selectivity is expected for chelated intermediates, yet both SnC14 and TiC14 perform poorly relative to Et2AlC1 (1.4 equiv.). The formation of the SnC1~-N-acyloxazolidinone chelate has been confirmed by solution NMR studies [103]. These data suggest that other factors such as the steric bulk associated with complexes might contribute to stereoselectivity. Table 4. Stereoselectivity in the Lewis acid-promoted Diels-Alder reaction.

Ax +

Q

- box+ &cox

Lewisacid

x=

i-PC

Lewis acid

endo/exo (diastereomer ratio of endo adduct)

SnCI4 (1.1 equiv) TiCI4 (1.1 equiv) Et2AICI (1.4 equiv)

14.9 (3.1) 9.9 (9.9) 50.0 (17)

In Lewis acid-promoted Diels-Alder reactions of cyclopentadiene with the acrylate of (S)-ethyl lactate, good diastereofacial and endolexo selectivity are obtained with SnC14 (84:16; endolexo = 18:l) and TiC14 (85:15; endolexo = 16:l) [104]. It is interesting to note that boron, aluminum, and zirconium Lewis acids give the opposite diastereofacial selectivity (33:67 to 48:52). Cycloalkenones generally perform poorly as dienophiles in Diels-Alder reactions but their reactivity can be enhanced by Lewis acids [105]. SnC14 is effective in promoting the Diels-Alder reaction between simple 1,3-butadienes, for example isoprene and piperylene, and cyclopentenone esters (Eq. 67) [106]. Cycloaddition does not, however, occur in the presence of SnC14 when the diene contains an oxygen-bearing substituent such as an alkoxy or siloxy group. For such compounds, as is generally true for the Diels-Alder reactions of cycloalkenones, other Lewis acids such as zinc chloride are more effective.

The Diels-Alder reactions of cyclopentadiene with the unsymmetrical maleates or fumarates of axially chiral 8,8’-dihydroxy-l,1’-binaphthalenehave been investigated under different conditions in the presence of a Lewis acid [107]. Diastereo- and endol ex0 selectivity depends on the Lewis acid used. High diastereoselectivity has been achieved with TiCl(Oi-Pr)3 for the endo adduct of the maleate (Eq. 68), and with

Sn(II) and Sn(IV)Lewis Acids

423

SnC14 for that of the fumarate (Eq. 69). These results suggest that the free hydroxyl group of the auxiliary plays a crucial role in inducing the high level of diastereoselectivity in these cycloadditions.

+Q

% W M e /

4

Lewis acid CH2C12

*

C02Me C02R*

(68)

/

SnCI4: 100% yield, endo:exo=93:7, 48% de (endo) TiCl(Oi-Pr)3: 96% yield, endo:exo=86:14, 100% ee (endo)

+Q

Lewis acid CH2C12

C02R*

SnCI4: 56% yield, endo:exo=62:38, 98% de (endo) TiCl(Oi-Pr)3: 100% yield, endo:exo=53:47, 12% ee (endo)

The Lewis acid-promoted Diels-Alder reaction has been employed in the assembly of steroid skeletons [108]. The cycloaddition reaction between a substituted bicyclic diene and 2,6-dimethylbenzoquinoneproduces two stereoisomers in a 1:5 ratio with a yield of 83 % when SnC14 is used in acetonitrile. Tic14 results in slightly higher selectivity (1%)but a lower yield (70 %) (Eq. 70).

q$ + $ Y

0

Lewis acid

HO

0

t

MeCN

#p

' +HO HO SnCI4 1 5 Tic14 1.8

The [4 + 21 cycloaddition reactions of N-sulfinylphosphoramidates,(preparedfrom the corresponding phosphoramidates by treatment with N-(chlorosulfiny1)imidazole) with 1,3-cyclohexadieneoccur diastereoselectively in the presence of SnC14(Eq. 71) [109].

424

Ishihara

Q( W Z F ; ;

SnCI4

-

(Et0)2K-'-

(71)

-78 "C, 15 min

0 90% yield, endo:exo=>95:5

When the dienophile N-a-methylbenzylmaleimideis reacted with 2-t-butyl-1,3butadiene in the presence of Lewis acids, cycloadducts are formed (Eq. 72) [110].

SnCI4 TiCI4

5: 1 151 15:l

EtAIC12

Under Lewis acid catalysis several imines react with the sterically hindered diene shown in Eq. (73) to form cyclic products. This acts as a useful means of construction of fused heterocyclic ring systems bearing an angular methyl group as a characteristic feature [lll].

(73)

0 X=H, SnCI4, 20 "C, 20 h: 65% yield X=H, TiCI4, 20 "C, 1 h: 74%yield

Oxyallyl cations [112], which react as C3 rather than components in cyclization reactions, are generated by the addition of SnC14 to substrates containing silyl enol ethers conjugated with a carbonyl moiety. Thus 2-(trimethylsi1oxy)propenal undergoes [4 + 31 cycloaddition with cyclopentadiene or furan (Eq. 74) [113]. Substituted 1,l-dimethoxyaxetones also form these intermediates and undergo subsequent cyclization (Eq. 75) [114]. This method complements the usual synthesis of oxalyl cations involving reductive elimination of halogens from halogenated ketones or electronically equivalent structures [115].

Sn(II) and Sn(IV)Lewis Acids

425

0

OMe

X=O, CH2

w

Organoaluminum and Sn(1V) Lewis acid-mediated [3 + 21 cycloadditions of oxazoles and aldehydes or diethyl ketomalonate have been observed [116]. The reactions are highly regioselective, with stereoselectivity highly dependent upon the Lewis acid used (Eq. 76). For example, the (BIN0L)AlMe-promoted reaction between benzaldehyde and the oxazole furnishes the oxazoline with a translcis ratio of 2:98. The selectivity is reversed with SnC14which results in a trunslcis ratio of 85:15. trans-5-Substituted 4-alkoxycarbonyl-2-oxazolines are synthesized under thermodynamic conditions in the aldol reaction of isocyanoacetates with aldehydes [117].

PhCHo

N Ar&$OMe

(BIN0L)AIMe

2:98

SnCI4 8515

Tandem pericyclic reactions are a powerful strategy for construction of complex, polycyclic compounds. In recent years tandem [4 + 2]/[3 + 21 chemistry of nitroalkenes and nitronates has been developed by Denmark et al. as a general approach to functionalized pyrrolidine-containing structures [118]. Within the subclass of inter [4 + 2]/intra [3 + 21 cycloadditions, they have documented the fused mode @-tether, Eq. 77), spiro mode (a-tether, Eq. 78), and bridged mode (a-tether, Eq. 79 or ptether, Eq. SO) constructions. These are highly stereoselective processes in the presence of Lewis acid such as SnC14and are amenable to asymmetric modification by use of chiral vinyl ethers. Finally, the nitroso acetals are readily transformed, by hydrogenolysis, into polycyclic, a-hydroxypyrrolidinones, 4-aminocyclohexanones, and cyclopentylamines. fused mode

426

Ishihara

spiro mode 0

Lewis acid [4+2]/[3+2]

'e

bridged mode (a-tether)

-0,2,0 R1%

R2

/

1. Lewis acid

OH

[4+2]

OR*

2. toluene, 1l [3+21

H2

ok R'

R*=Bu, R'=Me, R2=Ph, SnCI4: 73% yield

Regioselectivity in the [2+ 21 cycloaddition reactions of 2-alkoxy-5-allyl-1,4-benzoquinones with styrenes is controlled by the choice of Ti(1V) or SnC14 Lewis acid (Eq. 81) [119]. These reactions are a classic example of the mechanistic variability often associated with seemingly modest changes in Lewis acid.

X=H, 3,4-(OMe)2, 3.4-(-OCH20-); R=Me, R=Bn 0 : 100 SnCI4 (1 equiv) TiCI4 (excess) or TiC14-Ti(Oi-Pr)4 (excess) major : minor

Exclusive [2 + 21 cycloaddition reactions of 1-seleno-2-silylethenes with the highly occur in the preselectrophilic olefin dimethyl l,l-dicyanoethene-2,2-dicarboxylate ence of SnC14 (Eq. 82) [120a]. In contrast, the reaction of 1-seleno-2-silylethenes with methyl vinyl ketone or 2-phosphonoacrylates in the presence of SnC14, involving an unprecedented selenium-mediated 12-silicon migration, leads to the [2 + 11 adduct (Eq. 83) [120b,c].

Sn(l1) and Sn(ZV)Lewis Acids

427

9.3.1.12 Esterification and Etherification Reactions Amorphous Sn-, Si-, and Al-containing mixed oxides with homogeneous elemental distribution, elemental domains, and well-characterized pore architecture, including micropores and mesopores, can be prepared under controlled conditions by use of two different sol-gel processes. Sn-Si mixed oxides with low Sn content are very active and selective mild acid catalysts which are useful for esterification and etherification reactions [121]. These materials have large surface areas, and their catalytic activity and selectivity are excellent. In the esterification reaction of pentaerythritol and stearic acid catalytic activity can be correlated with surface area and decreasing tin content. The trend of decreasing tin content points to the potential importance of isolated Sn centers as active sites.

9.3.2 SnC14-ZnC12-CatalyzedReactions 9.3.2.1 Introduction The blend SnC&-ZnC12 [122] is one of many Lewis acid blends. These include Sn(OTf)2Bu3SnF [123], SnC14-Sn(OTf)2 [124], SbC15-Sn(OTf)2 [125], Me3SiC1-SnC12 [126], TrC1-SnC12 (Tr = trityl) [127], SnO-Me,SiOTf [128], and GaC13-AgC104 [129], which are effective catalysts in carbon-carbon bond-forming reactions. The active catalyst is believed to be 'ZnC1-SnC1; which is formed before addition of the organic reactants. Single Lewis acids (SnC14, TiC14, etc.) promote these reactions, but do not catalyze them [130]. 9.3.2.2 Alkynylationand Allylation Reactions The blend SnC&-ZnC12 is the most useful catalyst (10 mol YO)for the preparation of secondary propargylic ethers from 1-trimethylsilyl-1-alkynes and acetals (Eq. 84) [122]. Conventional promoters such as TrC1-SnC12 and Me3SiC1-SnC12 are not effective, and the blends Sn(I1)-Sn(IV), Sn(I1)-Ti(IV), and Zn(I1)-Ti(1V) lead to lower yields. Moderate yields (29-53 %) are obtained for acetals with large alkoxy groups (R2) but cyclic acetals, e.g. 1,3-dioxolane,do not react. Aromatic and conjugated dimethyl acetals give dipropargyl derivatives as side products. Ethynylation of aldehydes is accomplished by forming intermediate hemiacetal-like compounds from aldehydes and alkoxytrimethylsilanes in the presence of the Lewis acid blend. These intermediates then undergo reaction with 1-trimethylsilyl-1-alkynesto form the desired secondary propargylic ethers (Eq. 85).

428

Ishihara

10% SnC14-ZnCIz

Ri-(OR2 OR2

+ Me3Si-R3

(84)

13-85%

1. cat. SnC4-ZnC12

2. R~OTMS 3. Me3Si+R3

H

*

q2 (85)

R3 0-7870

Propargylic ethers are allylated by allyltrimethylsilane in the presence of the blend SnC14-ZnC12 (Eq. 86) [122]. Thus acetals can be transformed to 15-enynes in one pot with sequential nucleophilic additions. The blend also catalyzes the allylation of aldehydes by allyltrimethylsilane, yielding homoallylic alcohols in good yields (61-74 Yo).

+

Ph

Y‘

p.-,SM i e3

cat. SnC14-ZnC12* Ph<

(86)

56%

Ph

Ph

9.3.2.2 Aldol and Michael Reactions The blend SnCl4-ZnC12 is an effective catalyst in the a 301 reaction of silyl enol el iers with aldehydes (Eq. 87), acetals (Eq. 88), or ketones [122]. Product antilsyn ratios vary (32:69 to 89:ll). The blend also catalyzes the Michael addition of silyl enol ethers with a&-unsaturated ketones (Eq. 89), yielding alkylation products (84-100 Yo) with anti selectivity (antilsyn = 55:45 to 87:23). 0

OSiMe3

+

Ph

OSiMe3 Ph

P PhKH

OMe

+

SnC14-ZnC12 h

vph

(87)

99%

SnC4-ZnC12 p h v p :

PhAOMe

99yo

*

SnC14-ZnC12 Ph

87%

Ph

(89)

Sn(II) and Sn(IV)Lewis Acids

429

9.3.3 Carbometalation Reactions of Organotin Compounds Generated Using SnCI4-Bu3N Organotin compounds RSnC13 participate in carbometalation reactions with C-C triple bonds. When silyl enol ether and 1-alkyne are treated in the presence of SnC14Bu3N conjugated (E)-enone is obtained (Eq. 90) [131]. The reaction gives tetrasubstituted olefins stereoselectively with concomitant C-C double bond formation. The crucial step of this reaction is carbostannylation of the a-stannyl ketone with alkynyltin generated from silyl enol ether and 1-alkyne. The resulting y,y-distannylated intermediate has been isolated and its structure confirmed by X-ray analysis. Simple ketones can be used in place of silyl enol ethers [132]. Heating a mixture of ketones, SnC14,and Bu3N in acetonitrile-dichloromethane (4:l) under reflux followed by quenching with aqueous NaHC03 gives a-enones (Eq. 90), which are probably stannylated with SnC14 and Bu3N.

-k

1

==-R

SnCI4-Bu3N

Although vinylation of phenol is one of the most straightforward means of preparing vinylphenol, attempts at Friedel-Crafts vinylation failed, because of the instability of the product under the reaction conditions used. Low efficiency in generating the electrophilic species might have been another reason. Vinylphenol can be synthesized from phenol and ethyne by use of the SnC14-Bu3N reagent system (Eq. 91) [133]. The reaction can be applied to phenols with electron-donating or electron-withdrawing groups. That the reaction involves carbostannylation was verified by the isolation of P,P-bis-stannylated compound after treatment of the reaction mixture with methyllithium [134].

430

Ishihara

1

SnCI4-Bu3N

1-Alkynes and trimethylsilylethyne also react with phenol in the presence of SnChBu3N reagent to give a-alkylvinyl and /3-silylvinyl derivatives, respectively (Eqs 92,93). In the latter case methyllithium treatment gives P-monostannylated derivative.

up to 81%

OH I

+

*SiMe3

I

e S i M e 3 X

~

1) OH-

1) MeLi 2) Ac20

9.3.4 SnC14-BH (Bronsted Acid)-catalyzed Reactions 9.3.4.1 Enantioselective Protonation Using SnClcBINOL Derivatives Enantioselective protonation of prochiral silyl enol ethers is a very simple and attractive means of preparing optically active carbonyl compounds [135]. It is, however, difficult to achieve high enantioselectivity by use of simple chiral Bransted acids because of conformational flexibility in the neighborhood of the proton. It is expected that coordination of a Lewis acid to a Bransted acid would restrict the direction of the proton and increase its acidity. In 1994, the author and Yamamoto et al. found that the Lewis acid assisted chiral Brgnsted acid (LBA) is a highly effective chiral proton donor for enantioselective protonation (1361.

Sn(II) and Sn(IV) Lewis Acids

431

The LBA is generated in situ from optically pure binaphthol (BINOL) and SnC14in toluene, and is stable in solution even at room temperature. In the presence of a stoichiometric amount of (R)-BINOL-SnC14, the protonation of the trimethylsilyl enol ether derived from 2-phenylcyclohexanone proceeded at -78 "C to give the S ketone with 97 YOee. This reagent is applicable to various ketene bis(trialkylsily1) acetals derived from a-arylcarboxylic acids. The enantioselectivity is independent of the steric features of the silyl groups. The observed absolute stereopreference can be understood in terms of the proposed transition state assembly. The trialkylsiloxy group is directed opposite to the binaphthyl moiety to avoid any steric interaction, and the aryl group stacks on this naphthyl group (Sch. 3 ) .

(R)-LBA

(1 equiv) SnC14 (0.1-1 equiv)

-

toluene, -78 "C

>95%, 97% ee (S)

Another example:

Cl The Proposed Transition State Assembly

Scheme 3

In further studies, the author and Yamamoto et al. succeeded in enantioselective protonation by use of a stoichiometric amount of an achiral proton source and a catalytic amount of (R)-2-hydroxy-2'-methoxy-l,l'-binaphthyl (BINOL-Me) in place of (R)-BINOL [137]. In the presence of 8 mol YOSnC14, 10 mol % (R)-BINOL-Me, and stoichiometric amounts of 2,6-dimethylphenol as an achiral proton source, the protonation of the ketene bis(trimethylsily1)acetal derived from 2-phenylpropanoic acid proceeded at 80 "C to give the S carboxylic acid with 94 YOee. (R)-BINOL-Me is far superior to (R)-BINOL as a chiral proton source during the catalytic protonation, and 2,6dimethylphenol is the most effective achiral proton source. In addition, for high enantioselectivity it is very important that the molar quantity of SnC14 should be less than that of (R)-BINOL-Me. For reaction of 2-phenylcyclohexanone, however, the use of tin tetrachloride in molar quantities lower than BINOL-Me substantially reduced the reactivity of the chiral LBA. Excess SnC14 per chiral proton source, in contrast, promoted this protonation. In the protonation of silyl enol ethers less reactive than ketene bis(trialkylsily1) acetals, chelation between excess tin tetrachloride and 2,6dimethylphenol prevents the deactivation of the chiral LBA (Sch. 4). This catalytic

432

Ishihara

system has been used for the enantioselective synthesis of a variety of 2-arylcarbonyl compounds, for example 2-phenylcycloheptanone, 2-(naphthyl)cyclohexanone and ibuprofen. BINOL-Me (10 mol%) SnC14 (8 rnol%) 2,6-dirnethylphenol(110 mol%) ph+

-

P h q MOTMS s

OH

toluene, -80 "C (addition over 1 h)

94% ee

100% conv. BINOL-Me (2 rnol%) SnC14 (50 mol%) 2,6-dirnethylphenol (1 10 rnol%)

cat. ( 4 - L B A

toluene, -80 "C (addition over 2 h) 100% conv.

-

phro. 90% ee

Scheme 4

The mechanism of the catalytic cycle has been investigated by 'H NMR analysis of 1-to-1 reaction mixtures of the silyl enol ether and chiral LBAs, (R)-BINOL-SnC14 and (R)-BINOL-Me-SnC14, at -78 "C. With the former, two singlets for the TMS groups of Me3SiC1and the mono trimethylsilyl ether of (R)-BINOL were observed at a molar ratio of 15235. With the latter, only one singlet for Me3SiC1was observed. The presence of Me3SiCl suggests the generation of tin(1V) aryloxide intermediates. The catalytic cycle can be reasonably explained by assuming that the tin(1V) aryloxide intermediate is reconverted to the chiral LBA on acquisition of a proton and a chloride from 2,6-dimethylphenol and Me3SiC1 or SnC14,respectively (Sch. 5).

[R3 = alkyl] [R3 = OSiMe3]

Scheme 5

Enantioselective protonation of prochiral allyl anion derivatives is a very simple and attractive route for the preparation of optically active olefins. The acid-promoted hydrolysis of allyltins or allylsilanes is an interesting alternative the enantioselectivity of which has not yet been investigated. Allyltrialkyltin, a synthetic equivalent of allyl anion, is more reactive than the corresponding allylsilane and can be isolated. The

Sn(II) and Sn(IV)Lewis Acids

433

LBAs, BINOL-SnC14 and BINOL-Me-SnC14, are highly effective proton donors for the enantioselective protonation of allyltrimethyltins to give optically active olefins [136c]. In the presence of 1.5 equiv. (R)-BINOL-SnC14 in toluene, the protonation of ( E ) 3-phenyl-2-butenyltrimethyltin proceeded rapidly at -78 "C to form (S)-3-phenyl-lbutene with good enantioselectivity and complete y-regioselectivity (Eq. 94). The enantioselectivity was increased by reducing the reaction temperature to -90 "C in dichloromethane, and was dramatically reduced by use of sterically bulky Sn-substituents. This latter tendency is interesting in that the enantioselectivity is independent of the steric features of the trialkylsilyl substituents in the protonation of silyl enol ethers with LBA. In the above protonation, a proton of (R)-LBA approaches the si face of whereas it approaches the the y-olefinic carbon of (E)-3-phenyl-2-butenyltrialkyltin, opposite enantioface in the protonation of the analogous ketene bis(trimethylsily1) acetal derived from 2-phenylpropionic acid [136a]. (R)-LBA

H

PhPSnMe3 phl'*P CH2C12, -90 "C*

(94)

>99% conversion (R)-BINOL-SnCI4: 87% ee (R)-BINOL-Me-SnCI4: 89% ee

In contrast, moderate enantioselectivity is observed in the protonation of 1-(trimethylstannyl)methyl-2-phenylcyclohexeneas a (2)-allyltrimethyltin, and the absolute stereochemical selectivity is analogous to that in the protonation of the silyl enol ether derived from 2-phenylcyclohexanone (Sch. 6). SnMe3 (R)-BINOL-Me-SnCI4 CH2C12, -90 "C *

1.03 OSiMe3

'"-0

67% ee (R)

Ph%

1

2.Me2S

(R)-BINOL-Me-SnCI4 toluene, -78 "C

Scheme 6

The (E)l (2)substrate-dependent absolute stereochemistry and the steric influence of Sn-substituents on the enantioselectivity observed in these reactions suggest that the mechanism is essentially different from that of silyl enol ethers. Although the detailed stereochemical course has not been ascertained, it is possible that the protonation occurs via a two-chlorine-bridged intermediate between allyltrimethyltin and LBA. Keck et al. have reported that transmetalation between allyltributyltin and free

434

Ishihara

SnCI4 (not complexed with aldehydes) proceeds even at -90 "C [59b]. Tin compounds with a less substituted ally1 group immediately and cleanly give the corresponding allyltrichlorotins by transmetallation through an SET pathway [56], whereas y-disubstituted compounds give precipitates [56]. Although the precipitates have not been well characterized, they are probably formed by cationic polymerization, as occurs with olefins [56]. In fact, protonation occurs when prochiral allyltrialkyltins are added to a solution of LBA. Although we still cannot exclude the possibility that protonation proceeds via transmetalation, this is rather unlikely for the reasons detailed above.

9.3.4.2 Stereoselective Isornerization Catalyzed by SnClCBIPOL Derivatives The two main problems in the preparation of silyl enol ethers are control of regioselectivity, kinetic and thermodynamic, and stereoselectivity, ( E ) and ( Z ) . Although many useful procedures are now available for the kinetic deprotonation of ketones by use of alkali metal dialkylamides, there are few practical procedures for thermodynamic deprotonation. Recently, the author and Yamamoto et al. found that the regio- and stereoselective isomerization of a 'kinetic' silyl enol ether to a 'thermodynamic' ether was catalyzed by LBA [138]. Protodesilylation and isomerization can occur during the reaction of silyl enol ethers with a Bronsted acid. Although the thermodynamic equilibration of trimethylsilyl enol ethers catalyzed by a Bronsted acid was first reported by Stork and Hudrlik in 1968 [139], this equilibration was not established as a synthetically useful procedure, because the use of a Bronsted acid was seriously complicated by the concurrent formation of higher-molecular-weight materials and ketones. The greater stability of the Si-0 bond in silyl enol ethers and the milder nucleophilicity of the conjugate base to the silicon atom favor the latter process. In the enantioselective protonation of silyl enol ethers with chiral LBAs, the conjugate base of (R)-BINOL-Me-SnC14 was less nucleophilic than that of (R)-BINOL-SnC14. Silyl transfer was, furthermore, much slower for the hydrolytically more stable TBDMS enol ethers. We envisaged the possibility that LBA would facilitate isomerization of kinetic silyl enol ethers rather than protodesilylation (Sch. 7).

OSiR3

b

HX

"kinetic"

Isornerization

L

J

"thermodynamic"

Scheme 7

'Kinetic' TBDMS enol ethers were isomerized to the 'thermodynamic' ethers in the presence of catalytic amounts of the coordinate complexes of tin tetrachloride and the monoalkyl ethers of BINOL or biphenol, whereas the use of the coordinate complexes with biphenol and other monoaryl alcohols predominantly afforded the corre-

435

Sn(II) and Sn(IV)Lewis Acids

sponding ketones. For the various structurally diverse substrates, the isomerization cleanly proceeded in the presence of 5 mol YOof the achiral LBA, the monoisopropyl ether of biphenol(BIPOL)-SnC14. The catalyst was effective not only for cyclic silyl enol ethers but also the acyclic ethers, and ( Z ) isomers were obtained stereoselectively (Eq. 95).

g $ s n c\ 1-Pr .1 4

OTBDMS

toluene -78 "C, 1-5 h

R*

&n-OTBDMS

98% rs

OTBDMS

(5 mol%)

R1+R3

OTBDMS

OTBDMS

OTBDMS

A +

99% rs

96% Z

99% rs

To demonstrate the synthetic usability of the isomerization, a one-pot procedure from the racemic silyl enol ether to the (S)-2-phenylcyclohexanone was developed by combining the isomerization with subsequent enantioselective protonation catalyzed by (R)-BINOL-Me in the presence of 2,6-dimethylphenol, tin tetrachloride, and Me3SiC1 (Eq. 96). We also succeeded in the enantiomer-selective isomerization of racemic silyl enol ethers. For example, during isomerization of the same racemic silyl enol ether with 5 mol YO (R)-BINOL-Me-SnC14 at -78 "C for 2 min, the (R)-silyl enol ether was recovered in 42 % yield with 97 YOee. This absolute stereopreference is consistent with that in the above enantioselective protonation (Eq. 97). (R)-BINOL-Me-SnCI4 (5 mol%)

' oTBDMs 0'"

toluene -78 "C. 3 h

(R)-BINOL-Me-SnC4 (5 mol%) +

toluene -78 "C, 2 min

OTBDMS Ph

8-

OTBDMS

1) 2,6-dimethylphenol (1.5 equiv)

2) SnCI4 (1.5 equiv) TMSCI (1.5 equiv) Addition over 3 h 3) -78 "C, 1 h

-8

,>\Ph (96)

85% yield 87% ee

OTBDMS

bPh + bPh

42% yield 97% ee (R)

53% yield

(97)

436

Iskikara

To identify the stereochemical course of the protonation of the vinyl carbon, cis and trans silyl enol ethers derived from menthone were isomerized by use of a deuterated achiral proton source. Surprisingly, only the identical syn isomer was obtained from both the silyl enol ethers. Thus reaction of the cis isomer occurs via an anti SE' mechanism whereas reaction of the trans isomer occurs via a syn SE' mechanism. Interestingly, this cis silyl enol ether was isomerized more rapidly than the trans isomer. In the cis silyl enol ether, deuterium was located at a pseudo-axial position in the isomerized product. Therefore, the anti-&' pathway can be explained by the product developing control via the product-like transition state assembly. The syn-SE' pathway for the trans silyl enol ether can be explained by substrate control via the favored intermediate. The relative contributions of the two pathways depend on the relationship between the free energies of their transition state assemblies (Sch. 8).

Me OTBDMS i-Pr+,,,

(1.5 equiv of D)

OTBDMS

+(1.5 equiv of

D)

toluene

toluene

-78"C, 30 s (84% d)

-78"C, 10 rnin (74% d)

anti-SE'

syn only

i-,,rd OTBDMS

syn-SE'

Scheme 8

9.3.4.3 Enantioselective Polyene Cyclization Catalyzed by SnC&BINOL Derivatives

Despite extensive studies on acid-catalyzed diastereoselective polyene-cyclizations, their enantioselective behavior have not yet been reported. The stereochemical implications of polyene-cyclizations can be explained by the Stork-Eschenmoser hypothesis [140], and the most important feature required for an artificial cyclase is asymmetric induction during the initial protonation. Very recently, the author and Yamamoto et al. succeeded in the first enantioselective biomimetic cyclization of polyprenoids catalyzed by LBA [141]. (-)-Ambrox@ is the most important commercial substitute for ambergris, because of its unique olfactory and fixative properties. Its limited availability has been a stimulus for chemical synthesis. The successful preparation of (-)-ambrox@ was achieved by enantioselective cyclization of homofarnesol promoted by (R)-LBA, although the enantioselectivity and diastereoselectivity were moderate (Eq. 98).

Sn(II) and S n ( N ) Lewis Acids

@

437

(R)-BINOL-Me-SnC14 (2 equiv) t

4

CH2C12 -78 "C, 3 days

W

O

+

+

(-)-Ambrox@ 54% yield

+&

&o

(98)

9-epi-Ambrox@

56 42% ee

26 20% ee

9

9

Cyclization of the more reactive o-geranylphenol with the (R)-BINOL-SnCI4 complex in dichloromethane at -78 "C was complete within 1 day, and the trans-fused tricyclic compound was obtained as a major diastereomer (84 YO ds) in good yield (Eq. 99). The optical yield, however, was only 36 % ee. The enantioselectivity was improved to 50 YOee by using the (R)-BINOL-Me-SnC14 complex. Finally, we found that the monobenzoyl ester of the (R)-BINOL ((R)-BINOL-Bz)-SnC14 complex enabled the most effective control of the absolute and relative stereochemistries (54 YOee, 95 YOds). It seems that the stereoselectivity depends on the activity of LBA, which decreased in the order BINOL-SnC14, BINOL-Me-SnC14, and BINOLBz-SnC14.

+

LBA(1 equiv)

(99)

* \

\

:

CH2CI2 -78 "c, 1 day (R)-BINOL-SnC14

\

H

H

>65% yield

84 (36% ee) : 16 (32% ee)

(R)-BINOL-Me-SnCI4

89% yield

270 (50% ee) : >20 (34% ee)

(R)-BINOL-Bz-SnC4

92% yield

95 (54% ee) :

5 (-)

We found that the same tricyclic ether was obtained with much better selectivity from geranyl phenyl ether (Eq. 100). Surprisingly, the reaction proceeded smoothly even in the presence of 20 mol % of this LBA to give the desired compound with 77 YOee and 98 YOds. Geranyl phenyl ether is more reactive than o-geranylphenol because of the lack of a hydroxy group. It is surmised that this reaction takes place via [1,3]-rearrangement and subsequent cyclization, although this has not yet been confirmed.

438

Ishihuru

( R)-BINOL-Bz-SnCI4 (0.2 or 1 equiv)

CH2C12, -78 "C >99% conv.

81% yield 78% yield

: :

98 (69Y0ee) 98 (77% ee)

2 2

[1,3]-Rearrangement

Other examples are summarized in Table 5. Without exception the use of this LBA resulted in the highest enantioselectivity and diastereoselectivity. The best result of 87 YOee was observed for the cyclization of p-bromophenyl geranyl ether. Table 5. Enantioselective cyclization of geranyl aryl ethers with (R)-LBA.

R (R)-BINOL-Bz-SnC14 CH2C12, -78 "C 299% conv. entry

1

2 3 4 5 6

substrate

(R)-LBA

time

R'

R2

(equiv)

(day)

H H Br Me OMe H

H H H H H Me

1.1 0.2 0.2 0.2 1.1 1.1

1 4 1 4 1 1

trans isomer yield (Yo)

98 98 85 94 84 80

ratio

ee (%)

trans :cis

69 77 87 67 70 62

98:2 98:2 89:ll 97:3 95:5 89:ll

To demonstrate the effectiveness of the LBA-promoted enantioselective cyclization, we biomimetically synthesized (-)-chromazonarol, a minor constituent of brown Pacific seaweed. The cyclization of 4-benzyloxyphenyl farnesyl ether with (S)-LBA gave the desired tetracyclic compound as the major diastereomer in 44 YOee (Eq. 101).

439

Sn(II) and Sn(IV)Lewis Acids

(S)-BINOL-i-Pr-SnC14 (1 equiv)

1. Hz, Pd/C

EtOH (1 01)

CH2C12, -78 "C 3 days

2. AcpO EtSN, DMAP CH2C12, rt

ca. 40% overall yield, 44% ee

The optimized structure of a BIPOL-SnC14 complex was determined at the B3LYP/LANL2DZ level to enable understanding of the absolute stereochemical outcome of the cyclizations (Fig. 3). It is noteworthy that two acidic protons are likely to be located at pseudo-axial sites parallel to an apical axis of the tin atom, and electrostatic interaction between the acidic protons and the apical chlorines is expected.

Figure 3. Optimized geometry of a biphenol-SnC14 complex.

One interesting possibility emerges from the likelihood that an n-z* interaction between an oxygen lone pair of LBA and z*electrons of the terminal carbon-carbon double bond of the substrates stabilizes the transition state of the cyclization or the initial protonation step. The transition-state assembly proposed on the basis of this assumption and the steric repulsion would clearly lead to predominant approach of (R)-LBA to the si face of the terminal isoprenyl group (Fig. 4).

favored Figure 4. Proposed transition-state assemblies.

disfavored

440

lskikavu

Non-enzymatic enantioselective polyene cyclizations are very attractive alternatives to multistep synthesis from naturally occurring chiral synthons.

9.3.4.4 Enantioselective SEM Addition Reaction Using SnC1,BINO

L(SEM)2

The asymmetric synthesis of a-hydroxymethyl carbonyl compounds is currently the subject of considerable interest because of their versatility as dual-function chiral synthons. There have been no reports of successful enantioselective hydroxymethylations of prochiral metal enolates with formaldehyde because of the instability and small steric size of gaseous formaldehyde. The author and Yamamoto et al. developed the enantioselective alkoxymethylation of silyl enol ethers by introducing suitable carbon-electrophiles in place of the activated-protons of LBA [142]. The reaction of the trimethylsilyl enol ether derived from 2-phenylcyclohexanonewith the bis[trimethylsilyl(ethoxy)methyl (SEM)] ether of (R)-BINOL, (R)-BINOL(SEM)2, was promoted in the presence of SnC14,and the (R)-a-SEM ketone was obtained in 91 YO yield and 75 % ee (Table 6). In contrast, the use of the benzyloxymethyl ether gave the corresponding R adduct in 55 % yield and 43 YO ee. This unique phenomenon can be explained by the interaction between silicon and a y positive charge as homohyperconjugation. Finally, the highest ee value of 94 % was achieved by performing the reaction in 1-chloropropane at -125 "Cfor long periods. Table 6. Enantioselective alkoxymethylation.

~

entry

~~

temp., time

yield

ee

R

("C, h)

("/.I

("w

1

Bn

-78,3

55

43

2

(CH2)2SiMe3

-78,1

91

75

3a

(CH&SiMe3

-125,l to -78,l

94

81

4a

(CH&SiMe3

-125,47

55

94

"1-Chloropropane was used.

Good enantioselectivity was observed in the reaction of aromatic R2-substituted silyl enol ethers and tert-alkyl R'- and small alkyl R2-disubstituted silyl enol ethers (Sch. 9). Interestingly, the absolute stereochemical course for aliphatic silyl enol ethers is the opposite of that for aromatic ethers. The (trimethylsily1)ethyl group was easily removed without racemization by treatment with hydrogen fluoride-pyridine.

Sn(II) and Sn(1V) Lewis Acids

441

*

PrCl or CHzClz HF-pyridine * R' %OH THF, rt R3 >95% yield

goMe gM a

*

R'+ArOSiMe3

.,CISEM

Bn

SEM

R3

82% ee, 91% yield -125 "C, 1 h to -78 "C, 1 h

86% ee, 57% yield -125 "C, 108 h

ca. 80% ee, 75% yield -78 "C, 17 h

77% ee, 76% yield -125 "C, 1 h to -78 "C, 1 h OSiMe3 t - R k

*

mu&

+sEM

71Yoee, 78% yield -97 "C, 3 h

SEM

74% ee, 87% yield -97 "C, 3 h

+ SEM

79% ee, 80% yield -97 "C, 6 h

Scheme 9. Enantioselective 2-(trimethylsilyl)ethoxymethylation

The optically active a-SEM ketone obtained in the reaction of Heathcock's silyl enol ether could be converted to a synthetically more useful aldehyde in high yield [143] (Sch. 10). OSiMe3

1. LiAIH4 (96%) 2. Pb(0Ac)a *

[

Enantioselective SEM addition

OHC

xM

1

3. LiAIH4 * H

(84%from 2nd step)

O

T SEM

Scheme 10. Conversion of Heathcock's silyl enol ether to a synthetically more useful aldehyde.

The optimized geometry of the biphenol MOM ether-SnC14 was obtained from a partial PM3 calculation of the MOM units on the basis of a B3LYP/LANL2DZ-optimized geometry for a biphenol-SnC14 complex (Fig. 5). It is noteworthy that the C50 4 bond is almost perpendicular to the C1-C3 axis, presumably because of the steric repulsive interactions with apical and equatorial chlorines. Also of interest is the observation that the C5-06 bond is shorter than the 04-C5 bond. This indicates that the C5-06 bond has a partial double-bond character because of the stereoelectronic effect and its most stable conformer would be the reactive oxonium intermediate.

442

Ishihara

CIap-Sn-04-C5= +33.0° Cl-C2-04-C5 CIe,-Sn-04-C4= -61.50 C3-C2-04-C5 Figure 5. The optimized geometry of the MOM ether-SnQ

= -85.7" = +92.4"

complex.

The absolute stereochemistries observed are best explained in terms of the acyclic extended transition-state mechanism which Noyori postulated in the TMSOTf-catalyzed aldol reactions of dimethyl acetals (Fig. 6) [144]. In the reaction of aromatic silyl enol ethers, the left transition state, which is stabilized by the z-attractive interaction between the phenyl and naphthyl groups, is favored over the right. In the reaction of

'

Interaction

Favored

Disfavored

'R

Disfavored

Favored

Figure 6. The proposed extended transition states (R: CH2CH2SiMe3).

Sn(II) and Sn(IV)Lewis Acids

443

aliphatic silyl enol ethers, on the other hand, the right transition state is preferable to the left, which is destabilized because of steric repulsion between the tert-alkyl group and an apical chlorine.

9.4 Organotin(1V)-catalyzed Reactions 9.4.1 Esterification The transesterification of carboxylic esters and the esterification of carboxylic acids are effected under mild conditions by catalysis by 1,3-disubstituted tetraalkyldistannoxanes (Eq. 102) [145]. A variety of functional groups remain unaffected and esters that are otherwise difficult to obtain are now accessible. An ester bearing a tertiary butyl group in the carboxylic acid moiety remained unchanged in competitive experiments with a less bulky ester, which undergoes transesterification quantitatively. The unique features of the reactions are attributable to the template effects of the dimeric structure of the distannoxanes (Sch. 11).The facility with which catalysts can be converted into alkoxydistannoxanes and the synergistic effect of their proximate tin atoms play key roles in enabling smooth reactions and high selectivity. Another notable feature of catalysts is their unusually high solubility in organic solvents, even though the compounds have a metaloxane core as a major part of the skeleton. The double-layered structure of the catalysts, in which the inorganic moiety is surrounded by eight alkyl groups, enables esterification to be driven to completion simply by heating a mixture of the carboxylic acid and the alcohol. The distannoxane-catalyzed esterification is irreversible, and thus no hydrolysis of the product esters occurs when distannoxanes are used as catalysts.

~

3

0

heat

R2=H or alkyl

0

*

~

R’

example: R=Bu, X=NCS, Y=OH

KoR3

444

Zshihara

L

x

Scheme 11

9.4.2 Transformation to Carbamate Chiral alcohols are smoothly transformed to the corresponding (R)-[1-(1-naphthyl) ethyllcarbamates by treating with (R)-1-(-naphthy1)ethyl isocyanates in the presence of distannoxane catalyst (Eq. 103) [146]. H

toluene, 24 h ROH +

9.4.3 Preparation of Cyclic Thioacetals Carbonyls and acetals are converted to 1,3-dithianes and -dithiolanes upon treatment with 2-stanna-l,3-dithianes and -dithiolanes under catalysis by organotin triflates [147]. In these competition reactions, various types of carbonyl and acetal are differentiated. Aldehydes react preferentially over ketones (Eq. 104), but the preference is completely reversed in the competition reactions between the corresponding acetals and ketals (Eq. 105). The reactivity of aliphatic aldehydes is greater than that of the acetals of aliphatic aldehydes and ketones. Conversely, an aromatic acetal is

Sn(II) and Sn(IV)Lewis Acids

445

more reactive than its parent aldehyde. In the competition between aromatic and aliphatic aldehydes, the reaction of the latter predominates, although aromatic acetals react in preference to aliphatic acetals. Ketones of different types are also differentiated. No such discrimination can be achieved by conventional methods. Organotin triflates are capable of detecting subtle differences in the reactivity of carbonyls and acetals. Such unique differentiation can be explained in terms of the dependence of the reaction path on the substrate- the reactions of carbonyls are initiated by coordination to tin, whereas the reactions of acetals proceed via oxocarbenium ion intermediates.

o

f

'

BupSn(OTf)2 (30mol%)

i

*

CICH2CH&I, 0 "C, 4 h BU2 1.2 equiv

74%

Z

M

e

+

n s, .s Sn

0%

Ei~~Sn(0Tf)~ (30 mol%) * CICH2CH2C1, -1 0 "C, 4 h

BUP

1.2 equiv

9.4.4 Chemoselective Michael and Aldol Reactions Dibutyltin bis(triflate), B U ~ S ~ ( O Tis~ )a ~mild , Lewis acid which catalyzes clean Michael addition of enol silyl ethers [148]. The new catalyst enables use of various labile acceptors such as methyl vinyl ketone and 2-cyclopentenone which do not undergo smooth reaction with conventional Lewis acids. A variety of enol silyl ethers are also employable and thus 2-(trimethylsiloxy)propene, the simplest of this class of compounds, can be used. The adducts of enol silyl ethers of cycloalkanones with vinyl ketones are readily cyclized to give the desired annulated enones free of isomers. Consequently, a practical version of the Robinson annulation has been realized. Organotin perchlorates and triflates, Bu3SnC104, B U & ( C ~ O ~ )and ~ , Bu&1(0Tf)~, catalyze the Mukaiyama reaction of ketene silyl acetals in a highly chemoselective but unusual manner [149]. The competition reaction between aldehyde and acetal leads to exclusive formation of the aldehyde aldols leaving the acetal counterpart intact, an unusual outcome in reaction under acidic conditions (Eq. 107). a-Enals react with ketene silyl acetal in preference to the corresponding alkanal (Eq. 106). In the compe-

446

Ishihara

tition between electronically different aldehydes, an electron-donating group increases the reactivity of aldehydes whereas the reverse is true with an electron-withdrawing group. This order of reactivity is the opposite of that in nucleophilic addition to free carbonyls. In contrast to ketene silyl acetal, enol silyl ethers derived from ketones are not activated by organotin perchlorates. Thus, these two enol silyl ethers can be discriminated from each other (Eq. 108). A disilyl enol ether derived from a keto ester undergoes the electrophilic attack by aldehyde and a-enone exclusively on the ester function. The catalytic activity of TBDMSC104, which would be formed if organotin perchlorates underwent transmetallation with ketene silyl acetal or silyl ether of the aldolate, is totally different from that of organotin perchlorates, indicating that organotin species work as the real active species. The reaction is interpreted in terms of the SN2 mechanism in which the initial coordination of the carbonyl group with organotin perchlorates plays a key role. The remarkable selectivities are ascribed to the weak acidity of the catalysts. ?SiMe2t-Bu

0

J , R

(1.0 rnrnol)

H

+

0

t-BuMe2SiO

A O E t

64-94%

(1.O-1.5rnrnol) Bu3SnC104(0.1rnrnol)

R *

(106) 0%

?SiMe2t-Bu

,j(, +

(1 .o rnrnol)

0

f-BuMe2Si0

A O E t

minor

R uOEt

(1.O-1.5rnrnol) Bu3SnCI04(0.1 mrnol)

+

*

(107)

aoEt

t-BuMe2Si0

+

PhCHO Ph Bu3SnC104or B U ~ S ~ ( C J O ~ ) ~ *

CH2C12, -78 "C

6345%

+

Me3Si0 QBu' Ph

(108) 0%

'Parallel recognition', a new concept for compacting synthetic processes in which different transformations are performed simultaneously on separate reaction sites, has been advanced by Otera and his colleagues [150]. Ketonesla,P-enones and aldehydes/ acetals react selectively with different silyl nucleophiles in parallel in the presence of

Sn(II) and Sn(IV)Lewis Acids

447

(C6F5)2SnBr2(Eqs 109-111) The subtle differentiation among substrates of similar reactivity has recourse to the strong preference of ketene silyl acetals for ketones/a,Benones. OMe 0 Me0

OSiMe3

+ &But

OSiMe2f-Bu

+AOEt 0

(C6F5)2SnBr2

t

CH2C12, -78 "C

OMe OSiMe2t-Bu

(log)

-C , OpEt Bu 73% yield

OSiMe3

L

o

+ A P h

OSiMe2f-Bu

+AOEt OSiMedBu

58% yield

0

9.4.5 Allylation 1,8-Bis(allyldibutylstannyl)naphthalene is highly effective for the selective allylation of aldehydes and ketones under neutral conditions (Eq. 112) [151]. Such a transformation is not realized with monostannane. The former reaction proceeds without any catalyst by taking advantage of the chelation-induced Lewis acidity of bidentate bis(stanny1) compounds.

448

Ishihara

PhCHO +

Bu2Sn I

SnBu2 I

50”c 12 days

Bu2Sn’ I

-0..

SnBu2 I

99% yield

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450 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89.

90. 91. 92. 93. 94. 95. 96.

97. 98. 99.

ishihara Keck, G. E.; Abbott, D. E.; Bodcn, E. P. Enholm, E. J. Tetrahedron Lett. 1984,2.5,3927. Shimada, T.; Yamamoto, Y. Tetrahedron Lett. 1998,39,471. (a) Thomas, E. J. ChemTracts Org. Chem. 1994,207. (b) Carey, J. S.; Thomas, E. J. Synlett 1992,585. Brain, C. T.; Thomas, E. J. Tetrahedron Lett. 1997,38,2387. (a) Keck, G. E.; Castellino, S. J. Am. Chem. Soc. 1986, 108, 3847. (b) Keck, G. E.; Castellino, S.; Wiley, M. R. J. Org. Chem. 1986,51,5478. Keck, G. E.; Castellino, S. Tetruhedron Lett. 1987,28,281. (a) Akiyama, T.; Nakano, M.; Kanatani, J.; Ozaki, S. Chem. Lett. 1997, 385. (b) Akiyama, T.; Yamanaka, M. Synlett 1996,1095. Rychnovsky, S. D.; Sinz, C. J. Tetrahedron Lett. 1998,39,6811. Review of Mukaiyama aldol reaction: Gennan, C. Comprehemive Organic Synthesis 1991,Vol. 2. (a) Reetz, M. T. Angew. Chem. Znt. Ed. Engl. 1984,23, 556. (b) Reetz, M. T.; Kesseler, K.; Jung, A. Tetrahedron 1984,40,4327. (a) Annunzuata, R.; Cinquini, M.; Cozzi, F.; Cizzu, P. G.; Consolandi, E. J. Org. Chem. 1992,57, 456. (b) Annunziata, R.; Cinquini, M.; Cozzi, F.; Cozzi, P. G. Tetrahedron Lett. 1990,31,6733. Nakamura, E.; Kuwajima, I. Tetrahedron Lett. 1983,24,3343. (a) Sato, T.; Wakahara, Y.; Otera, J.; Nozaki, H.; Fukuzumi, S. J. Am. Chem. Soc. 1991, 213,4028. (b) Otera, J.; Fujita, Y.; Sakuta, N.; Fujita, M.; Fukuzumi, S. J. Org. Chem. 1996, 61, 2951. (c) Fujita, Y.; Fukuzumi, S.; Otera, J. Tetrahedron Lett. 1997,38,2117. Fukuzumi, S.; Okamoto, T.; Fujita, M.; Otera, J. Chem. Commun. 1996,393. Scavo, F.; Helquist, P. Tetrahedron Lett. 1985,25,2603. Deng, M. Z.; Caubere, P.; Senet, J. P.; Lecolier, S. Tetrahedron 1988,44, 6079. Martin, 0. R.; Rao, S. P.; Kurz, K. G.; El-Shenawy, H. A. J. Am. Chem. Soc. 1988,210,8698. Showalter, H. D. H.; Putt, S. R. Tetrahedron Lett. 1981,22,3155. Wagner, D.; Verheyden, J. P.H.; Moffat, J. G. J. Org. Chem. 1974,39,24. Hori, H.; Nishida, Y.; Ohrui, H.; Meguro, H. J. Org. Chem. 1989,54,1346. Hopkins, M. H.; Overman, L. E. J. A m . Chem. Soc. 1987,109,4748. Overman, L. E.; Kakimoto, M. H.; Okazaki, M.; Meier, G. P. J. A m . Chem. Soc. 1983, 105, 6622. Herrington, P. M.; Hopkins, M. H.; Mishra, P.; Brown, M. J.; Overman, L. E. J. Org. Chem. 1987, 52,3711. Kita, Y.; Yoshida, Y.; Mihara, S.; Furukawa, A,; Higuchi, K.; Fang, D.-F.; Fujioka, H. Tetrahedron 1998,54,14689. Marson, C. M.; Campbell, J.; Hursthouse, M. B.; Malik, K. M. A. Angew. Chem. Int. Ed. 1998,37, 1122. Reviews of ene reactions: (a) Hoffman, H. M. R. Angew. Chem. Int. Ed. Engl. 1969, 8, 556. (b) Oppolzer, W.; Sniekus, V. Angew. Chem. Int. Ed. Engl. 1978,17,476. (c) Snyder, B. B. Acc. Chem. Res. 1980,13,426. Lindner, D. L.; Doherty, J. B.; Shoham, G.; Woodward, R. B. Tetrahedron Lett. 1982,23,5111. Nakatani, Y.; Kawashima, K. Synthesis 1978,147. (a) Yu, C.-M.; Jung, W.-H.; Choi, H.-S.; Lee, J.-K. Tetrahedron Lett. 1995,36, 8255. (b) Yu, C.-M.; Choi, H.-S.; Lee, J.-K.; Yoon, S.-K. .I. Org. Chem. 1997,62,6687. (a) Review of asymmetric alkene cyclization: Bartlett, P. A. Asymmetric Synthesis; Morrison, J. D., Ed.; Academic Press: New York, 1984; Vol. 3, Part B, p 341. (b) Review of thermal cycloadditions: Fallis, A. G.; Lu, Y.-F. Advances in Cycloaddition; Curran, D. P., Ed.; JAI: Greenwich, CT, 1993; Vol. 3, p 1. (a) Overman, L. E.; Blumenkopf, T. A,; Castaneda, A,; Thompson, A. S. J. Am.Chem. Soc. 1986,108, 3516. (b) Overman, L. E.; Castaneda. A.;Blumenkopf,T. A.J. A m . Chem. Soc. 1986,108,1303. Demailly, G.; Solladie, G. J. Org. Chem. 1981,46, 3102. Brimble, M. A,; Lee, C. K. Y. Tetrahedron: Asymmetry 1998, 9, 873. Murphy, W. S.; Waltanasin, S. J. Chem. Soc., Perkin Trans. 1 1982,1029. Zhao, C.; Romo, D. Tetrahedron Lett. 1997,38, 6537. Iwanek, W. Tetrahedron 1998,54,14089. (a) Kamigaito, M.; Maeda, Y.; Sawamota, M.; Higashimura, T. Macromolecules 1993, 26, 1643. (b) Takahashi, T.; Yokozawa, T.; Endo, T. Makromol. Chem. 1991,192,1207. (c) Ran, R. C.; Mao, G. P. J. Macromol. Sci. Chem. 1990, A27, 125. (d) Kurita, K.; Inoue, S.; Yamamura, K.; Yoshino, H.; Ishii, S.; Nishimura, S. I. Macromolecules 1992,2.5,3791. (e) Yokozawa, T.; Hayashi, R.; Endo, T. Macromolecules 1993,26,3313. (a) Tanaka, H.; Kato, H.; Sakai, I.; Sato, T.; Ota, T. Makromol. Chem., Rapid Commun. 1987, 8, 223. (b) Yuan, Y.; Song, H.; Xu, G. Polym. Int. 1993,31,397. (a) Rasmussen, K. G.; Hazell, R. G.; Jorgensen, K. A. Chem. Commun. 1997, 1103. (b) Rasmussen, K.; Juhl, K.; Hazell, R. G.; Jbrgensen, K. A. J. Chem. Soc., Perkin Trans. 2 1998,1347. Ha, H.-J.; Suh, J.-M.; Kang, K.-H.; Ahn. Y.-G.; Han, 0. Tetrahedron 1998,54, 851.

Sn(II) and Sn(IV)Lewis Acids

451

100. Birney, D. M.; Houk, K. N. J. Am. Chem. SOC.1990,112,4127. 101. Review of asymmetric Diels-Alder reactions, see: Ishihara, K.; Yamamoto, H. Advunces in Cata-

102. 103. 104. 105. 106. 107. 108.

109. 110. 111. 112. 113. 114. 115. 116. 117. 118.

119. 120. 121. 122. 123. 124. 125. 126. 127. 128. 129. 130. 131. 132. 133.

134. 135. 136. 137. 138.

lytic Processes; Doyle, M. P., Ed.; JAI Press Inc.: London, 1995; Vol. 1,pp 29-59. Evans, D. A,; Chapman, K. T.; Bisaha, J. J. A m . Chem. SOC.1988,110,1238. Castellino, S. J. Org. Chem. 1990,55,5197. Poll, T.; Helmchen, G.; Bauer, B. Tetrahedron Lett. 1984,25,2191. (a) Fringuelli, F.; Pizzo, F.; Taticchi, A.; Wenkert, E. J. Org. Chem. 1983, 48, 2802. (b) Fringuelli, F.; Pizzo, F.; Taticchi, A,; Halls, T. D. J.; Wenkert, E. J. Org. Chem. 1982, 47, 5056. Liu, H.; Ulibarri, G.; Browne, E. N. C. Can. J. Chem. 1992, 70,1545. Tanaka, K.; Asakawa, N.; Nuruzzaman, M.; Fuji, K. Tetrahedron: Asymmetry1997,8,3637. Arseniyadis, A,; Rodriguez, R.; Spanevello, J. C.: Thompson, A,; Guittet, E.; Ourisson, G. Tetrahedron 1992,48,1255. Zhang, Y.; Flann, C. J. J. Org. Chem. 1998,63,1372. Baldwin, S. W.; Greenspan, P.; Alaimo, C.; McPhail, A. T. Tetrahedron Lett. 1991,42,5877. Stanetty, P.; Mihovilovic, M. D. Chem. Commun. 1997,849. For a recent review of oxalyl cations, see: Mann, J. Tetrahedron 1986,42,4611. Masatomi, 0.;Kohki, M.; Tatsuya, H.; Shoji, E. J. Org. Chem. 1990,55,6086. Murray, D. H.; Albizati, K. F. Tetrahedron Lett. 1990,31,4109. Hoffman, H. M. R. Angew. Chem. Int. Ed. Engl. 1973,12,819; 1984,23,1. Suga, H.; Shi, X.; Fujieda, H.; Ibata, T. Tetrahedron Lett. 1991,32,6911. For examples of enantioselective synthesis of trans-4-alkoxy-2-oxaolines, see: Ito, Y.; Sawamura, M.; Shirakawa, E.; Hayashizaki, K.; Hayashi, T. Tetruhedron Lett. 1988, 29, 235; Tetrahedron 1988,44,5253. (a) Denmark, S. E.; Tnorarensen, A. Chem. Rev. 1996, 96, 137. (b) Denmark, S. E.; Stolle, A,; Dixon, J. A.; Guagnano, V. J. Am. Chem. SOC.1995,117,2100. (c) Denmark, S. E.; Guagnano, V.; Dixon, J. A,; Stolle, A. J. Org. Chem. 1997, 62, 4610. (d) Denmark, S. E.; Dixon, J. A. J. Org. Chem. 1997,62,7086. (a) Engler, T. A,; Wei, D.; Latavic, M. A. Tetrahedron Lett. 1993,34,1429.(b) Engler, T. A,;Iyengar, R. J. Org. Chem. 1998,63,1929. (a) Yamazaki, S.; Kumagai, H.; Yamabe, S.; Yamamoto, K. J. Org. Chem. 1998, 63, 3371. (b) Yamazaki, S.; Tanaka, M.; Yamaguchi, A,; Yamabe, S. J. Am. Chem. SOC.1994, 116, 2356. (c) Yamazaki, S.; Takada, T.; Imanishi, T.; Moriguchi, Y.; Yamabe, S. J. Org. Chem. 1998,63,5919. Storck, S.; Maier, W. F.; Miranda Salvado, I. M.; Ferreira, J. M. F.; Guhl, D.; Souverijns, W.; Martens, J. A. J. Catal. 1997,172,414. (a) Hayashi, M.; Inubushi, A.; Mukaiyama, T. Bull. Chem. SOC.Jpn 1988, 61, 4037. (b) Hayashi, M.; Inubushi, A,; Mukaiyama, T. Chem. Lett. 1987,1975. (a) Mukaiyama, T.; Uchiro, H.; Kobayashi, S. Chem. Lett. 1989, 1001. (b) Kobayashi, S.; Mukaiyama, T. Chem. Lett. 1989, 297. (c) Kobayashi, S.; Uchiro, H.; Fujishita, Y.; Shiina, I.; Mukaiyama, T. J. Am. Chem. SOC.1991,113,4247, Mukaiyama, T.; Shimpuku, T.; Takashima, T.; Kobayashi, S. Chem. Lett. 1989,145. Kobayashi, S.; Tamura, M.; Mukaiyama, T. Chem. Lett. 1988,91. (a) Iwasawa, N.; Mukaiyama, T. Chem. Lett. 1987,463. (b) Mukaiyama, T.; Wariishi, K.; Saito, Y.; Hayashi, M.; Kobayashi, S. Chem. Lett. 1988,1101. (a) Mukaiyama, T.; Kobayashi, S.; Tamura, M.; Sagawa, Y. Chem. Lett. 1987,491. (b) Mukaiyama, T.; Sugumi, H.; Uchiro, H.; Kobayashi, S. Chem. Lett. 1988,1291. Mukaiyama, T.; Uchiro, H.; Kobayashi, S. Chem. Lett. 1990,1147. Mukaiyama, T.; Ohno, T.; Nishimura, T.; Suda, S.; Kobayashi, S. Chem. Lett. 1991, 1059. (a) Mukaiyama, T.; Narasaka, K.; Banno, K. Chem. Lett. 1973, 1011. (b) Mukaiyama, T. Angew. Chem. Int. Ed. Engl. 1977,16, 817. (c) Narasaka, K.; Soai, K.; Aikawa, Y.; Mukaiyama, T. Bull. Chem. SOC.Jpn 1976,49,779. Yamaguchi, M.; Hayashi, A,; Hirama, M. J. Am. Chem. SOC. 1993,125,3362. Hayashi, A,; Yamaguchi, M.; Hirama, M. Synlett 1995,Sl. (a) Yamaguchi, M.; Hayashi, A.; Hirama, M. J. Am. Chem. SOC.1995,117,1151. (b) Yamaguchi, M.; Arisawa, M.; Omata, K.; Kabuto, K.; Hirarna, M.; Uchimaru, T. J. Org. Chem. 1998, 63,7298. Yamaguchi, M.; Kobayashi, K.; Arisawa, M. Synlett 1998,1317. Fehr, C. Angew. Chem. Int. Ed. Engl. 1996,35,2566. (a) Ishihara, K.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. SOC.1994, 116, 11179. (b) Ishihara, K.; Nakamura, S.; Yamarnoto, H. Croat. Chem. Acta 1996, 69, 513. (c) Ishihara, K.; Ishida, Y.; Nakamura S.; Yamamoto, H. Synlett, 1997,758. (a) Ishihara, K.; Nakamura, S.; Kaneeda, M.: Yamamoto, H. J. Am. Chem. SOC. 1996,118,12854. (b) Yanagisawa, A,; Ishihara, K.; Yamamoto, H. Synlett 1997,411. Ishihara, K.; Nakamura, H.: Nakarnura, S.; Yamamoto, H. J. Org. Chem. 1998,63,6444.

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139. (a) Stork, G.; Hudrlik, P. F. J. Am. Chern. Soc. 1968,90,4462.(b) House, H. 0.;Czuba, L. J.; Gall, M.; Olmstead, H. D. J. Org. Chern. 1969,34,2324. 140. (a) Stork, G.; Burgstahler, A. W. J. Am. Chem. Soc. 1955,77,5068. (b) Eschenmoser, A,; Ruzicka, L.; Jeger, 0.;Arigoni, D. Helv. Chirn. Acta 1955,38,1890. 141. Ishihara, K.; Nakamura, S.; Yamamoto, H. J. Am. Chem. Soc. 1999,121,4907. 142. Ishihara, K.; Nakamura, H.; Yamamoto, H. J. Am. Chem. Soc. 1999,121,7720. 143. Mori, 1.; Ishihara, K.; Heathcock, C. H. J. Org. Chern. 1990,55,1114. 144. Murata, S.; Suzuki, M.; Noyori, R. J. Am. Chern. Soc. 1980,102,3248. 145. (a) Otera, J.; Dan-oh, N.; Nozaki, H. J. Org. Chem. 1991,56,5307. (b) Otera, J. Chern. Rev. 1993,93, 1449. 146. Otera, J.; Fujita, Y.; Sato, T. Synlett 1995,433. 147. Sato, T.; Otera, J.; Nozaki, H. J. Org. Chem. 1993,58,4971. 148. Sato, T.; Wakahara, Y.; Otera, J.; Nozaki, H. Tetrahedron 1991,47,9773. 149. (a) Otera, J.; Chen, J. Synlett 1996,321. (b) Chen, J.; Sakamoto, K.; Orita, A,; Otera, J. Synlett 1996, 877. (c) Chen, J.; Otera, J. Tetrahedron 1997,53,14275.(d) Chen, J.; Otera, J. Synletf1997,29. 150. Chen, J.; Sakamoto, K.; Orita, A,; Otera, J. Tetrahedron 1998,54,8411. 151. Asao, N.; Liu, P.; Maruoka, K. Angew. Chem. Int. Ed. Engl. 1997,36,2507.

Lewis Acids in Organic Synthesis Edited bv Hisashi Yamarnoto Copyright 0WILEY-VCH Verlaa GmbH.2000

10 Preparation and Addition Reactions of Allylic and Allenic Tin and Indium Reagents James A . Marshall

10.1 Introduction In the thirty-some years since Konig and Neumann reported that ally1 triethyltin adds thermally to aldehydes to yield homoallylic alcohols, extensive studies on the mechanism and synthetic applications of numerous variants of this reaction have been reported by research groups around the world [1,2]. In the thermal version of these additions the Et3Sn moiety functions as a weak Lewis acid to afford the adduct via a cyclic transition state (Eq. 1).

It was later found that additions proceed more readily in the presence of Lewis acids such as BF3.0Et, [3]. These reactions, which can be conducted at -78 "C on a variety of aldehydes and ketones, involve an acyclic transition state. They are most commonly performed with allylic tributylstannanes and require a full equivalent or more of the Lewis acid (Eq. 2).

Another variation on the reaction involves Lewis acid exchanges with the Bu3Sn moiety to form transient allylmetal species which then add to the aldehyde through a cyclic transition state (Eq. 3) [4]. These additions proceed under mild conditions owing to the strong affinity of the electron-deficient metal of the allylic MXn-I reagent for the carbonyl oxygen.

m S n B u 3

-

MXn = Ti&, SnCI4, InC13

-& OH

+ Bu3SnX

R

(3)

454

Marshall

In all three versions of the ally1 addition reaction the homoallylic alcohol products are isolated after addition of a proton source, usually aqueous acid, to hydrolyze the intermediate metal alkoxide. Thus a major consideration in these reactions is the separation of the adducts from the organotin by-products and the safe disposal of these by-products. In reactions involving allylic Bu3Sn compounds, Bu3Sn halides, stannoxanes, and the pervasive Bu3SnSnBu3 constitute the principle by-products. The halides are most easily removed by treatment of the product or the reaction mixture with a tertiary amine, usually Et3N, to form organic-insoluble tin complexes. Tin halides can also be removed with aqueous ammonia during the extraction process preceding isolation. Bu3SnC1 is significantly more soluble in hexane than in acetonitrile. Because these solvents are immiscible, it is possible to extract the organic product from a hexane solution of the reaction mixture, after quench, with acetonitrile. Aqueous KF forms an insoluble polymer with Bu3SnC1which can be removed by filtration. The stannoxane, Bu3SnOSnBu3, is more difficult to remove because of its lower reactivity toward amines and KF. Several treatment cycles are usually needed and, even then, removal is rarely complete. Although hexabutyl ditin is readily separated from even moderately polar allylic stannanes by column chromatography, when the allylic tin reagents are nonpolar, removal is often not possible. Frequently small amounts of distannane impurity can be carried on to the addition reaction without an adverse affect on the yield. As the products of the additions are alcohols, subsequent removal of the distannane poses little problem.

10.2 Toxicity Another concern associated with organotin chemistry is the toxicity of tin compounds [5]. As roughly 200 000 tons of tin metal are consumed annually worldwide, it can be correctly assumed that considerable studies on toxicity have been conducted. Metallic tin is non-toxic upon oral administration to rats (LDSO> 2 g kg-'), or birds. Tin has long been used as a container for foodstuffs and has more recently been adopted as a replacement for lead foil capsules on wine bottles. The LDSO of many common tin salts orally administered to rats is > 2 g kg-' (Sn02 > 10 g kg-', SnS04 > 2 g kg-', SnClz 0.7 g kg-', SnF2 0.2 g kg-I). Both SnC14and SnC12are of low toxicity to freshwater algae. Tributyl-, triphenyl-, and dibutyltin compounds are moderately toxic but nonetheless have been used in commercial products worldwide for over 30 years with few reported adverse effects on humans. Trioctyl- and tridecyltin derivatives are essentially non-toxic. On the other hand, the lower alkyltin compounds Me3Sn- and Et,SnX are highly toxic and should be used with great caution in a well ventilated fume hood. The LDSOvalues of trialkyltin acetates in rats are reported as Me3Sn = 9 mg kg-', Et3Sn = 4 mg kg-', Pr3Sn = 118 mg kg-', Bu3Sn 130 mg kg-', (C8H17)3Sn= 30 000 mg kg-'. The anionic substituent (halide, carboxylate, etc.) of the trialkyltin compound is reported to have little affect on toxicity. Tributyltin compounds are significantly more toxic to marine organisms than to rats or (presumably) humans. For this reason, they have been used in marine paints as antifoulants for many years. Their economic benefit in such applications has been estimated at $3 billion annually, much of which is attributable to savings in fuel with a resultant decrease in engine emissions to the environment. The small amounts of tri-

-

Preparation and Addition Reactions

455

butyltin compounds released from these paints have a half-life in water of 1-3 weeks. In contrast to their effect on humans methyltin halides, including the trimethyl compounds, have relatively low toxicity to many marine organisms.

10.3 Preparation of Allylic Trialkylstannanes Allyl- and methallyltriphenyltin have been prepared by addition of the allylic halide and triphenyltin chloride to a solution containing Mg and a small amount of the allylic Grignard reagent in THF under reflux (Eq. 4) [6]. The tributyltin analogs can also be synthesized along these lines in the presence of PbBr2 as a catalyst (Eq. 5 ) [7]. A Barbier coupling of allylic bromides and Bu3SnC1 mediated by Zn in aqueous THF has also been reported (Eq. 6) [S].

R &SnPh3

R

+

Ph3SnCI

R=H,Me X = CI, Br

R&X

(70-80%)

+

Bu3SnCI

R = Ph, Me, H X = CI. Br

R&Br

(4)

Mg, THF

+ Bu3SnCI

Mg’ PbBr2

R & ,.S ,-nBu3

(5)

THF (70-95Yo)

-

Zn, THF-H20

R & ,.S ,-nBu3

(6)

(75-80%) R=H,Me

R = Me [60:40 (E):(Z) ]

A variety of allylic tributylstannanes has been synthesized through in situ displacement of allylic mesylates with Bu3SnLi (Eq. 7) [9]. The method is quite general for primary allylic stannanes. A free-radical approach has also been successfully applied to the synthesis of primary allylic tributylstannanes (Eq. 8) [lo]. The sequence involves a thermal [3,3] rearrangement of an allylic methyl xanthate then addition of a Bu3Sn radical to the double bond of the derived dithiocarbonate intermediate and subsequent loss of COS in a chain-propagating step.

456

Marshall

Bu3SnH R3

cyclohexane 3uBnS , , # , 2R

(7)

R'

R3

R~+OH 2. MsCl R' R' R' = H, Me, C5Hll, CH*ODPS, CH2CH2CH=CMe2 R2 = H, Me, CH2CH2CH=CMe2 R3 = H, Me

10.4 Additions of Trialkyl Allylic Stannanes to Aldehydes and Ketones As noted in the introduction, the first addition of an allylic stannane to carbonyl compounds was reported over thirty years ago and involved ally1 triethyltin and mainly aromatic aldehydes at elevated temperatures without solvent (Table 1) [l].In these experiments the triethylstannyl ether of the alcohol adduct was isolated by distillation before conversion to the final product. Table 1. Thermal additions of CH2=CHCH2SnEt3to aldehydes.

R

TemD. ("C) Time (h) Yield (YO)

Preparation and Addition Reactions

457

A more extensive study of the thermal addition revealed a strong preference for anti (2) adducts when substituted allylic stannanes are employed (Table 2) [ll]. These findings are consistent with a cyclic transition state in which the allylic substituent (Me) of the stannane adopts an axial orientation in a chair-like transition state. The preference for this axial orientation is the result of unfavorable steric interactions between an equatorial allylic substituent and the adjacent R groups of the trigonal bipyramidal stannane (Eq. 9). Table 2. Thermal additions of (E)-MeCH=C(R2)CH(Me)SnR3to aldehydes. OH 1. heat, 18:

R2 ,liH

2. H+

+Me"-fSnR3

R2

R1*

Me

Me

Fine R'

R2

R

Temp. ("C)

Bu Bu Bu Bu

150 80 110 150 150 150 80

72 87 70 62 55 74 80

150 80 150

89 69 50

Bu Ph Ph Bu Bu Bu

Yield ("A)

Additions of allylic stannanes to aldehydes can also be effected under high pressure without an added catalyst or promoter [12]. Interestingly, and in apparent contradiction to the thermal additions, mixtures of syn and anti adducts are formed from both ( E ) - and (Z)-allylic stannanes (Table 3). Moreover, the proportion of ( E ) syn and ( Z ) + anti products actually increases as the pressure is increased in contrast with what might have been expected from the thermal reactions. These findings have been interpreted as reflecting reduced activation volumes in the boat vs chair transition states, as illustrated in Eq. (10). The effect is also observed with propanal, 2-ethylbutanal, and 2-phenylpropanal. --f

458

Marshall

Table 3. Ratios of syn and anti adducts from nonanal and ( E ) - and (Z)-2-butenyl tributyltin as a function of pressure.

0

-

/AH+Me%&./SnBu3

C8H17

OSnBu

C8H17

P (atm) 2.55~10~ 3.92~10' 6.37~10' 7.65~10'

Stannane

(E) (E) (E) (E)

+ C8H17+

~

anti

Me

anti:syn Stannane

2.15:l 1.80:l 1:57:1 1.51:l

OSnBu3

(Z) (Z) (Z)

(Z)

SYn

Me

antisyn

1.16:l 1.33:l 1.52:l 1.53:l

chair

boat

The first studies on Lewis acid promotion of allylic stannane additions were conducted with BF3. OEtz (Table 4) [13]. Aldehydes were found to be more reactive than ketones and methyl ketones were more reactive than internal ketones. Addition to 4-tert-butylcyclohexanone favored equatorial allylation by 85:15.

Preparation and Addition Reactions

459

Table 4. BF3-promoted additions of allyltin compounds to aldehydes OH

R

R'

Ph Ph pMeC6H4 C6H13 pNCC6H4

H Me H H

R2

BF3*OEt2(equiv.) Yield (%)

2.0 1 .O 3.0 2.0 4.0

Me Bu Bu Me Me

H

92 90 80 73 85

In contrast with the thermal reactions, syn-homoallylic alcohols were found to be the major adducts of both ( E ) - and (2)-allylic stannanes (Table 5). These findings were interpreted by assuming an acyclic transition state for the addition in which steric interactions between the aldehyde substituent R and the Me substituent of the stannane were the controlling factor (Fig. 1) [14]. An antiperiplanar arrangement was initially proposed, but later work has implicated synclinal arrangements in certain cases. It has also been found that anti products may result as the major or exclusive isomers from such additions. The issue is a complex one and multiple factors, including orbital overlap, may be operative. Table 5. BF3-promoted additions of crotyl tributyltin to achiral aldehydes Me*SnBu3 RilH

+

(eor(4

syn Me

syn:anti

R Ph Ph Ph Ph i-Pr EtZCH i-Bu

BF3*OEt2(2 eq) CH2C12-78"C

1oo:o 9O:lO 60:40 0:lOO 1oo:o 1oo:o 1oo:o

98:2 98:2 96:4 99:1 91:9 98:2

9O:lO

Yield ("A)

90 90 90 90 90 92 90

460

Marshall

R 4 H H Y M e

.-BF3

r”y” 2 o.- BF3 ,

0-

H (€)-synclinal

H .. (Z)-synclinal

Figure 1. Possible acyclic transition-state arrangements for crotylstannane aldehyde additions leading to the syn adduct. Only one of two possible synclinal arrays is depicted.

The syn:anti ratios and the regiochemistry of adducts from additions of crotyl tributyltin to cyclohexanecarboxaldehyde have been found to vary with the nature of the Lewis acid (Table 6) [15]. Formation of the anti adduct in large excess when two equivalents of TiC14 are employed before addition of the aldehydes can be attributed to a transmetalation reaction leading to a crotyltitanium chloride reagent which reacts with the aldehyde through a cyclic transition state. The reduction of syn:anti selectivity and regioselectivity when MgBrz and SnC14 are used might result from steric interactions in the transition states leading to the syn adducts (Fig. 1). Table 6. Selectivity in additions of crotyl tributyltin to cyclohexanecarboxaldehyde as a function of Lewis acid.

SYn

anti

C-CGHllL M ; - c 6 H l , & linear ( E ) Lewis Acid

syn

anti

Linear (€)

BF3*OEt2 M!m2 SnCI4 TiCI4 Ti& (2x)

96 52 23 90

4 36 26 7 91

0 0 15 1 5

4

linear(Z)

Me

Linear (Z)

0 12 36 2 0

Additions of allyltributyltin to an a-oxygenated aldehyde are also influenced by the choice of Lewis acid (Table 7) [16]. The relative stereochemistry of the adduct is a result of the facial preference for attack on the aldehyde-Lewis acid complex by the stannane. The reaction involving BF3. OEt, is subject to Felkin-AhnKornforth control whereas MgBr2 and Tic& in CH2C12 proceed by chelation control. In THF the

Preparation and Addition Reactions

461

Felkin-AhdCornforth (anti)product is predominant with MgBrz as a consequence of strong solvent-Lewis acid association at the expense of chelation. The same trend is observed with the a-OTBS derivative and MgBr2 owing to the diminished capacity of TBS ethers to complex with MgBr2. Probable transition states for these additions are depicted in Fig. 2. Table 7. Stereoselectivity in Lewis-acid promoted additions of ally1 tributyltin to an a-oxygenated aldehyde.

R

Lewis Acid

Solvent

syn:anti

Bn

BF3*0Et2

CH2C12

Bn Bn

MgBr2 MgBr2

Bn TBS

Ti& MgBr2

CH2C12 THF CH2C12 CHZCIZ

39:61 1oo:o 20:80 1oo:o 5:95

LA

,

:4vrBu3 0’

R +’

R& ’

R20

Me

anti,syn

.LA

‘1

R26

Me

anti,anti

R20

Me

SnBu3 Cornforth/antiperiplanar

Cornforthlsynclinal

SnBua chelation/antiperiplanar

chelation/synclinal

Figure 2. Transition-state arrangements for Lewis acid-promoted additions of crotyl tributyltin to aalkoxy aldehydes . The enantiomeric aldehydes are depicted for each set of additions to aid visualization.

Interestingly, anti adducts predominate in MgBr2-promoted additions of /3-methylcrotyl tributyltin to a-oxygenated aldehydes (Eq. 11) [17]. Evidently the /3-methyl substituent causes the synclinal transition state to be favored in the chelation-controlled addition. The effect is not present in BF3. OEt2-promoted additions, which proceed as expected to afford the syn adducts. The two pathways are shown for enantiomeric aldehydes to assist in direct comparison of the two transition states. The actual additions were conducted with achiral (R = H) or racemic (R = Me) aldehydes)

462

Marshall

Br

-

BnO& -

OH Me -

.

-

R Me anti-adduct synclinal

(11) M e T S n B u 3 Me BnO

i

i

BnO Me syn-adduct

BF30OEt2

antiperiplanar

Comparison of reaction rates and selectivities for BF3-promoted additions of crotyl tributylstannanes to aldehydes revealed that the trans crotyl isomer reacts faster and is more syn-selective than the cis isomer (Table 8) [MI. It is proposed that the synclinal transition state arrangement for the trans-crotylstannane is stabilized by a favorable interaction between the LUMO of the carbonyl oxygen and the allylic tin sigma HOMO. The analogous transition state for addition of the cis-crotylstannane is destabilized by unfavorable steric interactions (Fig. 3). Table 8. Diastereoselection for BF3-promoted additions of trans- and cis-crotyl tributylstannanes to aldehydes. Me

BF3*OEt2

SnBu3

OH

OH

R+

CH2C12, -78 OC

+

R

Me

Y Me

anti

SYn

R

trans :cis

syn:anti

C-C6H11 Ph C - C d ii Ph

9O:lO 9O:lO 12:88 12:88

94:6 98:2 48:42 81:19

Preparation and Addition Reactions

HOMO

463

LUMO

faster

SnBu3 trans-antiperiplanar

1

Me trans-synclinal

slower

SnBu3 cis-antiperiplanar

cis-synclinal

Figure 3. Alternative transition states for additions of trans- and cis-crotylstannanes to aldehydes leading to syn adducts.

A parallel trend is observed for MgBr2-promoted additions of cis- and trans-crotyl tributylstannanes to a-benzyloxy aldehydes but the effect is much smaller (Table 9) [18]. In such reactions the orientation of the allylic stannane and the chelated aldehyde is governed by steric effects in which the vinylic y-hydrogen orients over the five-membered chelate (Fig. 4). Support for this picture is provided by competition experiments in which P,P-dirnethylallyl tributyltin was found to be markedly slower than the crotyl or ally1 derivatives in additions to a-benzyloxypropanal. The observed rate decrease was attributed to the disfavored relationship of a vinylic methyl substituent with the chelate ring resulting in unfavorable steric interactions. Table 9. Diastereoselectivity for MgBr2-promoted additions of trans- and cis-crotyl tributylstannanes to a-benzyloxypropanal.

F

BnO,,,, Me

BnO -

Me -

MgBr2 H+-%.p-./ SnBu3 *Me+/+Me CH2C12

trans and cis

BnO

Me

A ~

OH syn, syn

trans:cis

syn, syn:syn, anti

9O:lO 74:26 12:88

91 :9 88:12 85:15

OH syn, anti

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Marshall

53‘

B.r

Br

B.r

1”bO

I

H SnBu3

cis-synclinal

cis- or trans-antiperiplanar

trans-synclinal

trans-synclinal

Figure 4. Alternative transition states for MgBr2-promoted additions of cis- and trans-crotylstannanes to a-benzyloxypropanal.

The addition of allyltrimethylstannane to or-oxygenated aldehydes can be effected with 5 M LiC104 in ether [19]. These additions afford mainly the syn adducts with a variety of acyclic and carbohydrate-derived aldehydes (Eq. 12).

I

LiC104, Et20 (93%)

2955 syn:anti

Several 3,3-disubstituted allylic stannanes were examined in BF3 . OEt2-promoted additions to aldehydes [20]. The ( E ) isomers afforded mainly the syn adducts whereas the (2)isomers led to the anti adducts as major products (Tables 10 and 11).These results differ sharply from those obtained with simple 3-substituted allylic stannanes where both ( E ) and ( Z ) isomers tend to favor syn adducts, with exceptions as noted.

Preparation and Addition Reactions

465

Table 10. Addition of (E)-3,3-disubstituted allylic stannanes to aldehydes promoted by BF3. OEtz.

(€1

anti

SYfJ

R’

R2

Et Me2C=CHCH2CH2 Et

Ph Ph PhCH=CH

Me2C=CHCH2CH2 Et

PhCH=CH C6H13

Me2C=CHCH2CH2 Et

C6H13 C-C6H11

Me2C=CHCH2CH2

C-C6H11

Yield (%) syn:anti

a7

aa 20 48 91 a2 94 a5

am3 7a:22 a3:17 72:2a 9a:2 91 :9 >99:1 a2:1a

Table 11. Addition of (Z)-3,3-disubstituted allylic stannanes to aldehydes promoted by BF3. OEtz. 0

R’

R2

Et Me2C=CHCH2CH2 Et

Ph Ph PhCH=CH

Me2C=CHCH2CH2 Et Me2C=CHCH2CH2 Et Me2C=CHCH2CH2

PhCH=CH C6H13 C6H13 C-C6Hll c-C6H1

Yield (Yo) anti:syn

93 75 21 36 86 75 97 64

a0:20 73:27 73:27 5a:42 93:7 92:a 95:5 77:23

It is suggested that these findings are best accommodated by a synclinal arrangement in the transition state which is favored by HOMO-LUMO orbital interactions, as previously suggested for certain intramolecular additions (Fig. 5). It should be noted that antiperiplanar or the alternative synclinal orientation for these transition states would result in unfavorable steric interactions between the aldehyde substituent, R2, and the vinyl Me or (especially) R1.

466

Marshall

LUMO

LUMO

Figure 5. Transition state arrangements for BF3-promoted additions of y,y-disubstituted allylic stannanes to aldehydes.

The addition of allyltributylstannane to aldehydes can also be effected with equimolar amounts of MeSiC13 or MeSiCI(0Me)z (Eq. 13) [21]. The initial product is the silyl ether which is hydrolyzed in the aqueous work-up. An allylic silane intermediate was shown not to be involved in the addition. The reaction with benzaldehyde could be accomplished with 0.33 equiv. of trichlorosilane but at a much slower rate. The product of this addition was cleaved by treatment with KF or aqueous acetic acid in THE

0 PhKH

p.,SnBu3 MeSiC13, (0.33 ;e (>go%)

J?-

Ph

KF

&

Ph

0 ) 3 SiMe

10.5 Lewis Acid Catalysis of Allyltin Additions When these addition reactions are promoted by the more conventional Lewis acids, e.g. BF3. OEt2, TiC14, SnCI4, and MgBr2, they require at least a full molar equivalent of the promoter. Presumably the Lewis acid forms a stable alkoxide complex with the product of the addition which removes it from a possible catalytic cycle (Eq. 14). If the Lewis acid, MX,, could somehow be regenerated in situ it should be possible to employ catalytic rather than stoichiometric quantities. 0

RKH + p...,~n~u3

MXn

R

+

XSnBu3

(14)

Some progress along these lines has been made in recent years, although only the most reactive stannanes can be employed in the catalytic process. One approach utilizes Bu2SnC12as a catalyst for the addition of allyltributyltin to aldehydes [22]. The initial step of the sequence involves transmetalation of the tributylstannane to form ally1 chlorodibutylstannane, which then adds to the aldehyde leading to a homoallylic alkoxy chlorodibutylstannane (Fig. 6, steps 1 and 2). The Bu2SnC12catalyst is regenerated in step 3 by the addition of TMSCl or an acid chloride, leading to the TMS ether or ester derivative of the homoallylic alcohol adduct (Table 12).

Preparation and Addition Reactions

++...,-SnBu3

+ BuzSnC12

OSn(CI)Bu2 R'

+

-

&"Sn(CI)Bu2+

CISnBu3

467

(1)

OR2

R2CI

-k R'

+ Bu2SnCI2

(3)

Figure 6. Addition of Bu3SnCHzCH=CHZto aldehydes catalyzed by BuzSnCIZ (R2 = TMS or CH30CO).

Table 12. BuzSnClz-catalyzedadditions of Bu3SnCHzCH=CHzto aldehydes.

R' Ph Ph t-BU c-C6H11 C7H15 (Q-PhCH=CH

R2 Time (h) Yield (%) Me3Si 4 76 CH3OCO 3 89 CH30CO 58 48 CH3OCO 3 87 3 83 CH30CO CH~OCO 3 92

A similar ploy has been used for the addition of cinnamyl tributyltin to isobutyraldehyde [23]. In that reaction InC13 serves as the catalyst and TMSCl is used as the catalyst liberating reagent (Eq. 15). The diastereoselectivity of the addition is solventdependent, ranging from 88:12 anti:syn in acetonitrile at 25 "C, to 12238 anti:syn in dichloromethane at -30 "C. The former addition proceeds by transmetalation to the cinnamyl dichloroindium species, which adds to the aldehyde by way of a cyclic transition state. In the latter addition InC13 serves as a Lewis acid and the reaction proceeds by the usual acyclic transition state to give the syn adduct in predominance.

1 SnBu3 lnCl3

1

TMSCl

OTMS

+~e+ Me Ph 88: 12 syn:anti

TMSCl

OTMS M ~ W

Me Ph 88: 12 anti:syn

+

InC13

468

Marshall

Both Sc(OTfh and Yb(OTf)3 have been employed as Lewis acid catalysts for additions of allylic stannanes to aldehydes. Reactions with the former catalyst can be conducted in a variety of solvents and are not sensitive to water [24]. All four allyl groups of tetraallyltin are consumed in the addition (Table 13). The latter reaction is performed with allyl tributyltin in CHzClz (Eq. 16) [25]. Table 13. Sc(OTf)+atalyzed additions of (CH2=CHCH2)& to aldehydes. 0

Sn

5 mol YOSc(OTf), t

solvent R PhCH2CH2 PhCH2CH2 PhCH2CH2 PhCH2CH2 c-C~HI~ 2-pyridyl

Solvent 9:1THF-H20 9:l MeCN-H20 EtOH MeCN 9:lTHF-HpO 9:lTHF-H20

R

Yield (Yo) 92 96 86 94 93 99

Evidently the lanthanide triflate is only weakly bound to the alkoxide oxygen of the product enabling protonolysis to occur in the former case with protic solvents or cosolvents. In the latter case the Yb(OTf)2 alkoxide product must react with Bu3SnOTf to regenerate the catalyst (Eq. 17).

Bis-pi-ally1 Pd and Pt complexes have been found to catalyze the addition of allyl tributyltin to aldehydes [26]. These catalysts are formed in situ from Pd- and PtC12phosphine complexes and the allylstannanes (Fig. 7, step 1). The allylation step is depicted as a metallocene reaction of the aldehyde and an q3--q1bis-allylmetal complex (Fig. 7, step 3). The catalyst is regenerated by attack of the allylic stannane on the alcoholate-palladium complex formed in step 3. Representative additions of allyl and methallyl tributyltin to aldehydes with the pi-ally1 platinum catalyst are summarized in Table 14.

Preparation and Addition Reactions

469

Figure 7. Allylation of aldehydes by CHZ=CHCHzSnBu3catalyzed by a bis-pi-ally1palladium complex. Table 14. Pi-ally1 Pt-catalyzed allylations of aldehydes.

C5H11 C5Hii C-C~HI~ C-CcH11 pBrC6H4 0-6rCgH4

H Me H Me Me H

24 16 10 14 10 8

40 49 99 67 63 94

Recent work has shown that the highly hindered Lewis acid, methylaluminum bis(4-bromo-2,6-di-tert-butylphenoxide) (MABR) catalyzes the addition of ally1 tributyltin to aldehydes in CHzClz at low temperature (Table 15) [27]. The catalyst is selecTable 15. MABR-catalyzed allylations of aldehydes.

,8,

MABR (10 mol%)

3uBnS , +, p+

R o-MeOC6H4 m-MeOC6H4 p-BrC,& PhCH2CH2 PhCH(Me) PhCH=CH a

Temp. ("C) Time (h) Yield (%) -20 -20 -20 -78 -95 -20

0.75 0.75 0.75 5 3 2

99 93 90 75 92 a 90

MABR = MeA1(4-Br-2,6-di-tert-BuC6Hz). -95 to -78 "C, 1:l syn:anti.

470

Marshall

tive for unbranched aldehydes. Competitive addition to hexanal in the presence of an equimolar quantity of pivaldehyde afforded a 6:l mixture of the two adducts. Selectivity was higher when the more hindered Lewis acid A1 tris-(2,6-diphenylphenoxide) (ATPH) was employed as the catalyst. The hexanol product was favored over that of pivaldehyde by > 99:l and over cyclohexanecarboxaldehyde by 24:l with this catalyst. The competition between the latter aldehyde and benzaldehyde favored the benzylic adduct by 1O:l. In general, additions were significantly slower with this catalyst than with MABR.

10.6 Catalysis by Chiral Lewis Acids Association of Lewis acids with chiral ligands leads to Lewis acid complexes which coordinate to the carbonyl group of an aldehyde thereby creating a chiral environment [28].Consequently, additions to the two enantiotopic faces of the aldehyde carbony1 proceed through diastereomeric transition states with resulting preference for one of the diastereomeric addition products. Regeneration of the catalyst results in the formation of an enantioenriched product. Although this strategy has been successfully applied to a number of allylic stannane additions, because the Lewis acid-chiral ligand complexes are generally only weakly acidic, the reactions require relatively reactive stannanes such as ally1 and methallyl. One of the first applications of this concept to allylic stannanes employed a tartrate-derived acyloxyborane (CAB) as the catalyst (Eq. 18) [29].Catalyst turnover was relatively inefficient in this system and the highest yields and enantiomeric excess (ee) were obtained with molar or half-molar equivalents of the borane.

C02H Me Et&SnBu3 J

H

R = Ph, (€)-PhCH=CH, Pr syn:anti = 80:20-97:3; ee = 70-95%

Further studies with the CAB catalyst revealed that additions of crotyl tributyltin to aldehydes strongly favored the syn adduct [30].Best results were obtained with 50 mol % catalyst and a twofold excess of (CF3C0)20 to assist catalyst turnover (Table 16).

Preparation and Addition Reactions

471

Table 16. Additions of crotyl tributylstannanes to aldehydes catalyzed by a chiral acyloxyborane (CAB).

-

"";OAo 0.5 equiv.

4

*

(CF3C0)20, 2X

R

Y Me

CH2C12, -78 "C

R

Yield (%)

CsH13 DPSOCH2CH2 C-C6H11 (4-PrCH=CH

74 73 70 71

syn:anti

ee (anti),%

91 :9 88:12 92:8

92 70

91 89

78:22

Additions to the enantiomeric a-methyl-P-ODPS propanals resulted in relatively high catalyst control compared with additions conducted with BF3. OEt as the promoter (Eqs 19 and 20). In the mismatched case (Eq. 20) the chiral catalyst effectively reverses the intrinsic substrate preference observed in the BF3-promoted addition. The matched pairing (Eq. 19) results in enhanced preference for the product of substrate control (syn,syn) when the chiral catalyst is employed. OH

Me-sn6u3 DPSOHJ

Me ~

0 DPSO+H

Me

LA

*

- \ + DPSO+ Me Me Me Me syn,syn anti,syn LA = CAB syn,syn:anti,syn= 98:2 LA = BF3*0Et2syn,syn:anti,syn= 9O:lO

DPSO-

OH

Me-SnBu3 LA

*

OH

D

OH

S O V + DPsO* Me Me Me Me anti,syn syn,syn LA = CAB anti,syn:syn,syn = 9O:l0 LA = BF3*OEt2anti,syn:syn,syn = 10:90 P

(19)

(20)

Several other chiral Lewis acids have been developed for the addition of allyl and methallyl tributylin to aldehydes [28]. These additions usually proceed slowly with reaction times of days. Less reactive stannanes, for example crotyl tributyltin, require even longer times and diastereoselectivity is poor. The allyl and methallyl additions, however, afford products in high yield and ee. The most successful ligands are BINOL and BINAP as Ti or Zr complexes in the former case and an AgOTf complex in the latter. A TiClz complex of (P)-BINOL catalyzes the addition of cis- and trans-crotyl and P-methylcrotyl stannanes to the reactive aldehyde, methyl glyoxylate (Table 17) [31]. The diastereoselectivities of these additions are, however, poor and the ee of the adducts is modest to poor.

472

Marshall

Table 17. Additions of allylic stannanes to methyl glyoxylate catalyzed by a (P)-BINOL-TiC12 complex.

R1

R2

R3

Me H Me

H Me H

H H Me

Yield (Oh) syrt(ee) 53 38 80

75 (84) 56(34) 53(2)

SYn anfi(ee)

anti

25 (16) 44(38) 47(2)

Somewhat better results with this catalyst system are obtained in additions of allyl tributyltin to aldehydes (Table 18) [32]. Although it is also possible to catalyze the same additions with a (P)-BINOL.Zr(O-i-Pr)2 complex [33], the yields and ee of the adducts are generally lower. Table 18. Additions of allyl tributyltin to aldehydes catalyzed by a (P)-BINOL-TiClZ complex.

0 R K H +

e

~

n

~

(P) 3 4 8, sieves, CH2C12 ~

u

R

R

Yield (%)

ee, %

Cdll

75

98

C7H15 C-Cdll (€)-PhCH=CH Ph

83 75 85 96

97 93 89 82

A complex of (M)-BINOL and Ti(O-i-Pr)4 has been used to catalyze additions of allyl and methallyl tributyltin to aldehydes (Table 19) [34]. Yields and product ee are high with a variety of aldehydes. This catalyst also has a nonlinear effect suggestive of a dimeric structure [35].

Preparation and Addition Reactions

473

8::

Table 19. Additions of allyl and methallyl tributyltin to aldehydes catalyzed by an (M)-BINOL-Ti(O-i-Pr)2 complex.

10 mol%

0

R2

fW

R

R1

*

X

5 mol% Ti(O-i-Pr)4 4

R’

R2 Yield (%)

PhCH2CH2 j-pr H (E)-PhCH=CH H Ph H

97 98 78 95

A sieves, CH2CI2 ee (“h) R2 Me Me Me Me

87 96 77 92

Yield (“A) ee (%) 97 50 83 95

95 84 86 96

Complexes of AgOTf and Ph3P were found to catalyze the addition of allyl and methallyl tributyltin to aldehydes (Table 20) [36]. Results were significantly better with conjugated and aromatic aldehydes than with an aliphatic analog. Table 20. Additions of ally1 and methallyl tributyltin to aldehydes catalyzed by a (P)-BINAP-AgOTf complex.

0

R2

R

THF

R’ (E)-PrCH=CH (0-PhCH=CH Ph 2-fury1 PhCH2CH2

R2

H H H H H

R’

Yield (Yo)ee (%) 72 88 88 96 93

93 88 96 93 -

R2 Me Me Me Me Me

Yield (%) ee (Yo) 96 62 75 65 22

92 91 92 95 70

Addition of cis- and trans-crotyl tributyltin to benzaldehyde could also be achieved with this catalyst system (Table 21) [37]. Interestingly, the anti product was predominant and the anti:syn ratio was unaffected by the cis:trans composition of the crotylstannane. These results are suggestive of an acyclic synclinal transition state for the reaction.

474

Marshall

Table 21. Additions of cis- and tram-crotylstannane to benzaldehyde catalyzed by a (M-BINAP-AgOTf complex. (M)-BINAP-AgOTf

0 : P h K H- M

SnBu3 cis and trans

oH

20mol% *Ph/\(\\ THF, -20 "C = Me "C -rt

OH

anti

cis:trans 955 2:98 53147

Yield (Yo) anti(ee 56 72 45

Ph-

i

Me SYn

Yo) syn (ee Yo)

85 (4) 85 (91) 85 (94)

15 (64) 15 (50) 15 (57)

Complexes of various metal salts and chiral bis-oxazolines have also been examined as catalysts for allylations of aldehydes (Eq. 21) [38]. The most effective salts were ZnC12, ZnBr2, Zn12, Sn(OTf)2, and InC13. Octanal and cyclohexanecarboxaldehyde afford adducts of 4045% ee with complexes of zinc salts.

X = I, Br

ee 40-45%

10.7 Additions that Proceed by Transmetalation When Lewis acids such as SnC14 and TiC14 are used to promote additions of allylic trialkyltin reagents to aldehydes several reaction outcomes are possible, depending on stoichiometry and the mode of addition. If the Lewis acid is added to the aldehyde followed by the allylic stannane, the typical product (syn for crotylstannanes) derived from an acyclic transition state is formed. If, however, the stannane and Lewis acid are premixed and left to equilibrate, metathesis can occur forming the allylic halometal compound which reacts with the subsequently added aldehyde to give products (anti for crotyl) consistent with a cyclic transition state (Eq. 22). The initially formed allylic halostannane gives rise to the linear adduct, but if aldehyde addition is delayed, this initial secondary allylic metal halide can equilibrate to the primary isomer which then reacts with the aldehyde to afford the branched product. LJ

Preparation and Addition Reactions

475

Butyltin halides have also been used to mediate this process. One of the first examples involved addition of a 3:l mixture of trans- and cis-crotyl tributyltin and a variety of conjugated aldehydes to BuzSnClz without solvent to form (2)homoallylic linear adducts (Table 22) [39]. In this reaction, addition of the initially formed secondary allylic dibutylchlorostannane to the aldehydes must be faster than that of the tributyl crotylstannanes, and faster than 1,3-isomerization of the chlorostannane. Formation of the (2)isomer is consistent with a chair transition state in which the allylic methyl group of the stannane adopts an axial orientation to avoid steric interactions with the adjacent stannane substituents (Eq. 23). Table 22. Transmetalation of crotyltributylstannane with BuzSnClZand subsequent addition of enals.

Bu2SnCI2

R

I

~

+ HMe-SnBu3

~1

transxis = 3:1

R2

linear

R'

R2

Yield (%)

1inear:branched

H H Me Pr

H Me H H

82 90 83 85

98:2 98:2 91 :9 9O:lO

Me

The linear ( Z ) addition product was also formed from cis-crotyl tributyltin and BuSnCl3 at -78 "C (Eq. 24) [40]. Significant amounts of branched adducts (- 4:l-2:l syn:anti) were seen at 0 "C and when a 60:40 mixture of cis- and trans-crotyltributyltin was employed at -78 "C. Premixing the crotylstannane and the BuSnC13 followed, after 8 h or more, by the aldehyde gave the branched adducts nearly exclusively.

BuSnCI3 ___)

Me

-78 "C

R = Ph (96%);R = c-C6HI3 (94%)

Me linear

(24)

0 BuSnC13 +?

SnBu3 0PhAH* "C (93%) ph&

\

Me

+Ph

.

Me

+ linear (6)

476

Marshall

These findings are consistent with a process in which metathesis of the cis-crotyl stannane is faster than addition of that stannane to the aldehyde at -78 "C (Fig. 8). The resulting secondary BuSnClz intermediate adds rapidly to the aldehyde to afford the linear product. At elevated temperature, 1,3-isomerization of the secondary stannane competes with aldehyde addition resulting in more of the branched product. The trans crotyl stannane, on the other hand, is more reactive than the cis isomer and BuSnC13-promoted addition competes with metathesis when the aldehyde is added after short pre-equilibration (1 min). Longer pre-equilibration times enable metathesis and ensuing 1,3-isomerization to occur with the formation of cis- and trans-crotyl BuSnClz intermediates which react with aldehydes by a cyclic transition state to form the syn and anti branched adducts. OH Bu3Sn

OH

RCHO

1

BuSnCI RCHO fast

Me

+

slow

Me

,8,

+

OH

linear

Bu3SnCl BuSnCh

-

Bu3Sn-Me

RCHO fast

slow

&Sn(Bu)C12

Me

+

R&

RYOH

Me

Me

SYn

-

Me

Y

Me anti

SYn

7R%

dSn(Bu)C12

R

1 RCHO Me

d

CI*(Bu)Sn

+

CI2(Bu)Sn-Me

Figure 8. Metathesis and addition of crotyl tributyltin and BuSnC13 leading to branched and linear homoallylic alcohols.

Transmetalation of cinnamyl and crotyl tributyltin reagents by SnClz in acetonitrile has been proposed to explain the predominant formation of anti homoallylic alcohols from aldehydes (Table 23) [41]. In contrast, the syn adducts predominate when these reactions are conducted in CH2C12.The exchange reaction in acetonitrile was confirmed by the quantitative formation of Bu3SnC1. Presumably the putative allylic SnCl species is stabilized by complexation with acetonitrile (Eq. 25).

R*

SnBu3

+

-Bu3SnCl

+

,R .p.-,

SnCl

(MeCN),

(25)

Preparation and Addition Reactions

477

Table 23. Additions of allyiic stannanes to aldehydes promoted by SnC12.

R' Ph Me Me i-Pr (4-MeCH=CH Ph Ph C-C~HT~ C-C&11

R2

Solvent

Yield (%)

antisyn

Ph Ph Ph Ph Ph Me Me Me Me

MeCN MeCN CHzCIz MeCN MeCN MeCN CH2CI2 MeCN CH2Cl2

a3 64 55 77 a9 69 92 58 61

94:6 92:a 1a:a2 1oo:o 97:3 52:4a it3:a2 54:46 21 :79

Addition of crotyl tributyltin to cyclohexanecarboxaldehyde affords the anti adduct when the tin reagent is left to pre-equilibrate with TiC14 before addition of the aldehyde (Table 24) [15]. Addition of TiC14 (1 equiv.) to a mixture of aldehyde and stannane gives the syn adduct predominantly. When this protocol is employed with SnC14 a mixture of syn, anti, and linear adducts is formed. Evidently, transmetalation and subsequent 1,3-isomerization is a much faster process for SnC14than for TiC14. Table 24. Addition of crotyl tributyltin to C-C~HIICHO in the presence of TiC14 and SnC14.

OH

OH

c-C6.11* SnBu3

+ MC14

-& CH2C12

+ C - ~ 6 ~ J1 , H

Me-

C-C6H11'yn

Me

anti C - C ~ HLI ~

Me M

e

c-C6H11

(,+linear MCld TiCI4 ( 2 ~ ) ~ TiCI4 (1x) SnCI4 (lx)

SYn

anti

(2)-linear

4 90 23

91 7 26

0 2 36

Me

(€)-linear

(€)-linear

5 1 15

"Addition of the aldehyde was delayed for several hours.

A similar solvent effect has been observed in the InC13-catalyzed reaction of transcinnamyl tributyltin with isobutyraldehyde (Eq. 26) [42]. The anti adduct was favored in acetonitrile whereas the syn adduct predominated in CHzCI2. Catalyst regeneration was achieved by use of Me3SiC1.

478

Marshall 0 OSiMe3

B u 3 S n u P h

Fe*

Me*

Me InCI3 (10 rnol YO) Me3SiCI

Me Ph anti

Solvent

Yield

antisyn

CH3CN CHzC12

82% 89%

88:12 35:65

OSiMe3 (26)

Me Ph SYn

A novel route to allylic stannanes employs allylic alcohols as starting materials [43]. These are treated with catalytic PdC12.(NCPh)2 and excess SnC12 to form transient allylic trichlorostannanes which react with aldehydes in situ to form homoallylic alcohols (Eq. 27). The reaction is thought to proceed by way of an allylic chloride which is formed by reaction of the alcohol with SnC12. The SnC12 also serves to reduce the Pd(I1) salt to the Pd(0) catalyst which reacts with the chloride to form a pi-allyl-palladium complex of SnC13. This complex is converted to the allylic chlorostannane reagent.

The reaction is most efficient in polar solvents and tends to favor anti adducts, although the diastereoselectivity is not high (Table 25). The addition requires extended reaction times and is accelerated by added water. The added water results in some-

Table 25. Pd(0)-Catalyzed in situ additions of crotyl trichlorostannanes to benzaldehyde. 0

wOH

+

PdClZ*(NCPh)z PhWH

* P

SnCI,, solvent

h G Me SYn

+

Solvent

Time (h)

Yield (Yo)

syn:anti

DMF DMF-H20 DMla DMSO DMSO-H20 (CH20H)z EtOH THF EtpO

216 15 24 136 88 37 72 25 72

80 77 75 34 75 78 79 72 8

24:76 18:82 29:71 65:35 83:17 58:42 38:41 22:25 4:2d

P

h L Me anti

Preparation and Addition Reactions

479

what higher anti:syn ratios suggesting a greater preference for a cyclic transition state and the trans-crotyl isomer. In less polar solvents, greater amounts of linear adducts are formed. The effect of temperature on diastereoselectivity and regioselectivity can be quite dramatic, as illustrated in Table 26 for crotyl addition to benzaldehyde. Linear and branched products are formed in nearly equal amounts above room temperature and the ratio of anti:syn branched adducts is nearly 1:l. As the temperature is reduced to 0 "C and below, the amounts of linear products become negligible and the anti branched adduct becomes highly favored. Not surprisingly, longer reaction times are required at the lower temperatures. Table 26. Temperature effects in the addition of a crotyl trichlorotin reagent to benzaldehyde.

OH

Me*

PdC12*( PhCHO NCPh)'*

Ph&

THF, SnCl Temp. ("C)

P

h L Me anti

SYn

Time (h)

50 25 0 -1 0 -1 5 -20

+

Me

24 25 95 139 135 120

Yield (%)

+

p i - , k M e

linear

syn:anfi:linear

67 72 80 81 62 21

22:23:54 22:25:53 16:78:6 9:91 7:93 3:97

Methyl substitution on the allylic system strongly affects the syn:anti ratio of adducts (Table 27). Both cyclic and acyclic transition states have been proposed to account for these observations. In general, (Z)-allylic alcohols tend to give mainly syn adducts, and vice-versa. Table 27. Effect of methyl substitution on the addition of crotyl tributyltin reagents to benzaldehydes. OH R

R I A O H R'

+P

PhCHO, PdC12*(NCPh)' 25 OC * Ph+R3 DMSO-H20 SnC12

R3

R1

R'

R3

R

Me H Me H

H Me H Me

H H H H

H H Me Me

Me syn Time (h) 70 95 68 71

R

OH

Yield (%) 70 48 67 88

h

A

R

3

Me anti syn:anfi 16:84 79:21 3:97 81:19

10.8 Additions of Allylic Halostannanes to Aldehydes. Ally1 iodide undergoes an oxidative metalation upon treatment with SnF2 in 1,3dimethyl-2-imidazolidinone (DMI) [44]. The resulting ally1 iododifluorotin species adds to aldehydes to afford homoallylic alcohols (Table 28) The reaction can also be performed with SnClz or SnBr2.

480

Marshall

Table 28. Additions of allyl iododifluorotin to aldehydes.

R

Time (h)

Ph p-MeOC6H4 pCIC6H4 Ph(CH2)2 PhCH=CH C l l H23 PhCHMe

1 .o 0.3 1 .o 0.5 0.7 0.5 1 .o

Yield (Yo) 88 93 96 90 47 82 89

In a similar vein, allylic iodides and, to a lesser extent, bromides undergo Barbier addition to aldehydes in the presence of activated tin powder in THF (Table 29) [45]. The reaction is thought to involve a diallyltin dihalide intermediate. Similar results were obtained when diallyltin dibromide, prepared independently, was used for the addition. Table 29. Barbier additions of allyl halides/% to aldehydes.

-[ e 2 n x 2 ] Sn

OH

RCHO

ex

h

R

h

THF

X

R

I

Ph Ph(CH2)P PhCH=CH pCICtjH4 PhCHMe Ph

I I

I I Br

Time (h)

Yield (Yo) 82 87 79 88 76 82

0.5 0.5 0.5 0.5 0.5 12

10.9 Additions of Achiral and Racemic Oxygenated Allylic Stannanes to Aldehydes Both a - and y-oxygenated allylic stannanes add to aldehydes under thermal or Lewisacid-promoted conditions. These reagents are less reactive and more acid-labile than their non-oxygenated counterparts. Consequently, the best results are obtained with relatively reactive aldehydes. Strong Lewis acids cannot be used because they tend to cause decomposition of the stannanes. Initial studies employed thermal conditions to effect the additions. Thus, the trans-a-OMOM crotylstannane, prepared from crotonaldehyde by addition of Bu3SnLiand etherification of the alcohol adduct, afforded the anti-(2)adduct upon treatment with benzaldehyde under reflux in toluene (Eq. 28) [46]. H

Bu3SnLi Me+ S ,+ .,n,Bu3

MeOCHzCI

0 M~.,++,,,s~B~~

OH PhCHO, toluene +

OMOM

i-Pr2NEt

reflux (79%)

Ph& Me

OMOM

(28)

Preparation and Addition Reactions

481

A series of aldehydes was examined with this stannane (Table 30). These reactions were conducted neat with a twofold excess of stannane at 100-140 "C. The anti, ( Z ) adducts were always formed exclusively via a proposed chair transition state in which the OMOM substituent adopts an axial orientation to avoid interactions with the adjacent stannane substituents, as previously seen with alkylstannanes (Eq. 9). Unbranched aliphatic aldehydes gave the adducts in low yield because of a competing aldol self-condensation reaction. Pivaldehyde also proved unsatisfactory. Table 30. Thermal additions of trans-u-MOM crotyl tributyltin to aldehydes.

R Ph PhCH=CH PCICGH~ Et C6H13 i-Pr f-BU

Temp. ("C) Time (h) Yield (%) 140 140 100 140 140 140 140

11 11.5 36 40 36 40 40

70 60 76 33 47 72 5

a-Ethoxy allyltributyltin was prepared by reaction of ethoxychloromethyl tributyltin with vinylmagnesium bromide (Eq. 29) [47]. This stannane afforded the syn adduct upon treatment with BF3. OEt, and benzaldehyde at low temperatures. Evidently isomerization to a more reactive y-ethoxy allylic stannane must occur under these reaction conditions. Such isomerizations were not observed in the thermal reactions.

PMgBr

CH3COCI Bu3SnAOEt

Bu3Sn

0

(29)

EtO I Bu3Sn'

Hydrostannation of methoxyallene affords a mixture of cis- and trans-y-methoxy allylic stannanes, among other products [48]. These stannanes can be separated by chromatography. Treatment with aldehydes in the presence of BF3.OEtz affords the syn-1,2-diol methyl ethers as major products (Table 31). Formation of the syn adduct from both the cis and trans allylic stannanes is consistent with an acyclic transition state (see Fig. 1).

482

Marshall

Table 31. BF3-promoted additions of y-methoxy allylic stannanes to aldehydes.

Stannane

R1

03 (4 (4 (4 (4

H H H

Ph Ph pMeC6H4 i-Pr DC6H11 Ph

H H Me

1:2(E)/(Z)

syn:anfi

R2

93:7 9O:lO 60:40 > 95:5 85:15 95:5

It was subsequently shown that free-radical hydrostannation of methoxyallene affords at least five products [49]. Subsequent chromatography on silica gel enables elimination of those isomers with adjacent M e 0 and SnBu3 substituents leaving only the y-methoxy allylic stannanes in ca 25% yield for each. A more efficient preparation of these stannanes employs Pd(0)-catalyzed hydrostannation (Table 32). Table 32. Pd(0)-catalyzed hydrostannation of methoxyallene. OMe Bu3SnH

R?>*==(

R2

R2

R’

Pd(PPh3)4

R’

OMe

B u 3 S n a O M e+B u 3 S n u R 2

(4

(E) R’

R2

Yield (%)

H H H H Bu

H Bu SMe TMS H

72 45 52 82 41

(€):(a 25:75 55:45 53:47 0:lOO

45:55

y-Oxygenated allylic stannanes can also be prepared from allylic ethers by lithiation with s-butyllithium and subsequent addition of Bu3SnC1 (Eq. 30) [50]. The sequence leads to the cis isomers. These stannanes afford mainly syn adducts in Lewis-acid promoted reactions with aldehydes.

-

1. s-BuLi

R’O

LA

R2&

(30) OR’

R’ =TBS, Me

Several racemic a- and ,&oxygenated aldehydes were examined under chelation-controlled conditions in which MgBrz. OEt, served as the chelating Lewis acid. Reaction of a cis-y-OTBS allylic stannane with a-benzyloxybutyraldehyde was highly selective for the syn, syn adduct (Eq. 31). ,%Oxygenated butyraldehydes were somewhat less selective. In these additions, the anti, syn adducts predominated by 4:l (Table 33).

Preparation and Addition Reactions

BnO

483

(31)

MgBr2*OEt2 (67%)

OBn OTBS

Table 33. Additions of a cis-y-OTBS allylstannane to racemic P-oxygenated aldehydes.

PSnBu3 R20 OH R20 OH R

Y

V R3

+ R1-

’R

H OTBS MgBr2-OEt2

R3 OTBS anti,syn

R3 OTBS syn,syn

(Yo) anti,syn:syn,syn

R’

R2

R3

Yield

H H Me Me

BOM Bn BOM Bn

Me Me H H

50 65 52 75

-

80:20 80:20

The diastereoselectivity of BF3-promoted additions to benzaldehyde by cis-yethoxy allylic stannanes has been found to vary considerably with the nature of the a substituent [51]. Unbranched alkyl groups favor the syn adduct whereas branched alkyl substitution leads to mainly anti adducts (Table 34). Similarly, CHzTMS and CH2TBS substituents both afford a predominance of the anti adducts. Table 34. Diastereoselectivity of BF3-promoted additions of (E)-y-ethoxy allylic stannanes to benzaldehyde as a function of the a-substituent.

0

R

OEt

OH

OH R+ph

BF3oOEt2

+

OEt

R

V

p

h

OEt anti

syn:anti H Me Et BU i-Pr mu TMSCH2 TBSCH2

70 95 92 97 97 82 85 97

93:7 93:7 72:28 70:30 19:81 3:97 28:72 18:82

It is suggested that steric effects tend to destabilize the antiperiplanar transition state normally associated with the formation of syn adducts in such reactions (Fig. 9). The alternative synclinal arrangement might benefit from favorable HOMO-LUMO interactions (see Fig. 3).

484

Marshall

Figure 9. Transition states for additions of cis-y-ethoxyallylic stannanes to aldehydes.

10.10 Enantioenriched Oxygenated Allylic Stannanes 10.10.1 a-Oxygenated Allylic Stannanes Initial efforts in this area involved the addition of Bu3SnLi to trans-crotonaldehyde and conversion of the racemic hydroxy stannane adduct to diastereomeric (-)-menthyloxymethyl ethers by reaction with (-)-menthyloxymethyl chloride (Eq. 32) [52]. These diastereomers could be separated by careful chromatography. They formed diastereomeric anti, (2)adducts with aldehydes upon heating to 130 "C. The results parallel those seen for the racemic OMOM allylic stannanes (Table 25). Formation of the ( Z )double bond in these adducts is attributed to steric interactions between the allylic OR substituent and the adjacent stannane butyl groups in a chair-like transition state as pictured in Eq. (9). The excellent stereoselectivity of these additions is suggestive of a highly ordered transition state.

1. Bu3SnLi

Me-+----fH 0 2.R3N

S n B ,u 3 ~-M ,& -e , Me-+YSnBu3y

*

O-O? I RCHO

+

0 - OI RCHO 9

A sequence was later developed for the synthesis of enantioenriched a-oxygenated allylic stannanes that did not require resolution (Eq. 33) [53]. This sequence, like the former, starts with the addition of Bu3SnLi to an enal. The resulting lithio alkoxide is oxidized in situ to the corresponding acylstannane. Reduction of the acylstannane with (M)-BINAL-H affords the (S)-a-hydroxy allylic stannane in > 95% ee. The use of (P)-BINAL-H leads to the ( R ) enantiomer with comparable ee. These hydroxy

Preparation and Addition Reactions

485

stannanes can be converted to MOM, BOM, or TBS ethers in high yield by treatment with MOMCI, BOMCl, or TBSCl in the presence of i-Pr2NEt. Attempts to prepare alkyl, benzyl and allylic ethers from these alcohols were not successful owing to the lower SN1reactivity of these halides which requires the use of stronger bases. Under these conditions appreciable reversal of the Bu3Sn addition was observed with recovery of the starting enal. r

1

acylstannane Me&SnBu3

(33)

OR R = MeOCH2, BnOCH2,t-BuMe2Si

a ADD

(M)-BINAL-H =

=

0' 'OEt

0

Although the foregoing enantioenriched a-oxygenated allylic stannanes afforded the expected adducts upon treatment with aldehydes in the presence of stoichiometric or greater quantities of BF3. OEt, (Table 35), mixtures of diastereomers were formed. Nonetheless, each of these diastereomers was of high ee consistent with a transition state in which the Bu3Sn substituent is oriented anti to the forming carbon-carbon bond as depicted in Fig. 10. The favored products were syn, as expected from an antiperiplanar transition state arrangement in which steric interactions between the aldehyde substituent R and the y-alkenyl group are minimized, as first suggested by Yamamoto (Fig. 10). Electronic factors may also play a role as indicated by the higher selectivity for 2-heptenal than for heptanal. Table 35. Additions of an (S)-2-heptenyl-1-OBOM" stannane to aldehydes.

anti-(€)

R C13~13 (f)-C4HgCH=CH C4HgC zz C "BOM = BnOCHz

anfi-(z)

Yield (%) syn-(E):syn-(z):anti-(E):anti-(4 80 72

70 80

88

51

27 17 25

0 1

3 2

7

17

486

Marshall

0'

,BF3

F3B.

'0

Figure 10. Transition state arrangements for additions of non-racemic (5') a-oxygenated allylic stannanes to aldehydes.

Significantly higher diastereoselectivity was observed in reactions with a-branched aldehydes as illustrated in Eq. (34) [54]. Here the (S)-a-methyl-P-OMOM aldehyde substrate is matched with the (R)-a-OMOMstannane in a Felkin-Ahn acyclic transition state to afford the syn, syn adduct almost exclusively. Me Et Et-YSnBu3 OMOM M O M

ye

MoMo----i-rH 0

*

BF30OEt2, CH2C12 -78 "C (85%)

OMOM O ~(34)

OH >95% syn,syn

An even more impressive example is illustrated in Eq. (35). In this example the enantioenriched aldehyde substrate is treated with excess stannane reagent consisting of a 1:l mixture of diastereomers at the a-position. A kinetic resolution ensues with the (S)-stannane reacting preferentially to afford the syn, syn adduct exclusively. The recovered stannane is enriched in the a-(R)isomer. OTBS Me -&OBn . . SnBu3 BF3*OEb BnO -OMOM * . 0 BnO OTBS OMOM CH2C12 TBSO OH 2.5 equiv. racemic at * -78 "c (79%) syn,syn adduct

ye BnO--J-yH+ TBSO

(-y-4-y

(35)

Studies have been conducted to examine electronic effects in these addition reactions [55]. Interesting dependence of diastereoselectivity on the nature of the aldehyde was observed in some BF3-promoted additions of a-OBOM allylic stannanes (Table 36). The P,y-dimethyl allylic stannane (R'= R2 = Me) resulted in high syn-(E) preference with aliphatic and conjugated aldehydes but failed to react with benzaldehyde. The more reactive crotyl derivative (R' = Me, R2 = H), on the other hand, gave the s y n - ( 2 ) adduct with benzaldehyde; both syn adducts were formed with aliphatic aldehydes.

Preparation and Addition Reactions

487

Table 36. Additions of trans-crotyl and trans-/%methylcrotyl stannanes to aldehydes. 0

R' Me&SnBu3

OH

R~A * R2+O H BoM

6BoM

BF3*OEt2

R1

R2

Me H Me Me H Me

C6Hi3 C6H13 BuCH=CH c-C6H1, OCeHll Ph Ph

H

+

Me

CH2C12, -78 "C

OH

R'

80 76 72 51 45 0 68

R2*

Me

> 95 55 > 95 > 95 80 -

<1

OBOM

SYn-(z)

sYn-(E)

Yield ("A) syn-(E)

R'

sYn-(4 <5 45 <5 <5 20 -

95

The strong preference for the syn-(Z) adduct observed with the crotylstannane and benzaldehyde has been attributed to attractive interactions between the G* LUMO of the alkoxy group and the x HOMO of the aromatic substituent (Fig. 11).The facial preference might also be influenced by a favorable inside alkoxy effect. Another possible influence on selectivity might be the strong complexes formed between the carbony1 group of aromatic aldehydes and BF3. As a result of these the aromatic ring would be somewhat electron-deficient, leading to a favorable interaction with the unshared electrons on the alkoxy substituent of the allylic stannane. The lower reactivity of the P-methyl crotylstannane (R' = R2 = Me) has been attributed to steric effects.

0'

, BF3

F3B.

'0

..

"inside alkoxy effect"

Figure 11. Transition state arrangements for additions to alkyl and aryl aldehydes leading to diastereomeric addicts.

10.10.2 y-Oxygenated Allylic Stannanes Upon treatment with a variety of mild Lewis acids, a-oxygenated allylic stannanes rearrange to the y isomers (Eq. 36) [56]. The process is stereospecific and highly regioselective. Thus (S)-a afford (S)-y-allylic stannanes, and vice versa, with essentially no loss of ee.

488

Marshall

R1+

SnBu3

LA

*

OR2

(36)

R1% Bu3Sn

OR2

R1=alkyl, R2= MOM, BOM, TBS LA = BF3*OEt2,TBSOTf, LiClO4*OEt2

Because the foregoing rearrangement involves a net anti transfer of the Bu3Sn moiety, an intramolecular process is deemed unlikely. This was shown to be so by a crossover experiment in which equal amounts of two a-oxygenated allylic stannanes differing in the alkoxy group (MOM compared with p-MeOC6H4CH20CH2)and the tin substituent (Me3Sn compared with Bu,Sn) were mixed in the presence of BF3. OEt2 (Eq. 37) [57]. Four y-oxygenated allylic stannane products were isolated in approximately equal amounts; two had exchanged Bu3Sn and Me3Sn groups. It is presumed that BF,. OEt2 interacts with the stannanes to generate a reactive R3SnX electrophile which then adds to an a-oxygenated allylic stannane by the usual anti SE2’ process.

B

+ OMoM

BF3*0Et2

u

Me3Sn

n

B

OMOM

+

*

u

Bu3Sn

n OMOM

(37)

OPMBOM

When isomerization was effected by typical Lewis acids such as BF3-OEt2 and even LiC104.0Et2 only the y - ( 2 ) isomers could be detected. When Yb(OTf)3 was employed, however, an equilibrium mixture of y - ( 2 ) and y-(E)isomers were isolated, the former being favored (Eq. 38) [58]. The same ratio of products was formed from the a-(Z), y - ( 2 ) or y-(E)isomers as required for a true equilibrium process. The failure to detect significant amounts of the y-(E) isomer from isomerizations catalyzed by BF3. OEt2 is attributed to decomposition of this allylic stannane.

Men Yb(OTf)3

Bu3Sn OTBS -* 76%

11

Bu3Sn

- It -

Me-\,.SnBu,

OTBS

OTBS

Me*

24% (38)

.\OTBS SnBu3

y-Oxygenated (E)-allylic stannanes can also be formed by 1P-addition of a Bu3Sn cyanocuprate to enals and in situ trapping of the enolate with TBSCl (Eq. 39) [59]. The corresponding ( Z ) isomers are not produced in these reactions. Thus far the method has only been applied to the synthesis of racemic stannanes; a suitable chiral catalyst for the cuprate addition has not been found.

Preparation and Addition Reactions

- RPoLi - Ry-oTBs

BuSnLi,CuCN

R-H

489

Bu3Sn

0

TBSC'

(39)

Bu3Sn

An alternative route to enantioenriched y-oxygenated (2)allylic stannanes entails SN2' displacement by cyanocuprate reagents on a chiral acetal of P-Bu3Sn acrolein (Eq. 40) [60]. The (S) configuration was assigned to the major adducts by virtue of the sign and magnitude of the optical rotations, compared with y-oxygenated allylic stannanes of similar structure and known configuration.

BF,*OEt2

Me

Et20, -78 OC

Me

Me

R = Bu (6l%), 94:6 (Z):(€),78% de R=i-Pr (65%), 94:6(Z):(E), 68% de

A preparation of y-oxygenated allylic stannanes in which the chirality resides in the alkoxy function has been described (Eq. 41) [61]. The starting alcohol is derived from tri-0-acetyl D-glucal. Acid-catalyzed addition of (Z)-l-methoxy-3-tributylstannyl-lpropene afforded the mixed acetal which was converted to the (2)enol ether with TMSI and hexamethyldisilazane (HMDS).

HOQ TMS' * HMDS (71%)

CSA (80%)

I\

DPSO

DPSO

ov (41)

\\\x'

I

DPSO

Enantioenriched a-carbamoyloxy allylic stannanes can be prepared by lithiation of allylic carbamates in the presence of (-)-sparteine (Eq. 42) [62]. The resulting lithiated sparteine complex reacts with Bu3SnLi at the a-position to afford the substitution product. The crotyl derivative of 80% ee is thus prepared. This stannane undergoes thermal addition to benzaldehyde at 160 "C to afford the anti-(S) adduct of 79% ee in 79% yield.

490

Mnrshnll

BuLi

t

MeyHLi*sparteine

o v N ( i - P r ) z (-)-sparteine

Bu3SnCI

oKN(i-Pr)2

0

0

(42)

0 Me-

*

.

SnBu3 ,H oyN(i-Pr)Z

0 (80% ee)

PhKH 160 "C (79%)

ph&

Me

OKN(i-Pr)2

0 (79% ee)

Enantioenriched y-OMOM and y-OBOM allylic stannanes undergo BF3-promoted additions to aldehydes to afford syn adducts as major products (Table 37) [56]. The highest ratios are obtained with a-branched and conjugated aldehydes although the steric requirements of the allylic substituent R1 seems to influence diastereoselectivity also in the latter reactions. The ee of the syn adducts are generally equal to those of the starting stannanes-typically > 90-95%. Table 37. BF3-promoted additions of enantioenriched y-OMOM and y-OBOM allylic stannanes to aldehydes.

R' +

Bu3Sn

a

OR2 R3 R'

OH R' w

BFpOEt2 H CH2C12,-78 R2

Me MOM Bu MOM Me MOM Bu MOM C-c~H11 MOM Bu BOM Me MOM BU MOM Bu MOM c C ~ H ~ BOM I

R

oC'

OH

3R

+

'

R

3

OR2 anti

OR2 SYn

R3

Yield (7 ' .)

syn:anti

C6H13

75 81 74 80 78 62 84 73 61 67

96:4 85:15 95:5 98:2 98:2 96:4 94:6 90110 88:12 65:35

c-C~H~I C-C6Hi1 DCEH11 &6Hi1 (E)-BUCH=CH (E)-BuCH=CH (E)-BuCH=CH (€)-BuCH=CH

d

Diastereoselectivities are particularly high for (E)-y-silyloxy allylic stannanes (Table 38) [59]. Even the unbranched aldehyde heptanal affords the syn adduct as the exclusive diastereomer.

Preparation and Addition Reactions

491

Table 38. Additions of (E)- and (Z)-y-silyloxy allylic stannanes to achiral aldehydes. 0

Me

BF30OEt2

(4

(a (Z)

(E)

-

Bu3Sn

L (6

Me+RSYn

R

Stannane

(E)

OTBS

RKH

Bu3>0TBS

OH

Yield (%)

C6H13 C6H13 (E)-BuCH=CH (E)-BuCH=CH

86 79 81 83

Me syn:anti 97:3 >99:1 >99:1 >99:1

OTBS

ee (%) 95 95 95 95

y-Oxygenated allylic stannanes bearing a chiral ether auxiliary afford syn adducts as major products of Lewis-acid-promoted additions to achiral aldehydes (Table 39) [63]. Both diastereoselectivity and enantioselectivity are sensitive to the Lewis acid promoter. Aliphatic aldehydes seem to be rather poor substrates in this reaction. Table 39. Additions of a y-oxygenated allylic stannane bearing a chiral ether auxiliary to achiral aldehydes. OH

OH

LA, -78 “C ODPS

R

LA

Ph Ph Ph BU C7H15 C7Hi5

BF300Et2 AICIs.OEt2 TiCI4 AIC13.OEt2 AIC13.OEtz BF3*OEt2

Yield (%) 82 68 48 21 26 17

SYn syn:anti 97:3 97:3 73:27 96:4 93:7 1OO:O

anti dr 85:15 95:5 85:15 80:20 80:20 80:20

10.11 Reactions with Chiral a-Oxygenated Aldehydes The presence of an a-alkoxy substituent on the substrate aldehyde leads to the formation of a differentially protected l ,2,3-triol upon addition of a y-oxygenated allylic stannane (Eq. 43). Such additions are of potential use for the synthesis of carbohydrates and extended polyols. The resident double bond in the adduct can be further functionalized by dihydroxylation or epoxidation to extend the polyol chain.

492

Marshall

When the aldehyde and alkoxystannane are enantioenriched the issue of matching and mismatching must be addressed. An early examination of this issue involved ( S ) 2-benzyloxypropanal and the enantiomeric y-OMOM tributylstannanes derived from crotonaldehyde (Eq. 44) [64]. Two sets of experiments were performed. In the first BF3. OEt, was used as the Lewis acid promoter. Matching was observed with the ( R ) stannane and the anti, syn-(E)adduct was formed as the major component of a separable 92:8 mixture. The mismatched (S)-stannane gave a 67:33 mixture of syn, syn-(E) and anti, anti-(E)under these conditions.

flMe

OH

JewMe OH

MOM0

I

SnBu3

BFpOEt? (58%) -

+

BnO OMOM anti,syn-(E)

BnO OMOM syn,anti-(E)

92:8

OH

I Me$.

.Me*Me BF3oOEt2 (72%)

-

+

BnO OMOM syn,syn-(E)

M

67:33

e

OH w

M

e

BnO OMOM anti,anti-(E) (44)

BnO (74%) &Me

BnO OMOM syn,anti-(€) 75:25

h MgBr2

(74%)

Me&Me BnO

+

OMOM

syn,syn-(Z)

M

e

BnO

A

M

e

OMOM

A second set of experiments involved the use of MgBr, as the Lewis-acid promoter. In this case the (R)-stannane was mismatched resulting in a 75:25 mixture of syn, anti( E ) and syn, syn-(Z) isomers. The matched (S) stannane afforded a 93:7 mixture of syn, syn-(E)and syn, unti-(Z)adducts. These results can be understood on the basis of a Felkin-Ahn transition state arrangement for the BF3 experiments and a chelation transition state arrangement with MgBr, as the promoter. The matched transition states are pictured in Fig. 12. The latter additions are strongly substrate-controlled, which accounts for the formation of (2)products as the minor adducts. Evidently the methyl substituent is an efficient facially directing group in the chelated aldehyde substrate.

Preparation and Addition Reactions

493

FB

“0 Me matched

Bu3Sn

-

anti,syn-(E)

Felkin-AhnCornforth Me (R)

Figure 12. Matched transition states for additions of y-OMOM allylic stannanes to (S)-2-benzyloxypropanal.

With the previous experiments and the derived transition state models as guidelines it was possible to select matched pairings of protected threose and erythrose aldehydes with the foregoing stannanes to prepare potential hexose precursors (Eq. 45) [65]. 0

+

H*OTBS

-

OBn

BF3*OEt2 M

e /

OBn

(72%)

B~3Sfl

OMOM

H

~

O

T

S

>

MOMO

threose related +

OH OBn O T B

w

OBn

L-galacto OH OBn

B MgBrz S

OBn

Me*oTBS MOMO

(68%)

OBn L-ido

threose related

(45) +

B~3Sti

OMOM

H F O T B S BF3*OEt2 Me OBn erythrose related

-

-

(74%) D-altro

0 OBn +OTBS

MgBr2

OBn

(92%)

erythrose related

OH OBn

1

~

~

M

e

w

MOMO

OH OBn O T B OBn D-glUC0

S

494

Marshall

The MgBr2-promoted additions are strongly substrate-controlled. As a result it is possible to effect kinetic resolution of racemic y-oxygenated allylic stannanes thereby circumventing the need to employ enantioenriched stannane. The degree of enantio discrimination is somewhat dependent upon the y-oxygen substituent as illustrated by the additions to a threonine-derived aldehyde given in Eq. (46) [66]. OH Me

Me

0

Ro BOC‘ N % M -’eMe

Me

Men + H

Bu3Sn

”

+

syn,syn (from (R)-stannane)

oMgBra

(46)

OH Me

racemic (2x) R MOM TBS

~

OR

‘OC’ N % -M ’Me e threonine related

Yield (%) 84 87

syn,syn:syn,anti 87: 13 299:l

Me++o , / :

‘ 0BOC‘ N+Me Me syn,anti (from (Sjstannane)

This kinetic resolution has also been effected with a-oxygenated aldehydes (Eq. 47) [67]. Interestingly, in the example shown the mismatched product is the ( E ) anti diastereomer rather than the (Z)-synpreviously seen with the crotyl stannanes (Eq. 44). Presumably the greater steric requirements of isopropyl compared with methyl disfavors the formation of a ( Z )double bond thus rendering the (Z)-synpathway less favorable in this example. The (E)-synadduct served as a key intermediate in the total synthesis of bengamide E.

H

ue

Bu3Sn racemic (3x)

~

OBn

C02Me (85%)

OH OMe

M

e

w

C

O

z

M

+ OH OMeH

HO OH 0 Bengamide E

e

MOMO OBn (30) from (R)-stannane Me

OH OMe

MOMO OBn (70) from (S)-stannane

(47) ~I

Preparation and Addition Reactions

495

10.12 Transmetalations of Chiral Oxygenated Allylic Stannanes 10.12.1 SnC14 Transmetalations of ally1 tributyltin and crotyl tributyltin with Bu2SnC12 and SnC14 was discussed in an earlier section. Transmetalations of chiral oxygenated allylic stannanes have been the subject of more recent investigations. The strong Lewis-acidic character of SnC14 causes decomposition of a- and y-oxygenated allylic stannanes. When the oxygen substituent is situated at the &position, however, addition of SnC14 then different aldehydes leads to homoallylic alcohol adducts in high yield and with excellent diastereoselectivity (Table 40) [68,69]. Table 40. Additions of a transient oxygenated allylic trichlorostannane derived from a 6-benzyloxy allylic tributylstannane. OH ?H

1. SnCI4

M M e e vv S S n n B B u u 3 3 ORn OBn

Me+

0 R

Ph pC1CGH4 pMeOC6H4 2-fury1 Pr i-Pr MeCH=CH

R

OBn OBn > 98% SY/J-(Z)

Yield (YO) 90 77 77 72 84 78 70

These reactions proceed by initial S E T addition of SnCI4 to the allylic stannane to yield an intermediate trichlorostannane (Fig. 13). This trichlorostannane derives stability by coordination with the adjacent benzyloxy oxygen. Aldehyde addition proceeds through a cyclic transition state in which the allylic substituent adopts an axial orientation to minimize interactions with the tin substituents and to maintain effective coordination with the adjacent benzyloxy oxygen. As a result the (2)-homoallylic alcohol adduct is highly favored.

Figure 13. Reaction pathway for transmetalation of &oxygenated allylic stannanes and their ensuing addition to aldehydes.

496

Marshall

Additions of the presumed P-oxygenated allylic trichlorostannane to a-methyl, a benzyloxy and P-benzyloxy aldehydes are characterized by high reagent-controlled diastereoselectivity (Eq. 48) [70]. In the several examples examined aldehyde facial attack is little influenced by the resident chirality of the aldehyde. The result is particularly striking with the a-methyl aldehyde where the syn, syn adduct is the product of Felkin-Ahn addition and the anti, syn adduct is the anti-Felkin-Ahn or chelation-controlled adduct.

BnO t

(76%)

I

BnO Me

OH

-

.

BnOdH

-

BnO-

=VMe-

syn,syn

CI3Sn--O,

Me OBn

OH

Bn

BnO

OH B

-

n

(66%)

O

y

Me

Me syn,syn OBn

Additions to a-oxygenated aldehydes are characterized by more characteristic matching and mismatching with the chlorostannane reagent. The mismatched ( R ) enantiomers afford roughly 2:l mixtures of diastereomers favoring the syn, syn adducts (Eq. 49). Additions of the same chlorostannane to the matched (S) aldehydes are highly diastereoselective. Only the anti, syn adducts are produced in these reactions (Eq. 50). 0 OH e h

Me M +

i

RO

Bn

syn,syn OBn

R = Bn (89%) R = MOM (68%) R = TBS (65%) ’

RO

(49)

OH

=vMeMeY---Me CI3Sn--0,

Bn

e

RO

pH

*

R = Bn (90%) R = MOM {7’eo/d) R=TBS (72%)

e

anti, syn OBn

70:30 65:35 70:30

0 M

M

:

RO anti, syn OBn

(50)

Preparation and Addition Reactions

497

The presence of an oxygen substituent at the &-positionof the allylic tributylstannane enables stabilization of the intermediate trichlorostannane SE2’ substitution product as a result of participation in a five-membered chelate [71]. The ensuing addition reaction can then proceed by way of a bicyclic transition state, as before, in which the allylic substituent adopts an axial orientation (Fig. 14). The products of these additions contain a (2)double bond with an anti relationship between the alcohol and the R1 group. ,Bn

a

0

H

H

&

B u 3 S n w O B n A1

H

C13Sn

R1

Figure 14. Reaction pathway for transmetalation of &-oxygenated allylic stannanes and their ensuing addition to aldehydes.

Both aromatic and aliphatic aldehydes afford adducts in high yield with excellent diastereoselectivity (Table 41). The net result is efficient 1,5-stereoinduction [71]. Table 41. Additions of a transient oxygenated allylic trichlorostannane derived from an E-benzyloxy allylic tributylstannane. B u 3 S n v O B n

1. SnCI4 2. RCHO-

Me

R Ph p-CICcH4 pMeOC6H4 Et i-Pr

R

anti

-

Me

Yield (“A) anti, syn 86 67 65 70 81

96:4 96:4 96:4 95:5 95:5

The foregoing addition reaction is strongly reagent-directed. Both ( S ) - and (R)-2benzyloxypropanal afford adducts with high diastereoselectivity (Eq. 51). With the former the product might arise by Felkin-Ahn addition whereas a chelation controlled transition state could account for the latter.

498

Marshall

OH

OBn

Me

Me

OBn anti,anti

OBn

Me syn,anti

Somewhat lower diastereoselectivity is observed with &-oxygenated allylic stannanes lacking a stereocenter at the &position (Table 42) [72]. Surprisingly, branched aliphatic aldehydes do not give higher ratios of diastereoisomers than unbranched. Table 42. Transmetalation-addition of &-oxygenatedallylic stannanes.

R Yield ("/.) Ph 75 pCIC6H4 61 p M e o C ~ H 4 65 Me 72 Et 67 i-Pr 80

syn:anti 96:4 g%@r 93:7 91:9 84:16 85:15

The trend is also seen in additions to ( S ) - and (R)-2-benzyloxypropanal (Eq. 52). Both aldehydes afford mixtures of adducts comparable to those found with achiral aliphatic aldehydes. 0 Me&,

OBn

M

e

p

Me M -e

OH :

OBn

-

76:24 syn:syn OH

(52)

Me (73%)

OBn 88: 12 syn:anti

These findings suggest that a substituent R' at the &position is more effective than one at the &-positionin controlling facial discrimination toward the aldehyde carbonyl (Fig. 15). The origin of this effect has not been determined.

Preparation and Addition Reactions

499

highly diastereoselective highly diastereoselective moderately diastereoselective

Figure 15. Diastereoselectivity of allylic trichlorostannanes as a function of 6 and E substituents.

10.12.2 InC13 Additions of crotyl tributyltin to aldehydes in the presence of 1 equiv. of InC13 lead to mixtures of diastereomeric adducts favoring the anti isomer (Eq. 53) [73]. The reaction is most selective in donor solvents such as ethyl acetate, acetonitrile, or acetone. Premixing the stannane and InC13 in the absence of aldehyde causes an immediate precipitate to form. Subsequent addition of the aldehyde results in slow formation of product which is isolated in low yield.

M e w S n B u 3

-

InC13

Me

M e w l n C 1 2

This behavior contrasts with that of TiC14 with which premixing of the stannane is essential for optimum formation of the anti adduct. The reaction can also be conducted with a-oxygenated allylic stannanes which also afford anti adducts (Eq. 54).

OMOM

MedSnBu3MeCN a-OMOM

I

0

InClg_ Me ./-OMOM

fast

OMOM anti, a

BF3oOEt2 (54)

.

Me ./-OMOM Reaaent a-OMOM y-OMOM

a-OMOM Product(s) anti, a anti, y (80) anti, a (20)

anti, y

500

Marshall

These results are indicative of a reaction pathway involving transmetalation of the stannane by InC13 and subsequent addition to the aldehyde by via a cyclic transition state. Interestingly, the crotylstannane undergoes transmetalation with net allylic retention whereas the a-OMOM crotylstannane transmetalates with net allylic inversion. Presumably this contrasting behavior reflects rapid allylic isomerization in the crotyl system. This isomerization is relatively slow compared to aldehyde addition in the oxygenated crotyl system. The y-OMOM crotyl stannane gives rise to an 80:20 mixture of anti, y and anti, a adducts upon treatment with InC13 in acetonitrile. Formation of the latter adduct must entail isomerization of the kinetic a-OMOM InClz intermediate to the thermodynamically favored y-OMOM isomer. Enantioenriched a-OMOM allylic stannanes afford enantioenriched anti adducts in the presence of InC13 (Table 43). Stereoselectivity is not highly temperature-dependent. Similar results are obtained in acetone and acetonitrile as solvents, but EtOAc is usually better. Table 43. Transmetalation of enantioenriched crotyl a-MOM tributyltin with InC13 and in-situ addition to aldehydes. OMOM

+

H’R

OH

InC13 *v+R

M e d S n B u 3

MOM

ee > 95%

R

Temp. (“C)

&$ill c-C6H11 DC6H11 C6H13 (E)-BuCH=CH (€)-BuCH=CH (E)-BuCH=CH CeH13-

-784 rt -78-rt -78-rt -78-rt rt -784 -784

anti, ee > 95% Solvent

Yield (“/.)

antkyn

acetone MeCN EtOAC EtOAC acetone MeCN EtOAc EtOAc

88 88 95 99 76 87 85 85

98:2 96:4 98:2 95:5 84: 16 83:17 90: 10 90: 10

The high anti selectivity observed in these additions with both branched and unbranched aldehydes makes the oxygenated allylic indium reagents well suited for applications related to annonaceous acetogenins [74]. The following examples are illustrative (Eqs 55-58). OMOM

TBSO

OTBS

!?!?EL

M e *

2. TBAF (74%)

M e 4 ” ’ S n B u* 3 lnC13 (90%)

Me

Me MOMO

TBSO

OTBS

OMOM (55)

MOMO

OMOM

501

Preparation and Addition Reactions

H

H +

W TBSO

OSEM TBSOd " " S n B u 3

InC13,EtOAc, (71%) *

OTBS (56)

TBSO SEMO

TBSO

OTBS

OSEM OSEM

nTBSOO OTBS 4

B

T B S O 4 ' % B u 3 * InC13, EtOAc, (86%)

H

(57)

OH OTBS

BnO

2

OBOM '1OH21

e

MOMO

H OMOM

TBSod""SnBu3 * InC13, EtOAc, (90%)

The foregoing results are accommodated by the usual cyclic transition state in which the aldehyde substituent ( R ) adopts an equatorial orientation in a chair-like conformation (Fig. 16). Unlike the SnCI3 counterparts of this transition state, the allylic sub-

RCHO

1

Y C H O

RCHO H

Me*"Cl--ln--O+~ H

OMOM

OH OMOM

OMOM

Figure 16. Reaction pathways for SET addition of enantioenriched y-OMOM allylic indium chlorides to aldehydes.

502

Marshall

stituent (Me) prefers an equatorial orientation. This preference might reflect the different geometry of the adjacent InC12 and SnC13 substituents and the resulting reduced steric interaction with a neighboring equatorial alkyl group in the former. Additions of the transient y-OMOM crotyl indium chloride reagents to a-oxygenated aldehydes are strongly reagent-controlled. Thus the ( R ) and (S) reagents add to protected threose and erythrose aldehydes with high diastereoselectivity (Eq. 59) [75]. These additions are complementary to those previously effected with the y-Bu3Sn counterparts (Eq. 45). It is thus possible to prepare precursors to the eight diastereomeric hexoses and their enantiomers from threose- and erythrosederived aldehydes and their enantiomers plus the a-OMOM crotyl tributylstannane enantiomers.

*

0

OBn

S

lnCl

M

OH OBn w B

e

S

+ H OMOM

OBn

(88%)

MOMO

threose related

0 H

~e-nBy3

OBn

+

OMOM

OBn

L-talo

~

~ InC13 ~

OBn

~M

(95%)

e

OH OBn O T B

w

MOMO

S

OBn

L-gulo

threose related

(59) ~I

0 + ,OTBS

Me*SnBy3

OBn

InC13

~

M

OH OBn M O T B

e

S

’:

OMOM

Me*

OBn erythrose related

0

SnBu3 +

(85%)

OBn

lnCl

H

OMOM

MOM0

w B s OBn erythrose related

OBn D-manno

1

3M (82%)

e MOMO

OH OBn . w

/

OTBS

OBn D-all0

Attempts to access enantioenriched P’,y-dioxygenated allylic stannanes through Lewis acid-catalyzed 1,3-isomerization of the a,&dioxygenated isomers were unsuccessful owing to the facile elimination of Bu3SnOR from these intermediates (Eq. 60) [76]. Transmetalation with InCI3 in the presence of an aldehyde proceeds without elimination, however, to afford the anti adduct as the major diastereomer (Table 44). In additions to unbranched aldehydes, higher yields were obtained with

RlO?

,

OR2

‘-lnC12

R3CH0

R’O OR2

Preparation and Addition Reactions

503

the OTBS reagents but the corresponding OMOM analogs were more diastereoselective. Remarkably, additions to alkynyl aldehydes are more diastereoselective than additions to crotonaldehyde. The opposite trend is seen with allylic stannanes. Table 44. Additions to aldehydes of transient allylic indium dichlorides from a,d-dioxygenated allylic stannanes.

TBS MOM TBS MOM TBS MOM

oC6Hll C-C6Hll (0-MeCH=CH (0-MeCH=CH C6H13CzC CsH13C-C

99 99 64 58

99:l 99:1 67:33

87

93:7 97:3

65

80:20

A possible explanation might lie in the experimentally determined relatively poor reactivity of enals, compared with ynals, toward these allylic indium reagents. The slower rate of addition would enable equilibration of the kinetic ( E )allylic indium intermediate to a mixture of ( E ) and ( Z )isomers. The latter would afford the syn adduct. Addition of the foregoing dioxygenated allylic indium intermediates to a-ODPS acetaldehyde then dihydroxylation of the double bond led to a potential precursor of the hexose D-(+)-altrose (Eq. 61). The overall transformation effects a four-carbon homologation of carbohydrates.

TBsodoM , “ r O D P S 1. InCI3 (82%) SnBu3 0 2. TBSOTf (82%;

oso4 NMO (81%)

-

OH OMOM

TBSO+

ODPS OH OTBS

-

OMOM

T B S o v O D P S OTBS OH OH (61) OH H OH OH D-(+)-altrose

10.12.3 Intramolecular Reactions The first Lewis acid-promoted intramolecular addition reaction was conducted as part of a study designed to ascertain the transition-state geometry of allylic stannane additions to aldehydes (Table 45) [77]. In all examples examined the syn adduct was strongly favored. It should be noted that the thermal reaction affords the syn adduct which must be formed via a synclinal arrangement because of the cyclic nature of the transition state. Two arguments were advanced to explain the preference for a synclinal transition state in Lewis acid-promoted additions. The first of these entailed Coulombic attractive forces between the developing positive charge at the /?-position of the allylic stannane and the electron-

504

Marshall

rich carbonyl center. A second argument invoked a favorable orbital interaction between the HOMO of the allylmetal and the LUMO of the complexed carbonyl group. It was, however, conceded that the intramolecular model does not bear an exact relationship to intermolecular additions because of the different relationships between the aldehyde and double bond substituents. In the intermolecular addition these groups can adopt an anti relationship thereby minimizing steric interactions. In the foregoing intramolecular additions, however, these groups are geometrically constrained in a syn relationship (see asterisked atoms in Table 45). Table 45. Effect of Lewis acids on the transition-state geometry of intramolecular allylicistannanelaldehyde additions.

kH

H IA I 0

SnBu3

Bu3Sn’ antiperiplanar

synclinal

I anti

SYn

Lewis Acid Temp. (“C) Yield (“7) syn:anti TiCI4 BF3*OEt2 AIC13 sncl, none

-85 -70 -70 -70 90

84 93 89 85 85

82:18 87:13 89:11 93:7 1OO:O

A more recent study reached a similar conclusion [78]. It was found that cyclizations of (2)-and (E)-3-phenyl-8-tributylstannyl-6-octenal were highly diastereoselective (Fig. 17). The (2)isomer yielded cis, trans-3-phenyl-2-vinylcyclohexanol as the major product (96:4) whereas the ( E ) isomer afforded the trans, trans isomer (95.5). A favorable HOMO-LUMO interaction was proposed as a decisive factor in stabilizing the favored synclinal transition states. This stabilization is lacking in the alternative synclinal and antiperiplanar transition states, neither of which has the correct geometry for orbital overlap. As in the previous study, the aldehyde and double bond substituents (asterisked carbons in Fig. 17) are unable to attain an anti orientation in the antiperiplanar transition states, as has been proposed for the intermolecular additions.

Preparation and Addition Reactions

Bu3Sn,, H '', H,,H+

___

3

Ph (Z)

A

+

Ph cis,trans

Ph

96:4

H *

Ph trans,cis

H antiperiplanar

Ph trans,trans

0'

Ph trans,cis

,Ht

_-- O .'

CHO C F 3 C O O H ~ H CHzCIz, Ph -78 "C

0'

H

B'3Sn,,

505

Ph 9 5 5 cis,trans

.H+

Ph trans,trans

Figure 17. Transition-state possibilities for intramolecular additions of ( Z ) -and (E)-allylic stannanes.

Intramolecular BF3-promoted addition of y-oxygenated allylic stannanes, in which the oxygen substituent of the stannane is linked to the aldehyde chain, afford 6- and 7-membered oxygen heterocycles in high yield (Eq. 62) [79]. The cyclizations leading to 6-membered rings proceed with poor diastereoselectivity (2:l in favor of the cis adduct) whereas the 7-membered cyclizations are highly diastereoselective in favor of the trans adducts. The products can be further transformed to homologous y-oxygenated allylic stannanes and thence, by the analogous cyclization procedure, to fused ring ethers related to polycyclic ether natural products such as the brevetoxins (Eq. 63). The preferred formation of cis products in the 6-membered cyclizations is consistent with the synclinal transition state arrangement for the (2)-allylic stannane depicted in Fig. 17.

506

Marshall

H BFpOEt2

+

H

\

H

SnBu3

BF3*OEtzt (83%)

HO: H O H

SnBu3

'

Lewis-acid promoted cyclizations of allylic stannanes have been successfully employed to prepare macrocyclic compounds. An enantioenriched a-oxygenated allylic stannane led to a 14-membered cembrane precursor in high yield with excellent diastereoselectivity (Eq. 64) [SO].

95:5 cktrans

An attempted application of the foregoing cyclization to afford a 10-membered ring led instead to a 12-membered isomer (Eq. 65) [Sl]. In this case isomerization of the a-OBOM stannane to the y isomer preceded addition to the aldehyde. Evidently the relatively strained transition state attending 10-membered ring formation must significantly retard the rate of this addition relative to that of the isomerization. The transition state energy leading to the 12-membered ring would expectedly be lower.

Preparation and Addition Reactions

507

Even so, the cyclic product was obtained in only 25% yield. A significant improve)~ of the ynal for the cyclization. ment was realized by employing the C O ~ ( C Ocomplex This improvement can be attributed to a reduction in transition-state energy by virtue of the more favorable geometry of the complex and the increased electrophilic character of the carbonyl group. BFpOEt:;,

*

~

1

CHO BOMO SnBu3 a-OBOM stannane

1

c:r;\""" OH 10-membered product

BF3*0Et2

y-OBOM stannane

(co)6c02BOMO

12-memberedproduct

SnBu3 HO

10.13 Preparation of Allenylstannanes Allenylstannanes are readily prepared by SN2' displacement of propargylic mesylates by stannyl cuprates (Table 46) [82]. When the reaction was performed on an enantioenriched (R)-mesylate the allene was deduced on the basis of the optical rotation and by use of Brewster's rules to be of the ( M ) configuration (Eq. 66). Thus it was surmised that the displacement had proceeded with inversion of stereochemistry. Table 46. Preparation of allenic stannanes from propargylic mesylates. R3SnCu

THF

R'

-

R'

R3Sn

R

R'

R2

Ph Ph Ph Me Me Ph Ph

H H H H H H Me

H H H Ph Me Me H Pr -(CH2)5H t-Bu Me Me

R3

Yield (Yo) 90 90 95 90 95 a0 90

508

Marshall

H

Displacement of a secondary 1-propynyl mesylate with Ph3SnCu afforded a mixture of allenyl and propargylic stannanes (Eq. 67). Presumably this mixture reflects the relative stability of the two isomers, determined in part by the steric environment of the bulky Ph3Sn grouping. OMS

56144

Later work showed that such displacements can be effected with a Bu3SnCu reagent [83]. With this reagent secondary mesylates afford allenylstannanes as the exclusive kinetic products (Eq. 68). The configuration of the allenic products was confirmed by an independent synthesis involving an orthoester Claisen rearrangement (Eq. 69).

TH F R1 = CH20TBS, R2 = Me (83%) R' = Et, R2 = C&3 (97%)

Bu3Sn, @

Propargylic bromides react with a Bu3SnMgCl reagent generated in situ from Bu3SnC1 and Mg in the presence of a PbBrz catalyst (Eq. 70) [84]. The reaction can be conducted on terminal acetylenes and acetylenic esters.

Preparation and Addition Reactions

509

R’ = H, C02Me R2 = H, Me

Allenylmagnesium bromide is converted to diallenyl dibutyltin upon treatment with Bu2SnC12 in ether (Eq. 71) [85]. This reagent undergoes ligand redistribution with additional Bu2SnC12to allenyldibutyltin chloride [86]. BrMg

)=.=

H

Bu2SnC12 EtpO

Bu2Sn

Bu2SnCIp CIBu2Sn

+.=

(71)

H

H

10.14 Addition of Allenyl and Propargyl Stannanes to Aldehydes Propargylic halides are converted to allenyl and propargylic tin halides upon exposure to SnC12 in a mixture of N,N-dimethylformamide (DMF) and 1,3-dimethyl-2-imidazolidinone (DMI) [87]. Subsequent addition of aldehydes leads to homopropargylic and/or allenic carbinols (Table 47). The ratio of the two regioisomeric adducts depends on the nature of R1 and R2. Alkyl substitution on the alkyne (R1 = Me) strongly favors the allenic adduct. On the other hand, the ratio of adducts from the TMS substituted alkyne (R’= TMS) is dependent on the aldehyde substituent. Table 47. In situ addition of propargylic/allenic halostannanes to aldehydes.

~1

~2

H H Me Me TMS TMS

Ph C8H17 Ph Ph CeH17

Yield (%) Pr0pargyl:allenyl 98 92 79 79 67 76

52:48 30:70 3:97 2:98 40:60 0:ioo

These results are suggestive of an equilibrating allenyl-propargyl reagent (Eq. 72). A priori the propargyl reagent might be the more stable isomer on the basis of steric considerations. If, however, the interconversion is facile, the product ratio will depend upon the relative transition-state energy of the addition reactions. The aldehyde and tin reagent both play a role in this step.

510

Marshall

A diallenyltin dibromide reagent can be prepared from propargyl bromide, metallic tin, and aluminum (Eq. 73) [88]. Addition to aldehydes leads to homopropargylic alcohols as the exclusive products.

R = Ph (94%),C6H13(77%), (€)-MeCH=CH (72%)

Similar treatment of TMS propargyl iodide affords a mixture of allenic and propargylic adducts (Table 48). The regioselectivity is strongly solvent-dependent. Allenic adducts predominate in MeCN-DMSO whereas in 1,2-dimethoxyethane (DME) the propargylic adducts are the major products. In these additions the structure of the aldehyde plays a minor role. Table 48. Preparation of bis-TMS propargyltin diiodide and addition to aldehydes.

3hMS+CH2)2Sn12 TMS

-

OH

RC+ =.

solvent

TMS

R

Solvent

C6H13 C6H13 Ph Ph (€)-MeCH=CH (€)-MeCH=CH

MeCN-DMSO (MeOCH& MeCN-DMSO (MeOCH& MeCN-DMSO (MeOCH2)2

+ / y H R TMS

Yield ("YO) Al1enyl:propargyl

89 75 88 69 60 64

95:5 8:92 9O:lO 1 1 :89 92:8 9:91

The allenic dibutyltin chloride described in Eq. (71) adds to aldehydes in water to afford mainly propargylic adducts (Eq. 74) [87]. In a related reaction, a mixture of allenyl tributyltin, BuzSnClz and an aldehyde in water affords a mixture of propargyl and allenyl adducts (Table 49). These results are suggestive of an equilibrating mixture of allenic and propargylic stannanes, as depicted in Eq. (72), where the ratio of adducts reflects the transition state energy of the two competing processes. It might be presumed that the propargyl dibutyltin chloride regioisomer is the kinetic product of the exchange reaction, in which case the allenyl adduct would be the kinetic adduct of reactions in which the addition step is rapid.

Preparation and Addition Reactions 0

-

=.+

SnBu2CI R K H

OH R%

-H+

R

.=

511

(74)

H H R = Et, i-Pr, tert-Bu, (€)-MeCH=CH ; propargyl/allenyl -9O:lO

Table 49. In situ addition of allenyl/propargyl tin halides to aldehydes in water.

0

7

~ n B u 3R K H

=.=(

R+ OH

Bu2SnC12 R

R

H20 Yield (%)

Me i-Pr t-Bu CH&H (E)-MeCH=CH CH2=CMe

.=

H Propargy1:allenyl

95 97 95 98 95 go

25:75 25:75 40:60 9O:lO 95:5 65:35

Additions of allenic tributylstannanes to aldehydes, like those of their allylic counterparts, require Lewis-acid promoters [83]. The favored promoter is BF3. OEt, (Table 50). Promotion can also be effected by MgBr;?, although less effectively. The use of other common Lewis acids, for example Tic& or AlC13, is complicated by competing exchange reactions. This type will be covered in a later section. Table 50. Additions of an allenyl tributylstannane to aldehydes promoted by BF3.OEt, or MgBr,.

R

Lewis Acid

CsH13 CSH13 i-Pr i-Pr t-Bu

BF3*OEt2 MgBr2 BF3*OEt2 MgBr2 BF3*OEt2

Yield (%) syn:anti

83 56 80 48 92

37:63 69:31 99:1 88:12 99:1

Enantioenriched allenylstannanes afford enantioenriched propargylic adducts of nearly identical ee to that of the mesylate precursors (Eq. 68) [89]. Additions to enantioenriched a-benzyloxy aldehydes are characterized by matching and mismatching characteristics with BF3. OEt as the Lewis acid promoter (Eq. 75). Mismatching is negligible for the MgBrz-promoted additions, implying highly substrate- or reagentcontrolled addition.

512

Marshall

OBn Me

Bu3Sn

OBn

Me

0 LA

M e. . , . (P)

OBn

OH

OAc syn,syn

OAc

anti,anti

LA = BF3*OEt2:syn,syn:anti,anti = 6535 LA = MgBr2: syn,syn:anti,anti = 1OO:O

HJn

Me

AcO >.Tslie 0 Bu3Sn

(M)

*

M

LA

p

OBn

M OH

Me

(75)

OBn

e +@Me

OH

OAc syn,anti

0'

anti,syn

LA = BF3*OEt2:syn,anti:anfi,syn = 9 5 5 LA = MgBr2: syn,anti:anti,syn = 2:98

Reactions of the foregoing allenylstannanes with enantioenriched a-methyl P-benzyloxy aldehydes are also characterized by double diastereoselection (Eq. 76). In this reaction the syn adducts are highly favored products of both BF3. OEtz- and MgBrzpromoted additions. Here again essentially no mismatching is observed for additions employing MgBrz. All proceed with 90% yield or better.

Me

Me

Me

Me

LA LA = BF3*OEt2:syn,anti:anti,syn =99:1 LA = MgBr2: syn,anti:anti,syn = 99:l (76)

ye

AcO

H p O B n

LA

Me .

Me -

Me -

Me .

OH

LA = BFpOEt2: syn,syn:anti,anti = 83: 17 LA = MgBr2: syn,syn:anti,anti = 1OO:O

The MgBr2-promoted additions to the (S)-a-benzyloxy aldehyde proceed via a chelation-controlled transition state (Fig. 18). Approach to the carbonyl face of the nearly planar five-membered magnesium chelate is directed by the methyl substituent resulting in re attack by the allenylstannane through the antiperiplanar geometry for the ( P ) stannane and the synclinal geometry for the ( M ) stannane. An antiperiplanar orientation of the ( M ) stannane would place the vinylic methyl substituent in close proximity to the chelate ring.

Preparation and Addition Reactions

513

!\SnBu3 AcO

Figure 18. Transition states for MgBr2-promoted addition of (P)- and (M)-allenylstannanes to an (S)-abenzyloxy aldehyde.

Although a chelated transition state can also be envisaged for the MgBr2-promoted addition of the (P)-allenylstannane to the (R)-a-methyl-/3-benzyloxyaldehyde (Fig. 19), the product derived from the (M)-allenylstannane is best explained as resulting from a Felkin-Ahn arrangement. The chelated synclinal alternative might now be less favorable compared with the a-benzyloxy analog for two reasons-chelation by Mg2+is more favorable for five- than for six-membered rings, and the somewhat puckered conformation of the six-membered chelate might result in increased steric repulsion between the vinylic methyl of the (M)-allenylstannane and the a-position of the chelated aldehyde.

i

SnBu3

AcO Br,

,Br

AcO

Figure 19. Transition states for MgBr2-promoted addition of (P)- and (M)-allenylstannanes to an (R)a-methyl-/3-benzyloxy aldehyde.

514

Marshall

10.15 Intramolecular Additions Allenylstannanes undergo remarkably efficient BF3-promoted intramolecular additions to aldehydes (Eq. 77) [90]. In this way 12-, 14-, and 15-membered rings have been prepared in high yield. The cyclic homopropargylic alcohol products can be converted into 2,5-bridged furan analogs of furanocembranes and pseudopteranes, as illustrated in Eq. (78).

OMOM

OMOM

Me

10.16 Transmetalations 10.16.1 SnC14 Allenyl tributylstannanes undergo transmetalation with SnC14, forming allenyl trichlorostannanes with overall inversion (Eq. 79) [91]. The reaction proceeds in two stages via an intermediate propargylic trichlorostannane. When conducted in the presence of an aldehyde the intermediate propargylic stannane is intercepted giving rise to the allenyl adduct as the sole product. If addition of the aldehyde is delayed for 10 min or longer the propargylic adduct is produced. Both products are formed enantioselectively. The relative and absolute stereochemistry of the two adducts is consistent with a cyclic transition state (Fig. 20). The relative stereochemistry of the propargylic adduct follows from the sterically favored anti arrangement of the allenyl Me

Preparation and Addition Reactions

515

and the aldehyde (R’) substituents. The relative stereochemistry of the allenyl adduct is less easily understood. Possibly the aldehyde substituent R2 interacts with the Sn ligands in a manner that favors the syn-1,4 Me/R’ orientation.

CI

Figure 20. Proposed transition states for SET additions of allenyl and propargyl trichlorostannanes to aldehydes.

The versatility of the methodology is illustrated in Eq. (80); it is possible to prepare syn or anti propargylic adducts or an allenyl adduct from a single allenic stannane by appropriate modification of reaction conditions. Both additions proceed with excellent diastereo- and enantioselectivity. Addition to an enantioenriched a-methyl$OBn aldehyde proceeds with excellent stereodifferentiation (Eq. 81).

516

Marshall

i-PrCH0

Me

Me

Me

Me

1. SnCI4, 10 rnin, -78 "C

(98%) 1. SnCI4,0 "C

AcO/Me 2. i-PrCHO

OH

(61Y0)

H&OBn

C7H15

+pFF BuaSn

Me

BF3aOEt2 (91Yo)

+oBn R1

I

Me

OH (81)

Me

1. SnC14, 10 min

Me

+oBn

R'

OH

2"oBn

(92%)

Matching and mismatching characteristics of propargylic chlorostannane additions have also been examined (Eq. 82) [92]. In these studies it was found that the use of BuSnC13 instead of SnC& afforded an intermediate propargylic stannane that underwent 1,3-isomerization more slowly than the analogous SnC13 intermediate. By increasing the effective lifetime of the propargylic stannane it was possible to minimize propargylic by-products from additions to aldehydes. The propargylic BuSnC12 species derived from the ( P ) allenylstannane afforded a 90:lO mixture of syn and anti allenyl adducts with (R)-a-methyl-fi-benzyloxypropanal. Only the anti adduct was produced when this addition was conducted on the ( S ) aldehyde. The former addition is thought to proceed through a Felkin-Ahn cyclic transition state whereas the latter might involve a chelated cyclic array.

517

Preparation and Addition Reactions

1OO:O anti:syn

An analogous study was conducted with allenyl trichlorostannane intermediates starting from (P)-allenyl tributyltin derivatives (Eq. 83) [92].Addition to the ( R ) aldehyde in CHzClz at -78 "C led to a 2:l mixture of anti, anti and anti, syn adducts in high yield. Surprisingly, the major adduct in this reaction is derived from the enantiomer of the starting aldehyde. Evidently the SnC14 (or derived acidic by-products) causes partial racemization of the aldehyde. Addition of the allenylstannane to the (S) aldehyde must be highly favored. In accord with this conclusion, when the foregoing addition was performed on the (S) aldehyde only the anti, anti product was formed. Addition of the allenylstannane to the racemic aldehyde led to an 87:13 mixture of anti, anti and anti, syn adducts.

ye O , Bn R = CH~OAC (90%)

OH anti,anti 67:33

OH anti,syn (83)

Me

R = CH~OAC (99%) R

R = C7H15 (92%)

Me

OH anti.anti

A likely transition-state scenario for these observations is presented in Fig. 21. Accordingly, the chelation controlled addition is highly favored with the (S) aldehyde. The analogous transition state is disfavored on steric grounds for the ( R )aldehyde. In this case a Felkin-Ahn arrangement is sterically favored. Apparently the chelationcontrolled process enjoys a significant rate advantage. The unwanted racemization could be minimized by use of hexane as the solvent or by substituting BuSnC13 for SnC14 in the transmetalation step. These modifications were thought to minimize the formation of HC1 in the reaction medium.

cyclic chelation

anti,anti

cyclic Felkin-Ahn

anti,syn

cyclic chelation

Figure 21. Transition state arrangements for additions of (M)-allenyl trichlorostannanes to (R)-and (S)-amethyl-b-benzyloxypropanal.

10.16.2 InC13 Upon treatment with InC13 allenic tributylstannanes undergo an apparent transmetalation to allenylindium intermediates (Eq. 84) [93]. The overall process is analogous to that previously described for SnC14 or BuSnC13, but differs in two important respects- the transmetalation can be conducted in the presence of aldehydes without the formation of allenylcarbinols, and the configuration of the major adducts is the opposite of that produced in the tin halide reactions. It can therefore be surmised that the transmetalation-isomerization process is fast compared to addition of the allenyl tributylstannane, and/or that isomerization of the transient propargylic indium chloride is rapid compared to its addition to the aldehyde substrate. The stereochemical outcome requires that transmetalation proceeds mainly with net retention of configuration.

I

I

InC13

WCHO slow

Me

-.7

1

R'CHO slow

.OH R'

R'CHO

(84)

H '

Although the transmetalations seem rapid, the ensuing aldehyde addition is relatively slow compared to the analogous sequence with SnC14 (Eq. SO). Furthermore, anti adducts of only low or modest ee are obtained. Evidently chiral allenylindium

Preparation and Addition Reactions

519

chlorides are more prone to racemization than the corresponding allenyltin species. Racemization was found to depend upon the identity of the halide. With InBr3, and more so with In13, adducts of significantly higher ee were produced (Table 51). Table 51. Transmetalation-addition of a chiral allenytributylstannane to /3-ODPS-propanal. ye

Ace+

Me H p O D P SS P DyMX, - - - / .+ 7H + 0 OAc MXn Temp. (“C) Time (h) Yield (“A)

.-.I>

Bu3Sn

SnC14 lnCl3 InBr3 InBr3 InBr3 a

-78 rt rt -78 -rt rt

1 0.5 0.25 10 0.5

ee (“A) 90 a 20 75 40 80

28 75 60 83 60

The product is the enantiomer of that shown

Further evidence for the racemization premise was obtained from experiments employing (R)-a-methyl-P-ODPS propanal (Eq. 85) [93]. Addition of the allenylindium chloride derived from an enantioenriched (P)-allenyl stannane yielded a 60:40 mixture of anti, anti and anti, syn adducts, not unlike that obtained when racemic allenylstannane was used to generate the transient allenylindium chloride. When the (S) aldehyde was employed for this addition a 40:60 mixture of anti, anti and anti, syn adducts was formed. Thus it can be concluded that substrate control (Felkin-Ahn or chelation) is, at best, only modest in these reactions, and that the rate of racemization is only slightly less than the rate of addition. The use of P-benzyloxy-a-methyl propaMe

Ace>

.

HwDPS < e;o

Bu3Sn (P) (ee = 95%)

InC13

Me Me l r v

>+ c

(83%)Ac0

/

Y

F MeD MeP

//

OH OH anti,anti (60) AcO anti,syn (40)

S

520

Marshall

nal in the foregoing addition at low temperature afforded a 70:30 mixture of anti, anti and anti, syn adducts. The improved diastereoselectivity under these conditions can be attributed to substrate control, the OBn group having greater chelating capacity than the ODPS group. The lower temperature might also account for the improved diastereoselectivity. Significantly higher diastereoselectivity was observed when InBr3 was employed as the transmetalating species (Eq. 86). These additions were significantly faster than those employing InC13. Me Me

Me

*

InBr3, -78-0

"C anti,syn (95:5)

(86) Me

H

0 InBr3, -78-0

*

"C

H

Me

boB OH anti,syn (92:8)

10.17 Concluding Remarks Some of the more interesting and useful methods for reactions involving allylic, allenic, and propargylic stannanes have been summarized in this chapter. Coverage is selective rather than exhaustive. Surveys of reactions catalyzed by chiral tin reagents [94]. and an overview of different tin reagents [95] have recently appeared.

Acknowledgments We thank the Alexander von Humboldt Foundation for a Senior Scientist Research Fellowship and Professor H. M. R. Hoffmann for providing facilities at the University of Hannover where some of the manuscript for this chapter was prepared. Our research in this area is supported by research grants from the National Science Foundation and the National Institutes of Health.

References 1. Konig, K.; Neumann, W. P. Tetrahedron Lett. 1967,495. 2. Reviews: (a) Marshall, J. A. Chem. Rev. 1996,96,31. (b) Yamamoto, Y.; Shida, N. Advances in Detailed Reaction Mechanisms 1994,3,1. (c) Yamamoto, Y.; Asao, N. Chem. Rev. 1993,93,2207. 3. Naruta, Y.; Ushida, S.; Maruyama, K. Chem. Lett. 1979,919. 4. Tagliavini, G.; Peruzzo, G.; Marton, D. Inorg. Chim. Acta 1977,24, L47. 5. Selwyn, M. J., Biological Chemistry of Tin, in Chemistry of Tin,Harrison, P. G., Ed. Chapman and Hall, N.Y. (1989) pp. 362-367.

Preparation and Addition Reactions 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. SO. 51. 52. 53. 54. 55. 56. 57.

58.

521

Seyferth, D.; Weiner, M. A. J. Org. Chem. 1961,61,4797. Tanaka, H.; Abdul Hai, A. K. M.; Ogawa, H.; Torii, S. Synlett 1993, 835. Carofiglio, T.; Marton, D.; Tagliavini, G. Organometallics 1992,11,2964. Weigand, S.; Brukner, R. Synthesis 1996,475. Naruta, Y.; Nishigaichi, Y.; Maruyama, K. Tetrahedron 1989,45,1067. Hull, C.; Mortlock, S. V.; Thomas, E. J. Tetrahedron 1989,45, 1007. Yamamoto, Y.; Saito, K. J. Chem. Soc., Chem. Commun.1989,1676. Naruta, Y.; Ushida, S.; Maruyama, K. Chem. Lett. 1979,919. Yamamoto, Y.; Yatagi, H.; Naruta, Y.; Maruyama, K. J. Am. Chem. Soc. 1980,102,7107. Keck, G. E.; Abbott, D. E.; Boden, E. P.; Enholm, E. J. Tetrahedron Lett. 1984,25,3927. Keck, G. E.; Boden, E. P. Tetrahedron Lett. 1984,25,265. Mikami, K.; Kawamoto, K.; Loh, T.-P.; Nakai, T. J. Chem. Soc., Chem. Commun.1990,1161. Keck, G. E.; Savin, K. A.; Cressman, E. N. K.; Abbott, D. E. J. Org. Chem. 1994,59,7889. Henry, K. J., Jr.; Grieco, P. A,;Jagoe, C. T.; Tetrahedron Lett. 1992,33,1817. Nishigaichi, Y.; Takuwa, A. Tetrahedron Lett. 1999,40, 109. Marshall, R. L.; Young, D. J. Tetrahedron Lett. 1992,33,1365. Whitesell, J. K.; Apodaca, R. Tetrahedron Lett. 1996, 37, 3955. A conceptually similar reaction in which aqueous HCl catalyzes the addition has been reported. Yanagisawa, A.; Morodome, M.; Nakashima, H.; Yamamoto, H. Synlett.,1997,1309. Yasuda, M.; Miyai, T.; Shibata, I.; Baba, A.; Nomura, R.; Matsuda, H. Tetrahedron Lett. 1995, 36, 9497. Hachiza, I.; Kobayashi, S. J. Org. Chem. 1993,58,6958. Aspinall, H. C.; Browning, A. F.; Grieves, N.; Ravenscroft, P. Tetrahedron Lett. 1994,35,4639. Nakamura, H.; Iwana, J.; Yamamoto, Y. J. Am. Chem. SOC.1996,118,6641. Marx, A; Yamamoto, H. Synlett.1999,584. Marshall, J. A,; Chemtracts- Organic Chemistry 1996,9,280. Marshall, J. A.; Tang, Y. Synlett 1992,653. Marshall, J. A,; Palovich, M. R. J. Org. Chem. 1998,63,4381. Aoki, S.; Mikami, K.; Terada, M.; Nakai, T. Tetrahedron 1993,49,1783. Costa, A. L.; Piazzo, M. G.; Tagliavini, E.; Trombini, C.; Umani-Ronchi, A. J. Am. Chem. SOC. 1993,115,7001. Bedeschi, P.; Casolari, S.; Costa, A. L.; Tagliavini,E.; Umani-Ronchi, A. Tetrahedron Lett. 1995,36, 7897. Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem. SOC.1993,115,8467. Keck, G. E.; Krishnamurthy, D.; Grieco, M. C. J. Org. Chem. 1993,58,6543. Yanagisawa, A,; Nakashima, H.; Ishiba, A.; Yamamoto, H. J. Am. Chem. Soc. 1996,118,4723, Yanagisawa, A.; Ishiba, A.; Nakashima, H.; Yamamoto, H. Synlett 1997,88. Cozzi, P. G.; Orioli, P.; Tagliavini, E.; Umani-Ronchi, A. Tetrahedron Lett. 1997,38,145. (a) Boaretto, A.; Marton, D.; Tagliavini, G.; Ganis, P. J. Organomet. Chem. 1987,321,199.(b) Boaretto, A,; Marton, D.; Tagliavini, G.; Gambaro, A. Inorganica Chimica Acta 1983,77, L196. Miyaki, H.; Yamamura, K. Chem. Lett. 1992,1369. Yasuda, M.; Sugawa, Y.; Yamamoto, A.; Shibata, I.; Baba, A. Tetrahedron Lett. 1996,37,5951. Yasuda, M.; Miyai, T.; Shibata, I.; Baba, A.; Nomura, R.; Matsuda, H. Tetrahedron Lett. 1995, 36, 9497. Takahara, J. P.; Masuyama, Y.; Kurusu, Y. J. Am. Chem. SOC.1992,114,2577. Mukaiyama, T.; Harada, T.; Shoda, S. Chemistry Lett. 1980, 1507. Mukaiyama, T.; Harada, T. Chemistry Lett. 1981, 1527. Pratt, A. J.; Thomas, E. J. J. Chem. Soc., Chem. Commun.1982,1115. (a) Quintard, J.-P.; Dumartin, G.; Elissondo, B.; Rahm, A,; Pereyre, M. Tetrahedron,1989,45, 1017. (b) Quintard, J.-P.; Elissando, B.; Rahm, A,; Pereyre, M. J. Org. Chem. 1983,48, 1560. Koreeda, M.; Tanaka, Y. Tetrahedron Lett. 1987,28,143. Koerber, K.; Gore, J.; Valel, J. M. Tetrahedron Lett. 1991,32,1187. Keck, G. E.; Abbott, D. E.; Wiley, M. R. Tetrahedron Lett. 1987,28,139. Waterlot-Bourdeau, S.; Parrain, J.-L.; Quintard, J.-P. J. Org. Chem. 1997,62,8261. (a) Jephcote, V. J.; Pratt, A. J.; Thomas, E. J. J. Chem. SOC.,Chem. Commun. 1984, 800. (b) Jephcote, V. J.; Pratt, A. J.; Thomas, E. J. J. Chem. Soc., Perkin 11989,1529. Marshall, J. A,; Gung, W. Y. Tetrahedron 1989,45,1043. Marshall, J. A,; Yashunsky, D. V.; J. Org. Chem. 1991,56,5493. Gung, B. W.; Smith, D. T.; Wolf, M. A,; Tetrahedron 1992,48,5455. Marshall, J. A,; Welmaker, G. S.; Gung, B. W. J. Am. Chem. SOC.1991,113,647. Marshall, J. A,; Gung, W. Y. Tetrahedron Lett. 1989,30,7349. Marshall, J. A,; Jablonowski, J. A,; Elliott, L. M. J. Org. Chem. 1995,60,2662.

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59. Marshall, J. A,; Welmaker, G. S. J. Org. Chem. 1992,57,7158. 60. (a) Parrain, J.-L.; Cintrat, J.-C.; Quintard, J.-P. J. Organomet. Chem. 1992,437, C19 (b) Watrelot, S.; Parrain, J.-L.; Quintard, J.-P. J. Org. Chem. 1994,59,7959. 61. Kadota, I.; Sakaihara, T.; Yamamoto, Y. Tetrahedron Lett. 1996,37,3195. 62. Paulsen, H.; Graeve, C.; Hoppe, D. Synthesis 1996,141. 63. Yamamoto, Y.; Kobayashi, K.; Okano, H.; Kodata, I. J. Org. Chem. 1992,57,7003. 64. Marshall, J. A,; Luke, G. P. J. Org. Chem. 1991,56,483. 65. Marshall, J. A,;Seletsky, B. M.; Luke, G. P. J. Org. Chem. 1994,59,3413. 66. Marshall, J. A.; Seletsky, B. M.; Coan, P. S. J. Org. Chem. 1994,59,5139. 67. Marshall, J. A,; Luke, G. P. J. Org. Chem. 1993,58,6229. 68. Thomas, E. J. Chemtracts-Organic Chemistry 1994, 7,207. 69. McNeill, A. H.; Thomas E. J. Tetrahedron Lett. 1990,31,6239. 70. McNeill, A. H.; Thomas, E. J. Tetrahedron Lett. 1992,33,1369. 71. Carey, J. S.; Thomas, E. J. Synlett 1992,585. 72. Carey, J. S.; Thomas, E. J. Tetrahedron Lett. 1993,34,3935. 73. Marshall, J. A,;Hinkle, K. W. J. Org. Chem. 1995,60,1920. 74. (a) Marshall, J. A.; Hinkle, K. W. J. Org. Chem. 1996,61,4247. (b) Marshall, J. A,; Hinkle, K. W. J. Org. Chem. 1997,62,5989. (c) Marshall, J. A.; Chen, M. J. Org. Chem. 1997,62,5996. 75. Marshall, J. A.; Hinkle, K. W. J. Org. Chem. 1996,61,105. 76. Marshall, J. A,;Garofalo, A. W. J. Org. Chem. 1996,61,8732. 77. Denmark, S. E.; Weber, E. J.; Wilson, T. M.; Willson, T. M. Tetrahedron 1989,45,10.53. 78. Keck, G. E.; Savin, K. A.; Cressman, E. N.; Abbott, D. E. J. Org. Chem. 1994,59,7889. 79. Yamamoto, Y.; Yamada J.-i.; Kadota, I. Tetrahedron Lett. 1991,32,7069. 80. Marshall, J. A,; Gung, W.-Y.; Tetrahedron Lett. 1988,29,1657. 81. Marshall, J. A,; Gung, W.-Y. Tetrahedron Lett. 1989,30,309. 82. (a) Ruitenberg, K.; Westmijze, H.; Meijer, C. J.; Elsevier, C. J.; Vermeer, P. J. Organomet. Chem. 1983, 241, 417. (b) Ruitenberg, K.; Westmijze, H.; Kleijn, H.; Vermeer, P. J. Organomet, Chem. 1984,277,227. 83. Marshall, J. A.; Wang, X.-j. J. Org. Chem. 1990,55,6246. 84. Tanaka, H.; Abdul Hai, A. K. M.; Ogawa, H.; Torii, S. Synlett 1993,835. 85. Boaretto, A.; Marton, D.; Tagliavini, G.; Gambaro, A. J. Organomet. Chem. 1985,286,9. 86. Boaretto, A,;Marton, D.; Tagliavinni, G. J. Organomet Chem. 1985,297,149. 87. Mukaiyama, T.; Harada, T. Chem. Lett. 1981,621. 88. Nokami, J.; Tamaoka, T.; Koguchi, T.; Okawara, R. Chem. Lett. 1984,1939. 89. Marshall, J. A,;Wang. X.-j. J. Org. Chem. 1992,57, 1242. 90. Marshall, J. A,; Wang, X.-j. J. Org. Chem. 1991,56,6264. 91. Marshall, J. A,; Perkins, J. F.; Wolf, M. A. J. Org. Chem. 1995,60, 5556. 92. Marshall, J. A,; Yu, R. H.; Perkins, J. F. J. Org. Chem. 1995,60,5550. 93. Marshall, J. A,; Palovich, M. R. J. Org. Chem. 1997,62,6001. 94. Kobayashi, S. in LewisAcid Reagents,Yamamoto, H., Ed.; Oxford University Press, 1999;pp 137-157. 95. Encyclopedia of Reagents for Organic Synthesis, Paquette, L. A,, Ed. in Chief; John Wiley and Sons: Chichester, 1995; pp 48884909.

Lewis Acids in Organic Synthesis Edited bv Hisashi Yamarnoto Copyright 0WILEY-VCH Verlaa GmbH.2000

11 Sb(II1) and Sb(V) Lewis Acids Kazuaki Ishihara

11.1 Introduction Trivalent antimony compounds have been used only to a very limited extent in organic synthesis. SbC13 has been used as a Lewis acid catalyst for Friedel-Crafts reactions. Although treatment of benzene with benzoyl chloride and SbC13 at 155 "C gives benzophenone in good yield [la], this conversion and other Friedel-Crafts reactions catalyzed by SbC13 are slower, require higher temperatures, and give lower yields than those with the more reactive Lewis acids AlC13, FeC13, and SbC15 [1]. SbFS is one of the strongest Lewis acids reported and is capable of forming stable conjugate superacid systems with HF and FS03H [2]. Its complex with CF3S03H is, however, less stable and cannot be stored for extended periods of time. CF3S03H-SbF5 can, nevertheless, be a useful acid system when prepared in situ [3]. The most important properties of SbF5 include its high acidity, strong oxidizing properties, and tendency to form stable anions [4]. The chemistry of SbFS is mainly characterized by these properties. The major applications of SbF5 in organic synthesis include oxidation, fluorination, and as a catalyst for Friedel-Crafts-type reactions and other acid-related chemistry. This chapter focuses on the synthetic applications of trivalent and pentavalent antimony compounds.

11.2 SbX3-CatalyzedReactions SbC13 has been used as a Lewis acid catalyst for electrophilic aromatic substitution reactions. Treatment of benzene with Clz and NOCI, then molten SbC13 (135-145 "C) gives chlorobenzene [5]. Treatment of 2-amino-6-substituted purine nucleosides with t-butyl nitrite and catalytic amounts of SbCl3 in a chlorinated hydrocarbon solvent gave 2-chloro-6-substituted derivatives smoothly (Eq. 1). The corresponding 2-bromo analogs were obtained when SbBr3 was used in a brominated hydrocarbon solvent (Eq. 1) [6].

t-BuONO, SbC13

or

OAc OAc R=CI or F (yields for R=CI)

t-BuONO, SbBr3 CH2Br2 * -1 0 "C, 2-3.5 h

X (11

OAc OAc 84% (X=CI) 78% (X=Br)

524

Ishihara

The Lewis acid-base reaction of SbC13 with DAST, (diethy1amino)sulfur trifluoride, can be used to catalyze the conversion of sulfoxides to a-fluorothioethers (Eq. 2) [7]. Zinc iodide was originally reported to be the catalyst for this fluoro-Pummerer transformation [sa], but SbC13 is markedly superior [7,8b].

Et0 E t o v S s o

Q

0

0

SF3-NEt2, SbC13 *

I, 4

(2)

91Yo

OMe

OMe

Sb(OEt), is highly effective for the metal-templated cyclization of tetramino esters to give macrocyclic spermine alkaloids such as buchnerine, verbacine, verbaskine, and verbascenine (Eq. 3) [9]. The accelerated rates and high regioselectivities suggest a mechanism in which the acyclic tetramino esters are covalently or coordinately attached to the antimony before the final cyclization step. In addition, Sb(OEt), is useful as an intermolecular amidation catalyst for reactions between esters or carboxylic acids and amines (Eq. 4) [9].

fC0OEt

H

4-MeOPdNwNoNANH2

azeotropic reflux Buchnerine

0

0

Ph H

H Verbacine

H

U

Ac Verbacenine

Verbaskine

RC02Me or + RC02H

Sb(OEt)3 (10 rnol%)

RWNH toluene, azeotropic reflux 42-91 Yoyield

-

RCONR’R*

(4)

Sb(III) and Sb(V) Lewis Acids

525

11.3 SbX5-CatalyzedReactions 11.3.1 Friedel-Crafts and Related Chemistry Aromatic compounds can be readily alkylated under SbCl5 catalysis [10,11], although competing chlorination can sometimes complicate the alkylation. The acidity of SbCls is comparable with that of AlC13 and A1Br3 in the reaction of s-butyl chloride with benzene [loa]. Both acyl halides and acid anhydrides have been used in the acylation of arenes under SbClS catalysis [12,13]. The reaction of 3-acetamidobenzo[b]furan with acid chlorides gives condensed 1,3-oxazinium salts [12d]. Treatment of these salts with ammonium acetate in acetic acid gives the corresponding benzo[b]furano[3,2-d]pyrimidines in good yields (Eq. 5). Although Friedel-Crafts acylation generally requires a stoichiometric amount of Lewis acid, catalytic acylation can be achieved with the use of SbCISin conjunction with AgC104, LiC104, or Ph2BCl [13].

x=O, S, NH; R=Me, Ph

70-80%

Much of the research on the SbC15-catalyzed halogenation of arenes has focused on the chlorination and bromination of perfluoroalkyl-substituted aromatics [14]. The reaction of organic disulfides with electron-rich aromatic compounds under catalysis with SbCIS and AgSbFh affords unsymmetrical aryl sulfides in modest yields [lsa]. Electrophilic sulfinylation and sulfonation can be similarly effected by SbClS [15a-c]. Alkyl- and halobenzenes give thiocyano derivatives when treated with a mixture of SbCISand Pb(SCN)2 in CC14 1161. Silyl enolates of a,a-dialkoxy ketones react with furans to form [3 + 41 cycloaddition products in the presence of SbCl5 (Eq. 6) [17]. Cycloaddition also occurs when 2,2-dialkoxycyclopropanecarboxylicesters and carbonyl compounds are treated with SbC15 1181.

T O M . OMe

+


MeN02, SbCIS -78 "C

6 eHMe OMe

38%

0

+

(6)

12%

0

In the presence of SbClS and Sn(OTf)2, a,P-unsaturated thioesters react with silyl enol ethers to form the corresponding Michael adducts stereoselectively in high yields [19]. Successive treatment of lactones with ketene silyl acetals and certain organosilane-based nucleophiles under SbClS-Me3SiC1-Sn12 catalysis affords a-amino- or a,a-disubstituted cyclic ethers (Eq. 7) [20].

526

Ishihara

SbC15, Me3SiCI Sn123

+OTBDMS OEt

CH2C12, -78 "C 39-95%

RfaCH2C02Et Nu

(7)

Nu=H, allyl, CN, SBn

Alkylation of arenes and perfluoro or perchlorofluoro compounds proceeds readily under SbF5 catalysis [4,21]. In addition to alkyl halides, alkyl esters and haloesters have also been used to alkylate arenes under these reaction conditions. For example, perfluorotoluene reacts with pentafluorobenzene to form perfluorodiphenylmethane in 68 % yield when the reaction mixture is quenched with HF. If H20 is used for quenching, perfluorobenzophenone is obtained in 93 % yield (Eq. 8) [21a]. 1. C6F5H, SbF5 2. HF

F F *

c6F5xc6F5

68%

(8)

F

0

1. C6F5H, SbF5 2. H20

*

C6F5/I'cBF5

93%

Acylation of pentafluorobenzene to form ketones either with acid halides or with anhydrides has been achieved with excess SbF5 [22]. Use of phosgene in place of acid chlorides results in the formation of pentafluorobenzoic acid in good yield [4]. The Friedel-Crafts sulfonylation of aromatics with alkane- and arenesulfonyl halides and anhydrides has been studied (Eq. 9) [23]. In the reaction of pentafluorobenzenesulfonyl fluoride with pentafluorobenzene, decafluorodiphenyl sulfone is formed with decafluorodiphenyl [23c]. Certain phenylacetylenes react with SO2and benzene in the presence of SbF5to form benzothiophene S-oxide 12241. (Eq. 10).Sulfinyl fluoride reacts similarly with arenes under SbF5catalysis to give sulfoxides (Eq. 11) [25].

R'SOzX, SbF5 (9)

X=CI, F, R'S03

PhCECX

SbF5, C6H6 S02, -78 "C

X=CI, Br, Ph

1644%

S02R'

t

x-$,Jp

(10)

s\

0

Sb(1II) and Sb(V)Lewis Acids

527

Oxidation of elemental sulfur and selenium with SbFS leads to the formation of doubly charged polyatomic cations [26]. These cations can react with polyfluorinated arenes to form diary1 sulfides or selenides (Eq. 12) [27].

X=F, CI; Ar=polyfluoroaryl

In the presence of SbFS, inorganic halides such as NaCl and NaBr can serve as electrophilic halogenating agents [21b,28]. The halogenation of alkanes with dichloro- or dibromomethane has been achieved in the presence of SbFS (Eq. 13) [29]. In this reaction, halonium ions are initially formed; these in turn abstract hydride from hydrocarbons. Quenching of the resulting carbocations with halides leads to the desired haloalkanes. CH2X2, SbF5 RH

*

RX

64-88%

(13)

RH=secondary, tertiary alkanes X=CI, Br

In the presence of SbFs, alkyl chlorides are ionized to form carbocations, which can be trapped with CO [30]. Quenching the reaction intermediates with water or alcohols yields the corresponding carboxylic acids or esters. For instance, halogenated trishomobarrelene reacts with CO in SbFs-S02C1F to give, after treatment with alcohol and water, a mixture of acid and ether (Eq. 14) [30a].

1. SbF5, CO, SO2CIF

u

2. NaOMe, MeOH 3. H20

-

zH +

u

(14)

u 53%

24%

Studies have been conduct on the alkylation of alkenes, especially fluoroalkenes, in the presence of SbF5 (eq 15) [31].

528

Ishihara

X=F, CFs

The acylation of alkenes can also be similarly effected with SbFS [32]. For example, a$-unsaturated carboxylic acid fluorides react with perfluoroalkenes to form a$unsaturated ketones (Eq. 16) [32b]. F

SbF5

'gF F

61 CF2CF2 -92%

*

O

R w C 2 F 5 F

( l 6,

The oxidation of dienes with molecular oxygen to form Diels-Alder-type adducts can be effected by Lewis acids and some salts of stable carbenium ions [33]. For ergosteryl acetate, SbFSis by far the most active catalyst (Eq. 17) [33a].

11.3.2 Isomerization and Rearrangements Along with many other Lewis acids, SbCls has been used to promote the Fries rearrangement [34]. More recently, it has been found that the SbClS-AgSbFh system is an efficient catalyst for Beckmann and pinacol rearrangements [35]. Methyl ba-chloropenicillanate rearranges to (3S)-6-chloro-2,3,4,7-tetrahydro-2,2-dimethyl-7-0~0-1,4thiazepine-3-carboxylatewhen treated with SbC15 in CH2C12. Under similar conditions, methyl penicillanate and methyl bj?-phthalimidopenicillanate undergo analogous isomerizations (Eq. 18) [36].

Sb(III) and Sb(V) Lewis Acids

529

Isomerization of perfluoroalkenes can be realized by use of SbFS catalysis [37]. The terminal carbon-carbon bonds of these alkenes are usually moved to the 2-position under the influence of this catalyst (Eq. 19). A further inward shift generally occurs only if H or C1 atoms are present at the 4-position of the alkenes. As a rule, isomerization leads to the predominant formation of trans isomers. Terminal fluorodienes also isomerize exothermally into dienes containing internal double bonds in the presence of SbFS.With a catalytic amount of SbFs, perfluoro-l,4-cyclohexadienedisproportionates to hexafluorobenzene and perfluorocyclohexene. SbFS promotes the rearrangement of perfluoroepoxides to carbonyl compounds (Eq. 20) [38].

11.3.3 Other Reactions 1,3-Dithianes can be converted to the corresponding carbonyl compounds in excellent yields in the presence of SbCIS [39]. When epoxides are treated with a catalytic amount of SbClS-AgSbF6 in the presence of alkoxytrimethylsilane and triethylsilane, sequential reactions involving rearrangement and reductive condensation give the corresponding ethers in good yields (Eq. 21) [40]. SbC15, AgSbFs

Ph

(211

t

PhAPh

Ph(CHz)20TMS, Et3SiH 60%

Ph&O-Ph

Although reaction of u,P-unsaturated carbonyl compounds with diazo compounds generally gives cyclopropyl compounds in low yields, in the presence of SbFs, the cyclopropanation of a,P-unsaturated carbonyl compounds with diazocarbonyl compounds proceeds very well to produce the desired products in good yields (Eq. 22) [41]. R’

0

0

SbF5

+ RzKcHN2

11-80%

P

R

l

U

R

R2C

II

R=H, OMe; R’=H, Me; R2=Ph, OEt

0

II

0

530

Ishihara

11.4 HX-SbFS-Catalyzed Reactions Of all the superacids, magic acid is probably the most widely used medium for the study of stable long-lived carbocations and other reactive cations. The general rule is that the stability of the carbocation generated increases with the acidity of the medium used. The acidity of the HS03F-SbF5 system as a function of SbF5 content has been studied [42,43]. The increase in acidity is very sharp at low SbFS concentration. The Ho value changes from -15.1 for HS03F to -19.8 for a mixture containing 10 YO SbF5 [42]. The acidity increases to an estimated value of Ho = -26.5 for 90 YO SbFS. The Ho value for a 1:l molar mixture of HS03F and SbFS, known as Magic acid@,was estimated to be ca -23 by a dynamic NMR study [43]. A major reason for the wide application of Magic acid compared with other super acid systems, besides its very high acidity, is probably the large temperature range in which it can be used. HF-SbFS is probably the strongest liquid superacid system, and has the widest acidity range [2]. Compared with the widely used magic acid system, fluoroaromatic acid is even more acidic with the same molar concentration of SbF5. For example, fluoroaromatic acid with 0.5 YOSbFS has a Ho of -21, whereas Ho for HS03F-SbFS with the same amount of SbFs is only -17 [44]. HSbF6 has an estimated Ho of -30 [2]. The X-ray structure of the 1:l HF:SbF5 complex has recently been established [4S].

11.4.1 Generation of Stable Carbocations Awide variety of aliphatic tertiary and secondary alcohols can be ionized to the corresponding alkyl cations by use of magic acid [46-521. Formation of the t-butyl cation (Eq. 23) [46] and a cyclopropyl-stabilized di-cation [53] are representative examples. Primary (and some secondary) alcohols are protonated only at temperatures lower than -60 "C [S4]. At more elevated temperatures, they might cleave to give the corresponding carbocations, which, however, immediately rearrange to the more stable tertiary cations [49,50].

t-BuOH

HSOSF-S b F5 t

-60 "C

t-Bd

(23)

Similar to alcohols, aliphatic ethers [54], thiols 5 1, and sulfides are also protonated on oxygen or sulfur, respectively, at -60 "C in magic acid; carbocations are subsequently formed upon raising the temperature. Promoted sulfides, excluding tertiary alkyl, are resistant to cleavage up to +70 "C [56]. Alkyl chlorides, fluorides, and bromides are convenient and frequently used precursors for the generation of alkyl cations in HS03F-SbF5 systems [%I. It should be noted, however, that the HS03F-SbFS system is less suitable than SbFs for the generation of alkyl, especially secondary alkyl, cations from the corresponding alkyl halides. Carbocations can be generated by the protonation of unsaturated hydrocarbons such as alkenes and cycloalkenes [49,52], cyclopentadienes [57], benzenes and naphthalenes (Eq. 24) [58], pyrenes and cyclophanes [59], unsaturated heterocycles [60], and their derivatives with carbon-heteroatorn multiple bonds [2], including carbonyl and nitrile compounds and diazoalkanes [61].

Sb(III) and Sh(V)Lewis Acids

a

531

HS03F-SbF5 SO2CIF,-83"C *

"

I.

, J

*.

-

(24) ,

Magic acid can abstract hydride from saturated alkanes, including straight-chain alkanes and branched and cyclic alkanes, at -125 to 25 "Cto give alkyl cations [47,62]. Its corrosive and toxic nature makes HF-SbFS a less frequently used acid system for the preparation of carbocations, compared to HS03F-SbFS. It is, however, preferred in the generation of arenium ions, because high acidity is required for their formation (Eq. 25) [63].

HF-SbF5

*

SO2CIF, -60 "C

11.4.2 Friedel-Crafts and Related Chemistry Although alkylations of deactivated aromatic compounds such as acetophenone are generally difficult to achieve [64], this problem can be overcome by use of HF-SbFS. It has been demonstrated that acetophenone is readily ethylated with ethyl chloride in the presence of HF-SbF5 (Eq. 26) [65]. Other primary and secondary alkyl chlorides also react well with the substrate under similar conditions, although poor results are obtained with tertiary chlorides.

+

78%

polyethylated acetophenones

(26)

22%

Upon treatment with HF-SbFS, para-substituted phenols (or their methyl ethers) can be diprotonated [66], first on the oxygen atom and then on the metu carbon [67]. The resulting dipositively charged species are exceedingly reactive towards a variety of arenes [67]. 4-Arylcyclohexanones, the primary products of the reactions, can be further transformed to 3-arylcyclohexanones. The ratio of the two isomers depends on conditions such as the reaction time, amount of acid, and the nature of the substrates. For example, when p-cresol is reacted with benzene in the presence of HF-SbFS, 4-methyl-4-phenylcyclohexenoneand 3-phenyl-4-methylcyclohexenoneare obtained in yields of 29 and 33 YO,respectively, after 90 s. By increasing the reaction time to 15 min, the yield of 3-phenyl-4-methylcyclohexenoneis increased to 90 YO whereas that of 4-methyl-4-phenylcyclohexenone decreased to 2-3 % (Eq. 27).

532

Ishihara

PhH, HF/SbF5 0 "C, 15 rnin

-

6 li;l

(27)

+

Ph

Ph

90%

2-3'/0

11.4.3 Isomerization and Rearrangements The high acidity of HF-SbFS makes fluoroantimonic acid an efficient isomerization catalyst for hydrocarbons [68,69]. ortho- or para-bromo phenols have been reported to isomerize to metu isomers in HF-SbFS via intramolecular 1,2-Br shifts. In contrast, CF3S03H-catalyzed isomerizations proceed through an intramolecular mechanism [70]. It has also been reported that rearrangements of 4-alkylated and 2,6-dialkylated phenolic ethers can occur in HF-SbF5. The alkyl groups originally attached to oxygen are rearranged to the meta positions of these compounds (Eq. 28) [71]. This dealkylating capacity of HF-SbF5 has been successfully used in the synthesis of ll-deoxyanthracyclines (Eq. 29) [72].

HF/SbF5 -40 "C

Et

4

Ph

(28)

Ph

Rearrangement of phenols to dienones occurs readily in superacids. Some simple bicyclic phenols and their ethers have been investigated as model compounds by use of HF-SbFS [73]. This method is also applicable to natural products [74]. For example, treatment of estrone derivatives in HF-SbF5, then aqueous bicarbonate work-up led to estra-4,9-diene-3,17-dione (Eq. 30). The opposite rearrangement, i.e. that of dienones to phenols, can also be achieved in an HF-SbF5 medium (Eq. 31) [75].

&yJ

2. 1.HF/SbF5,0°C NaHC03, H20

&o (30)

t

RO

\

I H

Fl

R=H, Ac, Me

70-80 % /

%(Ill) and Sb(V) Lewis Acids

533

n-Alkanes can be readily isomerized to branched alkanes in superacidic media; HF-SbF5 has been used for this process [76]. With a catalytic amount of HF-SbFS, endo-trimethylenenorbornane was converted to exo-trimethylenenorbornane at room temp. in 98 % yield [77]. With increasing amounts of acid, some adamantane was formed in the reaction mixture. Raising the reaction temperature to 100 "Cincreased the yield of adamantane to 47 YO(Eq. 32) [78]. HFISbF5

HFISbF5

100 "C 98%

47%

11.4.4 Cyclization HS03F-SbFS has been used as a high-acidity catalyst for the cyclization of acyclic isoprenoids at low temperature. The reaction course and the products of the cationic cyclization depend on the acidity of the catalyst and structural differences in the substrates. Structural changes also lead to dramatic changes in the reaction course and products. For example, whereas pseudoionone is cyclized to monocyclic derivative (Eq. 33) [79], geranylacetone gives a bicyclic ether (Eq. 34) [go]. 1. HS03F-SbF5

@

SO&IF, 2. MeOH -100 "C

pp

(33)

40%

HS03F-SbF5

SO*, -65 "C 60%

-

(34)

534

Ishihara

11.4.5 Formation of Aromatic Sulfoxides By treatment with HS03F-SbF5 (1:l) and sulfur dioxide, alkylbenzenes, halobenzenes, and alkylhalobenzenes are converted to their corresponding diaryl sulfoxides along with small amounts of diaryl sulfides as minor products (Eq. 35) [Sl]. In the absence of SO2 aryl sulfone formation is the dominant process, although sulfoxide is also formed. Unsymmetrical (mixed) sulfoxides can be prepared by adding one molar equivalent of an arene to the solution of the second arene and magic acid-S02 in Freon at low temperatures.

HSOsF-SbF5 (35)

R

-3OtoO"C

R=Me, 87%; F, 55%

11.4.6 Formylation and Carboxylation The electrophilic formylation of arenes with CO in the presence of acids (GattermanKoch conditions) is an efficient method for preparing aromatic aldehydes. HF-SbFSS02C1F is the most active system for this reaction [82]. It has been demonstrated that even diformylation can be achieved on polymeric aromatics such as biphenyl with the use of fluoroantimonic acid (Eq. 36) [83]. CO (60 atm)

93:7

Hydrolysis of the resulting acyl cations yields the corresponding carboxylic acids (Eq. 37) (Koch reaction) [84]. With excess alkane present, ketones can be obtained (Eq. 38). 1. HF/SbF5 2. H20 10% by GC

80%

Sb(ll1) and Sb(V)Lewis Acids

535

1. HF/SbF5, CO 2. methylcyclohexane

82% Me

An interesting method has been developed for the carboxylation of bicyclic enones in HF-SbF5 1851. It has been demonstrated that diprotonated a,P-unsaturated ketones react with CO to form acylium ions. Quenching of these acylium ions with methanol leads to the corresponding carboxylic esters in good yields (Eq. 39). 1. HF/SbF5

co, 0 "C 2.MeOH

*

0

&

,"C02Me

(39)

H

60%

Generally, alcohols with short carbon chains (C,-C,) are not carbonylated under the usual Koch conditions. It has, however, been shown that these alcohols react readily with CO in fluoroantimonic acid to give the corresponding carboxylic acids in high yields 1861. y-Butyrolactones react with CO at atmospheric pressure in HF-SbF5 containing excess SbF5 to give dicarboxylic acids in good yields [86c]. Methyl alkyl ketones with alkyl groups having five or more carbons can undergo a Koch reaction to form the corresponding 0x0 carboxylic acids (Eq. 40) 1871. 1. HFISbF5, CO

2.66% H20

*

~

C

O

Z (40)H

11.4.7 Oxyfunctionalization of Hydrocarbons The superacid-catalyzed oxygenation of alkanes has been well reviewed 1881. When treated with ozone 1891 or hydrogen peroxide [90,91] under magic acid catalysis, alkanes, including methane, ethane, butanes, and higher alkanes and haloalkanes [92] undergo electrophilic oxygenation followed by carbon-to-oxygen alkyl group migration giving, via alkoxycarbenium ions, ketones and alcohols (Eq. 41). Aliphatic alcohols, ketones, and aldehydes react with ozone in magic acid solution to give bifunctional oxygenated derivatives such as diketones, hydroxyl ketones, and glycols (Eq. 42) 1931. The relative reactivity of o-bonds in alkanes with protonated ozone was found to be R3C-H > R2(H)C-H > R(H2)C-H > C-C 1891.

,I,,

1. HS03F-SbF5 -78 to 0 "C

-

+ o ~ ~ ~ H ~ o ~ 2. H20

+ MeOH

(41)

536

Ishihara

03,

-OH

HS03F-SbF5 (42)

SO2CIF, -40 "C

The oxidation of 3-keto steroids with 0 3 has also been conducted in HF-SbFS [94]. When the oxygenation of ethers was performed under similar conditions, 0x0 alkyl ethers were obtained, with the 0x0 functionality generally three carbons away from the ether linkage (Eq. 43) [95].

ib,

HF/SbFS, 0

3

*

-40 "C, 15-90

min

86%

Aromatic compounds such as benzene, alkylbenzenes, and halobenzenes can be directly oxygenated with hydrogen peroxide in magic acid or other superacids, giving phenols [96]. The phenols formed are protonated by the superacids, and are thus deactivated against further electrophilic attack or oxidation. The strength of the acids used can play a significant role in the regioselectivity of the reaction. For example, hydroxylation of naphthalene in the weak acid 70 YOHF-30 YOpyridine yields 1- and 2-naphthols in a 98.4:1.6 ratio; when, on the other hand, superacidic HF-SbFs is used (Eq. 44) this ratio is 1.8:98.2 [97]. Benzaldehyde and aromatic ketones have been reported to be hydroxylated in HF-SbFS without the formation of products derived from Baeyer-Villiger oxidation [98]. By increasing the ratio SbFS:substrate, phenols can be further hydroxylated in HF-SbF5. Resorcinols and some other dihydroxyarenes have been prepared by this method (Eq. 45) [99,100]. Hydroxylation of anilines by H202in HF-SbFS yields all three possible isomers, with meta derivatives as major products [loll.

a

-

1. HF/py (70:30)or HF/SbF5 2.90% H202,O-20 "C

+

26%

WoH

98.4 : 1.6 (HF/py) 1.8:98.2 (HF/SbF5)

OH I

HF/SbFS

OH I

(44)

Sb(III) and Sb(V)Lewis Acids

537

11.4.8 Other Reactions HF-SbFS and other superacids, for example HF-TaF5 and HBr-A1Br3, are able to promote the hydrogenation of benzene and other aromatics to cyclohexanes and compounds derived from them in the presence of suitable hydride donors [102]. The reaction proceeds through an ionic hydrogenation mechanism. The best hydride donors are isoalkanes (cycloalkanes) with tertiary C-H bonds. The use of molecular hydrogen in ionic hydrogenation reactions is also possible in the presence of tertiary C-H bondcontaining hydrocarbons [102a]. Superacid-catalyzed ionic hydrogenation is not limited to aromatic compounds; it has been successfully applied in natural product chemistry (Eq. 46) [103-1051.

& -

0

methylcyclopentanf HFlSbF5

-

0 "C

/

76%

13%

Bromination of para-alkylated or 2,6-dialkylated phenols and their ethers with Br2 in HF-SbFS leads to the formation of rneta-brominated products (Eq. 47) [106]. Sodium or potassium bromide can also be used in place of Br2 in this reaction [107]. OH

HFISbFS

HF-SbFS is also an efficient cationic polymerization catalyst [2]. HF-SbF5 and other acids such as HF-BF3 readily oligomerize ethylene oxide to mixtures of cyclic ethers [lo81 which can be subsequently separated (Eq. 48). The key to cyclic ether formation is the presence of anhydrous HF in the conjugate acid systems; chain polymers would otherwise be obtained. HFISbF5

A

CHPCIP

(48)

538

Ishihara

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Sb(III) and Sb(V)Lewis Acids

28. 29. 30. 31.

32. 33.

34. 35. 36. 37.

38.

39. 40. 41. 42. 43. 44. 4s. 46. 47. 48. 49.

so. 51.

539

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Sb(III) and Sb(V) Lewis Acids

541

83. (a) Tanaka, M.; Souma, Y. J. Chem. Soc., Chem. Commun.1991,1551. (b) Tanaka, M.; Fujiwara, M.; Ando, H.; Souma, Y. J. Org. Chem. 1993,58,3213. 84. (a) Paatz, R.; Weisgerber, G. Chem. Be%1967,100,984. (b) Yoneda, N.; Fukuhara, T.; Takahashi, Y.; Suzuki, A. Chem. Lett. 1983,17. 85. Coustard, J. M.; Jacquesy, J. C. J. Chem. Res. (S)1977,280. 86. (a) Takahashi, Y.; Tomita, N.; Yoneda, N.; Suzuki, A. Chem. Lett. 197.5, 997. (b) Yoneda, N.; Takahashi, Y.; Sakai, Y.; Suzuki, A. Chem. Lett. 1978, 1151. (c) Yoneda, N.; Suzuki, A,; Takahashi, Y. Chem. Lett. 1981,767. 87. Yoneda, N.; Sato, H.; Fukuhara, T.; Takahashi, Y. Suzuki, A. Chem. Lett. 1984,1617. 88. Olah, G. A,;Parker, D. G.; Yoneda, N. Angew. Chem., Int. Ed. Engl. 1978,17,909. 1976,98,5261. 89. Olah, G. A,; Yoneda, N.; Parker, D. G. J. Am. Chem. SOC. 90. Olah, G. A,; Yoneda, N.; Parker, D. G. J. Am. Chem. Soc. 1977,99,483. 91. Yoneda, N.; Olah, G. A. J. Am. Chem. Soc. 1977,99,3113. 92. Olah, G. A,; Yoneda, N.; Parker, D. G. / A m . Chem. Soc. 1976,98,2251. 93. Olah, G. A,; Yoneda, N.; Ohnishi, R. J. Am. Chem. Soc. 1976,98,7341. 94. (a) Jacquesy, J. C.; Jacquesy, R.; Lamande, L.; Nabonne, C.; Patoiseau, J. F.; Vidal, Y. Nouv. J. Chim.1982,6,589. (b) Jacquesy, J. C.; Patoiseau, J. F. Tetrahedron Lett. 1977,1499. 95. Yoneda, N.; Kiuchi, T.; Fukuhara, T.; Suzuki, A.; Olah, G. A. Chem. Lett. 1984,1617. 96. Olah, G. A,; Ohnishi, R. J. Org. Chem. 1978,43,865. 97. Olah, G. A,; Keumi, T.; Lecoq, J. C.; Fung, A. l?; Olah, J. A. J. Org. Chem. 1991,56,6148. 98. Gesson, J. P.; Jacquesy, J. C.; Jouannetaud, M. P.; Morellet, G. Tetrahedron Lett. 1983,24,3095. 99. (a) Gesson, J. P.; Jacquesy, J. C.; Fung, A. P.; Olah, J. A. J. Org. Chem. 1991,56,6148. (b) Gesson, J. P.; Jacquesy, J. C.; Jouannetaud, M. P. Nouv. J. Chim. 1982,6,477. 100. Jacquesy, J. C.; Jouannetaud, M. P.; Morellet, G. Tetrahedron Lett. 1983,24,3099. 101. Jacquesy, J. C.; Jouannetaud, M. P.; Morellet, G.; Vidal, Y. Tetrahedron Lett. 1984,25,1479. 102. (a) Wristers, J. . I Am. Chem. Soc. 1975, 97, 4312. (b) Siskin, M. J. Am. Chem. Soc. 1978, 100, 1838. (c) Siskin, M. J. Am. Chem. Soc. 1974,96,3641. 103. Jacquesy, J. C.; Jacquesy, R.; Joly, G. Tetrahedron Lett. 1974,4433. (b) Coustard, J. M.; Douteau, M. H.; Jacquesy, J. C.; Jacquesy, R. Tetrahedron Lett. 1975,2029. 104. Jacquesy, J. C.; Jacquesy, R. Joly, G. Bull. SOC.Chim. FK 1975,2283,2289. 105. (a) Jacquesy, J. C.; Jacquesy, R.; Joly, G. Tetrahedron 197.5,31,2237. (b) Jacquesy, J. C.; Narbonne, C. J. Chem. Soc., Chem. Commun. 1979, 765. (c) Coustard, J. M.; Douteau, M. H.; Jacquesy, R.; Longevialle, P.; Zimmermann, D. J. Chem. Res. (S)1978,16. (d) Coustard, J. M.; Douteau, M. H.; Jacquesy, R. J. Chem. Res. (S) 1978,18. (e) Jacquesy, R.; Narbonne, C.; Ung, H. L. J. Chem. Res. (S)1979,288. 106. (a) Jacquesy, J. C.; Jouannetaud, M. P.; Makani, S. J. Chem. Soc., Chem. Commun. 1980,110. (b) Jacquesy, J. C.; Jouannetaud, M. P.; Makani, S. Nouv. J. Chim. 1980, 4, 747. (c) Jacquesy, J. C.; Jouannetaud, M. P. Tetrahedron 1981,37, 747. (d) Brittain, J. M.; de la Mare, l? B. D.; Newman, P. A. Tetrahedron Lett. 1980,21,4111. 107. Cherry, G.; Culmann, J. C.; Sommer, J. Tetrahedron Lett. 1990,31,2007. 108. Dale, J.; Borgen, G.; Daasvatn, K. Acta Chem. Scand. 1974,288,378.

Lewis Acids in Organic Synthesis Edited bv Hisashi Yamarnoto Copyright 0WILEY-VCH Verlaa GmbH.2000

12 Copper Lewis Acids in Organic Synthesis Mukund P Sibi and Gregory R. Cook

12.1 Introduction Copper, one of the earliest metals known to mankind, forms a variety of compounds with halogens, oxygen, nitrogen, phosphorus, and sulfur donors. Copper, a group 11 metal, can generally exist in three oxidation states; Cu(O), Cu(1) and Cu(I1). The Lewis acidity of copper depends on its oxidation state and on the counter ion. Of the three, a priori, compounds in the Cu(I1) oxidation states are more Lewis acidic. In the halide series, CuF2 and CuC12 are the most Lewis acidic. The copper bromides and iodides in either oxidation state are less reactive and find limited application as activators. A similar trend in the Lewis acidity of the copper is observed with changes in the electron-withdrawing capacity of the counter ion. For example, C U ( O C O C H ~is) ~less Lewis acidic than Cu(OCOCF3)2. The counter ions which impart substantial electrophilicity to the metal are the triflate (OS02CF3 = OTf), sulfate (SO4), perchlorate (Clod), and non-coordinating anions such as tetrafluoroborate (BF4), hexafluorophosphate (PF6), and hexafluoroantimonate (SbF6). This review will discuss the use of copper Lewis acids in organic reactions with emphasis on the chemistry described in the last 10 years. The most widely used copper Lewis acids are listed in Table 1 [l]. Table 1. The most widely used copper Lewis acids [l]

Commercially available

Prepared in situ

CuX (X = C1, Br, I)

CuC104.4CH3CN [2] CuX2 (X = F, C1, Br, I)

Commercially available

CuOCOCH3 (CuOTf)Z.PhH

CuSO4

CuPF6,4CH?CN[2]

Cu(OCOCH3)z

Prepared in situ Cu(SbF& [3]

CU(N03)2

C~(C104)2.6H20 Cu(BF4)2,6H20

Cu(0Tf)z

Copper Lewis acids have found many applications in the last decade in a variety of organic transformations and more notably in enantioselective reactions. In particular, Cu(OTf)2 and Cu(SbF& in conjunction with chiral bisoxazolines are the chiral Lewis acids of choice for cycloadditions, aldol reactions, ene reactions, and other selective transformations. Moderately Lewis acidic copper salts are also reagents for transesterifications, dehydrations, and hydrolysis. The thiophilic nature of copper makes them ideal for selective deprotection of thio acetals and thioesters and offer practical advantages over mercury salts.

544

Sibi/Cook

There are several reasons for the extensive use of copper Lewis acids in stereoselective transformations: (i) predictable coordination geometry about the metal, (ii) ready availability, (iii) two oxidation states, and (iv) moderate Lewis acidity. Copper(I1) complexes usually adopt a square planar, square pyramidal, or trigonal bipyramidal geometry, whereas Cu(1) complexes have a preference for tetrahedral geometry (Figure 1).

t

LC ,Q

Mostly Cu(l)

Both Cu(1) and Cu(1l)

Mostly Cu(ll)

Mostly Cu(ll)

Only Cu(ll)

L = Ligand: OR, OH2, NR2, SR, PR3

Figure 1.

The counter ions in the copper complexes play a key role in the type of geometry which the metal can adapt. Of the many commercially available compounds, copper(I1) triflate, copper(I1) perchlorate, and copper(1) bromide are the most widely used Lewis acids (see Table 1).The more reactive Cu(SbF& salt must be generated in situ from copper halides. Some copper(1) compounds are available as complexes with donor solvents such as benzene and acetonitrile or can be prepared in situ. They find application in the activation of single-point donors such as aldehydes and imines. In addition, Cu(1) compounds have a greater affinity for soft ligands (olefins, sulfur, phosphorus) than have Cu(I1) Lewis acids. The formation of the naked copper Lewis acids is important in transformations that require strong activation of the substrate or the reagent by Lewis acids. For example, when the counter ions are chlorine, bromine, or tetrafluoroborate, they do not dissociate very easily on addition of moderately strong Lewis basic donors (ligands). Even with Cu(OTf)Z, the displacement of both counter ions is not usually possible. Only when the counter ions are very strongly noncoordinating, for example antimony hexafluoride, is the complete dissociation of the counter ions observed. This review details the utility of copper compounds in a variety of organic transformations wherein their principal function is as a Lewis acid. Other important organic transformations such as conjugate additions, cyclopropanations, oxidations, and aziridinations are also mediated by copper species. Copper does not, however, function as a Lewis acid in these reactions but acts as a reagent and these reactions are not discussed here. The chemistry described in this review highlights the role of copper in facilitating synthetic transformations and the readers should consult the primary literature for experimental details.

12.2 Dehydration The dehydration of alcohols under mild conditions is affected by copper(I1) Lewis acids. Copper sulfate has long been utilized as a dehydrating agent. An example of its effectiveness for alcohol dehydration is demonstrated in the conversion of the sensitive propargylic alcohol 1 to enyne 2 (Sch. 1) [4]. A carbocation mechanism is suggested by the formation of bis ethers in these reactions [5]. The addition of pyridine

545

Copper Lewis Acids in Organic Synthesis

completely inhibited reaction with CuSO4, presumably via deactivation of the copper Lewis acid. CuSO4 supported on silica gel has also been employed for dehydration reactions [6].

cuso4 xylene

c

TBDMSO

51% 1

TBDMSO 2

Scheme 1

Copper(I1) triflate in nonpolar solvents (or neat) has been found to be an efficient catalytic dehydrating agent for a variety of alcohols, including primary, secondary, tertiary, and diols (Sch. 2) [7]. Carbocation mechanisms are thought to be likely, because the newly formed olefins show a preference for Zietsev orientation. This is demonstrated by the dehydration of 3 and 6 to provide the more highly substituted double bonds of 4 and 7.In contrast to dehydration with CuSO4, that with Cu(OTf)2 is not inhibited by addition of pyridine bases. Triflic acid is thought to be generated in the reaction, as is evidenced by the isolation of pyridinium salts. The role of triflic acid in the elimination is not clear, because Mg(OTf)2 and Zn(OTf)2, which would also generate triflic acid, were ineffective. 10 mol%

+ c

92%

3

4:5 = 9:l

45%

7:8 = 48:l

7

8

Scheme 2

The activation of alcohols with CuCl or CuC12 Lewis acids in conjunction with dicyclohexylcarbodiimide (DCC), developed by Corey [8], has been employed by Knochel and Seebach for the facile preparation of nitroolefins in high yield (Sch. 3 ) [9]. Sensitive dienoyl compounds can be prepared, as shown in the elimination of 11 to provide 12 in excellent yield [lo].

546

R1T

9

H '

Sibi/Cook

N O z

cat. CuCl DCC ether, 25-35 "C *

R2

"

0

Yo yield

(€:a

R1

R2

H

CH3 45 CH3 82 (70:30) n-hex 60 H 90 (83:17) 94 H H O'

iH3

R , y N o 2 R2 10

n-Bu t-BU CH&H=CH-

cat. CuC12 DCC ether, It 90%

11

O H Scheme 3

12.3 Hydrolysis Copper catalysts offer several advantages over protic acids in hydrolysis reactions. They are mild, non-acidic, and can control regioselectivity by chelation. An example of the latter is shown by the hydrolysis of the bis benzyl ester 13. Complexation with the amine activates the adjacent carboxylate selectively to afford 14 as the sole hydrolysis product (Sch. 4) [ll].

NH

1) CUSO~, pH 8 2) EDTA

NH2 c

BnOpC&.O2Bn

13

74%

+2Bn HO2C

"

14

Scheme 4

The mild deprotection of acetal 15 with CuSO4 in acetone was accomplished in high yield [12]. The mildness of copper Lewis acids for the hydrolysis of hydrazones [ 131 is advantageous for acid-sensitive substrates (Sch. 5). The P,a-unsaturated hydrazone 17 was effectively hydrolyzed without conjugation of the double bond to afford 18 in good yield (Sch. 5 ) [14]. SAMP-Hydrazones can be hydrolyzed without racemization [15]. The two-step alkylation and hydrolysis of 19 provided 20 in 84 YO overall yield and 94 YOee. Another advantage over other Lewis acids is the thiophilic nature of copper; this has led to its utility in the hydrolysis of thioacetals. Copper(I1) chloride in conjunction with copper(I1) oxide was introduced by Mukaiyama [16] for the deprotection of 1,3dithianes and this method has found utility in a variety of synthetic protocols (Sch. 6) [17]. This combination, in which copper oxide plays the role of a buffer to prevent the medium from becoming too acidic, has also found application in the hydrolysis of a-heteroatom substituted and vinyl sulfides [18]. Acetals, which are prone to epimerization under acid-catalyzed hydrolysis conditions (21), can be con-

547

Copper Lewis Acids in Organic Synthesis

verted into thioacetals (22) and subsequently hydrolyzed with CuClz-CuO to afford free aldehydes (23) [19]. Likewise, selenoacetals can by hydrolyzed under mild conditions [20]. This is demonstrated in the rapid and efficient conversion of 24 to 25.

n acetone 68% 15

16

j

17

18

MeO".

N 9

1 t-BuLi, BOMCl 21 aq. cuCl2

84%

O X 0 19

20

Scheme 5

C~C12-2H20 CUO +

acetone-H20 (1O:l) reflux

0 88% overall

23 SePh

C~C12-2H20 CUO

t-BU&%Ph 24

acetone-Hz0 rt, 6 min 99%

t-BU 25

Scheme 6

The CuC12-Cu0 promoted hydrolysis is not solely limited to thioacetals -a variety of acetals are also deprotected [21]. Treatment of 26 with the copper catalysts in acetone-water afforded the spiroacetals 27 and 28 via concomitant hydrolysis of the thioacetal and benzylidene dioxy and ethoxyethyl acetals (Sch. 7) [22]. Copper(I1) chloride dihydrate has also been shown to hydrolyze a variety of acetals [23] and trityl groups can also be removed in the presence of copper sulfate in benzene t o afford deprotected alcohols [24].

548

Sibi/Cook CuC12-2H20

& &[ +

acH -e :O :, * (1O:l)

Ho 80%

26

m ( C H 2 ) 4 0 H OH OH 0 Intermediate

7%

27

]

28

Scheme 7

Aldehydes and ketones can be generated from a-chloro sulfides with CuC12-CuO in high yields [25]. The copper promoters can be used both as reagents and as Lewisacid activators in this reaction to generate the chloro sulfide in situ from a-thio ketones, and 29 is converted directly to 30 in 80 % yield (Sch. 8). The 2-phenylthiotetrahydropyran 31 could be hydrolyzed to the 2-hydroxy derivative 32, and the bisphenylthio derivative leads directly to the lactone [26]. CUCIZ-~H~O 35 acetone-HzO "C, 20 rnin

i

80% 29

'

30

* 4 N H C 0 2 M e NHC02Me acetone-H,O quant. '"O C0,Me C0,Me 31 32

Scheme 8

The vinylogous thioacetal 33 was transformed into the cr&unsaturated ketone 34 upon CuOTf-mediated hydrolysis whereas the HgCl2-promoted reaction was less effective (Sch. 9) [27]. Similarly, vinyl sulfide 35, which bears an allylic alcohol, was converted into the a$-unsaturated ketone 36 with complete regiocontrol [28]. This regioselectivity is not dependent upon the heteroatom because the vinyl ether 37 hydrolyzes to the aldehyde or ketone 38 [29].

LPh fi , TMS

h O

Ph

CUCI 2HzO

c?iO

acetone-H,O rt, 4h

S-pToI

67%

-

TMSn

o

0

33

34

35

CUCIZ-PHZO

Me0 37

CUO acetone-H20

0

36

L 38

Scheme 9

The affinity of copper for cyanide aids the hydrolysis of a-aminonitriles (Sch. 10) [30]. Treatment of 39 with copper sulfate in aqueous methanol affords ketone 40 in good yield. The acid-sensitive substrate 41 was also hydrolyzed with ease under these conditions.

Copper Lewis Acids in Organic Synthesis

aq. MeOH

o"" 1

fi NMe2

40

39

549

CuS04-5H20 aq. MeOH

82%

41

Scheme 10

12.4 AlcoholysidAcylation etc. (Acetal Formation, Ester Formation, Amide Formation) Copper Lewis acids catalyze the addition of alcohols to a variety of functional groups. The dehydro-l,4-dioxane 43, an alternative to dihydropyran as a protecting group, can be installed at room temperature with the aid of CuBr2 to afford protected alcohols 44 (Sch. 11) [31]. The use of CuF,, CuC12, or AgBF4 was less effective. Hindered tertiary alcohols are efficiently protected in high yields. Alcohols also add readily to propiolates to generate acetals. Ethyl propiolate 45 was transformed into the diethoxy acetal46 in high yield [32]. The use of HCl/EtOH resulted in low product yields.

Scheme 11

Copper catalysis has been shown to have a dramatic effect on regioselectivity in the protection of sugar derivatives as the acetonide [33]. Compound 47 afforded the acetonide 48 upon treatment with dimethoxypropane and CuS04 in acetone. In contrast, the acid-catalyzed acetalization afforded 49 in 90 % yield (Sch. 12). It is suggested that the acid-catalyzed reaction occurs first at the primary alcohol and subsequently migrates to the secondary alcohols to afford 49 whereas the copper-catalyzed process is not reversible. CH(SW2 H---NHAc 0--H

acetone OH CH20H

72% 47

Scheme 12

48

OH with H2SO4, 90% 49

550

Sibi/Cook

The chelating capacity of copper Lewis acids has been exploited in a variety of selective alcoholysis reactions. Kobayashi used C U ( O T ~to ) ~ affect “remote activation” of the anomeric carbon for formation of a glycosyl bond (Sch. 13) [34]. The 2pyridinecarboxylate group was crucial for success of the alcoholysis of 50 to afford disaccharides 51. The 4-pyridyl derivative and simple dialkylamino derivatives were unreactive. A chelating Lewis acid was required, because BF3.OEtz or TMSOTf were ineffective, whereas Sn(OTf)* afforded a level of reactivity similar to that of Cu(OTf)2.

R O H = HO

83% (CL:P91:9)

“ BnO “ W O B OMe n

BnO H w BnO

O

B n OMe

93% (alp 59141)

Scheme 13

Chelation with copper(I1) Lewis acids has been used to change the reactivity of bis ketenes toward alcohols. The alcoholysis of 52 in the presence of copper acetylacetonate derivatives afforded the cyclic lactones 54 (Sch. 14) [35].The addition of alcohols to 52 without the Lewis acid led to the formation of ketene esters 53 which would not undergo cyclization upon treatment with the copper(I1) complexes. It is suggested that chelation of the bis-ketene in a z-fashion accounts for the lactone products. Although chiral Lewis acids were used, the products were obtained as racemates probably because of very facile epimerization.

’$OR‘

Cu(ll)

&R O’/

52

Y

+

Cu(ll)

54 Scheme 14

The transesterification of 2-pyridylthioesters can be conducted in high yield with the aid of copper(1) or copper(I1) Lewis acids [36]. The reaction is remarkable in that bulky alcohols react readily. The t-butyl ester 56 was prepared in high yield from 55 at room temperature with the aid of CuBr2, and the sterically encumbered ester 57 was likewise prepared in a similar 91 % yield (Sch. 15). The macrocycle 59 was obtained in an impressive yield from the thioester 58 [37]. Successful cyclization was highly

Copper Lewis Acids in Organic Synthesis

551

dependent on the use of copper Lewis acids. Catalysis with Hg(OCOCF3)2 afforded only the carboxylic acid by hydrolysis, and Masamune conditions employing HgC12CdC12 were ineffective [38].

55

58

56

57

59

91%

Scheme 15

Shibasaki has reported the preparation of p-lactams by cyclization of thiophenyl esters in the presence of CuOTf [39]. The P-aminothioester 60 was cyclized in 80 % yield to afford 61 (Sch. 16). The cyclization of 62 was noted to proceed with replacement of the trimethylsilyl group with a phenylsulfide group via the intermediacy of a PhSSPh-CuOTf complex which was formed in situ. Optimized conditions afforded 63 in 63 % yield. with some of the protonated product 64.

CaC03(1.2 CuOTf (2eq) eq) O x & O M e

SPh

toluene reflux 60

80%

c ac 03((3.6 CuOTf 6eq) eq) 0JTMS

,++OMe SPh 62

C6H6-dioxane 63

63%

OMe

64 7%

OMe

Scheme 16

The acylation of alcohols, thiols, and amines with acetic anhydride, or directly with acetic acid, can be accomplished with the aid of catalytic (2.5 mol %) Cu(0Tf)z [40]. Copper@)and (11) chloride has been used for the acylation of a variety of a&unsaturated acid chlorides (Sch. 17). Copper powder is usually added to prevent polymerization. The N-silylsulfonamide 65 was directly acylated without first deprotection to afford 66 in high

552

Sibi/Cook

yields [41]. The chiral auxiliary 67 could be coupled with acid chlorides 68 under mild conditians [42]. Copper Lewis acids have been employed in peptide couplingsto suppress racemization [43]. 95% RCOCI CuCI.2, c u TMS-

86%

*

toluene reflux 02

67

R

82%

65

Ph

86%

. 'U . -L

68

Scheme 17

Copper(]) and (11) Lewis acids affect the alkoxyselenation of olefins (Sch. IS). Thus, cyclohexene affords trans adducts 71 in the presence of PhSeCN and CuClz [44]. The Lewis acid enhances the electrophilic nature of the selenium by coordination to the nitrile. The reaction is regioselective as terminal olefins afford primary selenides (alcohol addition to the internal carbon) and vinyl acetates yield p-seleno-aalkoxyacetates.

0 70

PhSeCN cuc1.2 ROH

*

K

r

P

h

[

-

'

-

PhS&--CN- -Cu&

71

Scheme 18

Copper(1) chloride enhances the addition of alcohols to isocyanates (Sch. 19) [45]. The reaction is general and a variety of alcohols, including sterically hindered alcohols, add with ease.

Scheme 19

553

Copper Lewis Acids in Organic Synthesis

12.5 Elimination Thioacetals readily eliminate to vinylsulfides at room temperature in the presence copper(1) triflate [46]. Acyclic (75) and cyclic (77) substrates react equally well (Sch. 20). The a-ketothioacetal 79 furnished furan 80, presumably via a carbocation mechanism, and the diene 82 resulted from sequential elimination of two sulfides from 81. CuOTf 3h,rt

YPh

o;ih

CuOTf tornin, rt

k S P h c

92%

91%

SPh 75

76

77

78

'hS SPh 80

79

76%

81

a r i i

82

Scheme 20

Copper-mediated sulfide elimination can lead to ring opening reactions. The hydroxy thioacetal 83, when treated first with n-BuLi and then with CuOTf afforded 84 in 92 YOyield via a Grob fragmentation (Sch. 21) [47]. Two equivalents of the Lewis acid were required for the reaction because one equivalent complexes the alkoxide and a second is necessary to activate the sulfide for elimination. Ring enlargement occurred upon treatment of 85 with CuOTf in benzene through the intermediacy of the thio-substituted epoxide 86 [48]. a-Phenylthiocyclohexanone 87 was obtained in 83 YOyield. CuOTf

1) n-BuLi, -78 "C, THF 2) CuOTf, 20 "C, 3.5 h

EtN(iPr)p W

S PIS

84

P

h

83% 87

Scheme 21

12.6 Friedel-Crafts Although considered mild in comparison with other metals, copper(1) and (11) triflates are suitable Lewis acids for affecting Friedel-Crafts alkylation and acylation reactions (Sch. 22). The intramolecular acylaminoalkylation of the indole derivative 88 afforded the cyclized product 89 in high yield [49]. The nitrogen functionality was not a requirement for formation of the benzylic cation, because the benzylic alcohol 90 reacted similarly with 91, even with an electron-withdrawing ester group adjacent to the cationic center.

554

Sibi/Cook

-

Meox &Ye Cu(OTf);! 94%

\ /

*8

cat. Cu(0Tf)p

v

C

O

Me'

2 90

M

e +

Me

91

CH2C12 92%

\ /

*

C02Me

Me

Me

92

Scheme 22

Thio- and selenoacetals and esters are excellent substrates for mild Friedel-Crafts reactions, because of the affinity of sulfur and selenium for copper (Sch. 23). Anisole was readily acylated with methylselenoesters 94 at room temperature with activation by CuOTf to afford para-substituted (> 95 %) derivatives 95 [50,51]. Mercury(I1) and copper(I1) salts, which were effective for the activation of selenyl esters for reaction with alcohols, amines, and water, were not effective for the Friedel-Crafts reaction. Aromatic heterocycles 96 could be acylated in high yields, and the alkylation product 100 was obtained from dibutylthioacetal99 and anisole. Vedejs has utilized this methodology in the cyclization of 101 to afford 102 in 77 % yield [52].This intramolecular variant did not require the use of the more reactive bis copper triflate-benzene complex.

6

p

MeSeKRg4_ 0

CuOTf 3-40 rnin, rt

9

fi

0 93

95

R = (CHz)5CH3 R = CHzCHzCH=CHz R = CHzCHzCOCH,

97 ..

MeSeK(CH&CH3 CuOTf 15-20 rnin, rt

*

G ( c H Z ) 5 c H 3

98

96

x =o

81Yo 63% 60%

X=S X=NH

OMe TMS

100% 81% 64%

?Me TMS

CuOTf

(pamorfho;92:8)

93

Scheme 23

OMe 100

101

0

OMeOH 0 102

Copper Lewis Acids in Organic Synthesis

555

12.7 Epoxide and Aziridine Ring Opening Copper sulfate in the presence of pyridine has been shown to promote the opening of epoxides with water, chlorides, and alcohols (Sch. 24) [53]. Retention of configuration (syn opening) is observed as shown in the hydrolysis of 103 to afford, predominantly, diol 104. Pyridine is, presumably, involved in the ring opening to afford a pyridinium intermediate that is subsequently displaced with the nucleophile affording overall retention of stereochemistry. With added LiC1, chlorohydrin 107 was obtained from epoxide 106. Development of significant positive charge on the carbon is suggested by the regioselectivity obtained. In methanol the ring opening of 108 afforded 109 in high yield. Chiral bases can be employed to affect modest levels of kinetic resolution. The hydrolysis of 108 promoted by CuS04-nicotine (in place of pyridine) afforded (+)-indanediol in 45 YO yield and 23 YO enantiomeric excess (ee) (55 YO recovery of starting material, 18 YOee). The reaction of epoxides with anhydrous copper sulfate in acetone affords acetonides directly [54].

- ;%:+:xh.

cuso4, PY

phosphate buffer

P

PH 7

103

107

106

104

!

108

95:5

105

Y a 70

109

Scheme 24

The copper-mediated opening of epoxides with amines was found to be highly dependent on the type of amine used [55]. With 5 mol % Cu(OTf)Z, aryl amines reacted with inversion of configuration in high yield to afford aminoalcohols, whereas aliphatic amines failed to react. Presumably, the more basic aliphatic amines complex tightly with the Lewis acid, preventing it from activating the epoxide. Likewise, aromatic amines can be used in the ring opening of aziridines (Sch. 25) [56]. Reaction of 110 with aniline afforded the trans-diamine derivative 111 in 81 YO yield. The regioselectivity in the opening of aziridines was opposite that for epoxides. For example, the addition of phenylmethylamine to the terminal aziridine 112 gave the diamine

110

111

112

10 mol% Cu(0Tf)p

114

Scheme 25

THFlDME 6h,rt 76-89%

115

113

556

Sibi/Cook

113, which was the result of addition to the least substituted position. N-Acyl aziridines do not afford addition products with amines, but undergo rearrangement to form oxazolines 115 [57].

12.8 Decarboxylation The decarboxylation of amino acids is facilitated by copper Lewis acids. Treatment of tryptophan with copper(I1) acetate in HMPA afforded tryptamine 117 in 45 % yield (Sch. 26) [%I. Chelation is thought to activate the carboxylate for elimination. The stable chelate can be isolated and undergoes decarboxylation when heated. An asymmetric version of a similar decarboxylation of malonate derivatives has been reported; poor selectivity resulted from addition of chiral alkaloids [59]. OZH

d '

H N

2

Cu(0Ac)z 170°C HMPA 45%

[RJy~

&HZ '

N H

H

116

N/cu" H2

117

Scheme 26

12.9 Activation of Transition Metal Catalysts Copper(1) triflate was used as a co-catalyst in a palladium-catalyzed carbonylation reaction (Sch. 27). The copper Lewis acid was required for the transformation of homoallylic alcohol 118 to lactone 119. It was suggested that the CuOTf removes chloride from the organopalladium intermediate to effect olefin complexation and subsequent migratory insertion [60]. Copper(1) and copper(I1) chlorides activate ruthenium alkylidene complexes for olefin metathesis by facilitating decomplexation of phosphines from the transition metal [61]

Copper Lewis Acids in Organic Synthesis

557

12.10 Rearrangements The rearrangement of propargyl chlorides to chloroallenes occurs stereoselectively in the presence of BudNCuC12 (Sch. 28) [62]. Copper(1) dichloride performs as a reagent to deliver chloride, and CuCl might be acting as a Lewis acid to activate the propargylic chloride for elimination. CUClp

CI ph\\

Bu~NCUCI~

H

dryacetone *

Ph

120

d

C

' H

121 CuCl

Scheme 28

12.11 Free-Radical Reactions Although copper reagents, halides and triflates, are widely used in atom-transfer polymerization reactions (ATRP) [63], these processes do not fall under the category of Lewis acid-mediated reactions. Sherrington and co-workers have shown that a vinyl monomer coordinated to a chiral copper Lewis acid (122) undergoes stereoselective polymerization (Sch. 29) [64]. A chiral block-copolymer 124 was prepared under radical conditions.

122

123

il

124

Scheme 29

An example of conjugate free-radical addition to methyl acrylate mediated by a copper Lewis acid has been reported (Sch. 30) [65]. In this example the Lewis acid 127 activates the substrate for conjugate addition by the aryl radical which is followed by an enantioselective chlorine atom-transfer step. Chemical and optical yield for the transformation are both low.

0 AOCH, 125

+ CH3 126

Scheme 30

Bu~N+CI',CH3CN

H3C 128 38% yield; 5.8%ee

558

Sibi/Cook

12.12 Nucleophilic Addition to C=O and C=X Double Bonds Nucleophilic addition to C=O or C=X multiple bonds is facilitated by Lewis acid activation. The extent of activation required is dependent on the electrophilicity of the carbon atom and on the nucleophilicity of the reagent. Copper Lewis acids have found utility in a variety of reactions involving nucleophilic addition. Addition of TMSCN to aldehydes and ketones is catalyzed by Cu(OTf), to afford cyanohydrins in high yield (Sch. 31) [66]. Whereas aldehydes react readily in CH2C12, ketones require acetonitrile for optimum results. 5mol% CU(0Tf)z CHzCI2

PhAH 129

OH

rt, 3h * PhACN then H30+ 130 81YO

Ph%H3

5m0l%Cu(OTf)~ HO CH3CN rtP2Qh * Phxcc"H3 then H30+ 85%

131

132

Scheme 31

Kobayashi and co-workers, in an interesting study on the Lewis acidity of a large number of reagents in water, have shown that enol silanes can add to aldehydes (Sch. 32) [67].Thus, the enol silane derived from propiophenone (133) adds to benzaldehyde in moderate yields in the presence catalytic CuCI2.

Scheme 32

Allylstannanes can be employed as nucleophiles and they add efficiently to Lewis acid-activated aldehydes (Sch. 33) [68]. The chiral reagent 137 activates alkyl aldehydes towards allylation; no enantioselectivity for the alcohol 138 was observed.

H

K

C7H15

135

$03

'31

Ph TfO OTf Ph +

p./SnBu3

136

CH~CIZ,rt, 20 h

*

H15C7 138 60% yield; O%ee

Scheme 33

In contrast, enol silanes add to aldehydes with moderate to good enantioselectivity using Cu(OTf), and bisoxazoline 141 as a ligand (Sch. 34) [69]. The synlanti selectivity was low and generally ( Z )enolates gave higher yields.

559

Copper Lewis Acids in Organic Synthesis

Cu(OTf)2(0.2 eq), H20:THF = 1:9, tt, 1 2 h

he

(Z)-Rt = Ph, R2 = Ph

Yield 74

syn/anti 3.2:1

ee 67

(Z)-R1 = Ph, R2 = Et

81

2.6~1

81

(Z)-R1 = Ph, R2 = i-Pr

17

4.0:l

85

142

Scheme 34

The low face-selectivity in the previous example can be partially attributed to single-point coordination of the aldehyde to the Lewis acid. Evans and co-workers have used a-alkoxy aldehydes in aldol reactions with much success (Sch. 35) [70]. Thus a variety of silylketene acetals add to 144 in the presence of a copper(bisoxazo1ine) catalyst with very high selectivity and chemical yields. Reaction with 147, which contains an additional stereoelement, gave a single aldol product 148 with high syn selectivity. The dienol silane 149 also provides high selectivity in the aldol reaction. A square pyramidal model accounts for the observed selectivity. In this model, the substrate binds

OTMS BnOJH

ASt-Bu 143

144

B n O A H

+

Me 147 955 (Z:E)

U

0

Scheme 35

e

99%ee OH 0

Catalyst 145 *

BnO+SEt Me 148 90% yield; syn:anti 97:3; 97%ee

144

OTMS O M 149

146

0

OTMS

8 s E t

TMSO

CH2C12, -78 "C, 11 h

OH OH 0

1. Catalyst 145 t

+

BnOJH

2. Reduction 144

B

n

O

UOMe

1so 98% yield; antkyn 15:l; 97%ee

560

SibiICook

as a two-point donor to the metal with the carbonyl oxygen in an equatorial orientation and addition occurs from the si face. This model has received additional support from crystallographic studies [71]. Nucleophilic addition to less reactive ketone carbonyls by Lewis acid activation is also possible. Evans and co-workers have reported enol silane addition to pyruvate esters mediated by chiral copper Lewis acids (Sch. 36) [72]. The aldol reactions proceed with high facial selectivity to provide the tertiary alcohol products 153. The chemical efficiency is, however, reduced when a bulky alkyl group is present at the ketone carbonyl. Addition of more functionalized enol silanes (155) to keto esters enables the establishment of two contiguous chiral centers, a substitution pattern present in a variety of natural products. The stereochemistry of the major product is syn, irrespective of the enol silane geometry. Once again, bidentate coordination of the substrate to the Lewis acid was essential for obtaining high selectivity.

152

RI

R10

R2

%ee %yield

Me Me 99 151

153

143

Bn

Me 99

Et

i-Pr 36

Me Et OTMS Meo’&Me

0 154

+

CU(0Tf)Z + 152

t

94

96 95 84 84

Me O H o MeO#R2

&R2 R1

CHpCI2, -78“C, 1 1 h

R1

0

155

156

R1

R2

Me

tBuS

(Z)

Me

tBuS

(E)

Me

EtS

i-Bu

EtS

alkene sydanti geometry

%ee

%yield

94:6

96

96

955

98

88

(Z)

94:6

93

90

(Z)

90:lO

93

88

Scheme 36

Activation of C=N double bonds by copper Lewis acids for nucleophilic addition has also been reported (Sch. 37) [73]. The a-imino ester 157 undergoes alkylation at the imine carbon with a variety of nucleophiles when catalyzed by copper Lewis acids. The presence of the electron-withdrawing ester group increases the reactivity of the imine and also assists in the formation of a stable five-membered chelate with the Lewis acid. Evidence for Cu(1) Lewis-acid catalysis and a tetrahedral chelate was obtained by FTIR spectroscopy, from the crystal structure of the catalyst, and from several control experiments. The authors rule out the intermediacy of a copper enolate in these transformations. The asymmetric alkylation of N,O-acetals with enol silanes mediated by a copper Lewis acid proceeding with high selectivity has been reported [74].

Copper Lewis Acids in Organic Synthesis

561

OTMS 158 EtO T-s:o”

Ligand 160, CuCIO:

2-10 mol% 159

157

160 Yield

ee

anti/sYn

R = Ph, R1 = Me, R2 = 4-MePh 86 R = 4-OMePh, R 1 = Me, R2 = 4-MePh 75

98 95

25:l 25:i

R = Et, R 1 = Me, R2 = 4-MePh; (2)-

75

3:l

77

Scheme 37

12.13 Conjugate Additions Conjugate addition of carbon nucleophiles (162) to a&unsaturated enoates (161) mediated by copper Lewis acids has been reported (Sch. 38) [75].The MukaiyamaMichael reaction proceeds with moderate enantioselectivity. One note of interest is that the absolute stereochemistry of the product (164 or 165) depends on the counter ion on the copper Lewis acid. Evans and co-workers have reported high enantioselectivity in conjugate addition of silylketene acetals (143) to alkylidene malonates (166) using copper Lewis acids [76].The chemical yields of the conjugate addition product are high. The addition of two equivalents of hexafluoro-2-propanol is essential for obtaining high selectivity.

161

164 X = OTf, 66%ee

162

165 X = SbF6. 60%ee

R Cu(OTf)z+152

t - B u S ~ o T ’ M e o ~ e CH,CI,, 143

Scheme 38

R 166

Yield ee(%)

rf,

-78 OC, 1

t-BUS

2 eq (CF3),CHOH

167

i-Pr Me

93 91

93 -43

562

Sibi/Cook

12.14 Cycloadditions Cycloadditions are one of the most important bond-forming strategies in synthetic organic chemistry. Most of these reactions require some sort of activation if reasonable chemical yields are to be obtained. The traditional methods are heat, light, pressure, and use of a Lewis acid. Copper Lewis acids have found utility in a variety of cycloaddition reactions. They can activate carbon-carbon double bonds through a ncomplex and carbon-hetero atom multiple bonds by means of a sigma complex. An example of complexation of zbonds is illustrated in the isomerization reaction shown in Sch. 39. Use of copper chloride enables the efficient conversion of the cis olefin 168 to the trans olefin 169 [77]. (CuOTf)Z(CGH,j) can be readily prepared (or purchased) and has been used for [2 + 21 photocycloaddition. A n example of norbornene dimerization is shown below in which the Cu(1) forms a n complex with two molecules of the olefin and enables a facile cycloaddition.[51]

168

169

170

171

Scheme 39

An example of intramolecular [2 + 21 cycloaddition of a 1,6-diene 172 catalyzed by Cu(1) in the synthesis of grandisol is shown in Sch. 40 [78]. The bicycloheptanes can be prepared selectively by starting with chiral starting material, chiral catalysts or chiral auxiliaries. The reactions with chiral copper Lewis acids gave very poor selectivity (< 5 %ee).

172

173

174

175

Scheme 40

Dienes are also amenable for activation by copper Lewis acids (Sch. 41) [79]. The intramolecular Diels-Alder reaction of 176 under thermal conditions gave all the possible isomers. In contrast, the Cu(1) promoted reaction gave the isomer 177 as a major product, with minor amounts of 180. Copper(I1) Lewis acids were less efficient in the cycloaddition. It is also worth noting that the Lewis acid-catalyzed reaction proceeds at a much lower temperature.

Copper Lewis Acids in Organic Synthesis

176

177

178

179

180

(a) 150 "C, 11h

46%

10%

21%

3%

(b) CuOTf, 80 "C, 29 h

76%

<1 Yo

c1Yo

11%

563

Scheme 41

Diels-Alder reaction is one of the premiere reactions in synthetic organic chemistry. The traditional approach to the normal Diels-Alder reaction is to activate the dienophile by means of a Lewis acid such that the transformation can be carried out under practicable conditions. A variety of Lewis acids catalyze this reaction selectively and among these copper(I1) compounds have been very successful in enantioselective transformations. The use of bisoxazolines in combination with copper triflate or copper antimony hexafluoride has afforded high selectivity. Pioneering work in this area by Evans, JGrgensen, Kanemasa, and others has shed light on the different controlling features of the copper Lewis acids. Corey reported one of the earliest examples of dienophile activation by a copper Lewis acid (Sch. 42) [SO]. The copper tetrafluoroborate coordinates to the cyano group and facilitates the Diels-Alder reaction without marked isomerization of the diene.

181

182

183

184

Scheme 42

One of the first examples of enantioselective Diels-Alder reactions using copper Lewis acids was reported from the laboratory of Evans [81]. The cycloaddition of cyclopentadiene 185 to an oxazolidinone enoate 186 proceeds with excellent endolexo (189 or 190) and face selectivity when a chiral copper Lewis acid was#employed (Sch. 43). The reactions are complete in less than a day at low temperatures (-78 "C). The counter ion on the catalyst has a large impact on reaction rates. Reactions with catalyst 188 (10 mol %), containing a non-coordinating counter ion SbF6 proceeds much more rapidly than with catalyst 187 [82]. The high face selectivity, the sense of stereoinduction, and double diastereoselection experiments with 191 and 193 establish several key features of chiral copper Lewis acids of this type: (i) bidentate coordination of ligand and substrate to the Lewis acid; (ii) enhanced Lewis acidity of the metal with non-coordinating counter ions; and (iii) square-planar geometry around the metal atom. A transition state model (195) proposed by Evans, which accounts for the observed face selectivity, is shown. This model assumes square-planar geometry around the metal and the complete dissociation of the counter ions.

564

Sibi/Cook

CHzC12, -78 "C 187 X = OTf 188 X = SbFs

186

185

189 endo

Catalyst 187

Catalyst 187*

*

191

190 ex0

Q

Q

193 192 endo:exo = >99:1

OANJo

194 endotexo = 68:32 20% conversion

100%conversion

195

Scheme 43

The use of aminoindanol-derived bisoxazolines in conjunction with copper Lewis acids led to improvements in the enantioselectivity of the Diels-Alder reaction (Sch. 44) [83]. Changes in stereoselectivity with small changes in ligand structure have also been noted (compare 198 and 200) [84]. Copper also strongly coordinates phosphorus ligands. The use of PN chiral ligands in Cu(OTf)2-mediated Diels-Alder reactions has been reported [85].

Ligand 185

(S)-endoadduct

92%ee Scheme 44

196

(S)-endoadduct

98%ee

(@-endo adduct

73%ee

565

Copper Lewis Acids in Organic Synthesis

The thiophilic nature of copper can be used to activate the dienophile in DielsAlder reactions (Sch. 45) [86]. The copper forms a chelate with the enoate oxygen and sulfur in 201, accounting for the observed high facial selectivity.

Jy

Et

+

SPh

201

0 185

202 X = OTf 203 X = SbFs

4

0

CH2C12, -78 "C OAOEt 204

205

Catalyst 202: Yield 76% endo/exo = 7:l;ee >95% Catalyst 203: Yield, 92% endo/exo = 15:l;ee >95%

Scheme 45

The use of catalyst 187 or 188 (see Sch. 43) in cycloadditions requires anhydrous conditions. Recently, several practical alternatives for this requirement have been reported. Evans has shown that the easily manipulated aquo complex prepared from 187 and water can be dehydrated to the active catalyst in the reaction vessel by addition of molecular sieves, without any loss of reactivity or selectivity [87]. Copper(I1) perchlorate is available commercially as a hexahydrate. Ghosh and co-workers have reported that a complex 207 prepared from an aminoindanol-derived bisoxazoline and C U ( C ~ O 6H20 ~ ) ~ . is an excellent Lewis acid in Diels-Alder reactions (Sch. 46). It is interesting to note that the generally sluggish reactions with oxazolidinone crotonates proceed with very high selectivity at room temperature [88].

185

206

Scheme 46

Copper Lewis acids also find utility in Diels-Alder reactions in aqueous media. Engberts et al. have reported large rate acceleration of Diels-Alder reactions by C U ( N O ~in) ~water [89]. The higher Lewis acidity of Cu(I1) compared with Co(II), Ni(II), and Zn(I1) in aqueous media was also established in their study. An enantioselective variant of the Diels-Alder reaction using a catalyst derived from L-arbine and Cu(OTf), (210) in water was reported recently (Sch. 47) [90].

566

Q

Sibi/Cook

+

185

o$

Cu(OTf), = 1.OO rnM [L-arbine]=[Et3N]=1.75 rnM Water

>9O%endo 74% ee

211

Scheme 47

In an intriguing example of size discrimination, a dendritic Lewis acid derived from 214 and Cu(OTf)2 can selectively activate the smaller dienophile 212 (Sch. 48) [91]. Diels-Alder reaction of 185 and an equimolar mixture of 212 and 213 provides the adduct 215 in higher yield. A generation-three dendrimer is required to obtain adequate size discrimination.

Q 185

Scheme 48

The copper catalyzed Diels-Alder reactions of a variety of dienes have been elegantly exploited by Evans as a key step in the synthesis of natural products (Sch. 49). The synthesis of tetrahydrocannabinol (219) [92] employs the acyclic diene 217; furan is used as a diene in the synthesis of shikimic acid (222) [93]. Although the methodology uses the very reactive catalyst 188, the reactions are still slow, suggesting that less reactive dienes require longer reaction times and higher temperatures for completion. A copper Lewis acid-mediated intramolecular Diels-Alder reaction has served as a key step in the total synthesis of isopulo’upone [94].

567

Copper Lewis Acids in Organic Synthesis

Catalyst 188 C5H11

Me 57% 196

219 ent-A'-THC

217 73:27 exo:endo 98% ee (exo)

--

Catalyst 188

U

CHZCI,, -78 "C, 42 h

196

220

97% conversion

HO 222

endo:exo= 80:20 endo ee 97%

OH

ent-Shikimic Acid

Scheme 49

Copper Lewis acids have also found utility in hetero-Diels-Alder reactions. In these transformations the Lewis acid can activate either the diene or the dienophile and both types of reaction have been reported. Evans et al. have evaluated unsaturated acyl phosphonates [%I and acyl esters (amides) [87] as dienes in hetero-DielsAlder reactions. The reactions proceed with excellent chemical efficiency and high stereoselectivity with as little as 0.2 mol % of the catalyst (Sch. 50). The reaction tolerates a variety of substituents on the diene and the dienophile. A square-planar model 226 wherein the phosphonate and the carbonyl groups form a chelate with copper, and addition occurring from the less hindered face, accounts for the selectivity observed. It is interesting to note that the reaction of 185 with phosphonate 228 gives 230, an inverse-electron-demand product, in preference to the normal Diels-Alder adduct 229. This unusual reaction pathway has been attributed to the electron-withdrawing capacity of the phosphonate group.

223

224

228

185

225 endo/exo 16:l 96%, 97%ee

226

0 229 endo/exo87:13 84%ee

230 endo/exo >95:5 97%ee

>99% yield, 229:230 = 3265 Scheme 50

568

Sihi/Cook

In contrast to the above reactions, Jmrgensen et al. have also reported heteroDiels-Alder reactions wherein acyl esters are used as dienophiles and are activated by the copper Lewis acid (Sch. 51) [96]. Both keto (232) and aldehyde (235) groups can be used in the reaction. The reactions proceed with very low catalyst loading (0.05 mol %) attesting to the excellent activation by the copper Lewis acid. The authors have applied this methodology in the total synthesis of actinidiolide 237 [97]. OMe

0

+ MeKC02Me

TMSO

231

Catalyst 187 -78 "C, CH2Cl2

232

234

&(C02Me ; Me

L

233

R1 = H 96% yield, 99%ee

R1 = CH3 75 o/ yield, 96%ee

236 97% ee >95% de

235

237 (4-Actinidiolide

Scheme 51

Imines are also potential dienophiles in hetero-Diels-Alder reactions. Jmrgensen et al. have evaluated Cu(1) Lewis acids in enantioselective imino Diels-Alder reactions (Sch. 52) [98].

"TOS

+EtOOC"

TMSO

R 238

240 CuC104.4MeCN, -78 "C.CH2l:

'""COOEt

R 239

241 R = H 68% yield, 80%ee R = Me 70% yield, 96%ee

Scheme 52

Asymmetric Diels-Alder reaction of 2-azadienes with acrylates using Cu(OTf)2 as a Lewis acid has been reported (Sch. 53) [99]. The reaction gives the ex0 product (244) with high enantioselectivity. Copper Lewis acid-mediated Diels-Alder reactions of thiabutadienes with oxazolidinone acrylate 196 have also been reported [loo].

569

Copper Lewis Acids in Organic Synthesis

242

243

244 ex0

R1

R2

R3

245 endo

exo/endo

Yield, %

ee, %

Ph

Me

Me

>99:1

80

95.1

Ph Ph

H H

H

6.1:l

Me

>99:1

83 80

98.3 93

Scheme 53

Copper Lewis acids have also been used with effect in dipolar cycloadditions. Activation of both the dipolarophile and the dipole by copper Lewis acids has been reported. A copper(I1) phenanthroline complex coordinates to an oxazolidinone crotonate (dipolarophile) and facilitates addition of the nitrone even when catalytic amounts of the Lewis acid are employed (Sch. 54). The endolexo selectivity and chemical yield were modest [loll. The yields and selectivity of the reactions were higher when Mg(I1) Lewis acids were used in place of copper.

The dipole can also be selectively activated by Lewis acids. Similar to the results discussed above, reactions of a functionalized nitrone with electron rich alkenes proceed with moderate to good chemical yields and selectivity when catalytic copper Lewis acids are used (Sch. 55) [102]. The exolendo selectivity and the ee for the major isomer were dependent on the nature of the substitution on the dipole, alkene, and on the solvent. A model that involves a pentacoordinated intermediate (254) in which the copper is ligated to the dipole and the dipolarophile has been postulated to account for the selectivity observed.

570

Sibi/Cook

252 exo

250

L~?$' '

RO t-Bu &-o"Ju-N

'

Bfi'.&O\ '/N-o

Rl = Et, R2 = Et,

Yield

exo/endo

ee (exo/endo)

83

77:23

89116

R1 = E t , R z = R 3 = M e , R 4 = H

83

31:69

90194

I

R1 = Et, R, = R4 = (CH& R3 = H

43

R1=

5050 50:50

1210

i-6~

t-Bu,

R3 = R4 = H

253 endo

R2 = Et, R3 = R4 = H

52

010

254

Scheme 55

12.15 Ene Reactions Reaction of alkenes with carbonyl compounds or carbonyl derivatives in the presence of Lewis acids, the ene reaction, enables the stereoselective preparation of highly functionalized compounds. Copper Lewis acids activate both aldehydes and imines in ene reactions. Evans has reported that Cu(I1) Lewis acids catalyze glyoxylates in reactions with alkenes (Sch. 56) [103]. The homoallylic alcohols 257 and 259 are produced in high yield and enantioselectivity. The bis aquo complex 260 is a readily prepared and air-stable catalyst and gave high chemical yield and excellent selectivity in the ene reactions. Another point of note is that catalysts 260 and 261 furnish enantiomeric products even though they differ from each other only by the substituent at the 4-position of the oxazoline. 0

0"

Catalyst +

255

' G O E t 0 256

+

OTBDPS 0

Catalyst CH,CI~, 25 0;

H$oEt

o

W

256

260

Scheme 56

Cat. 261 99%, 87%ee (R) 257

OTBDPS

258

OEt Cat. 260 97%- 97%ee (s)

CH2C12,O"C *

0 259

261

.

t

Cat. 260 72%, 96%ee Cat. 261 85%, 91%ee

Copper Lewis Acids in Organic Synthesis

571

Vederas and co-workers have reported the ene reaction of an allylglycinate 262 with methyl glyoxylate using copper Lewis acids (Sch. 57) [104]. Chiral binaphtholtitanium complexes did not catalyze the ene reaction and only the starting material was recovered.

Catalyst 261

w C O p M e PhS NHCbz -+

262

' G0O M e 239

42%

-

HO PhS

NHCbz

263 -88%de

Scheme 57

Jorgensen [lo51 and Lectka [lo61 have reported the ene reactions of imines. Both used BINAP as ligands, and a variety of copper salts (Sch. 58). The ee of 266 depended on the counter ion on the copper-PF6 and C104 anions gave the highest selectivity. It is also important to note that CuPF6is safer to use than the perchlorate.

)"TS EtO '%i

264

(R,R)-BINAP Copper Salt

R1 = Ph, R2 =

R~

R1 = Ph, R2 = H; C U P F ~

R2\* R1'

265

H; CUCIO~

266

COzEt R1 = 4-OMePh, R2 = H; CuC104 R1 = CH3, R2 = H; CUPFE

Yield ee 80 99

82

98

81 62

91 78

Scheme 58

12.16 Conclusions This review has detailed the utility of copper salts as Lewis acids. Their ready availability, or ease of preparation, low toxicity, and counter ion-dependent tuning of the strength of Lewis acidity makes them ideal for use in a variety of organic transformations. The last decade has witnessed dramatic progress in catalytic methods for the preparation of enantiomerically pure compounds. Copper Lewis acids have played a key role in their development. The future holds a lot of promise for the identification of other processes for which copper will be the Lewis acid of choice.

References and Footnotes 1. For information on preparation, stability, solubility, etc, for most of the Lewis acids discussed in this review consult: Encyclopedia of Reagents in Organic Synthesis, Paquette, L. A. Ed., Wiley, New York, 1996. For information on geometry of copper complexes see: Irving, H.; Williams, R. J. P. J. Chern. Soc. 1953, 3192-3210; Venkataraman, D.; Du, Y.; Wilson, S. R.; Zhang, P.; Hirsch, K.; Moore, J. S. J. Chern. Ed. 1997,74,915-918; Johnson, J. S.; Evans, D. A. Acc. Chern. Res. 2000, 3.3, 325-335. 2. Kubas, G. J. Inorg. Synth. 1979,19,90-92. 3. Evans, D. A,;Peterson, G. S.; Johnson, J. S.; Barnes, D. M.; Campos. K. R.; Woerpel, K. A.J. Org. Chern. 1998,63,45414544. 4. Mori, K.; Watanabe, H. Tetrahedron 1986,42,273-281. 5. Hoffman, R. V.; Bishop, R. D.; Fitch, P. M.; Hardenstein, R. J. Org. Chem. 1980,45,917-919. 6. Nishiguchi, T.; Machida, N.; Yamamoto, E. Tetrahedron Left. 1987,28,45654568.

572 7. 8.

9. 10. 11. 12. 13. 14. 15.

16. 17.

18. 19. 20. 21. 22. 23. 24. 25.

26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43.

Sibi/Cook Laali, K.; Gerzina, R. J.; Flajnik, C. M.; Geric, C. M.; Dombroski, A. M. Helv. Chim. Acta 1987, 70,607-611. Corey, E. J.; Anderson, N. H.; Carlson, R. M.; Paust, J.; Vedejs, E.; Vlattas, I.; Winter, R. E. K. J. Am. Chem. Soc. 1968,90,3245-3247. Knochel, P.; Seebach, D. Synthesis 1982,1017-1018. Corev, E. J.: Letavic, M. A. J. Am. Chem. Soc. 1995,117.9616-9617. PresGdge, R. L.; Harding, D. R. K.; Battersby, J. E.; Hancock, W. S. J. Org. Chem. 1975,40,32873288. Hulce, M.; Mallomo, J. P.; Frye, L. L.; Kogan, T. P.; Posner, G. H. Org. Syn. Coll. Vol. 1990, 7, 495-500. Corey, E. J.; Knapp, S. Tetrahedron Lett. 1976,3667-3668. Mino, T.; Fukui, S.; Yamashita, M. J. Org. Chem. 1997,62,734-735. (a) Enders, D.; Hundertmark, T.; Lazny, R. Synth. Commun. 1999,29, 27-33. (b) Ziegler, R. E.; Becker, M. R. J. Org. Chem. 1990,55,2800-2805. (a) Narasaka, K.; Sakashita, T.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 1972,45,3724. (b) Mukaiyama, 1972,94,8641-8642. T.;Narasaka, K.; Furusato, M.J. Am. Chem. SOC. (a) Lucchetti, J.; Krief, A. Synth. Commun. 1983,13, 1153-1161. (b) Flores-Parra, A,; KhuongHuu, F. Tetrahedron 1986, 42, 5925-5930. (c) Taddei, M.; Mann, A. Tetrahedron Lett. 1986, 27, 2913-2916. (d) Nagano, H.; Masunaga, Y.; Matsuo, Y.; Shiota, M. Bull. Chem. Soc. Jpn. 1987,60, 707-711. (e) El-Jazouli, M.; Masson, S.; Thuillier, A. Bull. Soc. Chim. Fr., Part2 1988,875482, Grobel, B.-T.; Seebach, D. Synthesis 1977,357402. Negri, D. P.; Kishi, Y. Tetrahedron Lett. 1987,28, 1063-1066. (a) Burton, A,; Hevesi, L.; Dumont, W.; Cravador, A,; Krief, A. Synthesis 1979,877-880. (b) Lucchetti, J.; Dumont, W.; Krief, A. Tetrahedron Lett. 1979, 2695-2696. (c) Raucher, S.; Koolpe, G. A. J. Org. Chem. 1978,43,3794-3796. (a) Ref. 17d. (b) Mori, K.; Uematsu, T.;Yanagi, K.; Minobe, M. Tetrahedron 1985,41,2751-2758. Berrada, S.; Metzner, P.; Rakotonirina, R. Bull. Soc. Chim. Fr., Part 2 1985,881-890. Chandrasekhar, M.; Singh, V. K. Tetrahedron Lett. 1998,39,3091-3092. Randazzo, G.; Capasso, R.; Cicala, M. R.; Evidente, A. Carbohydr. Res. 1980,85,298-301. (a) Bakuzis, P.; Bakuzis, M. L. F. J. Org. Chem. 1977, 42, 2362-2365. (b) Maignan, C.; Raphael, R. A. Tetrahedron 1983, 39, 324-3249, (c) Carre, M. C.; Caubere, P. Tetrahedron Lett. 1985, 26, 3103-3106. (d) Gregoire, B.; Carre, M.-C.; Cauber, P. .I. Org. Chem. 1986,51,1419-1427. (e) Ishibashi, H.; Komatsu, H.; Ikeda, M. J Chem. Res. Synop. 1987, 296-297. (f) Arai, Y.; Yamamoto, M; Koizumi, T. Bull. Chem. Soc. Jpn. 1988, 61, 467473. (g) Hauser, F. M.; Caringal, Y. L Org. Chem. 1990,55,555-559. (a) Hatanaka, M.; Nitta, H. Tetrahedron Lett. 1987,28,69-72. (b) Hatanaka, M. Tetrahedron Lett. 1987,28,83-86. Cohen, T.; Bennet, D. A.; Mura, Jr., A. J. J. Org. Chem. 1976,41,2506-2507. Asaoka, M.; Aida, T.; Sonoda, S.; Takei, H. Tetrahedron Lett. 1989,30,7075-7078. Ruel, 0.;Bibang Bi Ekogha, C.; Julia, S. A. Tetrahedron Lett. 1983,24,48294832. Bdchi, G.; Liang, P. H.; Wiiest, H. Tetrahedron Lett. 1978,2763-2764. Fetizon, M.; Hanna, I. Synthesis 1985,806-807. Bertz, S. H.; Dabbagh, G.; Cotte, P.J. Org. Chem. 1982,47,2216-2217. (a) Miljkovic, M.; Hagel, P. Carbohydr. Res. 1983,111,319-324. (b) Morgenlie, S. Carbohydr. Res. 1975,41,77-83. (a) Koide, I.; Ohno, M.; Kobayashi, S. Tetrahedron Lett. 1991,32,7065-7068. (b) Furukawa, H.; Koide, K.; Takao, K.-i.; Kobayashi, S. Chem. Pharm. Bull. 1998,46,12441247. Dejmek, M. M.; Selke, R. Angew. Chem., Int. Ed. 1998,37,1540-1542. Kim, S.; Lee, J. I. J. Org. Chem. 1984,49,1712-1712. Huang, J.; Meinwald, J. J. Am. Chem. Soc. 1981,103,861-867. (a) Masamune, S.; Yamamoto, H.; Kamata, S.; Fukuzawa, A. J. A m . Chem. Soc. 1975,97,35133515. (b) Masamune, S.; Kamata, S.; Schilling, W. J. Am. Chem. SOC.1975,97,3515-3516. (a) Miyachi, N.; Kanda, F.; Shibasaki. M. J. Org. Chem. 1989, 54, 3511-3513. (b) Miyachi, N.; Shibasaki, M. J. Org. Chem. 1990,55 1975-1976. Saravan, P.; Singh, V. K. Tetrahedron Lett. 1999,40,2611-2614. Thom, C.; Kocienski, P. Synthesis 1992,582-586. Kriel, K. N.; Emslie, N. D. Tetrahedron Lett. 1997,38, 109-110. (a) Miyazawa, T.; Otomatsu, T.; Fukui, Y.; Yamada, T.; Kuwata, S. Int. J. Peptide Prot. Res. 1992, 39, 308-314. (b) Miyazawa, T.; Donkai, T.; Yamada, T.; Kuwata, S. Chem. Lett. 1989,2125-2128. (c) Miyazawa, T.; Otomatsu, T.; Fukui, Y.; Yamada, T.; Kuwata, S. J. Chem. Soc. Chem. Commun. 1988, 419420. (d) Miyazawa, T.; Otomatsu, T.; Yamada, T.; Kuwata, S. Tetrahedron Lett. 1984, 25.771-772.

Copper Lewis Acids in Organic Synthesis 44. 45. 46.

47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. 60.

61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83.

573

Toshimitsu, A,; Aoai, T.; Uemura, S.; Okano, M. J. Org. Chem. 1980,45,1953-1958. Duggan, M. E.; Imagire, J. S. Synthesis 1989,131-132. (a) Cohen, T.; Herman, G.; Falck, J. R.; Mura, Jr., A. J. J. Org. Chem. 1975, 40, 812-813. (b) Cohen, T.; Mura, Jr., A. J.; Shull, D. W.; Fogel, E. R.; Ruffner, R. J.; Falck, J. R. J. Org. Chem. 1976, 41, 3218-3219. See also: (c) Kwon, T. W.; Smith, M. B. Synth. Commun. 1992,22, 22732285. (d) Corey, E. J.; Seebach, D. J. Org. Chem. 1966, 31, 4097. (e) Cohen, T.; Kosarych, Z. Tetrahedron Lett. 1980, 21, 3955-3958. (f) Cohen, T.; Gapinski, R. E.; Hutchins, R. R. J. Org. Chem. 1979,44,3599-3601. Semmelhack, M. F.; Tomesch, J. C. J. Org. Chem. 1977,42,2657-2658. Cohen, T.; Kuhn, D.; Falck, J. R. J. Am. Chem. Soc. 1975,97,47494751. El Gihani, M. T.; Heaney, H.; Shuhaibar, K. F. Synlett 1996,871-872. (a) Kozikowski, A. P.; Ames, A. J. Am. Chem. Soc. 1980, 102, 860-862. (b) Kozikowski, A. P.; Ames, A. Tetrahedron 1985,41,48214834. For the first report of [(CuOTf)*PhH] see: Salomon, R. G.; Kochi, J. K. J. Am. Chem. Soc. 1973, 95,1889-1897; 3300-3310. Vedejs, E.; Nader, B. J. Org. Chem. 1982,47,3193-3915. Imuta, M.; Ziffer, H. J. Am. Chem. Soc. 1979,101,3990-3991. Hanzlik, R. P.; Leinwetter, M. J. Org. Chem. 1978,43,438440. Sekar, G.; Singh, V. K. J. Org. Chem. 1999,64,287-289. Sekar, G.;Singh, V. K. J. Org. Chem. 1999,64,2537-2539. Ferraris, D.; Drury 111, W. J.; Cox, C.; Lectka, T. J. Org. Chem. 1998,63,4568-4569. Kametani, T.; Suzuki, T.; Takahashi, K.; Fukumoto, K. Synthesis 1974,131-133. Toussaint, 0.;Capdevielle, P.; Maumy, M. Tetrahedron Lett. 1987,28,539-542. Ukaji, Y.; Miyamoto, M.; Mikuni, M.; Takeuchi, S.; Inomata, K. Bull. Chem. Soc. Jpn. 1996, 69, 735-742. Dias, E. L.; Nguyen, S. T.; Grubbs, R. H. J. Am. Chem. Soc. 1997,119,3887-3897. Muscio, Jr., 0.J.; Jun, Y.M.; Philip, Jr., J. B. Tetrahedron Lett. 1978,2379-2382. (a) Wang, J. S.; Matyjaszewski, K. J. Am. Chem. Soc. 1995,127,5614-5615. (b) For an example of Cu(OTf), as a catalyst see: Woodworth, B. E.; Metzner, Z.; Matyjaszewski, K. Macromolecules 1998,31,7999-8004. Royles, B. J. L.; Sherrington, D. C. Chem. Commun.1998,421423. Brunner, H.; Bluchel, C.; Doyle, M. P. J. Organomet. Chem. 1997,541,89-95. Saravanan, P.; Vijaya, R.; Singh, V. K. Tetrahedron Lett. 1998,39,3823-3824. Kobayashi, S.; Nagayama, S.; Busujima, T. J. Am. Chem. Soc. 1998,120,8287-8288. Cozzi, P. G.; Orioli, P.; Tagliavini, E,; Umani-Ronchi, A. Tetrahedron Lett. 1997,38,145-148. Kobayashi, S.; Nagayama, S.; Busujima, T. Chem. Lett. 1999,71-72. Evans, D. A,; Murry, J. A,;Kozlowski, M. CJ. Am. Chem. Soc. 1996,118,58145815. Evans, D. A,; Kozlowski, M. C.; Murry, J. A.; Burgey, C. S.; Campos, K. R.; Connell, B. T.; Staples, R. J. J. Am. Chem. Soc. 1999,121,669485. (a) Evans, D. A.; Kozlowski, M. C.; Burgey, C. S.; MacMillan, D. W. C. J. Am. Chem. Soc. 1997, 119, 7893-7894. (b) Evans, D. A.; Kozlowski, M. C.; Burgey, C. S.; Kozlowski, M. C.; Tregay, S. W..l. Am. Chem. SOC. 1999,121,.686499 (a) Ferraris, D.; Young, B.; Cox, C.; Drury, W. J. 111.; Dudding, T.; Lectka, T. J. Org. Chem. 1998, 63, 6090-6091. (b) Ferraris, D.; Young, B.; Dudding, T.; Lectka, T. J. Am. Chem. Soc. 1998, 120, 4548-4549. Ferraris, D.; Dudding, T.; Young, B.; Drury, W. J. 111.; Lectka, T. J. Org. Chem.1999,64,216%2169. Bernardi, A,; Colombo, G.; Scolastico, C. Tetrahedron Lett. 1996,37,8921-8924. Evans, D. A,;Rovis, T.; Kozlowski, M. C.; Tedrow, J. S. J. Am. Chem. Soc. 1999,121,1994-1995. Deyrup. J. A,; Betkouski, M. J. Org. Chem. 1972,37,3561-3562. Langer, K.; Mattay, J. J. Org. Chem. 1995,60,7256-7266. Hertel, R.; Mattay, J.; Runsink, J. J. Am. Chem. Soc. 1991,113,657-665. Corey, E. J.; Weinshenker, N. M.; Schaaf, T. K.; Huber, W. J. Am. Chem. Soc. 1969,91,5675-5677. (a) Evans, D. A,; Miller, S. J.; Lectka, T. J. Am. Chem. Soc. 1993, llS, 6460-6461. (b) Evans, D. A,; Lectka, T.;Miller, S. J. Tetrahedron Lett. 1993,34,7027-7030. Evans, D. A,; Murry, J. A.; von Matt, P.; Norcross, R. D.; Miller, S. J. Angew. Chem., Int. Ed. Engl. 1995,34,798-800. (a) Davies, I. W.; Senanayake, C. H.; Larson, R. D.; Verhoeven, T. R.; Reider, P. J. Tetrahedron Lett. 1996,37, 1725-1726. (b) Davies, I. W.; Deeth, R. J.; Larsen, R. D.; Reider, P. J. Tetrahedron Lett. 1999, 40, 123331236, (c) Davies, I. W.; Gerena, L.; Castonguay, L.; Senanayake, C. H.; Larson, R. D.; Verhoeven, T. R.; Reider, P. J. J. Chem. Soc., Chem. Commun.1996,1753-1754.

514

Sibi/Cook

84. For a study on variation of product stereochemistry with ligand substitution in copper catalyzed reactions see: Evans, D. A,; Johnson, J. S.; Burgey, C. S.; Campos, K. R. Tetrahedron Lett. 1999, 40,2879-2882. 85. Brunel, J. M.; Del Campo, B.; Buono, G. Tetrahedron Lett. 1998,39,9663-9666. 86. Aggarwal, V. K.; Anderson, E. S.; Jones, D. E.; Obierey, K. B.; Giles, R. Chem. Commun. 1998, 1985-1986. 87. Evans, D. A,; Olhava, E. J.; Johnson, J. S.; Janey, J. M. Angew. Chem., Int. Ed. Engl. 1998, 37, 3372-3375. 88. Ghosh, A. K.; Cho, H.; Cappiello, J. Terrahedron: Asymmetry 1998, 9, 3687-3691. 89. (a) Otto, S.; Bertonocin, F.; Engberts, J. B. F. N. J. Am. Chem. SOC.1996,118,7702-7707. (b) Otto, S.; Engberts, J. B. F. N.; Kwak, J. C. T. J. Am. Chem. Soc. 1998,120,9517-9525. 90. Otto, S.; Boccaletti, G.; Engberts, J. B. F. N. J. A m . Chem. SOC.1998,120,43284329. 91. Chow, H-F.; Mak, C. C.J. Org. Chem. 1997,62,5116-5127. 92. Evans, D. A,; Shaughnessy, E. A,; Barnes, D. A. Tetrahedron Lett. 1997,38,3193-3194. 93. Evans, D. A.; Barnes, D. A. Tetrahedron Lett. 1997,38,57-58. 94. Evans, D. A,; Johnson, J. S. J. Org. Chem. 1997,62,786-787. 95. Evans, D. A,; Johnson, J. S. J. Am. Chem. Soc. 1998,120,4895-4896. 96. (a) Yao, S.; Johannsen, M.; Audrain, H.; Hazell, R. G.; Jorgensen, K. A. J. Am. Chem. SOC.1998, 120, 8599-8605. (b) Thorhauge, J.; Johansen, M.; Jorgensen, K. A. Angew. Chenz., Int. Ed. Engl. 1998,37,2404-2406. 97. Yao, S.; Johannsen, M.; Hazell, R. G.; Jorgensen, K. A. J. Org. Chem. 1998,63,118-121. 98. Yao, S.; Johannsen, M.; Hazell, R. G.; Jorgensen, K. A. Angew. Chem., Int. Ed. Engl. 1998, 37, 3121-3 124. 99. Jnoff, E.; Ghosez, L. J. Am. Chem. SOC.1999,121,2617-2618. 100. Saito, 11;Takekawa, K.; Nishimura, J-i.; Kawamura, M. J. Chem. SOC. Perkin Trans. I 1997,29572959. 101. Gothelf, K. V.; Hazell, R. G.; Jorgensen, K. A. J. Org. Chem. 1996,61,346-355. 102. (a) Jensen, K. B.; Hazell, R. G.; Jergensen, K. A. J. Org. Chem. 1999,64,2353-2360. (b) Miura, M.; Enna, M.; Okuro, K.; Nomura, M. J. Org. Chem. 1995,60,4999-5004. 103. Evans, D. A,; Burgey, C. S.; Paras, N. A,; Vojkovsky, T. Tregay, S. W. J. Am. Chem. SOC. 1998,120, 5824-5825. 104. Gao, Y.; Lane-Bell, P.; Vederas, J. C. J. Org. Chem. 1998,63,2133-2143. 105. Yao, S.; Fang, X.; Jorgensen, K. A. Chem. Commun. 1998,2547-2548. 106. Drury, D. J. 111; Ferraris, D.; Cox, C.;Young, B.; Lectka, T.J. Am.Chern. Soc. 1998,120,11006-11007.

Lewis Acids in Organic Synthesis Edited bv Hisashi Yamarnoto Copyright 0WILEY-VCH Verlaa GmbH.2000

13 Ag(I), Au(1) Lewis Acids Akira Yanagisawa

13.1 Introduction Silver(1) salts have mild Lewis acidity and have been used as promoters and catalysts in organic synthesis. Among these salts, AgN03, AgC104, AgBF4, and AgOTf are the most popular reagents for inducing transformations which include cycloadditions, rearrangements, and glycosylation, which take advantage of their affinity for halogen and sulfur functional groups, and carbon-carbon unsaturated bonds rather than oxygen functional groups [l].In contrast, gold(1) compounds have attracted little attention as Lewis-acid catalysts for organic reactions. This chapter focuses on carbon-carbon bond-forming reactions catalyzed by silver(1) or gold(1) compounds. Cycloadditions and alkylations using achiral silver(1) compounds are surveyed in Section 13.2. The next section covers BINAP-silver(1) complex-catalyzed asymmetric reactions. This catalyst is effective in the promotion of enantioselective allylation, aldol, Mannich, ene, and hetero Diels-Alder reactions. In the Section 13.4 diastereo- and enantioselective aldol-type reactions of activated isocyanides with aldehydes catalyzed by a gold(1) or silver(1) complex of a chiral ferrocenylphosphine are reviewed. The last section presents examples of rate enhancement of catalytic asymmetric reactions by silver(1) salts.

13.2 Achiral Silver(1)-Catalyzed Carbon-Carbon Bond-Forming Reactions Silver(1) compounds are known to promote different kinds of cycloaddition. Reactions of 2-alkoxyallyl halides with 1,3-dienes in the presence of silver(1) compounds provide a beneficial route to cycloheptanones [2,3]. When a mixture of 2-(trimethylsi1oxy)allyl chloride 1 and cyclopentadiene (2) is treated with 2 equiv. AgC104 in THF-ether (1:2) at 0 "C, bicyclo[3.2.l]oct-6-en-3-one 3 is produced in 91 % yield [3] (Sch. 1). The 2-(trimethylsiloxy)allyl cation 4 is believed to be involved as a reactive species in the reaction.

Je3 0 CI

1

IFe3

AgC104 (2 equiv) THF-ether (I:*), 0

+

2 (5 equiv)

91% yield

-

3

4

Scheme 1

Eschenmoser and coworkers achieved 1,4-cycloadditions by using a-chloro nitrones as precursors of 1,3-dipoles which react with unactivated olefins [4]. For example, the cycloadduct 7 is obtained by reaction of cyclohexene (5) and a-chloro nitrone 6

576

Yanagisawa

(2.1 equiv.) via the N-alkenyl-nitrosonium ion 8 under the influence of AgBF4 (2.2 equiv.) followed by treatment with KCN in H 2 0 (Sch. 2). This method was further applied to intramolecular [4 + 21 cycloadditions of nitrosoalkenes with olefins by Denmark and coworkers [5].

J3 0 -0,;

*q 0

0, +

1) AgBF4 CICH2CH2C1, (2.2 equiv) 40 "C

+ C I Y

2) KCN, H20, r.t.

CN

85% yield

5 6 (2.1 equiv)

7

8

Scheme 2

a-Bromoacetone 0-methyloxime (9) is regarded as a masked acyl cation 11 which is a good reaction partner in cycloadditions [6]. Addition of 9 to a solution of AgBF4 and cyclohexene (5)in dichloroethane, then work-up with an aqueous KCN solution furnishes pyrrolidine derivative 10 as a 1:l mixture of diastereomers (Sch. 3). Stereoselective cycloaddition is also possible with cis and trans stilbene, producing the corresponding 3,4-cis and 3,4-trans pyrrolidine derivatives.

0

+

5

OMe 1) AgBF4 (2.5 equiv) I CICH2CH2C1, 25 "C Br&

9 (2.5 equiv)

2) KCN, H20 76% yield

H

OMe I

11 Scheme 3

Padwa and coworkers found that a-cyanoaminosilane 12a is a convenient synthon for azomethine ylide 15 which is extensively used in heterocyclic synthesis [7]. AgF has been adopted to generate the ylide 15 from 12a for the preparation of pyrrolidine derivative 14 (Sch. 4). Various dipolarophiles including N-phenylmaleimide (13) can be used for the cycloaddition. When N-[(trimethylsilyl)methyl]-substituted indole 16 is reacted with AgF in the presence of maleimide 13, pyrrolo[l,2-a]indole 17 is formed in good yield, retaining the CN group [S]. A silver-bonded carbonium ion is assumed to be a reactive intermediate. Reaction of a cyano-substituted azomethine ylide, derived from (silylmethylamino)malononitrile 12b and AgF, with methyl propiolate (18) provides 3-carbomethoxy-N-benzylpyrrole(19) [9]. Epibatidine, a novel alkaloid, was successfully synthesized by employing the [3 + 21 cycloaddition of azomethine ylide with electron-deficient alkenes as a key step [lo].

Ag(I), Au(I) Lewis Acids

'

HCGCCOzCH3

N

18 16

577

Ph 19

17

Scheme 4

Grigg and coworkers found that metal salts (Ag, Li, or Zn) in conjunction with triethylamine catalyze cycloaddition of arylidene imines of a-amino acid esters to dipolarophiles, probably via metallo-l,3-dipole formation at room temperature [ll]. Among the metal salts tested, AgOAc gave the best results. For example, proline derivative 21 was obtained in 71 YOyield by reaction of the imine 20 with N-phenylmaleimide (13, Sch. 5). Grigg also reported the AgOAc-mediated asymmetric 1,3-dipolar cycloaddition reactions of ester stabilized azomethine ylides to chiral dipolarophiles [12]. T6ke and his colleagues have shown that the 1,3-dipolar cycloaddition of azomethine ylides to P-arylated nitroolefins takes place with reverse stereochemistry, depending on the metal salts employed. When the glycine-derived imine 22 is reacted with nitroolefin 23 in the presence of AgOAc and Et3N, the isomer 24 is given as a major product (24:25 = 3:l). In contrast, use of LiBr instead of AgOAc results in the selective formation of the diastereomer 25 (2425 = 1:2.3) [13].

Ph I

AgOAc (1.5 equiv) Et3N (1 equiv)

Ph H N x o N -Ph

20 13

PhH 0 21

71% yield

H

H

PhA N /\C02Et 22

Me 23

Me 24

Me 25

Scheme 5

Grigg and coworkers have recently shown that AgOAc is a catalyst of choice for the cycloaddition of isocyanoacetates with olefins possessing conjugated electronwithdrawing groups to give dl- or d2-pyrrolines [14]. For instance, the reaction of

578

Yanagisawa

acrolein (26) with methyl isocyanoacetate (27) proceeds in 73 % yield at ambient temperature under the influence of 0.2 mol YOAgOAc (Sch. 6). A stepwise mechanism via a silver-coordinated isocyanide is proposed for the cycloaddition reaction.

+

6 C H O 26

rMe AgOAc (0.2 mol%) CHsCN, 20-22 'C

NC

OHC

73% yield

27

28

Scheme 6

Silver(1) compounds are often used as promoters for substitution reactions of aliphatic halides with carbon nucleophiles. A cyclic P-bromo ether 29 can be reacted with allyltrimethylsilane (30) under the influence of AgBF4, yielding a mixture of allylated products 31 and 32 (Sch. 7) [15]. Product 31 is formed by direct substitution of the bromine atom in ether 29 by an ally1 group and isomeric ether 32 arises from the carboxonium ion which is generated by debromination and subsequent [1,2]-hydrogen shift. A synthesis of optically active 4-allylazetidinone 33 (Ft = phthalimido) has also been achieved by employing the silver-promoted substitution reaction of 4-chloroazetidinone 34 with allylsilane 30 [16]

30 (2.5 eauiv)

66% yield F t HY HJ

F t H % H A

/

0

0

C02Me 33

/

C02Me 34

Scheme 7

A unique condensation is observed between 1,3-dimethoxy-l-trimethylsiloxybutadiene (35) and cinnamaldehyde (36) producing the acyclic adduct 37 in 72 YO yield when catalyzed by Ag(fod) (Sch. 8). In contrast, when Eu(fod)s or Yb(fod)s is used as the catalyst, a hetero-Diels-Alder reaction takes place exclusively [17]. The acyclic adduct 37 is believed to be formed by a [2 + 21 cycloaddition via an oxetane rather than through a six-membered ring transition state (Mukaiyama aldol type reaction). Me3Si0 L O M e + Me0

H

36

Ph Ag(fod) CH2C12, (5 rnol%) r.t. * M 72% yield

35

Scheme 8

OSiMe3 e

O

v

P

Me0 37 (dr 60:40)

h

579

Ag(I), Au(1) Lewis Acids

Jefford and coworkers have shown that silyl enol ethers also react with alkyl halides in the presence of AgOCOCF3 at low temperature to afford various alkylated products in good yield [18]. In the reaction of 2-trimethylsiloxyfuran (38) with primary alkyl iodides 39 (X = I), the corresponding 4-alkylated butenolides 40 are obtained regiospecifically (Sch. 9) [18b,c]. The same group has accomplished a short-step synthesis of (+)-eldanolide (41) via the silver(1)-promoted regioselective prenylation of 38 with prenyl bromide, followed by treatment of the resulting butenolide 42 with lithium dimethylcuprate [Ha]. They subsequently showed that ordinary silyl enol ethers such as 43, which is expected to be less reactive than 2-trimethylsiloxyfuran (38), can also be effectively alkylated in the presence of AgOCOCF3 [18d].

/o 0

Me3Si0

+

AgOCOCFB (1.3 equiv)

RX

CH2C12, -78 'C

* o 40

39 (1.3 equiv)

38

OSiMe3

0 41

42

43

Scheme 9

Padwa and coworkers applied the silver(1)-promoted alkylation of silyl enol ethers to synthesis of substituted furans [19]. For example, treatment of various trimethylsilyl enol ethers of cycloalkanones 44 and (E)-2,3-diiodo-l-(phenylsulfonyl)-l-propene (45) with 2 equiv. AgBF4 gives alkylated products 46 resulting from S N displacement ~ of the terminal iodide. These compounds 46 further cyclize with triethylamine to produce the 2-phenylsulfonylmethyl substituted furans 47 (Sch. 10) [19a]. OSiMe3

1 ' 9. S02Ph

AgBF4 (2 equiv) CHzCIz, 25 ' C

(CH2)" 44 (n = 1-4)

45

88-71yo

46

47

Scheme 10

Alkylating agents bearing a leaving group other than halide can be used for the silver(1)-promoted alkylation of silyl enol ethers. Benzylic chloroformates are convenient reagents for the preparation of benzylated ketones [20] and 2-pyridylthio groups are useful for stereoselective intramolecular cyclization of (S)-glycosidic silyl enol ethers [21]. The latter leaving group has been widely applied in carbohydrate chemistry. Stewart and Williams reported a mild method for the C-glycosidation of pyridyl thioglycosides using a silver(1) compound as an activator [22]. When the glucopyranose derivative 48 is treated with trimethylsilyl enol ether 49 and 2 equiv. AgOTf, C-glycoside 50 is formed in 81 % yield and with exclusive a selectivity (Sch. 11). Use of 2,3,4,6-tetra-O-benzyl-a-~-glucopyranosyl chloride (51) instead of 48 furnishes comparable chemical yield and an a/P ratio [23].The thiophilicity of silver(1) compounds has been further exploited in the acylation of 1-alkynyltrimethylsilanes with thiol esters in the presence of AgBF4 [24].

580

BnO B

Yanagisawa

n

O

a

s

BnO

a

e

3

Ph

/

48

X

+

Ph

49 (5 equiv)

81%

0 BnO BnO*

Brio

CI

51

Scheme 11

Acylnitrium ions, generated from isocyanomethylsilyl enol ethers and an acid chloride then exposure to AgBF4, were shown by Livinghouse and coworkers [25a] to be versatile intermediates in the synthesis of a variety of heterocyclic compounds. For example, dl-pyrroline 53 is formed in high yield by combining isocyanide 52 and pivaloyl chloride (Sch. 12). Similar six- and seven-membered ring heterocycles can also be efficiently prepared by this method. A total synthesis of (+)-dendrobine has been accomplished by silver(1)-mediated heteroannulation [25b].

H

52

87% yield

53

Scheme 12

Siloxycyclopropanes are known as homoenolate anion equivalents and have been favorably utilized in organic synthesis. Murai, Sonoda, and coworkers found that desilylative dimerization of the siloxycyclopropanes occurs on exposure to AgBF4 [26a]. The reaction of 54 gives 1,6-diketone 55 in good yield (Sch. 13). The p-silver ketone 56 is considered to be a key intermediate in the dimerization. The intermediary ,341ver ketone, generated from siloxycyclopropane 57 and AgF, can be successfully trapped with ally1 chloride to afford a d,&-unsaturatedketone 58 [26b].

Me3Si0

0

Et20, -20 - 15 'C

54

70% yield

57

Scheme 13

f l

AgBF4(1.5equiv)

55

58

[u] 56

Ag(I), Au(I) Lewis Acids

581

Silver(1) compounds are often used to generate cationic metal complexes from the corresponding metal halides. Suzuki and coworkers found that n-hexylzirconocene chloride (61), derived from 1-hexene and Schwartz reagent 60, can react with aldehydes in the presence of a catalytic amount of AgAsFh to give secondary alcohols [27]. The reaction with hydrocinnamaldehyde, for example, provides the alcohol 62 in 95 % yield (Sch. 14). Allylic alcohols are also obtainable by a similar procedure using 1-hexyne as a starting material.

Cp2Zr(H)CI(60, 1.7 equiv)

cP,

Ph(CH&CHO AgAsFG (10 mol%)

-B,

* cp'zr\cI 59 (1.8 equiv)

CH2C12, r.t.

OH

61

95%

62

Scheme 14

When treated with AgOTf or AgBF4, vinyl bromides and a-halo imines are transformed into cationic species that can react with aromatic compounds. For instance, vinylation of benzene (64) with vinyl bromide 63 occurs in the presence of AgOTf and DBMP affording the vinylated product 65 in high yield (Sch. 15) [28a]. Bromo-oxime ether 9 [28b] and a-bromo imidate 66 [28c] are also converted into a reactive intermediate which undergoes a similar electrophilic aromatic substitution promoted by AgBF4. This aromatic substitution reaction has been successfully applied to synthesis of vinblastine by using a-chloro imine 67 as a key intermediate [28d]. Br

AgOTf (1.5 equiv) DBMP (1.4 equiv)

* Me0

dPh 65

DBMP = 2,6-di-fert-butyl-4-methylpyridine ,Bn

67 Scheme 15

13.3 BINAP . Silver(1)-CatalyzedAsymmetric Reactions In 1996 Yanagisawa, Yamamoto, and their colleagues first reported the asymmetric allylation of aldehydes with allylic stannanes catalyzed by a BINAP .silver(1) complex [29]. The chiral phosphine-silver(1) catalyst can be prepared simply by stirring an equimolar mixture of BINAP and silver(1) compound in THF at room tempera-

582

Yanagisawa

ture. Sch. 16 and Table 1 show the results obtained by reaction of a variety of aldehydes with allyltributyltin (68) under the influence of 5-20 mol % (S)-BINAP.si1ver(1) triflate in THF at -20 "C. The reaction furnishes high yields and remarkable enantioselectivity not only with aromatic aldehydes but also with a$-unsaturated aldehydes, with the exception of an aliphatic aldehyde which gives a lower chemical yield (entry 7). In the reaction with a$-unsaturated aldehydes, the 1,2-addition takes place exclusively (entries 5 and 6). Enantioselective addition of rnethallyltributylstannane to aldehydes can also be achieved by use of this method [29a,30]. (S)-BINAP.AgOTf (5-20 mol%) e S n B u 3

+ RCHO

*

THF, -20 'C

68

R 69

Scheme 16

Table 1. Enantioselective allylation reaction of aldehydes with allyltributyltin (68) catalyzed by 5 mol % (S)-BINAP . AgOTf complex in THF at -20 "C.

Entry 1

2

Aldehyde PhCHO

Yield (%)"

ee (%)b(config)

88

96 (8

59

97

95

96

94

93

Meon CHO

3 CHO

4c Q C H O

5d

(a-PhCH=CHCHO

83

88 (S)

6e

(€)-/PC~H~CH=CHCHO

72

93f

7e

PhCHzCH2CHO

47

88

''

Isolated yield. Determined by HPLC analysis with chiral columns. 4 equiv. allyltributyltin (68) and 0.2 equiv. (S)-BINAP. AgOTf was used. 3 equiv. allyltributyltin (68) and 0.15 equiv. (S)-BINAP. AgOTf was used. The reaction was started by use of 2 equiv. allyltributyltin (68) and 0.1 equiv. (R)-BINAP' AgOTf, and 0.1 equiv. catalyst was added after 4 h. Determined by HPLC analysis (chiral columns) of the benzoate ester of the product.

Condensation of y-substituted allylmetals with aldehydes is a fascinating subject with regard to regioselectivity (aly) and stereoselectivity (EIZ or antilsyn). Addition of (E)-crotyltributyltin (70E, EIZ = 95I5) to benzaldehyde in the presence of

Ag(I), Au(I) Lewis Acids

583

20 mol YO(R)-BINAP . AgOTf in THF at -20 "C to room temp. gives exclusively the y adducts 71-anti and 71-syn with an antilsyn ratio of 85/15 [30]. The anti isomer 71anti is obtained in 94 YOee with a (1R,2R) configuration (Sch. 17). Use of (2)-crotyltributyltin (702, ElZ = 2/98) or a nearly 1:1 mixture of ( E ) - and (2)-crotyltributyltin results in a similar antilsyn ratio and enantioselectivity (Sch. 17).

w SnBu3 Y a

+

(R)-BINAP.AgOTf OH (20 mol%) THF, -20 "C - r.t. * Ph?

PhCHO

70 (4 equiv)

OH +

71-anfi(lR,2R) FZratio of crotyltin

Ph-

- Y

71-syn (1R,2S)

Yield, %

anti(% ee) : syn (Yoee)

56 72 45

85 (94) : 15 (64) 85 (91) : 15 (50) 85 (94) : 15 (57)

95 : 5 2:98 53 : 47

Scheme 17

Reaction of aldehydes with 2,4-pentadienylstannanes is also catalyzed by BINAP .silver(1) complex, and the corresponding y-pentadienylated optically active alcohols are obtained with high enantioselectivity [31]. When benzaldehyde is reacted with 1 equiv. pentadienyltributyltin (72,E/Z = 97l3) and 0.1 equiv. (S)-BINAP .AgOTf at -20 "C,the y product 73 is obtained in 61 % yield with 90 YOee (Sch. 18). Pentadienyltrimethyltin affords chemical yield and enantioselectivity comparable with those of pentadienyltributyltin (72).Ketones are inert under the standard reaction conditions.

-

SnBu3

E

Y

(S)-BINAP.AgOTf

+ PhCHO

a

72 (€/Z = 9713)

(10 mol%) THF, -20 'C

*

"$

Ph

\

61% yield

73,90% ee

Scheme 18

The BINAP. silver(1) complex can be further applied as a chiral catalyst in the asymmetric aldol reaction. Although numerous successful methods have been developed for catalytic asymmetric aldol reaction, most are the chiral Lewis acid-catalyzed Mukaiyama aldol reactions using silyl enol ethers or ketene silyl acetals [32] and there has been no report which includes enol stannanes. Yanagisawa, Yamamoto, and their colleagues found the first example of catalytic enantioselective aldol addition of tributyltin enolates 74 to aldehydes employing BINAP .silver(1) complex as a catalyst (Sch. 19) [33]. OSnBu3 R'

R2 +

R3 74 Scheme 19

(R)-BINAP.AgOTf (10 mol%) R4CH0

THF, -20 'C, 8 h

* R' v

R R2 R3 75

4

584

Yanagisawa

The tributyltin enolates 74 are readily prepared from the corresponding enol acetates and tributyltin methoxide in the absence of solvent [34]. The tin enolates thus obtained occur in the 0-Sn form and/or the C-Sn form, and both species can be used for the aldol reaction of this system. Although the tin enolates themselves have adequate reactivity toward aldehydes [34c], in the presence of the BINAP .silver(1) catalyst the reaction proceeds much faster even at -20 "C. Optimum conditions entail the use of THF as solvent and the results employing these conditions in the catalytic enantioselective aldol reaction of a variety of tributyltin enolates with typical aromatic, a,P-unsaturated, and aliphatic aldehydes are summarized in Table 2. The characteristic features are: (i) All reactions proceed to furnish the corresponding aldol adducts 75 in moderate to high yield in the presence of 10 mol % (R)-BINAP .AgOTf complex at -20 "C for 8 h, and no dehydrated aldol adduct is observed; (ii) with an a$unsaturated aldehyde, the 1,Zaddition reaction takes place exclusively (entry 3); (iii) a bulky alkyl substituent of tin enolate increases the enantioselectivity of the aldol reaction. For instance, the highest ee (95 % ee) is obtained when the tin enolate prepared from pinacolone 77 or tert-butyl ethyl ketone 79 is added to aldehydes (entries 2, 7, and 8); (iv) addition of the cyclohexanone-derived enol tributylstannane 78 ((17)Table 2. Diastereo- and enantioselective aldol reaction of tin enolates 74 with aldehydes catalyzed by 10 mol YO(R)-BINAP . AgOTf complex in THF at -20 "C.

Entry

Tin enolate

Aldehyde

Yield (%)a anti :synb ee (%)

0 sB uS n, , )

PhCHO

73

77

PhCHO

78

95

ph&CHo

69

86

-CHO Ph

75

94

76

0 t-BU S B 3 n u, ,)

77

OSnBu3

?SnBu3

PhCHO

94

92 : 8

93f

95

93 : 7

94h

81

<1:99

95

77

<1:99

95

Isolated yield. Determined by 'H NMR analysis. The value corresponds to the major diastereomer. Determined by HPLC analysis with chiral columns. 0-Sn:C-Sn < 1:99. 0-Sn:C-Sn > 99:l. The syn isomer: 25 YOee. 1 rnol % catalyst was used. The syn isomer: 33 YO ee. ' 0-Sn:C-Sn > 99:l. The E Z ratio for the 0-Sn isomer was < 1:99.

a

Ag(I), Au(I) Lewis Acids

585

enolate) to benzaldehyde under the influence of 10 mol YO (R)-BINAP.AgOTf in THF at -20 "C produces the optically active anti aldol adduct 75 (R1-R3 = (CH2)4 R2 = H; R4 = Ph) preferentially with an antilsyn ratio of 92/8, in contrast to the syn selectivity shown by typical chiral Lewis acid catalysts [32]. The anti isomer is obtained with 93 YO ee (entry 5). The amount of catalyst can be reduced to 1 mol YO without any loss of the chemical yield or diastereo- or enantioselectivity (entry 6). In contrast, the (2)-enolate derived from tert-butyl ethyl ketone 79 furnishes the syn aldol adduct 75 (R' = t-Bu; R2 = CH3; R3 = H) nearly exclusively with 95 Yo ee in combination with benzaldehyde and hydrocinnamaldehyde (entries 7 and 8). These results clearly show that the diastereoselectivity depends on the geometry of the enol stannane, and that cyclic transition-state structures (A and B, Fig. 1) are probable models. Thus, from the (E)-enolate, the anti-aldol product can be obtained via a cyclic transition state model A, and another model B connects the (2)-enolate to the syn-product. Similar six-membered cyclic models containing a BINAP-coordinated silver atom instead of tributylstannyl group are also possible alternatives when transmetalation to silver enolate is sufficiently rapid.

*

*

n

n ,P

p,

H

R'

l L H

d2

A

-+

anti

B

-

syn

Figure 1. Probable structures of cyclic transition states.

This BINAP.silver(1) complex was subsequently used by Lectka and coworkers as a catalyst for Mannich-type reactions [35]. Slow addition of silyl enol ether 49 to a solution of tosylated a-imino ester 80 under the influence of 10 mol % (R)-BINAP .AgSbFh at -80 "C affords the corresponding amino acid derivative 81 in 95 YOyield with 90 Yo ee (Sch. 20). They reported, however, that (R)-Tol-BINAP. CuC104. (CH3CN)2 was a more effective chiral Lewis acid for the reaction and gave the highest yield and ee at 0 "C.

EtO

(R)-BINAP.AgSbFe (1 0 mol%)

LNx~s OSiMe3

+

80

A p t , 49

THF, -80 "C, 24 ht 95% yield

HNNTsO

EtOOC

Ph

81, 90% ee

Scheme 20

The BINAP.silver(1) complex was further applied to ene reactions of a-imino esters independently by two groups [36,37]. For example, treatment of a-imino ester 80 with a-methylstyrene (82) in the presence of 5 mol YO(R)-BINAP. AgSbFh in benzotrifluoride at room temperature leads to ene adduct 83 with 71 YO ee (Sch. 21) [36]. Both groups have reported that the Tol-BINAP . Cu(1) complex is superior to BINAP . Ag(1) complex as a chiral catalyst.

586

Yanagisawa

(R)-BINAP.AgSbFe (5 mol%) EtOL N x T s + h 80

p

h

CeHsCF3, r.t., 18;

EtOOC H P ah 83,71Yo ee

82

Scheme 21

Catalytic asymmetric cycloaddition reactions including the Diels-Alder reaction can be performed by use of various chiral Lewis acids catalysts; there are, however, few methods available employing chiral silver(1) or gold(1) catalysts. In 1995, Grigg reported preliminary results of an asymmetric Id-dipolar cycloaddition reaction of azomethine ylides with electron-deficient olefins catalyzed by a chiral bisphosphine . AgOTf complex [12]. Jorgensen and coworkers more recently investigated different combinations of chiral ligands and Lewis acids for aza Diels-Alder reactions of a-imino carbonyl compound 80 with Danishefsky’s diene 84 and found that BINAP .Ag(1) complex also serves as a chiral catalyst for the reaction but with low ee (Sch. 22) [38]. OMe (R)-Tol-BINAP.AgC104 (1 0 mol%)

0 EtO

80

i

+ Me3Si0

84

THF, -78 ‘C 90% yield

*

0a l 1 2 E t 85,34% ee

Scheme 22

13.4 Gold and Silver-Catalyzed Asymmetric Aldol Reactions of a-Isocyanocarboxylates In 1986 Ito, Sawamura, and Hayashi showed that chiral ferrocenylphosphine 86-gold(I) complexes catalyzed the aldol-type reaction of isocyanoacetate with aldehydes to provide optically active 5-alkyl-2-oxazoline-4-carboxylates (Sch. 23) [39]. Since then, they have studied the chiral gold(1)-catalyzed reaction extensively [40] as have Pastor and Togni [41]. The gold complexes can be generated in situ by mixing bis(cyclohexy1isocyanide)gold(I) tetrafluoroborate and (R)-N-methyl-N-[2-(dialkylamino)ethyl]-l-[(S)-1’,2bis(diphenylphosphino)ferrocenyl]ethylamine (86). Examples of the reaction of methyl isocyanoacetate (27) and various aldehydes in the presence of 1 mol % 86c .Au(I) complex are summarized in Table 3. Benzaldehyde and substituted aromatic aldehydes, with the exception of 4-nitrobenzaldehyde, are transformed into the corresponding trans-oxazolines 87 with high enantio- and diastereoselectivity (entries 1-6). Secondary and tertiary alkyl aldehydes afford trans-87 nearly exclusively with high ee (entries 8 and 9). The trans-oxazolines 87 can be readily hydrolyzed to threo-P-hydroxy a-amino acids 88. The gold-catalyzed aldol reaction has been applied to asymmetric synthesis of biologically important compounds D-threo-sphingosine (89) [42], D-erythro-sphingosine (90) [42], and MeBmt (91) [43]. Enantioselective synthesis of (-)-a-kainic acid has also been achieved by use of this aldol reaction [44].

Ag(I), Au(I) Lewis Acids

RCHO

+

86.[Au(c-HexNC)2lBF4 (1 mol%)

(02Me

RcdC02Me+

Rc

O*N

O*N

1

trans-87

27

d

i Fe

-

N

R

'

G02Me

n

*

CH2C12,25 'C

NC

587

2

cis-87

H30+

PPh2 I Me

-PPhz

R q C 0 2 H 86a: NR'2 = NMe2 NH2 tbreo-88

3 n

86b: NR'2 = N

8 6 ~ NR'2 : = N

\p NH2

~ - C I + ~OHH ~ ~ OH D-tbreo-sphingosine (89)

t~-C13H27&OH OH D-erytbresphingosine (90)

JMe /

COpH

OH MeBmt (91)

Scheme 23

588

Yanagisawu

Table 3. Diastereo- and enantioselective aldol reaction of methyl isocyanoacetate (27) with aldehydes catalyzed by chiral ferrocenylphosphine 86c. gold(1) complex.

Entry

Aldehyde

1

Yield (%)"

trans :cisb

ee (%)'

93

95 : 5

95

86

95 : 5

96

3

98

92 : 8

92

4

98

96 : 4

95

97

94 : 6

94

80

8 3 : 17

86

PhCHO

2 .OMe

5

C

/

oCHO

O H + = = (6 - N * O

7d

MeCHO

99

8 9 : 11

89

8

i-BuCHO

99

96 : 4

87

9

t-BUCHO

94

>99: 1

97

10 a

lJ-Pr-

\ CHO

85

8 7 : 13

92

Isolated yield. Determined by 'H NMR analysis. Determined by 'H NMR spectroscopy with chiral shift reagent Eu(dcm)3. 0.2 mol % catalyst was used.

A proposed transition-state model for the reaction is shown in Fig. 2. The presence of the 2-(dialky1amino)ethylamino group in 86 is necessary to obtain high selectivity [45]. The terminal amino group abstracts one of the a protons of isocyanoacetate coordinated with gold and the resulting ion-pair leads to an advantageous arrangement of the enolate and aldehyde around the gold. In contrast, Togni and Pastor proposed an alternative acyclic transition-state model [41d].

Ag(I), Au(I) Lewis Acids

589

U

Figure 2. Transition-state model proposed for the gold-catalyzed asymmetric aldol reaction.

The chiral ferrocenylphosphine.gold(1)-catalyzed aldol reaction of a-alkyl a-isocyanocarboxylates 92 with paraformaldehyde gives optically active 4-alkyl-2-oxazoline-4carboxylates 93 with moderate to good enantioselectivity [46]. The absolute configuration (S) of the product indicates that the reaction occurs selectively at the si face of the enolate as illustrated in Fig. 2. These oxazolines 93 can be converted into a-alkylserine derivatives 94 (Sch. 24).

92

(54-94

(9-93 63-81 % ee

R = Me, Et, i-Pr, Ph L* = 86a or 86b Scheme 24

This enantioselective aldol reaction employing isocyanoacetate 27 is quite effective for aromatic aldehydes or tertiary alkyl aldehydes, but not for sterically less hindered aliphatic aldehydes as described above. Ito and coworkers found that very high enantioselectivity is obtained even for acetaldehyde (R = Me) in the aldol reaction with N,N-dimethyl-a-isocyanoacetamide (95) (Sch. 25) [47]. Use of a-keto esters in place of aldehydes also results in moderate to high enantioselectivity of up to 90 % ee [48].

RCHO

+

(E NC

L*.[Au(c-HexNC)z]BF4 (1 rnol%)

R,*.

CH2CI2, 25 "C

0-N

0-N

trans-98

Scheme 25

E .

*

*

E

R

L*

CONMe2 (95) CON(Me)OMe (96) PO(OPh)2 (97)

Me Me Ph

86b 86c 86b

Cis-98

trans (Yoee) : cis

91 (99) : 9 95 (97) : 5 >98 (96) : 2

590

Yanagisawa

The same group further developed the asymmetric aldol reaction of N-methoxy-Nmethyl-a-isocyanoacetamide (a-isocyano Weinreb amide) with aldehydes (Sch. 25). The reaction of the Weinreb amide 96 with acetaldehyde in the presence of 86c. Au(1) catalyst gives the optically active trans-oxazoline 98 (E = CON(Me)OMe; R = Me) with high diastereo- and enantioselectivities similar to those of 95 [49]. The oxazoline can be transformed into N,O-protected P-hydroxy-a-amino aldehydes or ketones. (1socyanomethyl)phosphonate 97 is also a beneficial pronucleophile leading to optically active (1-aminoa1kyl)phosphonic acids, phosphonic acid analogs of a-amino acids via truns-5-alkyl-2-oxazoline-4-phosphonates 98 (E = PO(OPh)*, Sch. 25) [50] . Ito and coworkers found that chiral ferrocenylphosphine-silver(1) complexes also catalyze the asymmetric aldol reaction of isocyanoacetate with aldehydes (Sch. 26) [51]. It is essential to keep the isocyanoacetate at a low concentration to obtain a product with high optical purity. They performed IR studies on the structures of gold(1) and silver(1) complexes with chiral ferrocenylphosphine 86a in the presence of methyl isocyanoacetate (27) and found significant differences between the isocyanoacetate-to-metal coordination numbers of these metal complexes (Sch. 27). The gold(1) complex has the tricoordinated structure 100, which results in high ee, whereas for the silver(1) complex there is an equilibrium between the tricoordinated structure 101 and the tetracoordinated structure 102, which results in low enantioselectivity. Slow addition of isocyanoacetate 27 to a solution of the silver(1) catalyst and aldehyde is effective in reducing the undesirable tetracoordinated species and results in high enantioselectivity.

86b.Ag(l) (1-2 mol%) RCHO

+ (Nc

solvent, 25-30 'C

*

0-N

0-N

trans-98

E

R

C02Me (27)a C02Me (27)a S02(pT01) (99) SO2(pTol) (99)

Ph i-Pr Ph i-Pr

solvent AgOTf AgCIO4 AgOTf AgOTf

cis-98

trans (% ee) : cis

CICH2CH2CI 96 (80) : 4 CICHpCH2CI 99 (90) : 1 >99 (77) : 1 CH2CI2 >99 (86): 1 CH2CI2

Scheme 26

100 -2711 +27

low ee

RCHO

102

Scheme 27

Ag(I), Au(I) Lewis Acids

591

The asymmetric aldol-type addition of tosylmethyl isocyanide (99) to aldehydes can also be catalyzed by the chiral silver(1) complex, giving almost exclusively truns-5alkyl-4-tosyl-2-oxazolines 98 [E = S02(p-Tol)] with up to 86 YO ee as shown in Sch. 26 [52]. The slow addition method described above is not necessary for this reaction system. Soloshonok and Hayashi applied chiral ferrocenylphosphine-gold(1) complexes to asymmetric aldol-type reactions of fluorinated benzaldehydes with methyl isocyanoacetate (27) and N,N-dimethyl-a-isocyanoacetamide (95). It is noteworthy that successive substitution of hydrogen atoms by fluorine in the phenyl ring of benzaldehyde causes gradual increase of both the cis selectivity and the ee of cis-oxazolines [53].

13.5 Rate Enhancement of Catalytic Asymmetric Reactions by Silver(1) Salts Heck reactions of alkenyl or aryl halides are generally accelerated by addition of silver salts [54]. In 1989, Shibasaki and coworkers reported the first example of a catalytic asymmetric Heck reaction of prochiral alkenyl iodides 103 in the presence of Ag2C03 to give the optically active cis-decalin derivative 104 with moderate enantioselectivity [55]. At almost the same time, Overman and coworkers reported the asymmetric Heck reaction of trienyl triflates without silver salts [S6]. The former group subsequently examined the effect of different silver salts on the asymmetric induction and found that Ag3P04 is among the most effective of these salts [57]. For instance, the decalin derivative 104 [R = CH20Si(t-Bu)Me2] is formed with 80 YOee from the corresponding alkenyl iodide 103 by treatment with 10 mol % (R)-BINAP.PdC12, Ag3P04 (2 equiv.), CaC03 (2.2 equiv.) in 1-methyl-2-pyrrolidinone (NMP) at 60 "C (Sch. 28) [S7a,b]. cis-Hydrindane derivatives 105 I581 and indolizidine derivative 106 [57b,S9] are also synthesized with up to 86 YOee by similar methods. (R)-BINAP.PdC12 (10 mol%) Ag3P04 (2 equiv)

103

CaC03 (2.2 equiv) NMP, 60 'C

105

H 104, 80% ee [R = CH20Si(f-Bu)Me*]

106

Scheme 28

The role of silver salts in the asymmetric Heck reaction is thought to be as in Sch. 29 [57b]. The Ag' ion abstracts the iodide from the palladium intermediate 107 to produce the square-planar 16-electron Pd' intermediate 108 which is indispensable for high asymmetric induction.

592

Yanagisawa

Pd

Pd p+' 1 I'

' I

LP 110

Pd )':

*

P

109

103

*

J

107

Y-

Pd+, P L P

-*

[ G e e )

108

Scheme 29

Overman and coworkers have shown that both enantiomers of a variety of spirocyclic compounds can be prepared by asymmetric Heck cyclization under two reaction conditions [60]. For example, the synthesis of (S)-enriched 3,3-spirooxindole 112 from the corresponding aryl iodide 111 was achieved with (R)-BINAP .Pd catalyst and Ag3P04 (cationic pathway), whereas employment of 1,2,2,6,6-pentamethylpiperidine (PMP) in place of Ag3P04 as an additive (neutral pathway) resulted in formation of (R)-112 with 66 % ee (Sch. 30). Less basic silver salts (AgOCOCF3, AgOCOCH3, AgN03) result in virtually no asymmetric induction. Silver phosphate is also an effective base for suppressing alkene isomerization during the Heck reaction by removal of HI generated in situ. The same group later found that halide additives can increase enantioselectivity in Heck cyclization of u&unsaturated 2-iodoanilides or their triflate derivatives in the absence of silver salts (neutral pathway) [61]. Other examples of the asymmetric Heck reaction using silver salts have also appeared [62]. 0 cat. Pd2(dba)3 cat. (R)-BINAP MeCONMe2 112

111

additive = Ag3P04: PMP:

Scheme 30

71% ee (S) 66% ee ( R )

593

Ag(I), Au(I) Lewis Acids

Cationic Pd complexes can be applied to the asymmetric aldol reaction. Shibasaki and coworkers reported that (R)-BINAP. PdCl+, generated from a 1:l mixture of (R)BINAP .PdCI2 and AgOTf in wet DMF, is an effective chiral catalyst for asymmetric aldol addition of silyl enol ethers to aldehydes [63].For instance, treatment of trimethylsilyl enol ether of acetophenone 49 with benzaldehyde under the influence of 5 mol YOof this catalyst affords the trimethylsilyl ether of aldol adduct 113 (87 YOyield, 71 YOee) and desilylated product 114 (9 YOyield, 73 YOee) as shown in Sch. 31. They later prepared chiral palladium diaquo complexes 115 and 116 from (R)-BINAP .PdClz and (R)-p-TolBINAP. P d Q , respectively, by reaction with 2 equiv. AgBF4 in wet acetone [@I. These complexes are tolerant of air and moisture, and afford similar reactivity and enantioselectivity in the aldol condensation of 49 and benzaldehyde. Sodeoka and coworkers have recently developed enantioselective Mannich-type reactions of silyl enol ethers with imines catalyzed by binuclear p-hydroxo palladium(I1) complexes 117 and 118 derived from the diaquo complexes 115 and 116 [65]. These reactions are believed to proceed via a chiral palladium(I1) enolate. (R)-BINAP.PdC12 (5 mol%) AgOTf (5 mol%)

OSiMe3

A

Ph

+

PhCHO

*Ph

MS 4A, DMF-H20,23 ‘C

49

113 (87% yield) 71Yoee

114 (9% yield) 73% ee

117, Ar = Ph 118, Ar = pTol

115, Ar = Ph 116, Ar = pTol

Scheme 31

1,3-Dipolar cycloaddition of nitrones to olefins is also catalyzed by chiral cationic palladium complexes [66]. When nitrone 119 is treated with 3-((E)-2-butenoyl)-l,3-oxazolidin-2-one (120) under the influence of (S)-BINAP.PdC12 (10 mol YO)and AgBF4 isoxazolidine 121 is obtained in 61 YOyield as a 4555 mixture of endo and (20 mol YO), exo forms. The endo isomer is obtained in 91 % ee (Sch. 32). The chemical yield and endo selectivity are improved by employing (S)-p-Tol-BINAPas chiral ligand. Me,

+O ,-

HAP, 119

+

dNKO 120

0

(S)-BINAP.PdC12 (10 mol%) AgBF4 (20 mol%) CHCI3, reflux, 48 h

.\.‘

0

’

*

n

..‘

n

Ph 0 0 endel21 exo-121 61Yoyield; endo/exo = 45 (91Yoee)/55 (25% ee)

Scheme 32

594

Yanagisawa

Mikami and Nakai have shown that chiral titanium perchlorate 123, prepared from chiral titanium dichloride 122 and AgC104 (2 equiv.), is an asymmetric superior catalyst to 122 in terms of the diastereo- and enantioselectivity of carbonyl-ene cyclization [67]. AgC104 alone does not catalyze the ene cyclization. One typical example is indicated in Sch. 33. Treatment of a-alkoxy aldehyde 124 with the chiral titanium catalyst 123 in the presence of 4-A molecular sieves in CH2C12at 0 "C gives the trans alcohol 125 selectively with 84 % ee. Employment of the titanium dichloride 122, in contrast, results in a nearly 1:l mixture of trans-125 and cis-125 with lower enantioselectivity. 0 catalyst

*

MS 4A, CH2C12,O "C 124

trans-1 25

cis-125

catalyst

o, x,

123: 50% yield; trans/cis = 80 (84% ee)/20 (74% ee) 122: 73% yield; trandcis = 47 (70% ee)/53 (79% ee)

122, X = CI [(i-Pr0)*TiCI2 (20 mol%) + (R)-BINOL(20 molYo)] 123, X = C104 [(i-Pr0)2TiC12(20 mol%) + (R)-BINOL (20 rnol%) + AgC104 (40 molYo)]

Scheme 33

13.6 Summary and Conclusions Described herein are examples of organic transformations using silver(1) or gold(]) Lewis acids. Achiral silver(1) compounds, especially AgBF4 and AgOTf, have been widely used in organic synthesis and numerous selective carbon-carbon bond-forming reactions, including cycloadditions and alkylations, have been developed. The BINAP .silver(1) catalyst has been used to realize allylation of aldehydes and the aldol reaction of trialkyltin enolates with high enantio- and diastereoselectivity. This silver catalyst is also effective in Mannich-type reactions, ene reactions, and hetero Diels-Alder reactions of a-imino esters. The chiral ferrocenylphosphine gold(1)-catalyzed asymmetric aldol reaction has afforded high stereoselectivity when the substrate is restricted to a-isocyanocarboxylates and their derivatives, and has proven to be an excellent synthetic method for optically active a-amino acid derivatives and amino alcohols. The remarkable affinity of the silver ion for halides is convenient for acceleration of the chiral palladium-catalyzed Heck reactions and other reactions. Enantioselectivity of these reactions is generally increased by addition of silver salts. These examples clearly indicate that silver(1) and gold(1) compounds in combination with chiral ligands are very promising as chiral Lewis acid catalysts for asymmetric synthesis.

Ag(I),Au(I) Lewis Acids

595

References 1. (a) [AgN03]: D. R. Rae, in Encyclopedia of Reagents for Orgunic Synthesis, Vol. 6 , (ed.: L. A. Paquette), John Wiley & Sons, Chichester, 1995, p. 4461. (b) [AgC104]: J. C. Lanter, in Encyclopedia of Reagents,for Organic Synthesis, Vol.6 , (ed.: L. A. Paquette), John Wiley & Sons, Chichester, 1995, p. 4469. (c) [AgBF4]: L.-G. Wistrand, in Encyclopedia of Reagents for Organic Synthesis, Vol. 6 , (ed.: L. A. Paquette), John Wiley & Sons, Chichester, 1995, p. 4472. (d) [AgOTf]: T. H. Black, in Encyclopedia of Reagents for Organic Synthesis, Vol.6 , (ed.: L. A. Paquette), John Wiley & Sons, Chichester, 1995, p. 4476. 2. A. E. Hill, G. Greenwood, H. M. R. Hoffmann,J. A m . Chem. Soc. 1973,95,1338. 3. N. Shimizu, M. Tanaka, Y. Tsuno,J. Am. Chem. Soc. 1982,104,1330. 4. U. M. Kempe, T. K. Das Gupta, K. Blatt, P. Gygax, D. Felix, A. Eschenmoser, Helv. Chim. Acta 1972.55,2187. 5. S. E. Denmark, M. S. Dappen, J. A. Sternberg, J. Org. Chem. 1984,49,4741. 6. S. Shatzmiller, E. Shalom, E. Bahar,J. Chem. Soc., Chem. Commun. 1984,1522. 7. A. Padwa, Y.-Y. Chen, Tetrahedron Lett. 1983,24,3447. 8. A. Padwa, J. R. Gasdaska,J. A m . Chem. Soc. 1986,108,1104. 9. A. Padwa, I? Eisenbarth, M. K. Venkatramanan, G. S. K. Wong,J. Org. Chem. 1987,52,2427. 10. (a) G. Pandey, G. Lakshmaiah, A. Ghatak, Tetrahedron Lett. 1993,34, 7301; (b) G. Pandey, T. D. Bagul, G. Lakshmaiah, Tetrahedron Lett. 1994,35,7439; (c) G. Pandey, T. D. Bagul, A. K. Sahoo, J. Org. Chem. 1998,63,760. 11. D. A. Barr, R. Grigg, H. Q. N. Gunaratne, J. Kemp, P. McMeekin, V. Sridharan, Tetrahedron 1988, 44,557. 12. R. Grigg, Tetrahedron: Asymmetry1995,6,2475. 13. M. Nyerges, M. Rudas, G. Tdth, B. HerCnyi, I. Kadas, I. Bitter, L. Tdke, Tetrahedron 1995, 51, 13321. 14. R. Grigg, M. I. Lansdell, M. Thornton-Pett, Tetrahedron 1999,55,2025. 15. H. Nishiyama, T. Naritomi, K. Sakuta, K. Itoh, J. Org. Chem. 1983,48,1557. 16. M. Aratani, K. Sawada, M. Hashimoto, Tetrahedron Lett. 1982,23,3921. 17. S. Castellino, J. J. Sims, Tetrahedron Lett. 1984,25,4059. 18. (a) C. W. Jefford, A. W. Sledeski, J. Boukouvalas, Tetrahedron Lett. 1987,28,949;(b) C. W. Jefford, A. W. Sledeski, J. Boukouvalas, J. Chem. Soc., Chem. Commun. 1988,364; (c) C. W. Jefford, A. W. Sledeski, J. Boukouvalas, Helv. Chim. Actu 1989, 72, 1362; (d) C. W. Jefford. A. W. Sledeski, P. Lelandais, J. Boukouvalas, Tetrahedron Lett. 1992,33,1855. 19. (a) A. Padwa, M. Ishida, Tetrahedron Lett. 1991,32,5673;(b) A. Padwa, D. J. Austin, M. Ishida, C. L. Muller, S. S. Murphree, P. E. Yeske, J. Org. Chem. 1992,57, 1161. 20. K. Takeda, A. Ayabe, H. Kawashima, Y. Harigaya, Tetrahedron Lett. 1992,33,951. 21. D. Craig, V. R. N. Munasinghe, Tetrahedron Lett. 1992,33,663. 22. A. 0.Stewart, R. M. Williams,J. A m . Chem. Soc. 1985,107,4289. 23. P. Allevi, M. Anastasia, P. Ciuffreda, A. Fiecchi, A. Scala,J. Chem. Soc., Chem. Commun.1987,101. 24. Y. Kawanami, T. Katsuki, M. Yamaguchi, Tetrahedron Lett. 1983,24,5131. 25. (a) G. Luedtke, M. Westling, T. Livinghouse, Tetrahedron 1992, 48, 2209; (b) C. H. Lee, M. Westling, T. Livinghouse, A. C. Wiiliams,.I. Am. Chem. Soc. 1992,114,4089. 26. (a) 1. Ryu, M. Ando, A. Ogawa, S. Murai, N. Sonoda, J. Am. Chem. Soc. 1983,105, 7192; (b) I. Ryu, H. Suzuki, A. Ogawa, N. Kambe, N. Sonoda, Teirahedron Lett. 1988,29,6137. 27. K. Suzuki, T. Hasegawa, T. Imai, H. Maeta, S. Ohba, Tetrahedron 1995,51,4483. 28. (a) T. Kitamura, S. Kobayashi, H. Taniguchi, Z. Rappoport, J. Org. Chem. 1982, 47, 5003; (b) S. Shatzmiller, R. Lidor, E. Shalom, E. Bahar, J. Chem. Soc., Chem. Commun. 1984,795; (c) S. Shatzmiller, S. Bercovici, Liebigs. Ann. Chem. 1992, 997; (d) M. E. Kuehne, P. A. Matson, W. G. Bornmann, .I. Org. Chem. 1991,56,513. 29. (a) A. Yanagisawa, H. Nakashima, A. Ishiba, H. Yamamoto, J. Am. Chem. Soc. 1996, 118, 4723. See also: (b) C. Bianchini. L. Glendenning, Chemtracts-lnorg. Chem. 1997,10,339: (c) P. G. Cozzi. E. Tagliavini, A. Umani-Ronchi, Gazz. Chim. Ital. 1997,127,247. 30. A. Yanagisawa, A. Ishiba, H. Nakashima, H. Yamamoto, Synlett 1997,88. 31. A. Yanagisawa, Y. Nakatsuka, H. Nakashima, H. Yamamoto, Synlett 1997,933. 32. Reviews: (a) T. Bach, Angew. Chem. Int. Ed. Engl. 1994, 33, 417; (b) T. K. Hollis, B. Bosnich, J. Am. Chem. Soc. 1995,117, 4570; (c) M. Braun, in Houben-Weyl: Methods of Organic Chemistry, Vol. E 21, (eds.: G. Helmchen, R. W. Hoffmann, J. Mulzer, E. Schaumann), Georg Thieme Verlag, Stuttgart, 1995, p. 1730; (d) S. G. Nelson, Tetrahedron; Asymmetry 1998, 9, 357; (e) H. Groger, E. M. Vogl, M. Shibasaki, Chem. Eur. J. 1998,4,1137. 33. A. Yanagisawa, Y. Matsumoto, H. Nakashima, K. Asakawa, H. Yamamoto, J. A m . Chem. Soc. 1997, II9,9319.

596

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34. (a) M. Pereyre, B. Bellegarde, J. Mendelsohn, J. Valade, J. Organomet. Chem. 1968,l I , 97; (b) I. F. Lutsenko, Y. I. Baukov, I. Y. Belavin, J. Organomet. Chem. 1970, 24, 359; (c) S. S. Labadie, J. K. Stille, Tetrahedron 1984, 40, 2329; (d) K. Kobayashi, M. Kawanisi, T. Hitomi, S. Kozima, Chem. Lett. 1984,497. 35. D. Ferraris, B. Young, T. Dudding, T. Lectka, J. Am. Chem. SOC.1998,120,4548. 36. W. J. Drury, 111, D. Ferraris, C. Cox, B. Young, T. Lectka, J. Am. Chem. SOC.1998,120,11006. 37. S. Yao, X. Fang, K. A. Jorgensen, Chem. Commun.1998,2547. 38. S. Yao, M. Johannsen, R. G. Hazell, K. A. Jorgensen,Angew. Chem. lnt. Ed. Engl. 1998,37,3121. 39. (a) Y. Ito, M. Sawamura, T. Hayashi, J. Am. Chem. Soc. 1986, 108,6405; (b) Y. Ito, M. Sawamura, T. Hayashi, Tetrahedron Lett. 1987, 28, 6215; (c) T. Hayashi, M. Sawamura, Y. Ito, Tetrahedron 1992,48,1999. 40. Reviews: (a) M. Sawamura, Y. Ito, Chem. Rev. 1992, 92, 857; (b) M. Sawamura, Y. Ito, in Catalytic AsymmetricSynthesis, (ed.: I. Ojima), VCH, New York, 1993, p. 367. 41. (a) S. D. Pastor, Tetrahedron 1988,44,2883; (b) S. D. Pastor, A. Togni,J. Am. Chem. Soc. 1989,111, 2333; (c) A. Togni, S. D. Pastor, Helv. Chim. Acta 1989, 72,1038; (d) A. Togni, S. D. Pastor, J. Org. Chem. 1990,55,1649; (e) A. Togni, R. Hausel, Synlett 1990,633; (f) S. D. Pastor, A. Togni, Tetrahedron Lett. 1990,3I, 839; (g) A. Togni, S. D. Pastor, G. Rihs, J. Organomet. Chem. 1990,381, C21; (h) S. D. Pastor, A. Togni, Helv. Chim. Acta 1991, 74,905. 42. Y. Ito, M. Sawamura, T. Hayashi, Tetrahedron Lett. 1988,29,239. 43. A. Togni, S. D. Pastor, G. Rihs, Helv. Chim.Acta 1989, 72,1471. 44. M. D. Bachi, A. Melman,J. Org. Chem. 1997,62,1896. 45. M. Sawamura, Y. Ito, T. Hayashi, Tetrahedron Lett. 1990,31,2723. 46. (a) Y. Ito, M. Sawamura, E. Shirakawa, K. Hayashizaki, T. Hayashi, Tetrahedron Lett. 1988, 29, 235. See also: (b) Y. Ito, M. Sawamura, E. Shirakawa, K. Hayashizaki, T. Hayashi, Tetrahedron 1988,44,5253. 47. Y. Ito, M. Sawamura, M. Kobayashi, T. Hayashi, Tetrahedron Lett. 1988,29,6321. 48. Y. Ito, M. Sawamura, H. Hamashima, T. Emura, T. Hayashi, Tetrahedron Lett. 1989,.?0,4681. 49. M. Sawamura, Y. Nakayama, T. Kato, Y. Ito,J. Org. Chem. 1995,60,1727. 50. (a) A. Togni, S. D. Pastor, Tetrahedron Lett. 1989,30, 1071; (b) M. Sawamura, Y. 110, T. Hayashi, Tetrahedron Lett. 1989,30,2247. 51. T. Hayashi, Y. Uozumi, A. Yamazaki, M. Sawamura, H. Hamashima, Y. Ito, Tetrahedron Lett. 1991,32,2799. 52. M. Sawamura, H. Hamashima, Y. Ito, J. Org. Chem. 1990,55,5935. 53. (a) V. A. Soloshonok, T. Hayashi, Tetrahedron Lett. 1994,35,2713;(b) V. A. Soloshonok, T. Hayashi, Tetrahedron: Asymmetry1994,5,1091;(c) V. A. Soloshonok, A. D. Kacharov, T. Hayashi, Tetrahedron 19%,52,245. 54. (a) K. Karabelas, C. Westerlund, A. Hallberg, J. Org. Chem. 1985, 50, 3896; (b) K. Karabelas, A. Hallberg, J. Org. Chem. 1986,51, 5286; (c) M. M. Abelman, T. Oh, L. E. Overman, J. Org. Chem. 1987,52,4130. 55. Y. Sato, M. Sodeoka, M. Shibasaki, J. Org. Chem. 1989,54,4738. 56. N. E. Carpenter, D. J. Kucera, L. E. Overman, J. Org. Chenz. 1989,54,5846. 57. (a) Y. Sato, M. Sodeoka, M. Shibasaki, Chem. Lett. 1990,1953; (b) Y. Sato, S. Nukui, M. Sodeoka, M. Shibasaki, Tetrahedron 1994,50, 371; (c) Y. Sato, S. Watanabe, M. Shibasaki, Tetrahedron Lett. 1992,33,2589. 58. Y. Sato, T. Honda, M. Shibasaki, Tetrahedron Lett. 1992,33,2593. 59. S. Nukui, M. Sodeoka, M. Shibasaki, Tetrahedron Lett. 1993,34,496.5. 60. (a) A. Ashimori, L. E. Overman, J. Org. Chem. 1992,57,4571;(b) A. Ashimori, B. Bachand, L. E. Overman, D. J. Poon, J. Am. Chem. Soc. 1998,120,6477. See also: (c) A. Ashimori, T. Matsuura, L. E. Overman, D. J. Poon, J. Org. Chem. 1993,58,6949. 61. (a) L. E. Overman, D. J. Poon, Angew. Chem. lnt. Ed. Engl. 1997,36,518;(b) A. Ashimori, B. Bachand, M. A. Calter, S. P. Govek, L. E. Overman, D. J. Poon, J. Am. Chem. Soc. 1998, 120, 6488. See also: (c) T. Matsuura, L. E. Ovcrman, D. J. Poon, J. Am. Chem. Soc. 1998,120,6.500. 62. (a) T. Sakamoto, Y. Kondo, H. Yamanaka, Tetrahedron Lett. 1992, 33, 6845; (b) L. F. Tietze, R. Schimpf, Angew. Chem. lnt. Ed. Engl. 1994,33,1089. 63. M. Sodeoka, K. Ohrai, M. Shibasaki, J. Org. Chem. 1995,60,2648. 64. M. Sodeoka, R. Tokunoh, F. Miyazaki, E. Hagiwara, M. Shibasaki, Synlett 1997,463. 65. E. Hagiwara, A. Fujii, M. Sodeoka,J. Am. Chent. Soc. 1998,120,2474. 66. K. Hori, H. Kodama, T. Ohta, I. Furukawa, Tetrahedron Lett. 1996,37,5947. 67. (a) K. Mikami, M. Terada, E. Sawa, T. Nakai, Tetrahedron Lett. 1991,32,6571; (b) K. Mikami, E. Sawa, M. Terada, Tetrahedron; Asymmetry1991,2,1403.

Lewis Acids in Organic Synthesis Edited bv Hisashi Yamarnoto Copyright 0WILEY-VCH Verlaa GmbH.2000

14 Transition Metal Lewis Acids: From Vanadium to Platinum E. Peter Kiindig and Christophe M. Saudan

14.1 Introduction Lewis acids accelerate a wide range of organic reactions by binding to and thereby activating reactants. This activation often results in rate increases of many orders of magnitude compared with the thermal reaction. The milder reaction conditions and the potential of the Lewis acid to act as template both contribute to an increase in the selectivity of the transformations. Much attention has focused on the development of Lewis acid catalysts and on chiral Lewis acids for asymmetric synthesis. Important conditions for the catalytic, rather than stoichiometric, use of a Lewis acid are: (i) that activating bond-formation is reversible, and (ii) that Lewis acid-reactant binding is stronger than Lewis acid-product binding (to avoid product inhibition of the reaction). For asymmetric synthesis, high efficiency of induction is desired and, for in situ prepared chiral Lewis acids (e.g. by combination of a metal halide and a chiral ligand) it would be advantageous if the mode of action of the Lewis acid is ligand-accelerated, to suppress competitive achiral background reactions. These features are not commonly realized in a single Lewis acid. The classic Lewis acids consist of, or are derived from, main group (e.g. B, Al, Sn) halides or from early transition metal (Ti) halides. Their high oxophilicity makes most of their derivatives very sensitive to traces of water and reactions thus often require relatively high catalyst loadings. We note, however, that a water-tolerant boron Lewis acid has recently been reported [1]. Rapid equilibration between different structures via ligand exchange processes introduces uncertainty about the nature of the catalytically active species, making catalyst optimization difficult and hampering interpretation of observed selectivities and asymmetric induction. Transition metal Lewis acids are promising because the reagent precursor is often structurally well-defined and steric and electronic ligand tuning to a particular reaction is easier. This chapter reviews the use of transition metal Lewis acids of groups 5-10 of the periodic table with particular attention to stereoselective and to catalytic reactions. We exclude from the review the vast area of chemistry of transition metal complexes of 7tbound unsaturated ligands (e.g. arenes bound to electrophilic metal fragments such as Cr(C0)3, CpFe', etc; or alkene complexes or intermediates with Pd(II)L,, etc.). The focus of this review are thus transformations in which a Lewis acid, via in situ procedures, activates a substrate by forming a o-bond to a Lewis basic atom of the reacting substrate. Largely excluded are also electrophilic aromatic substitution reactions, because a literature survey showed that major advances in that area mainly concern Lewis acids of elements other than those treated here. An exception here are optically active (2-fluoroacy1)benzeneswhich were prepared from an optically active 2-fluorocarboxylic acid chloride in high optical yield via Friedel-Crafts reaction using anhydrous FeC& as catalyst (Sch. 1) [2].In this case, A1Cl3 and SnC&were ineffective as catalysts.

598

Kiindig/Saudan

X

n-C,H,, c-C,H,, Ph

solvent neat neat (CICH,),

T ["CI

time

yield

ee

[hl

["/.I

["/.I

0 0 20

18 24 20

58 35 38

84 90 88

Scheme 1

14.2 Ethers, Acetals (Including Thioacetals), Carboxylic Acid Derivatives, and Epoxides The affinity of Lewis acids for oxygen is documented throughout this handbook, and transition metal Lewis acids are no exceptions. This chapter will review these uses that range from simple ether cleavage (and ether formation) to highly enantioselective epoxide opening. FeC13 (anhydrous, as hexaquo-complex or immobilized on Si02) dominates this chapter but Lewis acids of other metals have also found useful applications and are included here.

14.2.1 Cleavage and Formation of Ethers FeC13 cleaves silyl ethers to give the alcohols in high yield [3]. Time for completion of the reaction varies from TMS (1 min) to TBDPS (3 h) (Table 1, entries 1,2). C U ( N O ~reacts )~ likewise but cleavage is slower for TBDMS (12 h), and TBDPS is inert to this reagent. Another mild Lewis acid reagent is PdCl2(MeCN)* (1-5 %, room temperature to reflux in acetone) which catalyzes the cleavage of silyl ethers except TIPS and TBDPS ethers [4,5]. TBDMS ethers can be cleaved selectively in the presence of MOM, benzyl, and acetate protecting groups. Anhydrous FeC13 (2 equiv.) in CH2ClZat room temperature also cleaves benzyl ethers (Bn) (15-30 min) and p phenylbenzyl ethers (PhBn) (3-4 min) efficiently (entry 3) [6]. 1,6-Anhydro sugars were prepared using this procedure [7]. Methyl ethers, acetates, benzoates, and p-phenylbenzoates (PhBz) are not cleaved under these conditions. FeCI3. 6 H 2 0 is not efficient in this reaction but SnC14is [6].

Transition Metal Lewis Acids: From Vanadium to Platinum

599

Table 1. FeCI3-mediated cleavage of ethers. Entry

1

Reaction

5- 6 Me/VV\A/\OTBDPS

I

Catalyst reagent

Conditions remarks

Yield

FeC13 (1 equiv.) MeCN

1 min

FeCI3 (1 equiv.) MeCN

3h

FeC13 (>2 equiv.) CH2C12

r.t, 15 min

85 (UV)

F ~ C (10%) I~ Ac2O

0"C, 15 min

83

FeC13 ( 15-22%) Ac2O

R=Me 24h, 80°C racemization

64

R = TBDMS 0"C, 15 min, 88% retention

92

FeC13(5%) ACZO

O-4O0C, l h 100% retention

80

FeC13 (10.30%) Ac2O (3-5 equiv.) Et2O

r.t.. 15h

Ref.

[%I 100

93 (GC)

M O e -H

3

-

RO

R'O

OMe

OMe

R = Bn R = PhBz

4

I

8-

t-Bud

AcO

290

Adsorption of FeC13.6Hz0 on silica gel produces a reagent (FeC13/SiO$ [8] that cleaves benzyl phenyl ethers to give phenols when the reaction mixture is taken to dryness [9]. Alkyl-, MEM, and silyl ethers can be directly transformed into the corresponding acetates with ferric chloride in neat Acz0 or AczO/EtOAc (entry 4) [10,11]. The reaction proceeds by 0-acylation of the ether and nucleophilic substitution by acetate. Benzyl and alkyl ethers require heating to 80 "C for several hours for completion and reactions of optically active ethers of secondary alcohols lead to racemization under these conditions (entry 5). Silyl and t-butyl ethers, however, react smoothly at 0 "C to give the products with partial or complete retention of configuration (entries 6 [lo] and 7 [12]). For the cleavage of t-butyl ethers of sensitive alkenes and enynes, the use of 3-5 equiv. Ac20 in diethyl ether is the method of choice (entry 8 [13,14]).

600

Kiindig/Saudan

Uses of FeC13/Ac20methodology in synthesis include the taxusin synthesis of Holton et al. (Sch. 2) [15], the Forsyth and Clardy synthesis of (+)-didemnenones A and B [16], and the synthesis of a nodulation factor (NodRf-111) by Fraser-Reid and coworkers [17].

1) FeCI,, Ac,O, -45"C, 4h 2) NaOMe, MeOH, 25"C, 1h 3) T s P , PY

Me Me 0.Ao1

,Me

87% Medo

Y H n

"

;I

Scheme 2

The direct transformation of silyl ethers into esters can also be performed by reaction with an acid chloride in CHZClZ (0 "C to room temperature) in the presence of FeC13 (1.5 equiv.) [18]. The formation of ally1 ethers from allylic alcohols and methanol is catalyzed by RuC13 [ 191. The reaction is likely to occur via a x-ally1 Ru intermediate. Allylic rearrangements and racemization of optically active allylic alcohols take place.

14.2.2 Reactions Involving Acetals 14.2.2.1 Acetal Cleavage, Exchange and Formation Transition metal Lewis acids can be used to effect deacetalization under mild conditions. Thus, 1,3-dioxolanes are hydrolyzed by PdC12(MeCN)2in wet acetonitrile but a better procedure is transacetalization of the dioxolanes by the same complex (1-5 %, room temperature in acetone) [6]. A good example of this method is the clean deprotection of an oxolane of a /3-hydroxyketone that is susceptible to elimination (Table 2, entry 1) [20]. TBDPS ethers and epoxides are tolerated [21]. Another reagent is FeC13 adsorbed on silica gel [8,22,23]. This selectively cleaves acetals in the presence of other acid-sensitive groups such as TBDMS and trityl and benzyl ethers. The selectivity acetal > silyl ether deprotection can be inverted by conducting the reaction in acetone in which the oxolane + diol equilibrium lies on the oxolane side (entry 2) [22]. The conditions FeC13/Si02 are sufficiently mild to enable acetal hydrolysis in the presence of an easily epimerizable center (entry 3) [24]. Another example, involving selective acetal cleavage in the presence of an aryl methyl ether, and MOM and benzyl ethers is shown in Sch. 3 [25]. FeC13.6 H Z 0at room temperature or in CH2C12 under reflux has also been shown to cleave acetals [26]. [Ru(M~CN),(TRIPHOS)](OT~)~ in acetone catalyzes the deprotection of THP derivatives of phenols and of 1,3-dioxolanes of ketones. The THP derivative of benzyl alcohol was not cleaved under these conditions (entry 4) [27].

Transition Metal Lewis Acids: From Vanadium to Platinum

601

Table 2. Metal mediated deprotection of 0,O-acetals by hydrolysis or transacetalization. Entry

Rcaction

1

Catalyst reagent

Conditions remarks

PdCIZ(MeCN)z (cat.) acetone

OTBDMS

FeCl3iSiO~

f::

CHC13

OH

/OTBDMS

(OTBDMS

CQ,,- Oq.., Me

OH

Yield

Ref.

r.t., 2h transaeetalization

94

[20]

rS., 4h

74

[22]

FeCl3iSiO2 acetone

r.t., 12h transacctalization

66

[22]

FeC13iSi02

r.t., 4h

85

[24]

r.t., 16h transacetalization

83

[27]

79-99

[29]

rw

-

Me

OH

2 OTBDMS

3

CHC13

4

[Ru(MeCN)3

(TRIPHOS)](OTf)z (0.05%) acctone

#Me _

5

ROH

+

M

~

'

j

~

V

~

'

M

~

1 R.O,O.Me

+

r.t., 1-2h

FeCl3 3A MS CH2C12

MeOH

r.t., l h a:D = l9:l

'6 '4 OMOM

H H .,

OMOM

Scheme 3

OMOM

OBnFeCI,/SiO,,86% CHCI,, :r.

HH

H

OMOM

H OBn

602

Kiindig/Saudan

Cleavage of acetals can also be effected by reaction with WC16 [28]. 1,3-dioxolanes of aldehydes are cleaved in 5-15 min (0.15-0.25 equiv. WC16, CH2C12,room temperature) whereas slightly different conditions are required for dioxolanes of ketones (1020 min, 0.6-0.8 equiv. WC16, MeCN, room temperature). Transacetalization results when dimethoxymethane in CH2C12is treated with a primary or secondary alcohol with anhydrous FeCl3 dispersed on molecular sieves (3 p\) (entry 5) [29]. FeC13 was also used for the anomerization of P-glycopyranosides into the a anomers (entry 6) [30]. a-Glycosidation using FeC13 was also reported for peracetylated sugars [31], whereas P-thioglycosides were the major products on reaction with thiols [32]. Aldehyde diacetates are deprotected by anhydrous ferrous sulfate in CH2C12,benzene or toluene under reflux [33]. Although the focus in the above cited references is on acetal cleavage, it is clear that the same catalyst systems also promote acetal formation. Table 3. Metal-mediated formation of 0,O- and S,S-acetals. Entry

Reaction

p

n

3

n

HO

OH

OH

fi

OH OH

$F

Catalyst reagent

Conditions remarks

Yield

FeCI3, A q O

r,t., <30 min

64

Fe 3f-montmorillonite Ac~O

r.t., 10 min

98

[R u ( M e W 3 (TRIPHOS)](OTf),

azeotropic distillation 40h

94

[Ru(MeCN), (TRIPHOS)](OTf)2 (0.05%) benzene

azeotropic distillation 72h

99

FeC13/Si02 CH2C12

r.t., 1 min

99

TaCls/Si02 CHzC12

r.t., 5 rnin

91

[(DPPB)Pt(yOH)](BF& (0.2%) DCE

82"C, 5h

(0.05%)

[%I

benzene

OH

5 PhLCHO

83 (GC)

Ref.

Transition Metal Lewis Acids: From Vanadiumto Platinum

603

Acetic anhydride and benzaldehyde react in the presence of anhydrous FeS04 to give phenylmethanediol diacetate (98 %) [33]. Diacetates from aldehydes are also obtained in Ac20 in the presence of FeC13 (Table 3, entry 1) [34], or by treatment of aldehydes with A c 2 0 in the presence of Fe3f-montmorillonite (entry 2) [35]. Anhydrous FeCI3 is a good catalyst for the acetonation of sugars [36] and [Ru(MeCN)3 (TRIPHOS)](OTf)2 gives good yields in the acetalization of hydroxybenzaldehydes, substrates that do not undergo efficient acetalization under acid conditions (entry 3) [37]. Thioacetalization of ketones and aldehydes is promoted by FeC13/SiO2 (entry 4) [38],and WCl6 in CHZC12 catalyzes the formation of 1,3-dithianes and 1,3dithiolanes from either aldehydes (in minutes), ketones (15 min-48 h) or 0,O-acetals [39]. Rapid thioacetalization of aldehydes and tetrahydropyranylation of alcohols is brought about by TaCI5/SiO2 (entry 5) [40]. A cationic diphosphine complex of Pt(I1) catalyzes the acetalization of a,/j’-unsaturated aldehydes with ethylene glycol, avoiding the side reactions that lead to formation of undesired by-products as a result of conjugate addition (entry 6) [41]. Finally, a simple and efficient protocol for the conversion of alcohols, ethers, and ketals to acetates involves FeCI,-catalyzed reaction with acetic acid (neat or in CH2C12) [42].

14.2.2.2 Acetal Transformations The cyanation of acetals with Me3SiCN proceeds under almost neutral conditions in the presence of a catalytic amount of transition metal compounds such as NiC12, PdC12, CoC12, Co(acac)z, or [Rh(COD)C1]2 [43,44]. Catalytic activity decreases in the order [Rh(COD)C1I2 > CoC12 > NiC12. Suitable solvents include ethers, toluene, CH2C12,MeCN, and DMF. The solvent of choice for CoClz is CH2C12 and for the Rh(1) complex MeCN. Representative examples are shown in Table 4. Selective cyanation of a bis acetal is achieved in the CoC12-catalyzed reaction (entry 4) whereas reaction with more TMSCN and the Rh(1) catalyst affords the dicyano compound as sole product (entry 5).

604

Kiindig/Saudan

Table 4. Activation of acetals: synthesis of a-alkoxynitriles [44]. Entry

Reaction

1

Catalyst reagent

Conditions remarks

NiClz (2%), CH2C12

r.t., 3h

81

CoC12 (2%), CH2CIz

r.t., 3h

91

r.t., 3h

88

rs., 3h

0

r.t., l h

90

r.t.. 3h

96

CoC12 (2%), CH2CI2

r.t., 18h

0

[Rh(COD)C1]2 (2%) MeCN

r.t.. 3h

96

CoC12 (5%), CH2C12

r.t.. 15h

87

[Rh(COD)C1]2 (2%), MeCN

r.t.. 3h

88

Ph2iMe

I

TMSCN

[Rh(COD)C1]2 (2%) MeCN

Yield

wi

PhN Ji

NiCl2 (2%), CH2C12

1 I

CoC12 (2%),CH2C12

TMSCN

MeO-OMe

[W(COD)Cl]2 (2%) MeCN

CN

1

TMSCN

OMe

-t

Me0 M e

o

w

O

I 1

M

e

TMSCN

TMSCN

Transition Metal Lewis Acids: From Vanadium to Platinum

605

The Rh(1) complex also catalyzes aldol reactions between acetals and silyl enol ethers or ketene silyl acetals (Table 5 ) [44]. Table 5. Activation of acetals: reactions with silyl enol ethers and ketene silyl acetals [44]. Entry

1

Catalyst reagent

Conditions remarks

[Rh(COD)C1]2 (2%) TMSCN (0.2 equiv.) MeCN

r.t., 3h

97

[Rh(COD)C1]2 (2%) TMSCN (0.2 equiv.) MeCN

r.t,, 3h

98

OTMS [Rh(COD)C1]2 (2%) kMe TMSCN (0.4 equiv.) Ph

r.t,, 3h

89

[Rh(COD)C1]2 (2%) TMSCN (0.5 equiv.) MeCN syn:anti = 50:50

r.t,, 3h

95

[Rh(COD)C1]2 (2%) TMSCN (0.2 equiv.) MeCN

r.t., 3h

100

Reaction

ph4OMe OMe

+ Ph

r”

M e O G o M e OMe

+

Yield

[%I

MeCN syn:anti = 71:29

f l

Ph

Me0

4

OTMS

+

Ph M e:d

MeAOMe

1

OMe 0 Ph+OMe Me

5

606

Kiindig/Saudan

Table 5. (Cantnd.)

6

[Rh(COD)C1]2 (2%)

OMe

+

Ph(CH,),--(OMe

MewoTMS TMSCN (0.5 equiv.) Me OMe

r.t., 15h

93

MeCN

In the presence of MoC15, acetals and thioacetals act as electrophiles towards trimethylstyrylsilanes [4S,46]. WC16 and TiC14 can also be used in this reaction but they are less efficient (Sch. 4) [45].

phbSiMe3

+

Ph<

OEt OEt

ph&SiMe3

+

Me--<

MoCI, (0.5 equiv.) CH,CI, -78 to -2O"C, 4h 61%

*

Ph&ph

MoCI, (1 equiv.) CH,CI, SPh -78 to -2O"C, 4h

OEt

42%

Ph

Scheme 4

14.2.3 Transformation of Carboxylic Acid Derivatives Microwave irradiation of a mixture of an acid anhydride, an amine adsorbed on silica gel, and TaC15/Si02is a solvent-free method for the synthesis of N-alkyl and N-arylimides [47]. Ni(I1) promotes the conversion of an acrylamide to ethyl acrylate via a Diels-Alder adduct with (2-pyridy1)anthracene [48]. Aromatic carboxylic acids [49] and mandelic acid [SO] are efficiently esterified with Fe2(S04)3.xHzO as catalyst. Co(I1) perchlorate in MeOH catalyzes the methanolysis of acetyl imidazole and acetyl pyrazole [Sl]. Hiyama et al. used FeC13 as a catalyst for the acylation of a silylated cyanohydrin. The resulting ester was then cyclized to 4-amino-2(5H)-furanones (Sch. 5 ) [S2].

Transition Metal Lewis Acids: From Vanadiumto Platinum

R

)co

1) TMSCN, Znl, 2) FeCI,, Ac,O

OAc THF,-78"C

R'

CN

R'

R

a

b

yield

yield [Oh]

[Oh]

i-Pr n-C,H,, Ph PhCH, Et

Me Me Me Me Et

65 82 90 63 66

0

R HN ,

a

607

b

62 63 87 96 65

Scheme 5

One means of stereoselective cleavage of biaryl lactones [53] is activation of the carbonyl group with a Lewis acid and subsequent attack with a chiral nucleophile. Conversely, activation can be effected with a chiral Lewis acid followed by attack of an achiral nucleophile. Complexation of a biaryl lactone to the chiral fragment [CpRe*(NO)(PPh3)]' then reduction with K(S-BU)~BH (K-selectride) and ring opening of the intermediate rhenium lactolate gives the metalated aldehyde (dr = 7525) which is converted to the alcohol without essential loss of optical purity (Sch. 6) [54].

\

PPh,

T

e

O

H

2) 1) HCI K(s-Bu),BH

CHO

4

[Rel'oQMe Me er = 7426

Me dr = 7325

Scheme 6

Better results are obtained with ruthenium complexes of the corresponding thionolactones. Reductive ring cleavage with LiA1H4, then methylation and decomplexation, leads to the thioether (76 O h ee). The chiral ruthenium complex recovered in this step can be converted back into the starting complex in two steps (Sch. 7) [55].

608

Kiindig/Saudan

\

recycling Me

Me I-[Ru]

1

Me

76% ee Scheme 7

Achiral ruthenium fragments can also be used with a chiral reductant. The reduction of a [CpRu(DPPE)(thionolactone)]+ complex with BINAL-H and decomplexation as above gave the thioether in 84 % ee [S3].

14.2.4 Epoxides 14.2.4.1 Formation of Enantiomer-Enriched Epoxides via Lewis Acid-Promoted Asymmetric Cyclization Kinetic resolution in the catalytic conversion of racemic chloro propanols to optically active epoxides has been achieved by use of a chiral Co(sa1en) type complex in combination with K2C03.Although enantioselectivity was modest (< 35 % ee), this first use in asymmetric epoxide formation of the chiral ligand system that was later brought to fame through the Jacobsen-Katsuki asymmetric epoxidation is noteworthy [56,.57]. When applied to the prochiral 1,3-dichloro-2-propanol, asymmetric induction of up to ca. 60 % ee was achieved (Sch. 8 ) [SS].

Transition Metal Lewis Acids: From Vanadiumto Platinum

C l T c I OH

+ K,CO,

(R,R)-(salen)Co(II) (1Yo) CH,CI, 25"C, 4d

c

Q 4;

. , & #H

H

cI

conversion

O "<+

CI

609

cf-.--Y/i (s)O

Pol

yield ["h]

53 84

51 65

ee ["h] 59 54

CI CI

(R,R)-(salen)Co(ll)

Scheme 8

14.2.4.2 Catulytic Ring Opening and Ring Transformations of Epoxides

Achiral Catalysts Iron(II1) tetraphenylporphyrin, Fe(TPP)OTf, is an efficient catalyst for the regioselective rearrangement of simple monoalkyl-substituted epoxides into the corresponding aldehydes (Sch. 9) [59]. Fe(TPP)OTf (2%) dioxane. reflux

R

a:b

yield

CH,(CH& Ph CH2=CH(CH,),

96:4 94:6 94:6

100 100 100

["/I Ph-

Ph Fe(TPP)OTf (X = OTf)

Scheme 9

Metal halides/PPh3 (1:3-6) catalyze the formation of a cyclic carbonate from methyloxirane and carbon dioxide at ambient pressure and temperature. MoC15/PPh3 (15) in neat methyloxirane performed best (78 % yield after 7 days) [60]. Although turnover numbers (TON) remained in the two digit range in the metal halide/PPh3promoted reaction, the chromium(1V) complex Cr(TPP)Cl is a significantly more active catalyst with TON approaching lo4 at 60-100 "C (Sch. 10) [61]. Cyclopentene oxide gives the carbonate with cis stereochemistry whereas cyclohexene oxide gives a polycarbonate which, on pyrolysis affords pure trans-carbonate.

610

KUndig/Saudan Cr(TTP)CI (0.013-0.07%) N-Melm or DMAP (cat.) 6O-7O0C, 16-48h

“‘
“ Y o 0-4

+

100%

R = Bn, CH,CI, Me

0

? Ar

Ar

/ \

Ar Cr(TTP)CI (Ar = p-Tol)

Scheme 10

Regio- and trans-stereoselective opening of terminal epoxides can be effected in good yield with several nucleophiles (halides, NO;, H20, ROH, AcOH) by use of catalytic amounts of FeCl3.6H20 adsorbed on silica gel (Sch. 11) [62]. Group 6 metal-imido complexes catalyze the ring-opening of styrene oxide by trimethylsilyl azide and amines with good regioselectivity (best: [W(Nt-Bu)z(NHt-Bu)z)]) [63]. FeCI;6H,O/SiO, r.t. to 100°C 0.25-12h

‘

R

Y X OH a

R

solvent

nucleophile

X

Ph CICH, allylOCH, PhO Ph CICH,

MeOH MeOH EtOH n-PrOH MeCN MeCN

MeOH MeOH EtOH n-PrOH CIBr

OMe OMe OEt On-Pr CI Br

+

R V O H X b

a yield

[%I

b yield

[%I

95 91 94 91 86 90

Scheme 11

Anhydrous RuC& catalyzes the reaction of epoxides with acetone (in acetone under reflux, 1.5-5 h) to give 1,3-dioxolanes [64]. The same catalyst, in the presence of ammonium thiocyanate, converts epoxides into thiiranes. The reaction takes place with inversion of configuration: (R)-(+)-styrene oxide was converted into (S)-(-)-styrene sulfide of 78 % optical purity [65]. This transformation is also mediated by catalytic amounts (2 %) of an Fe(II1) pentafluorophenylporphyrin complex [66]. Chlorohydrins are formed on treatment of epoxides with stoichiometric amounts of FeC13 in ether [67].

Transition Metal Lewis Acids: From Vanadium to Platinum

611

[(q6-Arene)($-cyclopentadienyl)Fe](X) (X = SbF6, AsF6, PF6, BF4) complexes are thermally very stable but the metal-arene bond is photolabile. Upon irradiation a Lewis acid is formed that has found application as a cationic photoinitiator of epoxides. Applications of this process with the cumene complex (marketed by Ciba Specialty Chemicals as Irgacure 261) include the production of printed circuit boards, solder masks, and offset printing plates [68,69]. The polymerization of epoxides with the Fe complex acid is a two-step process (Sch. 12). Irradiation with UV light generates the active Lewis acid species, generally formulated as a (cyclopentadieny1)tris (epoxide)iron(II) complex [70]. The second step, the thermal rupture of the C-0 bond of a coordinated epoxide, leads to the polymerization-initiating carbocation.

-

hv,

-

0 4 R

'

A

f

R-

R

lrgacure 261

-

polymerization

Scheme 12

Chiral Catalysts cis-Limonene oxide reacts with water in the presence of P-ketophosphonate complexes of Mo(V1) to give the trans-diol. Under the same conditions, trans-limonene oxide remains largely intact. With a chiral camphor-derived catalyst, the diastereoselective epoxide opening of (+)-limonene oxide is essentially substrate-controlled with the ratio of cis:trun.s-limonene being 1:99 in the matching case ((+)-camphor derived catalyst) and 15235 in the mismatching case ((-)-camphor derived catalyst) (Sch. 13) [71]. MoO,CI,L* (1Yo) CH,C',, H,o, r'tl

Me

0 cis

OH trans

Me MoO,CI,L*

+

Me

Me-

trans

:

Scheme 13

Heterogenous metal tartrates were screened for their efficacy in the catalysis of the asymmetric ring opening of rneso-2,3-disubstituted epoxides with thiols, aniline, and trimethylsilyl azide [72]. Whereas the enantioselectivity of Zn(1I) tartrates is in the 15-85 % ee range, selectivity with the Mn(II), Fe(II), and Co(I1) tartrates was lower (< 40 % ee). With Nugent's Zr(Ot-Bu)4/C3-symmetric tetradentate ligand catalyst

612

Kiindig/Saudan

system enantioselectivity was in the > 80 % ee range [73] and another major advance in this area was described by Jacobsen and coworkers in 1995-chiral (salen)Cr(III) complexes promote the reaction of trimethylsilyl azide with a range of meso-epoxides to give the corresponding P-azido alcohols with excellent enantiomeric excess (Table 6, entries 1-3) [74,75]. Applications of this methodology include the synthesis of enantiopure (R)-4-( (trimethylsilyl)oxy)-2-cyclopentenone [76], a solid-phase synthesis of cyclic RGD peptide derivatives [77], and a key intermediate in the synthesis of the protein kinase inhibitor balanol (Sch. 14) [78]. Table 6. Enantioselective ring-opening of epoxides catalyzed by chiral salen chromium and cobalt complexes. Entry

Reaction

c>

+

TMSN,

HO

0

0

+

TMSN,

0

TMSO

Conditions remarks

Yield [%I

(R,R)-L*CrCl

1) r.t., 18h

80

88

1741

94 97 95

99 98 96

1751

r.t., 30h

65

62

(741

0-4"C, 40h

98

77

[81]

r.t., 144h

92

92

1811

(R,R)-L*CrCI (2%) neat

N,

3

(R,R)-L*CrCl 0

TMSO

N,

4

HO

0

Ph

ph

Ph

t07' +

PhC0,H

-

HO

OCOPh

[%I

X = CHz 0 NCOCS

Etzo (S,S)-L*Co (2.5%) TBME i.pr2NEt

(S,S)-L*Co (5%) o c o p h TBME i-Pr2NEt ph

ee

2) CSA

N,

-p

Ref.

Catalyst reagent

613

Transition Metal Lewis Acids: From Vanadium to Platinum

(S,S)-L*Cr(N,) -1O"C, 24h (7.5%)

0

l2 steps

0 +TMSN3

31%-

O:;MS

90-95%

d H \ , N P o B n

92% ee

Bn

f-BuGy+ h3 \ / O \

f-BU

\ /

O

t-Bu

/

f-BU

(S,S)-L*Cr( N3)

Scheme 14

Mechanistic studies of the opening of the epoxide point to catalyst activation of both nucleophile and electrophile in a bimetallic array [79]. The Cr complex results in moderate ee only when used with thiol nucleophiles but enhancement is feasible by using a dithiol in a two-step selection process [BO]. Enantioselective epoxide opening with carboxylic acids is more efficient with (salen)Co(III) complexes (often obtained via in situ oxidation of the Co(I1) complex) than with the Cr analogs (Table 6, entries 4 and 5) [Bl]. This methodology was successfully extended to intramolecular desymmetrization of meso epoxy alcohols [82]. The same complexes catalyze the kinetic resolution of terminal epoxides via highly regio- and enantioselective ring opening with the nucleophiles TMSN3 [83], H 2 0 [84,85], and phenols [86]. Examples are shown in Sch. 15. gem-Dialkyl epoxides have also been shown to undergo efficient kinetic resolution with TMSN,I(R,R)L*CrN3 [87]. R

(R,R)-L*Cr(N,) (1-3%) TMSN, (0.5 equiv.) OOC, 18-50h

Scheme 15

R L N 3

(S,S)-L*Co(OAC)(H,O) (0.2-0.8%) H,O (0.5-0.7 equiv.) rA., 8-44h R K O H

p+b R

OTMS

\

(R,R)-L*Co(OC(CF,),) (4-9%) phenol (0.45 equiv.), TBME -20 to 25"C, 4-18h

OH R&OPh

yield

ee

[%J

I%]

Me Et CH,CI CH,OTBDMS CH(OEt), CH,CN

49 42 47 48 48 40

97 97 95 96 89 92

Me CH,CI vinyl

50 38 49

98 86 94

(CH,),CH, CH,CI CH,Oallyl COEt C0,Me

49 49 47 48 49

98 99 97 96 96

614

Kiindig/Saudan

This methodology has been extended successfully to polymer-supported chiral (sa1en)Co complexes [88] and to intramolecular kinetic resolution of epoxy alcohols (with (R,R)-L*Co(OAc)) [82]. The ceiling of SO % yield in kinetic resolution reactions can be extended if the starting material undergoes racemization under the reaction conditions. This has been shown to be possible with epichlorohydrin in reaction with TMSN3, the dynamic kinetic resolution process affording now a 76 YOproduct yield (97 YOee) and 12 YOeach of the dichloro and diazido products [89]. The kinetic resolution of epoxides provides valuable, highly enantioenriched building blocks which find application in the synthesis of interesting bioactive targets (Sch. 16) such as the antibacterial agent U-100592 [89], the cytotoxic compound muconin [90], taurospongin A, a DNA polymerase /3 and HIV reverse transcriptase inhibitor [91], the cytotoxic agent corossolin [92], and P-adrenergic blocking agents such as (S)-moprolol [93].

H O J , ,

L

N F

n x N

Me muconin

O


H H03S-, 0 taurospongin A

(S)-moprolol

corossolin

Scheme 16

Kinetic resolution has been reported for diethyl oxiranephosphonate in the presence of (R,R)-L*Co(OAc) [94], and of dihydronaphthalene oxide and indene oxide upon irradiation in the presence of catalytic amounts of a (salen)Ru(NO) complex (Sch. 17) [9S].

Transition Metal Lewis Acids: From Vanadium to Platinum

615

mno

(salen)Ru (2%) hv, AcOEt

&$;& H IQ ,,

H

/ /

n conversion [%] 54 1 52

ee

[%I 89 98

(salen)Ru

Scheme 17

14.2.5 Aziridines A tridentate Schiff base Cr(II1) complex derived from 1-amino-Zindanol catalyzes the enantioselective ring opening of meso N-2,4-dinitrobenzyl aziridines with TMSN? (Sch. 18) [96]. The chiral (sa1en)metal complexes, used in the enantioselective ring opening of epoxides, were found to be much less effective (for Cr) or inactive (for Co).

SiPh,Me

02NPNo2 A (1 0%)

+

R

acetone, 4A MS

TMSN,

R

R

R

R

(CH,), CH,CH=CHCH2 (CH2)3 CH,OCH, Me Me

Scheme 18

T ["CI

time [hl

yield [%]

[Yo]

ee

-30 -30 -30 -15 -30

48 100 72 90 96

95 75 87 73 80

94 88 87 90 83

R

616

KUndig/Saudan

14.3 Lewis Acid-Promoted Additions to C=O, C=N and C = N Bonds, Including Conjugate Additions The use of organometallics as nucleophilic reagents is one of the most important methods for formation of C-C bonds. Two of the most widely used reactions are additions of organolithium or Grignard reagents to carbonyl groups and conjugate addition of organocopper or -zinc reagents to a,P-unsaturated carbonyls. The scope of reagents has recently been extended to include organoboron compounds. Rh(1)-catalyzed additions of aryl- and alkenyl-boronic acids [97,98] and -trifluoroborates [99] to both aldehydes and enones have been reported. Because the catalytic cycle probably involves the insertion of a n-coordinated double bond (C=C or C=O) into a Rh-C bond, a Lewis-acid mechanism is not invoked and this type of reaction is not further developed in this chapter.

14.3.1 Reduction, Alkylation, Allylation, Cyanation, and Phenylation of Aldehydes and Ketones Extensive studies on the Lewis acid [($-C5H5)Re(NO)(PPh3)]+ have yielded detailed insight into transition metal Lewis acid-Lewis base interactions and the question of CJ or n coordination of carbonyl groups [loo]. The Re Lewis acid binds aldehydes via the n-system whereas ketones coordinate to form M-0 0-complexes. Both react with Et,N'CN- to give Re-bound cyanohydrins. Diastereoselectivity ranges from 53 to 89 % de for additions to aldehydes and 71 to 99 % de for additions to ketones (Sch. 19) [loll. Diastereoselective reductions to primary and secondary alcohols have also been reported [102].

R

R'

Me Et BZ

Ph Et

f-Bu Ph

Scheme 19

yield

I".[/

84 92 78 95 70 75 88

de config. ["h] 53 80 71 89 71 299 85

R R R R

Transition Metal Lewis Acids: From Vanadiumto Platinum

617

The Lewis acid-mediated addition of ally1 silanes and allyl stannanes to carbonyl compounds has been a topic of interest for many years [103,104]. Stereochemical studies of reactions of allylsilanes and allylstannanes with aldehydes have included FeC13-mediated intramolecular reactions (Sch. 20) [105].

R

SYn

anti

R SiMe, SnBu,

syn:anti

70:30 98:2

Scheme 20

Recent focus has been predominantly on chiral Lewis-acid-catalyzed additions and successful approaches include (acy1oxy)borane (CAB) complexes [106], chiral titanium complexes [107], and chiral silver complexes [log]. These reactions are reviewed in other sections of this book. Transition metal Lewis acid complexes of metals treated in this chapter, and that catalyze the Sakurai-Hosomi allylation of aldehydes or the closely related reaction with allyl tin reagents, have been reported. Thus, [M(CO)(PPh3)2C104](M = Ir, Rh) catalyze the addition of allylstannane to benzaldehyde (1-3 % cat., CH2C12,25-45 "C, 1-2 days, 93-97 YO yield) [IOY] and TaC15 has been used to mediate the same type of reaction with extension also to aliphatic aldehydes (0.5 equiv., CH2Cl2, 0 "C, 1 h, 55-70 % yield after acetate formation) [110]. The complex [Rh(COD)((-)-DIOP)](BF4) affords the homoallylalcohol derived from the reaction of allylstannane with benzaldehyde with 17 YO ee [lOY]. Greater symmetic induction is obtained with a cationic Rh complex incorporating a chiral pyrrolidine-derived ligand (up to 50 % ee) [ l l l ] and another significant advance was made with a chiral (bis(oxazoliny1)phenyl)Rh complex (up to 80 % ee) [112]. Examples of these transformations are shown in Sch. 21. 3-Phenylpropanal reacts with allylsilane with 1:2 stoichiometry and cyclopropane ring formation when NbC15 is used as the Lewis acid catalyst (Sch. 22).

618

KundigISaudan

[ML'] :

(5%)

45°C 31h R = H, 90% yield, 17% ee

&-)~~'\ Ro,

N , CI,Rb

b

r.t., 7h, 414 MS

1'BF, OR

0°C to r.t., 12h

R

H

Me TBS Me TBS TBS

H CI CI OMe

R

H

i-Pr t-BU Ph Bn Bn Bn

H H H Br OMe

(10%)

R

R

yield

[%I

80 50 88 40 50

yield

ee [%]

88 43 42 88 94 99

51 46 6 61 43 80

[%I

ee

[%I

6 40 5 40 50

Scheme 21

H +

+ 2mSiMe3

NbCI, CH,CI,

r.t., 0.5h 48%

Scheme 22

The carbonyl ligand in the complex [HC(py)3W(NO)2(CO)](SbF& is labile and its dissociation gives rise to a dicationic 16-electron complex that reversibly forms 1;1'complexes with carbonyl compounds 11131. The W-complex catalyzes the addition of trimethylsilyl cyanide to aldehydes and ketones in nitromethane to give the O-silylated cyanohydrins in good yield. Cyclic ketones containing stereogenic centers react with fair to good diastereoselectivity and the catalyst precursor is readily recovered by passing CO through an acetonitrile solution of the material precipitated by addition of CH2C12to the reaction mixture (Table 7) [114].

Transition Metal Lewis Acids: From Vanadiumto Platinum

619

Table 7. [HC(py)3W(N0)2]Z+-catalyzedaddition of TMSCN to aldehydes and ketones.

Entry

RCOR'

Product

Conditions

Yield ["h]

de

[%I

PhCHO

PhCH(CN)(OTMS)

1h, r.t.

85

PhCH(Me)CHO

PhCH(Me)CH(CN)(OTMS)

1h, 0°C

82

PhCOMe

PhC(Me)(CN)(OTMS)

]Oh, r.t.

88

1h, 0°C

91

42

Ih, 0°C

91

76

lh, 0°C

86

94

23h, r.t.

68

43

Qo

Me

19

Me

Po

Me

,

B

e

0

Me Me&oTMs CN Me

0

14.3.2. Conjugate Additions FeC13 catalyzes the addition of secondary amines to methyl vinyl ketone and to methyl acrylate (Sch. 23) [115].

OR R,NH

FeCI, (1 0%) CH,CI, 25"C, 42h

+

0

79-96%

0

R,NH : Et,NH, Bu,NH, pyrrolidine, piperidine, rnorpholine R = Me, Et

Scheme 23

Ni(II)(OAc)2bpy and Co(II)(OAc)2bpy catalyze the Michael addition of nitromethane, malononitrile, and aniline to aJ-unsaturated ketones, methyl acrylate, and acrylonitrile in DMF under neutral conditions [116]. FeC13 . 6 H 2 0 is a highly efficient catalyst of Michael reaction of 1,3-dicarbonyl compounds with a$-unsaturated ketones under mild and neutral conditions (Sch. 24) [117]. There is literature precedent for this reaction with dual catalysis: Ni(I1) immobilized on a clay support and FeC13 to activate the enone [118].The mechanism proposed for the single-center catalysis involves coordination of the enone to a diketonato complex [119]. The chemo-

620

Kiindig/Saudan

selectivity is superior to that of the classic base-catalyzed Michael reaction. Attempts to develop an asymmetric version by use of different chiral bi- and tridentate ligands and metals have not yet yielded useful enantioselectivity (< 23 % ee) [120,121]. FeC13.6H,0 (1%) neat, r.t.

0

P

O

E

t + d

M

e

97% (n = 1) * 94% (n = 2)

FeCI3.6H,O (5%) CH,CI,, 12h, r.t.

0 0

FeC13.6H,0 (5%) R

neat, r.t. R

R

Me Ph Me

C0,Et C0,Et COMe

-

R

w R'

M

e

yield

1%1 90 87 77

Scheme 24

The CpRe-Lewis acid shown in Sch. 25 forms stable complexes with cyclohexenone and cyclopentenone. The enones coordinate to the metal forming an Re-0 a-bond. Addition of organocuprates followed by treatment with HI yield enantiomerically enriched 3-alkylated cycloalkanones and an optically active Re-I complex. MeMgBrether and MeLi-ether gave low yields in these reactions. The data shown in Sch. 25 reflect the problem that the yields and enantioselectivity of the organocuprate additions vary widely with the reaction conditions used and the preparation of the organocuprate [122], and must be optimized for every reaction.

621

Transition Metal Lewis Acids: From Vanadium to Platinum

G 3

1) R,CuLi

ON''

. Ae+

A

"PPh,

ON"

n

R

. Re

"PPh,

I

n

R,CuLi/solvent

solvent

T ["C]

2 2 2 2 1 1

Me,CuLi/THF n-Bu,CuLi/ether t-Bu,CuLi/THF Ph,CuLi/ether Me,CuLi/ether Ph,CuLi/THF

CH,CI, THF THF THF THF CH,CI,

-80 -29 -98 -80 -29 -98

yield

ee ["A]

config.

41 64 53 83 73 50

83 74 77 64 79 93

R

["/.I

R S R R S

Scheme 25

a$-Unsaturated aldehydes and ketones undergo Lewis acid (e.g. BF3.OEtz)mediated conjugate addition of HPPhz. Interestingly, in the presence of NbClS, the 1,Caddition is followed by a 1,2-addition with concomitant intramolecular oxidation/ reduction. Oxidative work-up yields 1,3-bis(diphenylphosphinoyl)alkanes.Cyclohexenone selectively yields the trans product (Sch. 26) [123,124].

- [Rupph,]

HPPh,, BF,.OEt, NbCI, (0.5 equiv.) CH,CI, -78°C to r.t.

-

'PPh,R

R

6

O'PPh

H,O,

, hR PPu

1) HPPh,, BF,.OEt, NbCI, (0.5 equiv.) 2) I;i2, -78°C to

78%

R

RuPPh, 0

R

R

H H H Me

H Ph Me H

yield

[%I

PPh, 0

"

71 75 78 79

Scheme 26

Asymmetric conjugate addition of thiols to 3-crotonyl-2-oxazolidinone is effectively catalyzed by the aqua nickel(I1) complex of (R,R)-DBFOXIPh to produce conjugate adducts in high chemical yields and with high enantioselectivity [125] (Sch. 27).

622

KUndig/Saudan

A RSH

+

O y N p M e

0

(R,R)-DBFOWPh (10’6) Ni(CI0,),.6H20 (10%) proton sponge (10%) CH,CIflHF (lO/l), 0°C

0

time [hl phenyl 24 etolyl 96 1-naphthyl 96 2-naphthyl 96 R

04

LJN Ph

0

0

Ph

yield

[“/.I 84 99 92 88

SR

ee

[“/.I 94 95 55 91

(R,R)-DBFOWPh Scheme 27

Ru(I1) catalyzed Michael reactions of nitriles involve a-C-H activation; these reactions are detailed in Section 14.3.6 (Lewis Acid Activation of Nitriles).

14.3.3 Mukaiyama Aldol Reactions Transition metal acetates with 2,T-bipyridine are reported to catalyze cross-aldol condensations of aldehydes with ketones, with Co(II), Ni(II), Cu(II), and Zn(I1) being the most efficient catalysts [126]. More recently, anhydrous RuC13 has been shown to be effective in this transformation [127]. Much attention has focussed on the Mukaiyama aldol reaction as a powerful means of preparing P-hydroxy carbonyl compounds with wide application in organic synthesis [128]. Transition metal compounds can catalyze this reaction either via Lewis acid-activation of the carbonyl electrophile or via the formation of metal enolates (the latter are not covered by this chapter) [129]. Attribution to one or the other class of reaction is not always clear, however -one example being catalysis by the neutral cyclopentadienyl iron complexes [CpFe(CO),X] (X = C1, Br, I) [130]. The question of catalysis by transition metal compounds of the Mukaiyama aldol reaction and of the Sakurai-Hosomi reaction is further complicated by the in situ generation of efficiently competing, achiral Lewis acid catalysts in the course of the reaction. These lead notably to erosion of enantioselectivity in asymmetric catalysis. A good example here is TMSOTf, formed from the silylated precursor and a metal triflate and which is an efficient catalyst for these reactions [131]. This problem is now well documented [132]. Lewis acids can, moreover, also act as acceptors in electron-transfer-mediated processes. Evidence in the Mukaiyama Michael reaction of ketene silyl acetals stems from the preferential coupling of highly substituted centers, indicative of a radical pathway [133]. Metal compounds of the V to Ni triads that are reported to act as Lewis acids are the cationic complexes [CpFe(DPPE)( acetone)] (PF6) [1341, [Ru(salen)(NO)(H20)](SbF6) [1351, [W(HC(py)3)(NO)2(CO)](SbF6)2[136], and an oxovanadium (IV) complex [136]. Examples of these reactions are listed in Sch. 28.

623

Transition Metal Lewis Acids: From Vanadium to Platinum

TMSo+(R' R R'

R PhO Me0 Ph Me0 Ph Me0 EtO EtO

R H Me H Me H Me H Me

+

R

go

H

R catalyst

R'

Ph Ph Ph Ph Ph Ph 4-N0,-C6H4 Ph

[Fe] (2%) [Fe] (2%) [Ru] (0.05%) [Ru] (1%) [WI (5%) [WI (5%) [V] (10%)

[Vl(lO%)

R solvent CH,CI, CH,CI, CD,NO, CD,NO, MeNO, MeNO, CH,CI, CH,CI,

T ["CI -78 to -20 -78 to -20 r.t. r.t. r.t. r.t. -20 r.t.

time

yield

[%I 24h 18h <6 min <3 min 3h 2h 6-12h 48h

55 90 90 (NMR) 90 (NMR) 75 88 91 62

H

2 SbF, [WI

[Fel

L = N-Melm [VI

Scheme 28

A recent notable finding in this field is Mukaiyama aldol reactions in aqueous medium (THF:H20 = 9:l) catalyzed by metal salts. Lewis acids based on Fe(II), Cu(II), and Zn(II), and those of some main group metals and lanthanides are stable in water. Remarkably, the aldol reaction shown in Sch. 29 occurs more rapidly than the hydrolysis of the silyl enol ether [137]. In the presence of surfactants (dodecyl sulfates or dodecane sulfonate salts), reactions of thioketene silyl acetals with benzaldehyde can be performed in water [138].

PhCHO +

ue&

OTMS Ph

MX, (20%) THF/H,O (9/1) r.t., 12h

* P h v P h Me

Scheme 29

14.3.4 Carbene Additions to Aldehydes and Imines Diazo compounds react with aldehydes and ketones to give homologated carbonyl compounds and epoxides. Lewis acids accelerate these processes, and in some cases direct the reactions to single products. trans-Epoxides result from aldehydes and ethyldiazoacetates in the presence of MeRe03 (although this can occur via a metal carbene pathway rather than a Lewis acid mechanism) [139], whereas

624

Kundig/Saudan

[CpFe(CO)2(THF)](BF4) gives cis-epoxides as minor product and ketones as major product with phenyldiazomethane (Sch. 30) [140]. Evidence presented suggests that a Fe-Lewis acid-catalyzed process is operative rather than a metal carbene mechanism. The use of ethyldiazoacetate in this reaction gives, besides the expected P-ketoester (minor product), the 3-hydroxy-2-phenylacrylic acid ethyl ester [141].

a

BF,

I +

PhCHO +

N,CHPh (slow addition)

(CO),Fe(THF) (10%) CH,CI,, r.t., 12h k Ph

P

h

56%

+

/%

Ph

Ph

30%

Scheme 30

The same iron complex also catalyzes the reaction of imines and diazo compounds to give cis-aziridines (Sch. 31) [142].

a

BF,

I +

(CO),Fe(THF) (10%) I

WR Ph

AH

,

* A

CH,CI,, +

r.t., 12h

NzCHR (slow addition) R

Ph

R

R

yield

1%1 Ph C0,Et Ph Ph ~ - B u Ph

40 95 72

Scheme 31

14.3.5 Other Addition Reactions to Imines Doubly activated imines undergo intramolecular electrophilic cyclization reactions in the presence of Lewis acids and this provides an efficient route to annulated pyrrolidine, piperidine and azepine lactones (Sch. 32) [143]. TMSOTf and GaC13 give different product ratios and yields.

Transition Metal Lewis Acids: From Vanadium to Platinum FeCI,/AI,O, -78°C CH,CI, to r.LD

E

&te E

O

+ e :&

E

O

+

&

625

Me

Me H Me

Me

E = CO,R

H Me b

a

n

R

yield

C

a:b:c

[%I 1 2 3

i-Pr Et i-Pr

36 81 68

3:-:I 1.8:-:1 5.6:l:-

Scheme 32

1,2-additions of nucleophiles to isoquinolines coorL.nated to a chira. i.,enium Lewis acid are reported to be highly diastereoselective. Subsequent reaction of the enamine complex with reactive electrophiles then reduction affords 1A-dialkyl tetrahydroisoquinolines. The Re Lewis acid can be recycled (Sch. 33) [144].

0

0

TfO-

. Fie+

ON"'

A

"'pph,

TfO-

I

RM THF,

. Re

RM TMSCH,Li EtMgBr allylMgBr

T ["CI -55

-100 -100

de

[%I

88 78

46

R = D,Me,TMSCH,

1

1) NaBH, 2) Et,N+CN-

Scheme 33

The complexes (S,S)-(Phebox)Pt(OTf) and [(S,S)-(Phebox)Pt(H20)](BF4) react with N-phenylbenzaldimine to afford the corresponding chiral aldimine complexes. Addition of organolithium reagents gives, after work-up, the corresponding enantiomerically enriched amines (Sch. 34) [145].

626

Kiindig/Saudan

PhyH + RLi

[Pt] (1 equiv.) CH,CI,, -78°C

PhVR D

N-Ph

N.

R

(S,S)-(PHEBOX)Pt(L)

(S,S)-(PHEBOX)Pt(OTf) [(S,S)-(PHEBOX)Pt(H,O)]( BF,) (S,S)-(PHEBOX)Pt(OTf) [(S,S)-(PHEBOX)Pt(H,O)](BF,)

Ph yield [“A]

ee [%I

66 71 72 88

78 78 82 81

Me Me n-Bu ~-Bu

Scheme 34

14.3.6 Lewis Acid Activation of Nitriles After the success of the Au(I)-catalyzed aldol reaction of methylisocyanoacetate with aldehydes utilizing chiral ferrocenylamine ligands [146], Pd(I1) and Pt(I1) Lewis acids were investigated and the question of catalysis by chiral complexes received attention. Initial reports do show catalytic activity with both metals with a somewhat lower trans/&-selectivity than the gold catalysts but with negligible asymmetric induction when chiral phosphines were used [147]. Tridentate chiral PCP ligands in combination with Pd(1I) give better asymmetric induction [148,149] but the Au catalysts still outperform Pd and Pt catalysts in both diastereoselectivity and enantioselectivity. A selection of the results obtained are shown in Sch. 35. Low-valent Ru(II) [150] and Rh(I) complexes catalyze aldol and Michael reactions of 2-nitrilo esters. The sequence is thought to be initiated by nitrile complexation to the transition metal. This Lewis acid-activation is followed by an oxidative addition to give a metal hydride and a nitrile complexed enolate as shown in Sch. 36. Examples including diastereoselective Ru(I1) catalyzed reactions [151] and enantioselective Rh(1)-catalyzed reactions [152-1541 with the large trans-chelating chiral ligand PhTRAP are shown in Tables 8 and 9.

Transition Metal Lewis Acids: From Vanadium to Platinum

0

RKHCNJ +

entry

OMe

R

catalyst conditions

R0d.N Y O z M e+

frans:cis

RHcozMe O.&N yield Pol

[Pd(MeCW,I(BF,), Et(i-Pr),N (10%) CHCI,, reflux, 6h

(1%)

[Pd((R)-BINAP)(MeCN),I(BF,), Et(i-Pr),N (10%) CHCI,, reflux, 6h

(1%)

[Pd((S,S)-PYBOX)(Bz)(MeCN)](BF,), (1%) Et(i-Pr),N (1OY0) CHCI,, reflux, 12h

Ph,P-Pt-PPh,

I

627

ee (trans) [%I

ref.

Ph

61:39

90

Ph

60:40

100

2

[I471

Ph

59:41

91

6

[I471

Ph o-MePh p-MeOPh Et

70:30 85:15 72:28 75:25

96 96 89 92

65 61 64 18

~481

Ph o-MePh p-CIPh Et

78:22 79:21 7525 91: 9

85 90 87 91

24 3 30 30

[I491

11471

OTf

(1.5%) Et(i-Pr),N (12%), CH,CI,

r.t.

OTf

(1%) Et(i-Pr),N (lo%), THF, r.t.

Scheme 35

0

Scheme 36

628

Kundig/Saudan

Table 8. Ru(I1)- and Rh(1)-catalyzed aldol reaction of nitriles. Entry

Cata1y st reagent

Reaction

2

3

0 HCHO

+

I 0 H O g O R Me CN

Me

Rh(acac)(CO),

(1%) (S,S)-(R,R)PhTRAP (1.1%) B u ~ OH2O ,

Conditions remarks

Yield ["h]

ee

Ref.

pi]

r.t,, 24h

69

-

[I511

R=Me -3O"C, lOOh

67

35

[I521

R = CH(~-BU)~

86

93

[I521

-1O"C, 24h

Transition Metal Lewis Acids: From Vanadiumto Platinum

629

Table 9. Ru(I1) and Rh(1) catalyzed Michael reactions of nitriles. Entry

Reaction

2 EtO,CnCN

+

Catalyst reagent

Conditions remarks

C0,Et MeACOzEt

Yield

ee

[%I

[%I

r.t., 24h

85

-

[151]

r.t., 24h

90 d.r. = 69:31

-

[151]

r.t., 24h

68

-

[151]

3"C, 10h

97

86

[153]

0"C, 6h

93

72

[154]

3"C,22h

98

93

[153]

I CN

Ref.

C0,Et

Et02C+C02Et Me

I M

5

eMe

0

Me

(1.1%)

benzene Rh(acac)(CO), (1%) (R)-L* (1.1 %) benzene

CN w OiPi

0

+ Me

RhH(CO)(PPh3)3 (1%) (S,S)-(R,R)-PhTRAP

NC+N.OMe Me

Me

Rh(acac)(CO), (1%) (S,S)-(R,R)-PhTRAP (1.05%) benzene

M e W Me N CNMe * O M e

(S,S)-(R,R)-PhTRAP :

@

(R)-L*:

P

h

2

P

Ph,P PPh, Me

\

gOMe Me

630

Kiindig/Suudun

Under neutral conditions Ru(I1) complexes catalyze the nucleophilic addition of water to nitriles to yield amides [155]. The reaction proceeds via external nucleophilic attack of water to the transition metal-activated nitrile. Under similar conditions dketonitriles are converted into ene-lactams, a reaction that has found elegant application in a short diastereoselective synthesis of (-)-pumiliotoxin C (Sch. 37) [156].

(-)-purniliotoxin C

Scheme 37

Similarly, reaction of nitriles with amines or with alcohols yields amides (Sch. 38) [157] or esters, respectively (Sch. 39) [158].

R' RCN + HN + H,O R"

RuH,(PPh,), (3%) DME, 160"C, 24h

0 RAN,R

+

I

R' R

R

R'

yield

["/.I Me Me Me MeOCH,

n-Bu

H

(CH2)5

Bn n-Bu

Me H

93 97 95 93

Scheme 38

RCN

+

ROH

+

H,O

RuH,(PPh,), (3%) DME 140to18OoC,24h

RCN

ROH

RCO,R

yield

[%I MeCN C,,H,,CN PhCH,CN

Ph(CH,),OH MeOH i-PrCH,OH

OTHP

Scheme 39

73 86 57

+

NH,

NH,

Transition Metal Lewis Acids: From Vanadiumto Platinum

631

Under neutral conditions iridium hydride complexes catalyze addition between nitriles to give cyanoenamines (Sch. 40) [159]. This reaction implies simultaneous activation of both the a-C-H bond of the nitrile as a pronucleophile and the CN triple bond of the nitrile as an electrophile.

+

NC-CO,Et

Ncao IrH(CO)(PPh,), (3%) THF, 120°C, 12h

-

Me

59%

rcN lrH5(Pi-Pr3)2 (3%)

toluene, 140°C, 12h*

CN

W

C

91%

NHZ

IrH5(Pi-PrJz(3%)

toluene, 140"C, 12h Ph-CN

87%

N

*

phTrph Ph

NH,

Scheme 40

14.4. Cycloaddition Reactions 14.4.1 Diels-Alder Reactions 14.4.1.1. Two Point Binding

The Diels-Alder reaction is a key reaction in organic synthesis. Its high versatility in the synthesis of six-membered ring compounds and its potential for the control of up to four stereogenic centers have attracted much attention. Lewis acid catalysis has further enhanced the scope of this reaction. Lewis acids activate the dienophile by coordination to a Lewis basic substituent (usually a carbonyl group) and direct the stereochemistry. Boron Lewis acids are often the catalysts of choice for the DielsAlder reaction. Early (Ti(1V)) and late (Cu(I1)) transition metal complexes in combination with chiral ligands have also been used with much success and the reader is referred to the relevant chapters in this book. Unlike main group Lewis acids, catalysts for the Diels-Alder reaction containing metals reviewed in this chapter are of recent origin. Major expectations in this area are linked to desirable properties such as catalyst stability, selectivity and effectiveness, tolerance of impurities (e.g. water), and asymmetric modification. Over the past few years an increasing number of literature reports show this to be an area of high potential. Much has been published on Lewis acid-catalyzed Diels-Alder reactions between the bidentate dienophile 3-acryloyl-1,3-oxazolidin-2-one and the prototypical diene component cyclopentadiene; these afford the endo cycloaddition product with good selectivity. This reaction has become the prototype for two-point binding, Lewis acid catalyzed, asymmetric Diels-Alder reactions. For easier comparison, the data in Sch. 41 include,

632

Kiindig/Suudan

beside the Cr(I1) [160], Mn(I1) [160], Fe(1I) [160], Fe(II1) [160-1631, Co(I1) [160], Ni(I1) [160] and Pd(I1) [164] catalysts, also Lewis acids based on elements other than the subject of this chapter: Zn(I1) [165],Mg(I1) [160,166],and Cu(I1) [165,167-1691. 0

catalyst (5-10%) ligand/M (1/1) CH,CI,, -78 to -40°C

0

O

uN entry

catalyst

ee

ref.

["/I 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19

( R)-aCr(ClO,),.GH,O (R)-a.Mn(ClO,),.GH,O (R)-a~Fe(CIO,),.GH,O (S)-b.FeCI,I (S)-b.Fel, + I, (S)-e.Fel, + l2 d.Fel,+ ,1 (R)-aCo(CIO,),.GH,O (R)-a~Ni(ClO,),~GH,O [Pd((S)-BlNAP)(PhCN),I(BF,), (S)-b.Cu(OTf), (R,R)-f.Cu(OTf), (S)-g.CU(OTf), (S)-b.Znl, (R)-a~Zn(CIO,),.3H2O (S)-e.MgI, + 1, (R)-b'Mg(C104)2 (R)-b.Mg(CIO,), + 2H,O (R)-a.Mg(C104)2

20 (S) 83 (S) 97 (S) 80 (R) 82 (R) 85 (R) 56 (S) 99 (S) 99 (S) 99 (R) 98 (S) 92 (R) 97 (S) 92 (R) 97 (S) 90 (R) 70 (S) 65 (R) 91 (S)

Me, .Me

Ph

Ph a

Me

b (R = Ph) c (R = t-BU)

d

f

9

Me

'Ao Me N 2 M e

Me M e 5 N Ph

Ph e

Scheme 41

Transition Metal Lewis Acids: From Vanadium to Platinum

633

Accumulated data on the reaction with the two-point binding dienophile shows that the coordination geometry of the dienophile-catalyst complex and the chirality of the bis(oxazo1ine) or bis(imine) ligand (L*) determine product chirality. It is readily apparent that a different face of the dienophile is shielded in a tetrahedral M(dienophile)(L*) complex than in a square planar complex containing the same bidentate chiral ligand. Examples of tetrahedral geometries are the catalysts containing Zn(I1) and Mg(II), and also Fe(II1) (if, as proposed by the authors, the dienophile occupies one axial and one equatorial site with the ligand bound to two equatorial sites in the octahedral Fe(II1) coordination-geometry). Cu(II), having a distorted square planar geometry consistently results in asymmetric induction opposite to that resulting from the other catalysts. The switch in induction (compare entry 16 with entry 17) in the Mg(I1) catalyst has been interpreted in terms of change from tetrahedral to octahedral because of the coordination of H20 to axial coordination sites. A comparative study showed the Cu(II)/c catalyst to be superior to the Zn(II)/b catalyst. The former gave a consistently high product ee over a wide range of temperatures whereas with the Zn(II)/b catalyst asymmetric induction dropped rapidly with increasing temperature [165]. The tridentate trans-chelating ligand a leads to very successful catalysts with several metal perchlorates, with the Ni complex being the system of choice because catalyst loading can be reduced to 2 YO.Other features of this catalyst are remarkable tolerance to water and high chiral amplification [160]. Reactions with substituted alkenes are slower. In water Co(II), Ni(II), Zn(II), and, particularly, Cu(I1) nitrates accelerate the reaction shown in Sch. 42 by a factor of up to 79 000 [170]. When the reaction is performed with the copper catalyst and in the presence of the a-amino acid ligands L-tyrosine or L-abrine product ee of 74 YOare obtained. Other ligands result in lower asymmetric induction (0-67 YOee) [171].

X = NO,, CI, H, Me, OMe, CH,SO,Na M : Cu > Ni > Co. Zn

86:14 < endo:exo < 93:7 CO,H

L-tyrosine

Scheme 42

L-abrine

634

Kiindig/Saudan

14.4.1.2 One-Point Binding Simple enals and enones are activated by Lewis acid catalysts via monodentate coordination [172]. In addition to a large rate acceleration the Lewis acid also markedly increases the endo:exo selectivity of the cycloadditions. Lewis acids of the metals discussed in this chapter are relative newcomers in this field [173]. In 1987 Hersh and coworkers reported the cycloaddition reaction shown in Sch. 43 [174]. The catalyst precursor is the complex [(cis-PMe3)(CO),(N0)W-FSbF5]. Dissociation of the loosely bound S b K generates the cationic catalyst. Diene polymerization and aldehyde cyclotrimerization are competitive side-reactions in ether but in CH2C12 good yields of cycloadducts are obtained with as little as 0.1 % of the W complex. With butadiene these reactions have been extended to acrolein, methyl vinyl ketone, and methyl acrylate, though the latter requires very long reaction times to go to completion.

Me,P,..

NO I .,CO

ocr WI kco FSbF,

endo:exo = 84:16

Scheme 43

This study was subsequently enlarged to include the complexes shown in Sch. 44 [175]. The order of apparent catalytic activity is as shown but this did not match that of Lewis acidity, as measured by the downfield shift of H(3) of crotonaldehyde upon coordination or that of rate determinations of stoichiometric reactions. The authors of this very thorough and carefully carried out research concluded that for the iron complex (and possibly the Mo complex also) catalysis results from the presence, as impurities, of much more reactive materials.

Scheme 44

Replacement of a carbonyl ligand in [CPF~(CO)~(THF)]'by PPh3 inhibits catalytic activity completely but some activity is maintained when P(OMe)3 is used (Sch. 45) [176].

Transition Metal Lewis Acids: From Vanadium to Platinum

635

BF,

i€?+ OC"? \ L

THF (10%)

L = P(OMe),

CHZCIz,4"C,4hm 100%

H

4H4

CHO

+

CHO H endo:exo = 86: 14

no catalytic activity with L = PPh, Scheme 45

A chiral analog of [CPF~(CO)~]' is the test of Hersh's conclusion and this was probed for the Fe complex using a chiral bidentate phosphorus ligand. Stereoselectivity in onepoint binding catalysts is more difficult to control than in the two point binding substrates because the Lewis acid-dienophile complex is less rigid. To account for this and also to mimic the bonding characteristics of the carbonyl ligands in the [CpFe(CO)2]' fragment, the CO ligands were substituted for electron-poor chiral phosphorus ligands. With reactive diene-dienophile combinations and in the presence of a hindered pyridine to capture acid impurities, the asymmetric induction achieved is high (Sch. 46) [177] attesting to the role of the metal center as the catalytic site. endolexo Ratios of the products in reactions of methacrolein and a-bromoacrolein with cyclopentadiene are ca 4:96 whereas the opposite selectivity (90:lO) is obtained from reactions with cyclohexadiene [178].

(5%)

(2.5%)

diene [equiv.]

yield [%I

ee [%I

yield [%]

ee ["h]

1 5

46

84

44 76

87 81

1

62

90

69

83

97 97

5

wMe

+ JcHo

Me

Scheme 46

p-2o"C, M 20h e D

Me

'

C

Br H O

1

87

95

83

95

5

a8

>99

86

>99

1 5

92

97

73 90

97 >98

636

Kiindig/Saudan

Y = SbF, (19h, 92%, 92% ee)

100

80

GC yield

(43h, 88%, 93% ee)

60

I%] 4o (45 h, 60%. 92% ee)

20

-

(70h, 1 I%, 87% ee) I

0

0

2

4

6 time [h]

Scheme 47

8

Transition Metal Lewis Acids: From Vanadium to Platinum

637

Whereas at temperatures above -20 OC the chiral Fe catalyst slowly decomposes in CH2C12,the more recently reported Ru analogs are stable at room temperature and can be recycled nearly quantitatively after the reaction [179]. The immediate catalyst precursor, CpRu(B1PHOP-F)I is available via an efficient one-pot synthesis from R U ~ ( C O ) ~ ’ and the catalyst is then generated by reaction with a silver(1) salt. The enantioselectivity of the Diels-Alder reactions are high (90-93 YO ee) but slightly lower than with the Fe catalyst. This presumably reflects the size of the chiral pocket. An attractive feature of this family of Lewis acids is that the immediate catalyst precursors are amenable to structural characterization. Interpretation of observed enantioselectivity is thereby placed on firmer ground than those advanced for in situ-prepared catalysts. The cycloaddition product is thought to result from ans-trans conformation of the dienophile in the chiral pocket and a diene approach from the Cp side of the catalyst. The nature of the counter ion has a large effect on the rate of the reaction with the Ru+ catalyst, as shown in Sch. 47. On the basis of the X-ray structure of a catalyst-substrate adduct and on the observation of binding interactions of both the catalyst and the bound substrate with the S b E anion, the authors tentatively attribute the rate changes to the effect of the anion on aldehyde exchange. This is an alternative explanation to that of competition of the substrate and the anion for the same coordination site [180]. Several catalysts with similar characteristics have been reported. They are cationic and dicationic half-sandwich Lewis acid complexes of the elements Rh, Ir, and Ru and incorporate non-C2-symmetric bidentate phosphorus and nitrogen ligands. The best results obtained with these Lewis acids in the reaction of methacrolein with cyclopentadiene are shown in Sch. 48. Ligand variation afforded less active and/or less selective catalysts. Although enantioselectivity has not yet reached the same level as that reported for the CpFe and CpRu catalysts in Sch. 46 and 47, the performance of the [(arene) Ru(L-L’)]’’ [181], [Cp*Rh(L-L’)I2+ [182], and [Cp*Ir(L-L’)]’+ [183] catalysts shows that non-C2-symmetric ligands can be used and that reactivity can be tuned with the choice of capping ligand and the charge on the metal. Overall, these very recent reports firmly establish complexes containing group 8 and group 9 transition metals as Lewis acids and as powerful and promising asymmetric catalysts. The possibility that metallocenes might function as Lewis acids in Diels-Alder reactions was probed with ferrocenium hexafluorophosphate [184]. The answer is affirmative; the cycloadditions studied include methacrolein, crotonaldehyde, and methyl vinyl ketone as dienophiles and butadienes and cyclopentadienes as diene components. Yields are in the range 60-80 YOwith reaction times of 3-36 h at 0 to 20 “C. Fair to good yields were also obtained in reactions of isoprene and cyclopentadiene with acrolein and methyl (in CH2C12, room temvinyl ketone in the presence of 1 YO [Pd(PPh3)2(MeCN)2](BF4)2 perature). Methyl acrylate resulted in low yields, and chiral modification with (S)-BINAP is reported to give the cycloadducts with modest enantioselectivity [164]. Diels-Alder reactions of cyclopentadiene and methacrolein with crotonaldehyde are also catalyzed by complexes formed in situ between NbClS or TaC15 and bidentate ligands (2 equiv.) such as L-tartrate esters, or a-amino acids (e.g. tryptophan, alanine). Yields with the Ta catalysts are often somewhat better (14-78 YO) than with the Nb catalysts. Good exo:endo ratios are obtained but enantioselectivities are still low (740 YO ee) [185]. Methylrhenium trioxide is an efficient catalyst in these reactions and its best performance is in aqueous solution. Acrolein derivatives and methyl vinyl ketones react with a variety of dienes to give single diastereoisomers in very high yield with as little as 1 YOcatalyst loading [186]. Examples are shown in Sch. 49. The reaction is sluggish with disubstituted dienophiles and dienes.

638

Kiindig/Saudan Me M e w M : e 2 Me Rh2+

(5%) CH2CI,, -2O"C, 72h 90%, 81% ee [181a]

SbF,-

(1 0%) CH,CI,, -5O"C, 27h 73%, 71% ee [182a]

2 SbF,

Me (5%) CH,CI,, -5O"C, 96h 21%, 46% ee [I 831

Me

(5%) CH,CI,, r.t., 20min 91%, 46% ee [181b]

(2%) CH2CI,, O"C, 72h 81%, 68% ee [182b]

Scheme 48 MeReO, (1%) r.t.

0

R

solvent

time

yield

isomer ratio

H H Me Me

HZO CHCI, HZO CHCI,

2.5h 18h 2.5h 18h

91 90 90 90

>99:1 >99:1 >99:1 >99:1

H H Me Me

HZO CHCI, H2O CHCI,

16h 4d 16h 4d

91 94 91 94

>99:1 98:2 >99: 1 >99:1

H H Me Me

H2O CHCI,

16h 4d 4h 12h

90 94 90 94

>99: 1 >99: 1 >99:1 98:2

HZO CHCI,

["/.I

Scheme 49

The strong Lewis acids H C ( P ~ ) ~(NO)z M (M = Mo, W) (see also Section 14.3.1), with Lewis acidities comparable with that of BF3, were shown by Faller et al. to coordinate and activate a&unsaturated carbonyl compounds via formation of an M-0 o-bond. These complexes, in nitromethane, catalyze Diels-Alder reactions with dienes (e.g. butadiene). They also readily polymerize butadiene when a less basic dienophile com-

Transition Metal Lewis Acids: From Vanadium to Platinum

639

ponent is used (e.g. methyl acrylate) [187]. These preliminary studies have recently been extended to cycloaddition reactions involving cyclopentadienes and cyclohexadienes with catalyst loading reduced to 0.3 YO [188]. FeC121was shown to be the Lewis acid of choice in non-racemic diastereoselective Diels-Alder reactions of cyclopentadiene with 1,l-dicarbonylethenes containing different carbonyl groups. The authors' rationale for the high exolendo selectivity is an out-of-plane conformation of the benzoyl Ph group (Sch. 50) [189].

u

81%

A

Me

Scheme 50

The readily prepared and air-stable complex truns-[Ru(salen)(NO)(HzO)](SbF6), when added (1 mol YO)to Diels-Alder reactions in nitromethane, leads to acceleration by as much as lo5. The presence of water slows the reaction, but does not inhibit it. The Ru catalyst is 1 or 2 orders of magnitude more efficient in catalyzing these reactions than trifluoroacetic acid (Sch. 51) [190]. Asymmetric versions of the Ru methodology have not appeared in the literature but chiral oxo(salen)Mn(V) complexes show some promise; the results of the best (of ten compounds tested) are included in Sch. 51 [191].

640

Kiindig/Saudan

[Rul (2%) CD,NO,, r.t [I 901

~

R

+

Me

A,,,-

R

C

H

R

catalyst

time [h]

yield [“h]

isomer ratio

[%I

O H Me

[Ru] [Ru]

4.4 48

90a 90a

98: 2 70:30

-

99: 1 93: 7

-

aCHo R

H Me

Me

WI

[Ru]

5 3

90a 90a

ee

a: NMR yield

Scheme 51

14.4.2. Hetero-Diels-Alder Reactions It has been reported that several transition metal complexes catalyze the heteroDiels-Alder reaction between a variety of aldehydes, in particular benzaldehyde, and Danishefsky’s diene (Sch. 52). With the [CpRu(CHIRAPHOS)]’ complex the ee is modest (25 %) (entry 1) [192]. The chiral complex VO(HFBC)2 performs better in this reaction (entry 2) [193]. In experiments directed towards the synthesis of anthracyclones, this complex was used in cycloadditions between anthraquinone aldehydes with silyloxy dienes. One example is shown in Sch. 53 [194]. Compared with the chiral aluminum catalyst developed earlier by Yamamoto and co-workers [ 1951, the vanadium catalyst results in lower enantioselectivity but has advantages such as ease of preparation, high solubility, stability towards air and moisture, and selective binding to an aldehyde carbonyl oxygen in the presence of others Lewis-basic coordination sites on the substrate.

641

Transition Metal Lewis Acids: From Vanadium to Platinum 1) catalyst solvent 2) TFA

+

PhCHO

entry catalyst

1 2 3 4

-

0aPh

TMSO

[CpL,Ru] (5%) [VO(HFBC),](5%) [(salen)Cr] (5%) [(salen)Ru] (2%)

0':;

0

't-Bu

solvent

T ["CI

time

yield [%I

ee [%I

ref.

CHCI, toluene TBME TBME

r.t. -78 -30 r.t.

24h 15h 24h 7d

60 82 85 54

25 68 87 79

[I921 [I931 [I961 [I981

t-Bu

t-B;

[(salen)Cr]

Scheme 52

mCHo TEsoq & VO(HFBC), (0.5 equiv.) -78"C, CH,CI, 75h

+

/

Me

OTES

\

77%

OMe 0

Me

~

Me

/

/

Me OMe 0 53% ee

Scheme 53

Chiral (salen)Cr(III) have also been used (entry 3) [196] and have found application in the total synthesis of muconin (see also Sch. 16) [197]. This reaction is also catalyzed by irradiation of a chiral (salen)Ru(II)(NO) complex in the presence of the diene and the hetero-dienophile (entry 4) [198].

642

Kundig/Saudan

FeC13 catalyzes the intramolecular hetero-Diels-Alder reaction of L-prolinal-derived N-arylimine to yield the trum,truns-diazacyclopenta[a]anthracenederivative with a dr of 84:16 (Sch. 54) [199].ln this reaction, S n Q results in higher truns,truns selectivity (99:l) and RAlCl2 (R = Me, Et) gives the cis,cis isomer with high selectivity (99:l).

FeCI, (2 equiv.) CH,CI, r.t., 42h

80%

*

H" Me

Me

dr = 84116

Scheme 54

Cationic palladium(I1) complexes, [PdL2(PhCN)2](BF4)2 (Lz = DPPP, DPPF), catalyze the reaction of non-activated dienes with aldehydes, affording the corresponding 5,6-dihydro-2H-pyrans (Sch. 55) [200].

Mex \

Me

CHCI,, [Pd(DPPF)(PhCN),](BF4), 5OoC, 20h (2%)

Me#"

*

+RQ

CHO

50% (R = Me) 75% (R = NO,)

Me

Scheme 55

In the course of a formal total synthesis of 3-deoxy-~-manno-2-octulosonic acid (KDO), a chiral (salen)Co(II) complex was used to catalyze a highly double-stereoselective hetero-Diels-Alder reaction between an electron-rich chiral diene and ethyl glyoxylate (Sch. 56) [201]. This reaction was subsequently extended to achiral dienes [202]. TBSO C0,Et

-

(salen)Co(ll) (10%) CH,CI,, 20°C, 10 min

85%

TBSO

2

,.,CO,Et

0

Me M 'e endo:exo = 93:7 si: re = 85:15 t-BU t-Bu

t-Bu

(salen)Co(ll) Scheme 56

Transition Metal Lewis Acids: From Vanadiumto Platinum

643

Iron(II1) 2-ethylhexanoate is a catalyst for the stereoselective hetero-Diels-Alder reaction of ethyl (E)-4-oxobutenoate with alkyl vinyl ethers to give cis-2-alkoxy-3,4dihydro-2H-pyran-4-carboxylic acid ethyl esters with a high diastereoselectivity (Sch. 57) [203].

co

Fe(BuEtCHCO,), (10%) 23"C,66h

ljoR

+

A

I

C0,Et

C0,Et

R Et n-Bu i-Bu

GLC yield

de

["/.I

Pol

72 79 71

98 98 98

Scheme 57

The chiral Ni(I1) complex shown in Sch. 58 catalyzes the enantioselective heteroDiels-Alder reactions of thiabutadienes with 3-(2-propenoyl)-2-oxazolidinoneto afford optically active dihydrothiopyrans [204]. Similar results are obtained with analogous Cu(I1) complexes where catalyst loading can be reduced when molecular sieves are added. Ph

L*, Ni(CIO,), +

d N a o

L

R

CH,CI,,

Ph

0

0

r.t.

f

R

Ph SMe

catalyst ["h]

yield

50 100

99 53

endo:exo

[%I

ee

[%I 76:24 7822

96 89

L*

Scheme 58

Non-activated dienes react with arylglyoxals and glyoxylate esters in the presence of chiral BINAP-palladium(I1) or platinum(I1) complexes (Sch. 59) [205]. With glyoxylate esters, ene products are formed competitively. Chiral tridentate chromium(II1) complexes catalyze highly enantio- and diastereoselective hetero-Diels-Alder reaction between various aldehydes and dienes with one oxygen substituent (Sch. 60) [206]. Complex formation between catalysts and aldehydes could not be detected by IR and the successful use of acetone as a solvent casts doubt on a simple Lewis acid mechanism.

644

Kiindig/Saudan

0

+

M

R

T ["CI

time [hl

yield [%I

ee [%I

Pd Pt Pd

Ph Ph OEt

0 0 r.t.

24 24 20

67 60 36

99 97 95

[M((S)-BINAP)(PhCN),I(BF,), (2%) 3AMS,CHCI,

H&R

-

0

M Pd Pt Pd

R Ph Ph OEt

T

&O :R

time [hl

yield

ee

Wl

[%I

[%I

0 0 r.t.

24 24 20

69 74 77

>99 >99 98

Scheme 59

0

M

e

O

A

+

T B os,-k, H

1) [Cr] (3%) 4A MS 2) TBAF 91%

o.,

*

Me0 "" 0

'I

OTBS > 99% ee 1) [Cr] (3%) 4A MS acetone, r.t. 2) TBAF

+ RCHO Me

R I

Ph CH,OTBS

yield

[%I

ee [%]

72 90

90 99

Transition Metal Lewis Acids: From Vanadiumto Platinum

645

14.4.3 Ene and Hetero-Ene Reactions 14.4.3.1 Ene Reactions FeC13 is superior to Al, Sn, and Zn Lewis acids in the intramolecular ene reaction of the Knoevenagel adduct from citronellal and dimethyl malonate (Sch. 61) 12071.

M

e

Me0,C

FeCI, (10%) -78°C CH,CI, to r.t., 4h,

5

/

Me

94%

Me

C0,Me

C0,Me dr = 99:l

Scheme 61

14.4.3.2 Hetero-Ene Reactions The complex truns-[Ru(salen)(NO)(H~O)](SbF6)catalyzes the conversion of (+)citronella1 to I-isopulegol via an intramolecular hetero-ene reaction. This reaction is an important step in the industrial production of Z-menthol. This ruthenium complex also catalyzes the intermolecular hetero-ene reaction between activated enophiles and olefins to give homoallylic alcohols by a stepwise process (Sch. 62) [208].

fLo Me

(salen)Ru (1%) MeNO,, 25"C, 6h

*

80%

Me

&OH Me& I-isopulegol

(+)-citronella1 (salen)Ru (2%) MeNO,, 50°C

+b

0 ArKH

n -N,

y?t-

SbF,

d o ' ! $ p h (salen)Ru

Ar

time

yield

[hl

[%I

p-NO,Ph c6F.5

10 5

83 88

p-CNPh

50

82

Ar

Scheme 62

Analogous cyclizations of citronellal can also be effected, albeit with lower diastereoselectivity and in the racemic series with carbonyl M(I1) complexes (M = Mo, W) 12091.

646

Kiindig/Saudan

FeC13 mediates the carbonyl-ene reaction of a 5-(2-propenyl)-imidazolidinonewith butyl glyoxylate to give the ene product without the subsequent rearrangements observed when SnC14 is used in this reaction (Sch. 63) [210].

FeCI, (4 equiv.) CH,CI,, 25"C, 3h D

78%

Scheme 63

The imines shown in Sch. 64, obtained from alanine, leucine, or phenylalanine, react diastereoselectively in the presence of FeC13 to give 3-amino-2,4-dialkyl-substituted piperidines (Sch. 64) [211]. Different product distribution and diastereoselectivities are obtained when Tic14 is used. Ph

Ph

I Rqp

7

FeCI, (2.5 equiv.) M~ CH,CI,, r.t.

R

Me i-Bu Bn

Scheme 64

time

yield

PI

[%I

19 17 19

60 66 41

Me

FeCI, (2.5 equiv.) CH,CI,, r.t., 43-72h 65% (n = 1) 59% (n = 2)

62% (n = 1) 68% (n = 2)

Scheme 65

Transition Metal Lewis Acids: From Vanadium to Platinum

647

&-Substituted indolizidines and quinolizidines result in the Fe(II1)-mediated intramolecular cyclization shown in Sch. 65 [212] whereas the trans product is obtained from the corresponding imines. FeC13 mediates the carbonyl-ene reaction between methyl glyoxylate and simple alkenes [213].

14.4.4 1,3-Dipolar Cycloadditions The asymmetric 1,3-dipolar cycloaddition of nitrones to 3-((E)-2-butenoyl)-2-oxazolidinone [214] is catalyzed by nickel(I1) [215] and palladium(I1) [216] complexes (Sch. 66). The resulting isoxazolidines are of interest because they are readily converted into y-amino alcohols, precursors to alkaloids and p-lactam antibiotics. R

n O Y N P M e 0 0

+

Me endo

R

catalyst

Me Bn Ph Me Bn Ph

[Nil [Nil [Nil [Pd] [Pd] [Pd]

solvent CH,CI, CH,CI, CH,CI, CHCI, CHCI, CH,CI,

Ni(CI04),~6H,0

4A MS “il

Scheme 66

T [“CI

time [hl

yield [%I

endo:exo

r.t.

72 48 48 48 48 48

72 76 96 89 94 94

98:2 >99:1 98:2 60:40 93:7 28:72

r.t. r.t. reflux reflux reflux

ex0 ee (endo) ee(exo) [%I [%I

>99 95 89 91 89 54

648

Kiindig/Saudan

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Transition Metal Lewis Acids: From Vanadiumto Platinum SO. 51. 52. 53. 54.

55.

56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. 92. 93. 94. 95. 96.

649

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Lewis Acids in Organic Synthesis Edited bv Hisashi Yamarnoto Copyright 0WILEY-VCH Verlaa GmbH.2000

15 Titanium(1V) Lewis Acids Hirokazu Urabe and Fumie Sat0

15.1 Introduction The utility of titanium compounds as Lewis acids has been widely accepted in organic synthesis. When a Lewis acid-mediated, new synthetic transformation is to be investigated, titanium compounds will be considered as a possible candidate as the Lewis acid and will usually be examined. Several review articles deal with the use of titanium Lewis acids in organic synthesis 11-11]. Additional relevant reviews cited in the following sections will be also helpful. A few articles surveying the reactions of organotitanium reagents, which will not be described extensively in this chapter, should be also useful 112-171. Because fundamental and established reactions can be found in the aforementioned reviews, this chapter on titanium Lewis acids will mainly cover most recent developments and examples appearing in the latest publications. Compounds of the type TiX4 are usually used as titanium(1V) Lewis acids; the Lewis acidity of these is readily modified by changing the anionic group X in TiX4. The Lewis acidity is changed from mild to strong by changing X from alkoxide to halide to OTf. Although titanium tetraalkoxides have limited use as a Lewis acid, they still find occasional application. Fine tuning of the strength of the Lewis acidity of TiX4 is possible by manipulation of mixed ligand systems of formula TiX,Yn ..., etc. Alteration of the reactivity of titanium species in this way sometimes dramatically improves the product yields and/or the product composition; this will be illustrated in the following discussion. In general, compounds of the type TiX4 (X = halide or alkoxide) are inexpensive and are accessible in quantity from commercial sources. Even such titanium compounds that are not readily available are basically easy to prepare by the metathesis reaction starting from simpler compounds according to the equations:

TiX4 + nMY

+

TiX4,Y,,

+ nMX

where M = H or metal and MX must be removed [12,17-191. Liquid materials can be purified by distillation with protection against moisture [20].Solid compounds can be recrystallized to give pure samples [20]. Because these titanium reagents are usually moisture-sensitive, their storage and reactions should be performed under an inert atmosphere. Some cyclopentadienyl complexes of titanium, for example CpTiX3 or Cp2TiX2,are also commercially available, although these complexes find much less use as Lewis acids. Titanium silicate molecular sieves (TS-1) are used as a solid titanium Lewis acid and an improved method for the preparation of these was recently reported [21]. The toxicity of titanium metal itself has not been emphasized, but its compounds effective as Lewis acids might have caustic properties and should, therefore. be handled with due care.

654

Urahe/Sato

The structures of titanium-Lewis base complexes are helpful in enabling understanding of the Lewis acidic behavior of titanium compounds [S]. The crystal structures of ethyl acetate-TiC14 and ethyl p-methoxybenzoate-TiC14 have been reported to be dimeric, as shown in Fig. 1 [22,23] (see the original references for the exact ORTEP drawing and the parameters of Figs 1-3,5, and 6), involving the double chlorine bridges between two titanium metal atoms. Crystal structures of other carbonyl compound-TiC14 complexes, for example ~is-[(2,4,6-Me&,H~CHO)~TiCl~], [((Mez. CO)TiC13)2(LL-C1)2],and [((thiol e~ter)TiCl3)~(LL-Cl)~], shown in Fig. 2 [24] have been reported. It is interesting to note that the 1:l complex of mesitaldehyde and TiC14, prepared separately, had 'H and 13C NMR spectra (CD2C12)very similar to those of the 2:l complex characterized in Fig. 2 (left), suggesting disproportionation to similar species in solution. In contrast to the aldehyde, the 1:l acetone-TiC14 complex was obtained as crystals with a structure consisting of chlorine bridges (Fig. 2, middle). Thiol ester-TiC14 complexes (Fig. 2, right) [24] and an isonitrile-TiC14 complex [25] have similar dimeric structures.

Figure 1. Crystal structures for esters coordinating to TiCI4.

Y 0

I

R+ySPh

CI

0

R=H,Me

Figure 2. Crystal structures for aldehydes, ketones, and thiol esters coordinating to TiC14.

Some crystal structures of chelate complexes have been reported. An O-acryloyllactate-TiC14 complex (Fig. 3) [26,27] has rare out-of-plane (Fig. 4) coordination of the acryloyl carbonyl group to the titanium; a further study has been conducted [28]. Diethyl phthalate-TiC14 [29], 1,2-diketone-TiC14 [25], and achiral [24] or chiral [30] acyloxazolidinone-Tic14 complexes have been reported to involve in-plane coordination as shown in Fig. 5. The P-alk~xyketone-TiCl~complex shown in Fig. 6 [31] is characterized by a rare out-of-plane coordination geometry (dihedral bond angle of

Titaniurn(IV) Lewis Acids

655

Ti-O-C3-C4 = 57.6 "). This out-of-plane coordination was proved by NOE experiments to persist in solution. Treatment of the diastereomeric P-alkoxyketone with TiC14 generates the titanium chelate with in-plane coordination geometry (Eq. 1) [31]. NMR study of these out-of-plane and in-plane complexes of the /3-alkoxyketones revealed that the titanium portion in the former complex acts as a stronger Lewis acid than that of the latter [31,32]. CI CI-Ti-0 CI'I

I .p

OEt

?-

Figure 3. 0-Acryloyllactate-Tic& complex.

L.A.

in-plane (o-bonding)

out-of-plane (x-bonding)

Figure 4. Mode of coordination.

Cl

OEt

Figure 5. Crystal structures for chelates involving TiCI4.

656

Urabe/Sato 2.9% NOE in solution

Figure 6. Crystal and solution structure.

In addition to the aforementioned X-ray analysis to disclose the structure of a few crystalline titanium chelates, 'H and 13C NMR studies have been performed to provide evidence for the chelation structure of a- and P-oxycarbonyl compounds in solution [33-351. Approximate solution structures for P-alkoxyaldehydes are as shown in Fig. 7 [34]. The mechanism of chelation-controlled reactions of organotitanium reagents has been investigated experimentally [5] and theoretically [36], and the subject has been reviewed [lo]. The formation of a chelate structure with titanium metal at the center plays a pivotal role in determining the reactivity and selectivity [37] in many synthetic reactions as shown in the following discussion.

ci

CI

Figure 7. Solution structures of ~-alkoxyaldehyde-TiCI4complexes determined by NMR spectroscopy (aldehyde H omitted for clarity).

15.2 Aldol and Related Reactions The directed aldol reaction is an important means of selective carbon-carbon bond formation. This reaction is efficiently achieved by the transformation of one carbonyl group to a silylated enol derivative, which subsequently couples with another carbonyl compound with the aid of a Lewis acid, typically TiC14, as formulated in Eq. (2). This type of directed aldol reaction is called the Mukaiyama aldol reaction, a standard and practical synthetic protocol with broad application which has, accordingly, been reviewed extensively [3842] in addition to the reviews cited in the introductory section. The fundamental reactions between enol silyl ethers and an aldehyde or a ketone

Titanium(IV)Lewis Acids

657

are shown in Eqs ( 3 ) and (4) [39, 431. Because the cationic intermediate generated from benzaldehyde and TiC14 is a reactive species, the aldol reaction occurred with a difluoroenol silyl ether, although the yield was moderate (Eq. 5 ) [44]

phq?TiCI4

+

PhCHO

38%

F

0 OH P h v P h

(5)

F ‘F

Although both aldehydes and ketones also participate in the directed aldol reaction, the former are generally more reactive, as is exemplified in Eq. (6) [45]. Thus, the aldol reaction of an enol silyl ether with an aldehyde could be performed in the presence of a ketone. Equation (6) also demonstrates that the base (LDA)-mediated aldol reaction and the Mukaiyama-type reaction took place at the different position in a complementary manner to give the isomeric aldols.

Ph 11) LDA

TiCI4 80%

0

0 Ph

77%

OH

658

Urabe/Sato

The directed aldol reaction in the presence of Tic& found many applications in natural product synthesis. Equation (7) shows an example of the aldol reaction utilized in the synthesis of tautomycin [46], in which many sensitive functional groups survived the reaction conditions. The production of the depicted single isomer after the titanium-mediated aldol reaction could be rationalized in terms of the chelation-controlled (anti-Felkin) reaction path [37]. A stereochemical model has been presented for merged 1,2- and 1,3-asymmetric induction in diastereoselective Mukaiyama aldol reaction and related processes [47].

TiCI4

HF

0

OH 0

OH

H

f -

-78 + -20 "C

OMe single isomer >42%

tautomycin

In addition to enol silyl ethers, other derivatives of aldehydes and ketones, i.e. enol ethers (Eq. 8) [48] and enol esters (Eq. 9) [49, 501, serve as a partners for the cross aldol reaction, although the lower reactivity of these compounds compared with enol silyl ethers often makes the reaction more complicated. For example, the products isolated in Eq. (8) were ether derivatives or uJ-unsaturated carbonyl compounds rather than the expected aldol itself.

~

-1 R'CHO

+ R2JR3

4

0

~

Titanium(ZV)Lewis Acids

fl

-Tic14

+

@CHO

0

EtOH

OH 0 a C 0 2 \

E

t

659

(9)

93%

Acetals are a versatile alternative to aldehydes and ketones which have wide applicability in the titanium-mediated aldol reaction [51]. Equation (10) shows the difference between an acetal and the parent aldehyde in the diastereoselective aldol reaction [52]. In this example the latter results in better diastereoselectivity than the former. The reactivity of an aldehyde and its acetal have been compared (Eq. 11) [53]. More examples of the directed aldol reaction starting from enol derivatives of aldehydes and ketones are summarized in Table 1.

i-PrCHO TiCI4 78%

-

(10)

OCOBU-t

6Mel PhCHO

+

I

I

TiCI4 99%

OCOBU-t

Wphpe 0

OMe

TiCI4

PhAOMe

77%

OH(SiMe3)

+

59 : 41

Ph ( 1 1 )

660

Urabe/Sato

Table 1. Aldol reactions of the enol silyl ethers of aldehydes and ketones. Enol silyl ether

Carbonyl compound

Titanium salt

Product

Yield (%)

Ref.

79

54

73

55

74 97

56 57

OTBS

J

+ + + OSiMe3

CF3 Tic14

TolS

o h

0

54:46

R

OSiMe3

TiCI4

92: 8 71:29

R = CF3 R=Me

OSiMeg

jK.,,.e-. 0

xT

X = OBn single X = NHC02Bn 72:28

&TBnAT: re, Tic14

Ph

COPh

>95:5

R'

T % E t

k 0

Tic14

R2

N2

>61 52

56 56

67

58

/

R2v Ho N2

60-80

59

C02Et

TIPSO,,,,/\ M

e

O

q

o H c L O T I P S

TiC14

76

60

Titanium(IV)Lewis Acids

661

Table 1. (Contnd.) Enol silyl ether

M

Carbonyl compound

Titanium salt

~ +sO:

e

Product

Yield (%)

Ref.

s

'O,,

OH 0

Tic14

?A\

Bno2cc*/ 0

TESO

>42

46

90

61

OMe

Bn02C

single isomer

TBSO PhCHO

TiCI4

0

? & h P OBn / ,

l:i

62

Me3SiO OSiMe3 U O M e

R)C ' Ho

Tic14

X

R = alkyl X = NBn2, TBS, SBu- t

HO R+C02Me

0 54-87

E,i

x >93% de

70-92

65, 66

0 73

9o:i 0

67

662

UrabeISato

Table 1. (ContndJContnd.) Enol silyl ether

Carbonyl compound

Titanium salt

Product

Yield (%)

Ref.

88

67

63-85

68

64

69

38

44

60

70

58-84

71

50

72

45-99

733 50

93

49, 50

0 Me Me &CHO

TiCI4

96:4

'v

Me

OMe

OSiMe3

BnO/\(-'CHO OTBS

PhCHO

TiC14

O

W OMe OH 0

TBSO

TiCI4

P h q : h F F

F

TiCI4 SiMe3 (after decomplexation)

RCHO

cp'.

TS-1

synlanti = 71:29-49:51 HO Me3Si+S + ,iP -r

PhCHO

SPr-i

TiC12(O-i-Pr)z Ph

d

0

C02Me RCHO

Tic14 HO (after methanolysis)

Jf

0

(after ethanolysis)

663

Titaniurn(IV) Lewis Acids

The intramolecular aldol reaction in the presence of a titanium Lewis acid is a viable means of preparation of cyclic compounds. The cyclization is most conveniently performed between an enol silyl ether and an acetal, because the former is a reactive enol derivative and is readily prepared by silylation of the corresponding ketone in the presence of the acetal moiety in the same molecule. Equation (12) exemplifies a substrate undergoing intramolecular ring closure mediated by TiC14 [74]. The conversion of sugar derivatives to carbocycles (called the Ferrier reaction [75,76]) has been reported to occur in the presence of a Lewis acid. This process involves the aldol reaction between the enol ether and acetal moieties in the same molecule promoted by a titanium salt, as illustrated in Eq. (13) [77]. The similar reaction of a different type of substrate was also reported [78].

o

\OTBDPS

7:1

Imines and their derivatives could be used in an analogous way to aldehydes, ketones, or their derivatives; this subject has been reviewed [79]. A competition experiment between an aldimine and the corresponding aldehyde in the addition to an enol silyl ether under titanium catalysis revealed that the former is less reactive than the latter (Eq. 14) [go]. In other words, TiC14 works as a selective aldehyde activator, enabling chemoselective aldol reaction in the presence of the corresponding imine. (N,O)-Acetals could be considered as the equivalent of imines, because they react with enol silyl ethers in the presence of a titanium salt to give p-amino carbonyl compounds, as shown in Eqs (15) [81] and (16) [79,82]. 0 PhAH

NPh

+ PhKH

OSiMe3

+

Ph

TiCI4

-

0

OH

+

P h v P h I Me

PhK/-Ph Me

1%

86%

Tic14

a

(15)

Q C02Me O M e

,

C02Me

NHPh

0

(14)

664

Urabe/Sato

Under the influence of TiC14, acylation of a ketone via its enol silyl ether can be performed with acyl halides [2,3]. Acyl cyanides can also be used to acylate enol silyl ethers, as illustrated in Eq. (17) [83].

0

0

Titanium-mediated condensation of ketene silyl acetals with carbonyl compounds or their derivatives, e.g. acetals, affords P-hydroxy or P-alkoxyesters according to the general scheme shown in Eq. (18) [84]. Although arylacetaldehydes are relatively base-sensitive, this Lewis acid-mediated method enables introduction of the acetate side chain to this type of aldehyde, as shown in Eq. (19) [85]. High diastereoselectivity is often observed in the reaction of cyclic ketene silyl acetals with aldehydes in the presence of a titanium salt (Eq. 20) [70]. A siloxyfuran behaves as a cyclic ketene silyl acetal, to give a single isomer in the reaction with a chiral aldehyde in the presence of Ti(O-i-Pr)2C12 (Eq. 21) [86,87]. If this Lewis acid, Ti(O-i-Pr)2C12, is replaced with TiC14, the regioisomer arising from the siloxydiene moiety was also produced. More examples of the aldol-type reaction of ketene silyl acetals are collected in Table 2. R~CHO

OH C )/. 02R’

*

TiX4 0

R2

~

3 0133

R2AoR3 *

TiX4

).../C02R1 R2

Titanium(IV)Lewis Acids

665

Table 2. Aldol reactions of ketene silyl acetals with aldehydes, ketones, and acetals. Ketene silyl acetal

Carbonyl compound

Titanium salt

Yield (%)

Product

Ref.

OTBS A O M e OTBS

OTBS

OSiMe, TiCI4 R*OSiMe3

210

88, 89

95

90

51-88

70

61

92

OSiEt, OHC L O B n 98: 2

OHC L O B n

TiCI4 MeOZC O q O B n 99: 1

6; n = 1,3

92:8-95:5

OSiMe, Y O E t

COzBu-t 0 ; q O B u - t OSiMe3

BnOzC

Ti(O-i-Pr)3CI KCiZHZ5 0

Bno2C >90%de

666

Urube/Suto

Table 2. (Contnd.) Ketene silyl acetal

Carbonyl compound

‘.Y:SiMe3

Titanium salt

“‘2;Me

Br

Product

OMe MeO&C02Me

TiCI4

U

OSiMe3 O

M

B

n

O

Ref.

--

93

76

94

53 59

86, 87

28

95

87

70, 97

Me Br

n = 1,2

Me3Si0

Yield (“A)

A

Meo2c&oBn Me

Tic14

0

e

OH j!OSiMe3 0

RCHO

R

q

~

R%

I

0

0 R=Ph

~

oBn

TiCI4 78 : 22 Ti(O-i-Pr)2C12 100 : 0

Me TBSO

% !-0

TiCI4

M 0e o*H

.LO

/JCHO

Ph‘

Ph’ major product

M

BOH u

-

f

OSiMe3 MedSBu-t

Me3Si+CH0

TIC14

Me3Si 95: 5 e

OSiMe3 Me&

SBU-t

Me3SiTCHO C02(CO)f3

Tic14

Me3Si

B OH U

-

-9 >99:<1

(after decomplexation)

1

667

Titanium(IV)Lewis Acids

Me0

OMe

Me0

OMe

OTBS

OTBS

TBSO j!OSiMe3 0

PhL OTBS CI H O

+

OBn

Ti(O-i-Pr)2CI** 59%

P

h OBn 0

single isomer

5

(21)

0

The relative reactivity of aldehydes and acetals toward a typical ketene silyl acetal in the presence of TiC14 has been revealed by use of competition reactions (Eqs (22) [98, 991, (23) [98], and (24) [98]). Although yields are not necessarily high, perhaps because these experiments were conducted solely to compare the reactivity of the compounds, the results shown in these equations are quite informative: (i) acetals are more reactive than the corresponding aldehyde, (ii) aliphatic aldehydes are more reactive than aromatic aldehydes, and (iii) electron-rich aromatic aldehydes are somewhat more reactive than the electron-deficient variety.

x:zt

+

PhCHO +

.

OMe TiCI4 OTBS t E2 0C , , . . - ) PhAOMe -78°C ph

+

12%

x:zt

+ PhCHO

+

TiCI4

C7H15CHO

-78°C

OTBS L C 0 2 E t Ph 23-26%

OMe /CC02Et Ph

(22)

26%

+

r C O 2 E t C7H15 34-42%

(23)

668

Urabe/Sato

OTBS

66

+

-

+

A O E t

TiCI4

-78 “C

OMe

fi

CN OTBS

p

C

0

z

E

+

t

Me0

Et

(24)

NC

34%

23%

A pair-selective aldol reaction proved to be possible and is illustrated in Eq. (25); from the four starting materials, only two products were obtained [loo]. This clearly indicates that the coupling of the ketene silyl acetal and acetophenone and that of the enol silyl ether and benzaldehyde dimethylacetal are very favorable paths, whereas the reactions of other combinations are not. A similar phenomenon is illustrated by Eq. (26) [loo].

AOEt

+

PhAMe

OSiMe3

++

OMe +PhAOMe

I

TiCI4

55%

+

-78 “C

+

PhAMe

(25)

30%

TBSO

OTBS A O E t

OTBS L C O z E t PhMe

0

OTBS

PhMe &C02Et

OH 0

+ PhMe G

P

h

The pair-selective reaction was also seen in the one-pot preparation of bicyclic compounds by addition of a diketone to the bis-silyl derivative of an acetoacetate in the presence of T i Q (Eq. 27) [94]. The product of the bridged structure was formed under almost complete regiocontrol, showing the high pair-selectivity of the first step.

Titaniurn(IV) Lewis Acids

669

The electron-rich nature of silyl ketene acetals enables their facile coupling with imines in the presence of a titanium salt [101,102]. Interesting results are obtained from comparison of the efficiency of a titanium salts of the type TiX4. Switching the halogen X from F to C1 to Br to I, uniformly increases the product yield and diastereoselectivity of the TiX4-catalyzed reaction between a ketene silyl acetal and an imine (Eq. 28) [103]. The finding illustrated by Eq. (28) was further applied to diastereoselective carbon-carbon bond formation as shown in Eq. (29) [103]. More examples of the titanium-mediated reaction of ketene silyl acetals and imines or their derivatives, for example (N,O)-acetals, are summarized in Table 3. OSiMea 6 O E t

+

Ph-NBn

TiX4 (lo -780c

NHBn

mo'yol C ,-.J0 ,.2Et ( 28 ) Ph

Me

~

Me X=F

x = CI X = Br x=I

92:8 93:7 955 97:3

42% 53% 98% 99%

99:i TBSO

OMe

Meu O S i M e 3

+

& ,

Ti14

N-An

96%

AnHN

) ( 29 1

( C02Me 99: 1

If the reaction between enol silyl ethers and a,B-unsaturated ketones is attempted in the presence of a titanium Lewis acid, the mode of the reaction switches to 1,4-addition with reference to the unsaturated ketone [109-1131. The reaction of an enol silyl ether is shown in Eq. (30) [114]. Ketene silyl acetals react with a,P-unsaturated ketones in similar 1,4-fashion, as exemplified in Eq. (31) [115]. Acrylic esters, which often tend to polymerize, are also acceptable substrates for a,P-unsaturated carbonyl compounds [ l l l ] . A difluoroenol silyl ether participated in this cationic reaction (Eq. 32) [116], and an olefinic acetal can be used in place of the parent a-methylene ketone [ l l l ] to give the 1,5-diketone in good yield (Eq. 33) [117]. More results from titanium-catalyzed 1,4-addition of enol silyl ethers and silyl ketene acetals to a,Punsaturated carbonyl compounds are summarized in Table 4.

670

UrabeISato

Table 3. Aldol reactions of ketene silyl acetals with imines and their derivatives. Ketene silyl acetal

lmine or its derivative

Titanium salt

Yield (“7)

Product

Ref.

Ph

Ph TiCI4

HN /\I \/IphOH 68:32 f

Et02C

44

104

52

104

Ph

/\I

BnN EtO~C,,J+.,phOH

11

91: 9

7:

f

NHBn tEzO C, , ) Ph

TiX4

Me

103 ~

Me X = F 92:8 X = C I 93:7 X = Br 95:5 x = I 97:3

42 53 98 99

99: 1 TBSO

OMe

Meu O S i M e 3

G,N-An

96

Ti14

103

Me 99: 1

LR,,,3

90->98%de

Me

Meo2Y40

TiCb

Ti(O-CPr)4

0 j!oSiMe3

PhHN

73-81

105, 106

80

92

63-80

107

40

108

OTBS

R+%

TiCI4

hN-PMP 0 9218 - >98:<2

R = alkyl

v:

COSEt

MePh-NPh

TiCI4

hpY ---C -S oE t

NHPh . COSEt

Titanium(W)Lewis Acids

671

Table 4. 1,4-Addition of enol silyl ethers and ketene silyl acetals. Silyl derivatives

A O S i M e 3

Carbonyl compound

&

xe3

Titanium salt

Product

K

TiCI4-

H

O

Ref

83

114

88

94

Ti(O-i-Pr)4

TiC14B Ti(O-i-Pr)4

B n O y ' 0

C

Yield (%)

n

0

O

m

0

f-BUSC(0) ,,

t-BuSC(0),,,, TiCI43Ti(O-i-Pr)4 0 TBSO

: $H

R% H. R'

CO2Et

TiCI4

N C02Bn

R' = H, Me R2 = alkyl

OSiMe3 Me+OEt Me

n=l,ll

Rk;;

H,N Bn02C

87-99

118

90

115

C02R2

R = alkyl, EtO

b

TBSO

TiCI4 TBSO

672

Urube/Suto

In addition to enol silyl ethers, an optically active boryl enolate underwent the highly anti-stereoselective aldol reaction with a wide variety of aldehydes in the presence of Tic14 (Eq. 34) [120]. The vinyl sulfides shown in Eq. (35) reacted with a,& unsaturated ketones via the 1P-addition pathway in the presence of a titanium salt, but the reaction was followed by the cleavage of a carbon-carbon bond in the cycloalkane to give open chain products in a stereoselective manner [121]. The 1,2type addition was observed, if the olefinic acetal was used instead of the corresponding carbonyl compound, as shown in Eq. (36) [121]. The successive scission of the carbon-carbon bond took place analogously to give the same type of products as shown in Eq. (35).

V

TESO

TiC13(O-i-Pr)

Me+

R

R2 1

4 R3

43-aa% *

..

SMe n = 1,2; R', R2, R3 = H,alkyl

Bu

Titaniurn(ZV)Lewis Acids

.

OMe

TiCI4 69%

d O -M e

BuB *u

0

MeS

673

(36)

OMe

SMe

Trichlorotitanium enolates are directly prepared from a ketone, TiC14, and a tertiary amine [122,123] and undergo aldol reactions with aldehydes [124-1291, ketones [129], and imines [130,131]. Intramolecular condensation with esters is also known [132-1371. Although these reactions, based on a titanium enolate [16], which often results in high diastereoselectivity in aldol and related reactions [122], will not be discussed in detail in this article, the success of the alkylation of this titanium enolate with SN1-active electrophiles should be discussed owing to the high Lewis acidity of the metal center [123]. Equation (37) shows stereoselective alkylation with an orthoacetate, which is usually inert to alkali metal enolates [138]. Aminoalkylation of trichlorotitanium enolates with (a-chloroalky1)amine has been performed analogously [139,140].

II

‘0

0

TiC14

~

EtN(i-Pr)2

Ph

Et

O1 N kAr

U

Ph

Cross aldol reaction between two different aldehydes and/or ketones without prior activation or protection should provide a straightforward methodology for the synthesis of aldols. Mahrwald recently reported that treatment of aldehydes with TiC14 and NEt3 (or TMEDA) gives rise to syn-aldol reaction in good yields (Eqs 38 and 39) [141]. This method was extended to the aldehyde-ketone cross aldol reaction catalyzed by TiC14 [142], an advantage of which is that reaction occurs at the more encumbered a-position of unsymmetrical ketones, as illustrated in Eqs (40) and (41) [143]. The use of aliphatic aldehydes instead of PhCHO usually reduced stereoselectivity. When TiC14 was replaced by a catalytic amount of BuTi(O-i-Pr),Li, the aldol reaction was followed by the Tischenko reaction [144]. Methyl vinyl ketone trimerized to give a chlorinated cyclic product with TiC14 [145].

EtCHO

’ E t q C k l o TMEDA

84%

Me

1

>96: 4

(38)

674

Urabe/Sato

>96: 4

0

, ( ,

+ PhCHO

-

0

TiCI4 83%

OH

Y

P

OH 0 h

f

& (40)

Ph

-t

97:3

95: 5

95:5

84: 16

Combination of the reagents TiC14, Bu3N, and TMSOTf, was reported to be effective for Claisen condensation, as exemplified in Eqs (42) and (43) [129]. When acyloxazolidinones were subjected to reaction with TiC14 and a tertiary amine, homocoupling reaction at the a-position of the acyl group took place to give succinic acid derivatives [146]. The lithium enolate of an ester or amide has been alkylated with an (N,U)-acetal in the presence of Ti(O-i-Pr)4 (Eq. 44) [147,148]. eM20C, , - , Ph

+

C

CI AC02Me

TiCI4, NEt3

C02Me

Me3SiOTf

I

OTBS CONMe2

+

C

P h T o M e NHC02Me

l

Me3SiOTf * 73%

C02Me

-

1) LDA 2)Ti(O-i-Pr)4 61Yo

e Me ( 42 ) Ph

-%

C02Me

91Yo

TiC14, NEt3

(43)

Phd::NMe2 NHC02Me

(

(44)

90: 10

Titanium tetrachloride and a tertiary amine are a useful catalyst for Knoevenagel condensation [149] as shown in Eq. (45) [150]. Because the reaction can be performed under mild conditions, acid-sensitive functional groups survive the reaction conditions and the optically active center at the enolizable position did not racemize (Eq. 45). More examples of the titanium-catalyzed Knoevenagel condensation are shown in Table 5. Alkylation of an (unsaturated) (N,O)-acetal with active methylene compounds was performed analogously in the presence of TiC14 and NEt3 (Eq. 46) [154]. Depending on the structure of the active methylene compounds, carbon-carbon bond

Titaniurn(ZV)Lewis Acids

675

formation occurred at different positions, probably because of steric reasons. The same reagent combination effected the alkylation of an ester with an acylpyridinium salt [1551.

Table 5. TiCL-amine-mediated Knoevenagel reactions. Carbonyl compound

Active methylene compound

Amine

Product

Yield (%)

Ref.

84

151

71

150

,COZEt pyridine C02Et

CI

CI

&

SiMe3

q

pyridine

C02Me C02Me

Me

RCHO

R = i-Pr, Ar

(COzMe NO2

n

OWNMe

46-88 152 dCozMe NO2

R

pyridine

69

CN Et2N

Et2N

CN

153

676

Urabe/Sato

PMe A C02Me

*

I

TiCI4 NEt3 68% O O M e C02Me

( 46 1

C02Me

R
*

TiCI4 NEt3 52-91Yo R = Me,Ph, SPh

XozMe Y

C02Me

15.3 Reaction of Allylsilane and -Stannane and Related Compounds The first allylation of aldehydes and ketones with allylsilanes in the presence of Tic14 as illustrated by Eq. (47) was reported by Hosomi and Sakurai [156], although relevant reactions of allylsilanes were already known at that time. This reaction giving homoallyl alcohols is of wide applicability in organic synthesis. In addition to the review articles cited in the introductory section, others are available [51,157-1631. Among Lewis acids, T i Q continues to be the most general promoter for this reaction. This allylation has several advantageous features-including complete SE2' regiospecificity with regard to the allylic system [156]. This strength is reinforced by the availability of many regioselective preparations of allylsilanes [2,3,164]. Later, Hayashi and Kumada established the acyclic stereochemical outcome of this allylation with a few electrophiles in the presence of TiC14, and demonstrated the anti-SE2' mode of the reaction [165-1671 (Eqs 48 and 49) [166]. In conjunction with the rapid development of the selective (particularly asymmetric) synthesis, these characteristics of the Lewis acid-mediated reactions of allylsilanes are very favorable. This section presents new results reported in the latest literature; the aforementioned reviews and those cited in the Introduction will be useful for surveying earlier results.

>99:<1

H

85% ee

47%

Me 88% ee

'

Titanium(IV)Lewis Acids

677

>99:<1 TiCI4

Me3Siph\ H Me

+

tCHO Me

27%

24% ee

24% ee

Compatibility of functional groups in the titanium-mediated allylation of aldehydes is illustrated in the following equations. For example, allylation of aldehydes can be performed in the presence of carboranyl alcohol (Eq. 50) (1681, ester and peroxide moieties (Eq. 51) [169], and dibromocyclopropane (Eq. 52) [170]. The last example shows that sterically hindered aldehydes can be allylated by this method.

I

O L 70

Me

h e bSiMe3

This allylation works quite well for ketones [2,3,157-159,161,1621. Their silicon analogs, acylsilanes, were allylated equally well (Eq. 53) [171]. During the reaction of achloroacylsilanes in the presence of TiC14, migration of the silyl group was found to give a-(silylalkyl) ally1 ketones (Eq. 54) [172]. PhtN Ph*$OSiMe2Ph

+M 33 e,..@ ./-

TiCl A

PhtN HO SiMeZPh & \P h

(53)

75-8070 n=O,1

single

f

678

Urabe/Sato

$SiMe2(t-Bu)

+

-

Me &SiMe3

Tic14

ci

Acetals, ketals, and their parent carbonyl compounds participate in this reaction [51]. Both simple and functionalized acetals undergo this reaction, as shown in Eq. (55) [173]. Double allylation was noted for the spiro-acetals with 2 equiv. allylsilane in the presence of Tic14 (Eq. 56) [174,175]. Poly-acetals with the structure shown in Eq. (57) underwent clean production of a single product [176].

II

M e 0 Js\/

90%

Me

In mixed acetals the identities of the carbon-alkoxy bond cleaved or retained are a synthetically important issue. Equations (58) [177,178] and (59) [179] illustrate discrimination between oxy groups. In the former the isopropoxy group more accessible to the Lewis acid seems to be eliminated whereas in the latter reaction, a better leaving group, the hydrogen peroxide anion, is eliminated and, at the same time, the more cation-stabilizing methoxy group remains in the product. TBSO ECHBr2 i-Pro

+

TiCI4

/hSiMe3

98%

TBSO d C H B r 2 /

(58)

Titanium(IV)Lewis Acids

Y

O

o

H OMe

+

S M ,-i,-/e/3

679

___ 63%

OMe

The selective cleavage of (N,O)-acetals was exemplified in the reaction illustrated by Eq. (60), even though the yield is moderate [ISO]. Selective reaction of a cyclic (N,O)-acetal with an alkoxy substituent on the nitrogen heterocycle is illustrated in Eq. (61) [ M I . Other related reactions are listed in Eqs (62) [182,183], (63) [179], (64) [184], (65) [183], and (66) [185]. It should be noted that in the reaction depicted by Eq. (63) the stereochemical integrity of the epoxide moiety is almost lost in the product, showing the free ionic character of the intermediate. A weaker Lewis acid, such as Ti(O-i-Pr)4, is totally ineffective in this allylation of epoxides. A vinylogous (N,O)-acetal shown in Eq. (64) was regioselectively allylated at the carbon bearing the nitrogen atom.

I

C02Me

I

C02Me

n = 0,l

C02Et

C02Et n = 0 70% cisltrans = 2:1 n = 1 72% cisltrans = 1:1

PH

680

Urabe/Sato

0 HNKNH M e o Me02C

TiCI4

+

w

SiMe3

0 “

W

H

(65)

30% Me02C

OBn

OBn

A cyclic sulfonium salt incorporated in the (0,s)-acetal-like structure shown in Eq. (67) was allylated with allylsilane with the scission of the most labile S+-C bond “61. The (0,Se)-acetal underwent selective cleavage of the carbon-selenium bond to give an allylated ether rather than the selenide (Eq. 68) [187]. This phenomenon is easily explained by the cleavage of the weak carbon-selenium bond, further assisted by the stabilization of the resulting cationic intermediate with the methoxide oxygen in the transition state, although NMR study suggested that TiC14 preferably complexes with the methoxy group rather than with the methylseleno group. Me0

Me0

CI

h

-

i e3 /fiOMe-/SM TiCI4

*

OMe

OMe OMe S A & r\

(67)

I

82%

1.4:l

Ar TiCI4

C6tij34seMe OMe

+

SeMe

eSiMe3 C ~ H I ~ Y / C H ,< 6 3 1 OMe 54%

(68)

0%

Titanium tetrachloride promoted a three-component cyclization involving a carbony1 compound, an allylsilane, and an acetal, as shown in Eq. (69) [188]. The reaction was initiated by ally1 addition to the aldehyde; this was followed by acetal exchange and intramolecular Friedel-Crafts-type alkylation of the olefinic moiety.

r

H T In

R

W O T i X 3

]

Titanium(ZV)Lewis Acids

681

The functionalized allylsilanes shown in Fig. 8 [183,189,190] have been used for allylation in the presence of TiCI4 to give functionalized unsaturated compounds which facilitate further synthetic elaboration. Equation (70) illustrates the utility of (ch1oromethyl)allylsilane for the preparation of a bicyclic structure [183].

Me3Si&OSiMe3

Me3SiI .&

Me3Si&SPh

Figure 8. Functionalized allylsilanes.

TBSO

TBSO

. Tic14

SiMe3

> 95% de

,&~,z),

75%

0

A polymer-supported allylsilane was prepared by the cross-metathesis of the simpler immobilized allylsilane and an olefin and was used as a new reagent for allylation of an acetal in the presence of TiC14 (Eq. 71) [191].

OEt Ph + Me--(

OEt

TiC14_

xih (71)

\

Diastereoselective allylation of carbonyl and related compounds with allylsilanes, mediated by TiCI4, has been studied intensively and extensively. One of the most fundamental reactions is addition to GI- or P-oxyaldehydes, a useful method for construction of stereogenic centers, as repeatedly surveyed in the review articles cited both in the introduction and in this section. For the a-oxyaldehyde shown in Eq. (72), the syn product was obtained via the chelation intermediate and its diastereoselectivity was always excellent, irrespective of the use of excess TiC14 up to two equivalents [192]. This might be attributable to rigid five-membered chelation, even in the presence of extra TiC14. This observation was not, however, the same as for the P-oxyaldehyde shown in Eq. (73): the highest selectivity for the anti product, again produced via the chelation model, was achieved with 1 equiv. TiC14, but the stereoselectivity gradually decreased when the amount of Tic& used exceeded one equivalent. The stereoselectivity finally dropped to ca 40 % de when 2 equiv. TiC14 was used [192]. The generation of the open-chain complex of the type ( a l d e h ~ d e ) ( T i C l ~with ) ~ the excess tita-

682

Urabe/Sato

nium halide should account for the latter observation. If the hydroxy group of an aoxyaldehyde is protected with a very bulky group such as that in Eq. (74), the chelation effect is no longer valid and the reaction proceeds according to Felkin-Anh induction [37] to give the anti adduct as opposed to the reaction of Eq. (72) [193]. Other related reactions starting with more complex substituents are summarized in Table 6.

+/

.

( 72 1

OH

n=1 n=2

98-99% de 98-99% de

BnO

OH

. A ,

(73)

n=1 n=2

98%de 40%de

(-yCHO +

o , Si,

0. t-Bu’

Bu-t

0.

0 Me

Sic

t-Bu’

Bu-t

Titanium(IV)Lewis Acids

683

Table 6. TiC14-assisted reaction of oxyaldehydes with allylsilanes. Aldehyde and allylsilane

Structure of major product COPMe

MeYCHo BnO Me&

+

+

M e w 0 2 M e SiMe2Ph

BnO

BnO

e

v

BnO

>30:1

194

M

e

71

1O:l

194

13:l

195

79

--

196

82

6:l

197

76

15:l

198

84

97:3 199

Me

BnO

-S \M i e3

M

+

e

4

OBn H

OH

L d C 0 2 M e

d SiMe2Ph

TBSO C

OBn

BnO

C02Me X C H O

Me

O TBSO

+

L S i M e 3

OBn OHMe

OBn L C H O

87

OBn

+

TBSO

Ref.

Me

M

BnO+CHO BnO

A

Ratio

OH Et M e w c o z M e

SiMe2Ph

Yield (%)

+

M e V N M e 2

Me

SiMe2Ph

BnO

/ICHo +

w

.C

Me

O .

Me

M

e

2

Me

+\ OH

BnO -\SM i e3

N

58-74

>15:1

200

71

high

196

Me

OTBDPS OBn

+

y S i M e 2 P h Me

684

UrabelSato

Table 6. (Contnd.) Aldehyde and allylsilane

Structure of major product

Yield (%)

Ratio

Ref.

71

single

201, 202

78

12:l

198

83

5.5:l

198

90

28:l

203, 204, 205

90

>30:1

206

92

>30:1

193

90

>30:1

193

81

20:l

193

OTBDPS OBn Me

C02Me

x SiMezPh

.

.

Me

Me

PivO

OMeOH

\wSiMe3 \ -

+

p i v o q C H O

Me

Me PivO Me0

GCHO TBSO

OH

Me

+

Me4/.\/\Me

Mi SiMezPh

BnO Bn02CW H AcOMe Me

BnO2C -S \M i e3

+

TBDPSO V

H O

TBDPSO&4C02Me 3e4/co2Me SiMepPh

Me

Me

ecH0 /o

0.

f-BU’

OH

BnO

O

Me

) , . & , eM +

Si , Bu-t

0. O , Me Si , f-BU’ BU-f

SiMe2Ph

f-BU. ,Bu-t oSi,o

t-BU.

vu

CHO

Me

+

M e ~ ~ c o 2 M e

Me

i-Pr, TBSO

Bu-t

O a 4 C 0 2 M e SiMepPh

Me

Me

Me

Pr-i

Osi’O

W C H Me Me Me

i-Pr,

O

TBSO

C02Me

SiMepPh

Me

,Pr-i

OH Et

Osi‘O

Me

Me

Me

C02Me

Titanium(IV)Lewis Acids

685

Variation of the Lewis acid from a titanium salt can alter the course of the reaction, i.e. either chelation or non-chelation path, to give different diastereoisomers; this is exemplified in Eq. (75) [207]. With titanium halide the chelation intermediate is preferred, whereas with monodentate boron fluoride the reaction proceeds via a non-chelation transition state to give another diastereoisomer.

77%

0

TBSO

-VCO2Me SiMe2Ph

rOTBS N A Me02C A .+ .-

f

OH

( 75 )

3:l

Ligation of the two carbonyl groups in acylformamide to TiC14 is probably responsible for the stereochemistry of its allylation reaction shown in Eq. (76) [208]. The analogous allylation of the corresponding a-ketoiminium cation intermediate generated in the presence of TiC14 afforded an inferior results (9:l selectivity) [209].

686

Urabe/Sato

Advantageous chelation effect is not limited to open-chain substrates, but also seen in the cyclic substrate shown in Eq. (77), in which ally1 delivery occurred from the same side of the hydroxy group, most probably through the cyclic intermediate formed from the two oxygen functionalities of the a-hydroxyketone moiety and the titanium metal [210]. More examples of the diastereoselective allylation of cyclic substrates with allylsilanes are summarized in Table 7. In these reactions good to excellent selectivity was generally achieved. Other functional groups that behave as a stereo-controlling element in the TiQme di ated allylation reaction involve the sulfoxide and iodide groups shown in Eqs (78) [211] and (79) [178]. The quite high control exerted by the iodide moiety is unexpected. When a-iodoaldehydes or ketones were submitted to the reaction in place of the a-iodoacetals, no allylation occurred and trichlorotitanium enolate was generated [172,212].

Bnop - pJg BnO

+

m S i M e 3

Tic14 >61%

BnO Me

(77) 19:l

BnO Me

+

QMe

17c8

OMe

/ASiMe3

Ti&

84%

L I

H17C8

OMe

(79)

Titanium(IV)Lewis Acids

687

Table 7. TiCI,-assisted diastereoselective allylation of ring systems. Substrate

Me02C"' P O M e

Allylsilane

Major product

dsiMe3

Ratio

Ref.

80

--

213

96

--

214

H

Boc

0

0

HN ' 0

P;

Me0

Yield (%)

R

R = alkyl, Ph

p,R HN O '

R=Me

R =CH2CI

SiMea CI

93 64

215 >99:1 183

>%:I

48

94:6 183

74

9:l

175

688

UrabeISato

Table 7. (Contnd.) Substrate

Allylsilane

Major product

SiMe2Ph

Me

Yield (%) Ratio

Ref.

50

17:l

217

95

6.7:l

218

47 55

87:13 219 95:s 219

90

99.5:0.5220

OAc

OAc

R=Me R = Ph

H

>68

single

221, 222

COZMe

C02Me

In addition to linear allylsilanes, those incorporated in a ring structure, as shown in Eqs (80) [223] and (81) [224] showed that very high stereoselectivity is obtainable with regard to the reacting centers, but the directing effect of the C6Hll (Eq. 80) and C02Me (Eq. 81) groups is not very strong. The combined use of Tic& and another Lewis acid, A1Cl3, is an interesting device which increases the diastereoselectivity (Eq. 81). M,"

PhCHO

Me

+ C6Hll

76% 7525-f

-

TitaniumfIV)Lewis Acids

C02Me

689

-

Lewis acid

Ph SiMe2Ph

Ph

C02Me

TiCI4 TiC14/Me2AICI

54% 76%

+

Ph---”y

C02Me

(81 )

5.8:1 7.4:l

A chiral carbon present in the alcohol portion of acetals might control the stereochemistry of the allylation. A few examples conducted in the presence of a titanium Lewis acid are shown in Eqs (82) [225], (83) [226], and (84) [227]. In contrast, an allylsilane with a chiral auxiliary derived from arabinose on the silicon atom has been used for asymmetric synthesis, although diastereoselectivity was low [228].

Titanium tetrachloride is a useful Lewis acid for the addition of other electrophiles to allylsilane; these electrophiles include acid anhydrides (Eq. 85) [229], acyl halides (Eq. 86) [2,3,159,161,230], and SN1-active halides such as tert-alkyl halides (Eq. 87) [165] and a-halosulfides [2,3,159,161]. The allylation of the substrate shown in Eq. (88) was accompanied by stereoselective opening of the cyclobutane ring to give an open-chain triene with defined olefin geometry [231]. A benzylic selenonium

690

Urabe/Sato

ion generated in situ by the treatment of an optically active hydroxy selenide with Tic14 reacted with allylsilane to give the allylated selenide with complete retention of the initial enantiopurity of the benzylic position (Eq. 89) [232]. +

(CF3CO)zO

(2 equiv)

‘h Me3Si

Tic14

HOC:

70%

F3C

(85)

eSiMe3

\Me

( 87 )

‘r\ H

61%

85% ee

“‘Me

PhSlr..

3eMi S , , p+

Me 87% ee

T(O-i-Pr)Cla ( 88 )

+

64%

,

Bu-t

> 99.7% ee

BU-t > 99.7% ee

Intramolecular reaction of an allylsilane and an aldehyde was performed to prepare cyclic compounds as illustrated in Eq. (90) [233], which shows a high diastereoselectivity. The cyclization of optically active allylsilane proceeds stereoselectively in a manner consistent with the anti-SE2‘ mechanism (Eq. 91) [234]. Development of a new reagent with a bis-allylsilane moiety effected tandem inter- and intramolecular cyclizations to give cyclic compounds as exemplified in Eqs (92) [235] and (93) [2362381. In Eq. (92), the double addition product initially formed underwent a pinacoltype rearrangement under the influence of TiC14 to give, eventually, the methyl cyclopentyl ketone. Further examples of intramolecular cyclization of allylsilanes are summarized in Table 8.

R1, R2, R3 = H, Me n=O, 1

ds >30:1

TiCI4

r o O"-'OMe 98% ee SiMe3

-780c

'ro

co-1

SiMe3

__t

86%

691

-* (91)

' 0

o.sx~TiC14

90% ee

ML

I

SiMe3

-

Titanium(IV)Lewis Acids

1

1.22 : 1

TiCI4

1

B,'

SiMe3

Other important feature of the allylsilane-TiC14 reagent system can be seen in 1,4addition of an ally1 group to a$-unsaturated ketones [248,249], illustrated in Eq. (94) [249]. This reaction has been reviewed [2,3,110,159-161,2501; more examples can be seen in Table 9.

692

Urabe/Sato

Table 8. TiCl,-assisted intramolecular cyclization of allylsilanes. Substrate

Major product

Me. Me o.~i

HO.

OH -

R=Me R=Bu

\&R

R'" L C H O

Yield (%) Ratio

70 80

92:8 9O:lO

Ref.

239, 240

80-95 >30:1

233

85

single

241

36

36:16:

242

R', R2, R3 = H, Me n=O,l

trace:t race (With TiC14/PPh3) HO

rn

HO

28

--

243

SiMe3

CHO

% N

% H

99

>50:1

244, 245

86

48:l

246

76

single

247

SiMe3 SiMeB n

I

\vsiyo Me' 'Me

O

,

M

e

N'co~E~ Bn

Titanium(IV)Lewis Acids

693

Table 9. TiC14-assisted1,4-addition of allylsilanes. Unsaturated ketone

Allylsilane

6

Product

Yield (Yo)

Ref.

72

251

73

252

70

253

82

254

92

255

19-92

258

89

259

Bud

I1

Me

Me

,,.!,A\

Me,

\

Si Me3 80-96% ee

(after treatment with MeNHOH)

II

A Ar

Ar = 2-naphthyl

/I\ Ar

694

Urabe/Sato

Intramolecular 1,4-addition proved possible [160], as is shown in Eqs (95) and (96) [260], in which the stereochemistry of the products strongly reflects the geometry of the starting allylsilane moiety. Once the 1,4-addition of the allylsilane is complete, the species present in the reaction mixture before aqueous work-up must be a titanium (or silyl) enolate; this was, in fact, confirmed and utilized by trapping with a second electrophile (Eq. 97) [261]. The bis-allylsilane reagent shown in Eq. (98) underwent 1,4-addition twice to an u,P-unsaturated ketone to give a single diketone [262]. The origin of the high selectivity found in Eq. (98) is discussed in terms of aggregation of the three components, bis-allylsilane, ketone, and Tic& in the ratio 1:2:1.

TiCI4

89% 88:12

90: 10

OTiX,

TiCI4

QMe Me

,SMe Me

77%

Me ( 97 )

SiMe3

EIZ = 514

SiMe3 I

Tic14 Me ( 9 8 )

SiMe3

Allylsilanes work as allylating reagents if the transient /3-silyl cation smoothly collapses with desilylation to form a carbon-carbon double bond. In certain circumstances, however, desilylation is retarded and becomes a slower process than a second path, which might be an ‘unusual’ yet synthetically interesting reaction. Reaction of allyltrimethylsilane with a$-unsaturated carbonyl compounds in the presence of

Titaniurn(1V)Lewis Acids

695

TiC14 usually results in 1,4-allyl transfer, as described above. When, however, the same reaction is performed with an allylsilane having a bulky silyl group, the course of the reaction is completely altered to give cyclopentane derivatives in which the silyl group is retained but migrates from its original position [263-2661, as shown in Eq. (99) [267]. As the orientation of the silyl group in the product, and the stereoselectivity of the cyclization are often controlled with high selectivity, this transformation serves as a stereoselective synthesis of cyclopentanol derivatives based on the well-known conversion from silyl to hydroxy group. Equivalent reactions are also observed for related silicon reagents, for example allenylsilanes; these have been reviewed [161]. Typical trialkylsilyl groups effective in this cyclopentannulation reaction includes (i-Pr)3Si [268], Ph2MeSi [267], Ph3Si 12671, and (Ph3C)Me2Si 12691 groups.

Similar reactions, but not accompanied by the silyl migration, have also been reported. When a bulky allylsilane is reactcd with benzoylformates, the product obtained is an oxetane, as shown in Eq. (100) [270]. If this reaction is executed with allyltrimethylsilane, the expected homoallyl alcohol is produced in good yield. When, moreover, interception of the p-silyl cation with a neighboring nucleophile is faster than desilylation, even the trimethylsilyl group is preserved in the product (Eq. 101) [271].

R = Me, Ph Six3 = TBS, TBDPS, Si( i - P r ) ~

QOMe

+

-S /M i e3

. SiMe3

SiMe3

Allylstannanes are frequently used as allylation reagents in the presence of a titanium Lewis acid [162,272-2751. The greater reactivity of allylstannanes than the corresponding allylsilanes toward electrophiles 1272,2751 often enables the use of a

696

Urube/Sato

milder Lewis acid and/or relatively unreactive substrates (both electrophiles and ally1 stannanes themselves). This is obviously an advantageous feature of the tin reagents. Thus an a,a-difluoroacetal derivative has been allylated with allylstannanes in the presence of the mild Lewis acid Ti(O-i-Pr)2C12,resulting in high diastereoselectivity (Eq. 102) [276]. Chiral stannylacetals were allylated with a similar combination of reagents to give chiral stannanes with the stannyl group in the product remaining unaffected (Eq. 103) [277]. Optically active allylstannane reacted highly enantioselectively with aldehydes and even ketones (Eqs 104 and 105) [278-2801. Retention of the regiochemistry of the starting allylstannane in the product suggested that the course of the reaction consists of a double allylic rearrangement occurring on generation of the allyltitanium reagent in situ and its reaction with the carbonyl compounds. Allylstannanes react preferentially with acetals in the presence of the corresponding aldehyde (Eq. 106) [S3].

Ti(O-i-Pr)2C12 *

Ph

79%

, HO H J,-c'Ho

+

Bu3Sn

OCb

5 *ocb 96%

96% ee

(104) 96% ee

_ -HO, .,Me n = 2,3

R 4 0 M e + RCHO OMe

94% ee

+ /mSnBu3

94% ee

. L \+ TiCI4

81-87% R

RL\

86114- 88:12

(106)

Titanium(IV)Lewis Acids

697

A new synthetic design, based on a titanium Lewis acid consisting of two titanium centers in the same molecule, such as A in Fig. 9, has been reported. This titanium species is more active in allylation with an allylstannane than species B which has only one titanium center per molecule and is a conventional Lewis acid (Eq. 107) [281]. The intermediate C, in which double coordination of the oxygen functionality to both titanium atoms has been proposed, would account for the efficiency of the species A in this reaction.

*

(i-Pr0)3Ti,

.Ti(O-i-Pr)3

0

,Ti (0-i-Pr)* 0’ ‘0

0

.9, ’,

(i-Pr0)3Ti1,

,Ti(O-i-Pr)3

2

0 A

B

C

Figure 9. Titanium Lewis acids.

A (10 mol%) 67% B (10 mol%) 1%

Intramolecular allylation of functionalized allylstannanes is feasible. One application used in the synthesis of natural product is shown in Eq. (108) [282]. The yield is, however, moderate in this example. More examples of titanium-promoted inter- and intramolecular reactions of allylstannanes with carbonyl and related compounds are summarized in Table 10.

698

Urabe/Sato

Table 10. Titanium-mediated allylation with allylstannanes. Substrate

TBSO

Allylstannane

Titanium salt

Me

C H O +-- .J

Me0

+ / OH1

TBSO -/SnBu3

Tic14

Yield (%)

Product

Ref.

Me

'75

283

Me0

403

69

285

87

285

87

286

Titanium(ZV)Lewis Acids

699

Table 10. (Contnd.) Substrate

Allylstannane

Titanium salt

Product

Yield (%)

Ref.

SnBu3

RCHO

&

R

Ti(0-i-Pr)C13

OMe

R=

288

OMe

Ph pTol C-C~HII i-Bu

98:2 96:4 9614 91:9

53 93 58 52

HO H A

H

0

TiCI4 Bu3Sn

OCb

96% ee

96

278

84-91

278

96% ee

HO Me

TiCl4 EtO2CJ n = 2,3

B u ~ S ~OCb 94% ee

Me OCb 94% ee

+

700

Urabe/Sato

Table 10. (ContndJContnd.) Substrate

Allylstannane

BnO

Me & s ~ B ~ Ti(O-CPr)2C12 ~

OAI(BU-I)~

Titanium salt

Product

Yield (%)

BnO

Ref.

OHMe 77

276

A0&AOH95

277

t

CF3

93:7

Me

Me Bu3Sn+Ij

/ASnBu3

Me

Ti(O-i-Pr)zCIz Bu3Sn

t

Me

Me

93:7

85:i5

\...OH TiCI4

290

SnBu3 n=1 n=2

83:17 single

86 28

>95

290

84: 16

OH 291

TiCI4 92:8 Ti(O-i-Pr)2C12 955

83 67

Although allylation of imines with allylsilanes is encountered less frequently, that with allylstannanes seems more common, probably because of the enhanced nucleophilicity of the tin reagent compared with the silyl counterpart. Equations (109) [292] and (110) [293,294] illustrate the allylation of imines. In the former reaction, a catalytic amount of the Lewis acid, TiC1(OTf)3, is sufficient to bring the reaction to completion. Intramolecular allylation of imines [295] or hydrazones [296] led to the stereoselective construction of amino-cyclic structures, as shown in Eq. (111) [296].

Titanium(IV)Lewis Acids

701

nc'+ - L\ TiCI(0Tf)

pS -,nBu3

Ph

66%

HN

Ph

20:1-30:1

R = i-Pr, eC6H11, fury1

n = 1,2 X = NHTs, NPh2

The titanium-promoted 1,4-addition of allylstannanes to a,P-unsaturated ketones is also a known transformation (Eq. 112) [262].

SnBu3

-

Ph

0

95%

Analogous to the allylation with allylsilanes and -stannanes, the transformations, vinylallylation, propargylation, allenylation, alkenylation, alkynylation, and arylation, are viable by the use of an appropriate reagent in the presence of a titanium Lewis acid; these are surveyed in the review articles cited both in the Introduction and in this section. The stereochemistry of the reaction of a (vinylally1)silane in the presence of TiC14 has been reported [234]. Equation (113) shows that the major reaction of this silane and isobutyraldehyde occurred mainly in the anti sense with a ratio of anti to syn attack of 90:lO at the terminus remote from the silyl group. Essentially the same stereochemical outcome was observed for the same reaction with the corresponding trimethylsilyl derivative. The intramolecular reaction with an acetal, however, proceeded less selectively; the antilsyn ratio was 60:40 (Eq. 114) [234].

702

UrabdSato

El'

T v-

PhMe2Si

TiC14

SiMe2Ph v n

+

80% ee

-----

/JCHO

OH

'

OPO

kOMe

TiCI4 -78 85% "C

98% ee

i

90 El+ OH

v * -

+

40%, 64% ee

=++

lo

(113) not isolated

(114)

' 0

20% ee

Allenylsilanes and -stannanes combined with a titanium salt are versatile reagents for propargylation of aldehydes (Eq. 115) [297], ketones (Eq. 116) [298], (N,O)-acetals (Eq. 117) [299], and a&unsaturated ketones in a conjugate fashion (Eq. 118) [300]. Intramolecular reaction has also been reported (Eq. 119) [301] in which a Bu3Sn-carbon bond was cleaved exclusively in the presence of a TBS-carbon bond. That the isomeric starting material, propargylstannane, did not give the desired product (Eq. 120) demonstrates that the direct scission of the carbon-Sn bond by the electrophile under these reaction conditions is not a feasible path [301].

I

NH2+ CF3CO2-

Me3Si

I

%

0

+

'i"I 1 '

Me

Nu

uri

(116)

Titaniurn(IV) Lewis Acids

B

O

G

ryAofiho n

YMe n TiCI4

0 Me3Si +

H

n

+

II

(117)

/

LAC: IVlG3dl

1

Me

703

59%

Me

28%

,rSnPh3 . TiCI4

E L o +ir

82%

TiCI4

CHO

P

C4eySnBu3

70%

TBS

P C H O

TiCI4 decomposition

( 120 )

Propargylsilanes can transfer an allenyl group to electrophiles [302-3041, as is shown in Eq. (121) [302]. R

R

R = H, Me, i-Bu R’ = Me, Et

Alkenylsilanes and -stannanes, and arylsilanes and -stannanes are useful reagents for transfer of an sp2-carbon unit to electrophiles under titanium catalysis. Epoxides are opened by TiC14 to generate cationic carbon, which is successfully trapped with bis(trimethylsily1)propene as an alkenylsilane (Eq. 122) [305]. Other Lewis acids, for example ZnCl2, SnC14, and BF3. OEt,, proved less satisfactory. Cyclic epoxides such as cyclopentene and cyclohexene oxides gave poorer yields. An intramolecular version of this reaction proceeded differently (Eq. 123) [305]. Eqs (124) and (125) illustrate diastereoselective alkenylation and arylation of (N,O)-acetals that take advantage of the intramolecular delivery of alkenyl and aryl groups [306]. Cyclic ethers

704

Urahe/Sato

were prepared by titanium-induced ring closure of alcohols with a vinylsilane moiety (Eq. 126) [307-3091. The relative reactivity of alkenyl- and arylsilanes towards acylation with acyl chlorides in the presence of TiC14 has been reported [310].

R = H, Me, Et

SiMe3

TiCI4 Mefi >300:1 ( 124) MeHoMe HO NBn 57% (CH2=CH)3Si0 NBn C02Et

C02Et

MeHoMe NBn

(t-Bu)Ph2Si0

CO2Et

The stereochemistry of alkynylation of cyclic acetals with 1-alkynylsilanes has been investigated (Eq. 127) [311,312]. The type of silylacetylene, terminal or internal, dramatically changed the stereochemistry of the product. Vinylogous acetals are also alkynylated (Eq. 128) [313,314]. The remaining acyloxy group on the 6-membered ring critically controls the stereochemistry of the incoming alkynyl group, irrespective of the cis or trans orientation of the eliminated group. Chiral acetals prepared from an optically active diol underwent an asymmetric alkynylation [315].

Titanium(N)Lewis Acids

705

. M e 3 S i e

‘t1oo:o

R

*

TiCI4 64-81%

R = alkyl, Ph, SiMea

re3 TiCI4

73-99%

R

XO”“

X = Ac, f-BUCO R = alkyl, SiMea

15.4 Reduction with R3SiH or R3SnH A combination of R3SiH and a protic acid such as CF3C02His known to be useful for ionic hydrogenation. A variety of substrates such as olefins, cyclopropanes, dienes, carbony1 compounds, acetals, imines, alcohols, etc., were hydrogenated according to Eq. (129) [316]. Lewis acids could be a surrogate of the proton in Eq. (129), and a titanium Lewis acid such as TiC14 is quite effective in the reduction of acetals to the corresponding ethers with trialkylsilanes or -stannanes [2,3,272,275].The use of TiC14 seems to be critical for the reaction depicted by Eq. (130), because other reagents including Ti(O-i-Pr)4 or Cp2TiC12 with milder Lewis acidity did not promote the reaction even under forcing conditions [317]. Et3SiH

yi

- ><”

X = CR’R2, 0, NR, -CH2CH2-,etc

Et3SiH

Hf (X = 0)

H

(129)

706 Me

Urabe/Sato

Et3SiH

(1 equiv) OH

Additive(1 equiv) CH2C12

OH

-78"C 86:14 60% TiCI4 Ti(O-i-Pr)4 25 "C no react. Cp2TiC12 25 "C no react.

Additive:

Construction of stereogenic centers by this method is illustrated by Eq. (131) [318]. The use of bulkier and less reactive Ph3SiH as the hydride donor seems to result in much better stereoselectivity than Et3SiH. In addition, other Lewis acids including BF3.OEt,, Et2A1C1, EtAlCl,, A1C13, and Me3SiOTf were found to afford less effective control of the stereoselectivity under similar reaction conditions. The compatibility of the thioacetal moiety in this reduction is indicative of a chemoselective transformation. Comparison of the reduction of a ketone and its dimethyl acetal by Bu3SnH showed the latter to be more reactive than the former in the presence of TiC14, but reactivity was reversed by use of the newly introduced Lewis acid containing two titanium moieties in the same molecule (Eq. 132) [281]. Other results from reduction of acetals with trialkylsilanes are summarized in Table 11. HSiR3

Ph

-78"C

R = Ph 82:l 88% Et 7:l 75%

-

OMe Bu3SnH t - B u e O + t - B u a t - B u e O H + t - B u e O M e ( 132 ) OMe Additive Additive =

TiCI4

(i-Pr0)3Ti,

' 0

89%

36 : 64

Ji(O-i-Pr)3

'-d' 0

54%

100 : 0

707

Titanium(IV)Lewis Acids Table 11. Reduction of R-,SiH in the presence of T i Q . R3SiH

Substrates

Product OMe

0-OMe Et3SiH

Yield (%)

Ref.

__

31 9

HI1CSASnR3

H11C5ASnR3

R = Bu or c CsHl

R

BR OH

0

s ' > Ph3SiH

f i s r R

R = P h 82:l Me 1O:l

O

88 70

31 8

Et3SiH

85-94

320, 321

Et3SiH

75

322

62

325

R = alkyl

Et3SiH

0 a variety of R3SiH

f-BU

85:15-54:46

R=H,Me

OTBS

Et3SiH

OMe OBz

M + ,-.e Et3SiH OMe

O

H

+=

325

60

31 7

95

326

H .Me

Me

L

46

Et3SiH

OH

OH

86:14

Et3SiH NC O

O

H

708

Urabe/Sato

Secondary or tertiary amides have been converted to aldehydes with Ph2SiH2 in the presence of Ti(O-i-Pr)4 (Eq. 133) [327]. It has been proposed that a species such as ‘HTi(O-i-Pr)3’ is the active reductant in this reaction. A similar reduction of lactones to lactols has also been reported [328]. Ph2SiH2 ( 1 . 1 equiv)

0 RJ

NRo2

H+

R

Ti(O-i-Pr)L (1 equiv) r.t.

J

p

~

~

i

,

R-CHO

(133)

50-9OYo

An interesting conversion of nitrostyrenes to arylalkylhydroximoylchlorides has been conducted by reduction of the former with TiC14and Et3SiH (Eq. 134) [329,330].A plausible path for this reaction has been described [331]; in this the titanium halide plays an important role as a Lewis acid. When this reaction was performed with other silylated nucleophiles, e.g. Me3SiN3or Me$iCN, in place of EtSSiH, an N3 or CN substituent was incorporated at the position a to the hydroximoylgroup [332].

Et3SiH

Ar*N02

CI ArAN,OH

( 134 )

TiC14 63-80°/a

Cleavage of an acyloxy-carbon bond is possible with a trialkylsilane and TiCl4, if it is assisted by neighboring-group participation (Eq. 135) [333] or if it is promoted by release of the strain of a small-ring lactone (Eq. 136) [334-3371. Fairly good stereoselectivity was recorded. AcO H H 1 & i PhS ) X C 7SPh H15

Et3SiH(D) Ti& 76%

PhS H , H15C7))/C7H1 PhS ;H(D)

92:8

EtsSiH Me 0

82%

85:15

Other hydride sources can work analogously to R3SiH. For example, acetal cleavage has been effected by NaBH3(CN) and Tic14 (Eq. 137) [338]. The nitro group survived the reaction conditions. Deoxygenation of aromatic ketones to the corresponding hydrocarbons has been achieved with borane-dimethylamine complex and TiC14

Titarzium(IV)Lewis Acids

709

(Eq. 138) [339]. LiA1H4 and TiC14 cleaved the ether linkage to give a naphthalene (Eq. 139) [340], but reaction might be reduction by a low-valent titanium species, rather than simple hydride reduction.

ONo2 R=H.Me

Me2NH*BH3 (2 equiv)

*

Br &Br

TiCI4 (1 equiv) 80%

Br

LiAIH4

(139)

Ti& Et3N 60%

15.5 Diels-Alder, Ene, and Related Reactions The Diels-Alder reaction is one of the most fundamental means of preparing cyclic compounds. Since discovery of the accelerating effect of Lewis acids on the DielsAlder reaction of a,p-unsaturated carbonyl compounds [341-3441, its broad and fine application under mild reaction conditions has been amplified. Equations (140) [341] and (141) [345], respectively, illustrate typical dramatic effects from an early reaction and from one reported more recently. Lewis acid-promoted Diels-Alder reactions have been reviewed [7,8,346-3531. In addition to the acceleration of the reaction, other important feature is its alteration of chemo-, regio-, and diastereoselectivity; this will be discussed below. The titanium compounds used in Diels-Alder reaction are titanium halides (TiX4), alkoxides (Ti(OR)4), or their mixed salts (TiX,(OR),,; y1 = 1-3). A cyclopentadienyl complex such as c ~ ~ T i ( 0 Tis f )also ~ documented as a very effective promoter of a Diels-Alder reaction [354]. In addition to these titanium salts, a few compounds such as those in Eq. (142) [355] have recently been reported to effect the Diels-Alder reaction. The third, [(i-Pr0)2Ti(bpy)(OTf)(i-PrOH)](OTf), was estimated to be a more active catalyst than c ~ ~ T i ( 0 T f ) ~ .

710

Urabe/Sato

140 "C

AIC13, SnC14, BF3*OEt2, FeCI3, or TiCI4

"'< ConMe

{

+

-

Additive

+

Y c H O

75-80%

C02Me (141)

C12CHCHC12 r.t.

C02Me

Additive = Tic14 none

60%

AcO

AcO &HO

CHO

Catalys:

+

no reaction

( 142)

\ endo (i-Pr0)2Ti(OTf)2(i-PrOH)2 (3 mol%) [(i-PrO)2Ti(bpy)(i-PrOH)2](OTf)2 (1 mol%) [(i-PrO)2Ti(bpy)(OTf)(i-PrOH)] (OTf) (1 mol%) (i-Pr0)2TiC12 (1 mol%) Cp2Ti(OTf)2 (1 mol%)

ex0

r.t.; 5 min 50% 88:12

r.t.; 6 h r.t.; 1 h r.t.; 12 h r.t.; 1 h

99% 98: 2 98% 99: 1 0% -85% 99: 1

Other investigations of titanium Lewis acids include a study of the molecular imprinting of a titanium salt according to Eq. (143) [356]. In the Diels-Alder reaction of Eq. (144), this polymer-immobilized titanium salt has catalytic activity only 3-5 times less that of the analogous complex of the type (ArO),TiCI2 in solution.

polymerization

*

yellow

X = NEt2 yellow orange CI dark red

Titanium(IV)Lewis Acids

0

0 +

0

711

Polymer-Ti prepared in eq 143

*

P

N *

The Diels-Alder reaction of a relatively unreactive dienophile such as cyclopentenone can be effected with TiC14 at a low temperature, although the exocyclic double bond of the product migrates to the more stable endo position (Eq. 145) [357]. A weaker Lewis acid, Ti(O-i-Pr)zClz, resulted in no reaction even under forcing conditions. Acceleration of reaction and the improvement of diastereoselectivity were achieved in a titanium Lewis acid-mediated intramolecular reaction as shown in Eq. (146) [358]. Other relevant Diels-Alder reactions promoted by titanium Lewis acids are summarized in Table 12.

TiCI4

CnP""

+

Et

>jmrMe

%

quant.

M < e-

90%

150 "C

-

Br

100: 0

63 : 37

-

Et

Me

Br ( 146 )

712

Urabe/Sato

Table 12. Titanium Lewis acid-promoted Diels-Alder reactions. Diene

x

Me

Dienophile

Titanium salt

Product

,..cox

fox

0

Tic14

Me

MeOPC

VC

74-77

359

75

361

89

357

60

345

C02Me

9515 - 1oo:o regioselective

X = SPh, SePh

Me3Si

Yield (%) Ref.

Ti&

E E = C02Me

Me0

6%

4

0

TiCI4 double bond migrated

Me

Me0

Me0

&

Me4!)

NcK

migrated

TiCI4 Me0

TiCI4

Titanium(IV)Lewis Acids

713

Table 12. (Contnd.) Diene

-

Dienophile

Titanium salt

Product

Yield (%) Ref.

/\\\.%COX Me3Si0

TiCI4

Rfox

R = Me, C02Me X = SPh, SePh

{NBn

35-53

359

53

362

44

31, 32

0 9 5 5 - 1oo:o regioselective

Ti(O-CPr)&I

0

0 \

Efox I

cox

X = SPh, SePh, E = C02Me

0

E

82:18 - 85:15

TiCI4

1

P(O)(OMe)2

0 Tic14

( endo)

TiCI4

endo ex0

h*

30 0.4

0

(% /g 02Et

-

363

+

""Me

Br n = l 85:15 n = 2 100: 0

Et

H"'-

Me Br

quant. 358

714

Urabe/Sato

Control of the stereochemistry of the Diels-Alder reaction by means of a chiral center in the substrate is a versatile means of synthesizing cyclic systems stereoselectively [347]. For preparation of ring systems with multi-stereogenic centers, in particular, the diastereoselective Diels-Alder reaction is, apparently, one of the most dependable methods. The cyclization of optically active substrates has enabled asymmetric synthesis. Equation (147) shows a simple and very efficient asymmetric DielsAlder reaction, starting from commercially available pantolactone [364,365], in which one chlorine atom sticking out in front efficiently blocks one side of the enone plane. A fumarate with two chiral auxiliaries afforded virtually complete stereocontrol in a titanium-promoted Diels-Alder reaction to give an optically active cyclohexane derivative (Eq. 148) [366,367]. A variety of diastereoselective Diels-Alder reactions mediated by a titanium salt are summarized in Table 13.

diene

100%

98% d e

Titanium(IV)Lewis Acids

715

Table 13. Titanium-promoted diastereoselective Diels-Alder reactions. Diene

Dienophile

0

Titanium salt

Product

0

Ph

Yield (“A) Ref.

ph

single

9416- 96.513.5

n

f\

TiCI4

s - f0 81:19

0

OKPh

endolexo = 90: 10 R

Jo

.

oxph .

(1/3)(ArH~)~ *TiCI4

enddexo = 78:22

90

370

96

371

716

Urabe/Sato

Table 13. (Contnd.) Diene

Dienophile

Titanium salt

Yield (%) Ref.

Product

Boc.

Boc

S(0)Tol

TiCI4

0

0

0

84:16

TiCI4

f0*O 0

0

364, 365

64

373

0

qPh

0

75

TiCI4

0

Hetero-Diels-Alder reactions starting with unsaturated compounds with heteroatom-carbon or heteroatom-heteroatom multiple bond(s) are also enhanced by Lewis acids [374-3811. Aldehydes and imines work as dienophiles under the influence of TiC14. Electron-rich dienes are generally a preferable partner, as shown in Eq. (149), in which the product was obtained virtually as a single isomer [382,383]. The importance of the choice of the Lewis acid in determining the stereochemical outcome of the reaction is illustrated in Eq. (150) [384]. The notion of chelation and of Felkin-Anh models, respectively, is valid for these Diels-Alder reactions. Diastereoisomers other than those shown in Eq. (150) were not detected. The stereochemistry of the product in Eq. (149) could be also explained by the chelation model.

MeBSiO .exoMe Me

+

B n O pH

TiCI487% H+

Bnogr (149)

__)A

Me Me single isomer (after desilylation)

Titanium(W)Lewis Acids

TBSO,,,

),

717

(after desilylation) 81:19

NBn

(150)

MA Ph

OTBS

*

2377

90%

+SiMe3

a&Unsaturated ketones, a&unsaturated thiones, nitroalkenes [385], and related compounds serve as heterodiene units and give heterocyclic compounds. Electronrich olefins seem to be suitable dienophiles for this reaction. Although there is a possibility that the reaction proceeds via a stepwise, cationic path, especially in the presence of a Lewis acid, a concerted mechanism has been proposed for the hetero-DielsAlder reaction between an a&unsaturated ketone and a vinyl ether mediated by a titanium compound (Eqs 151 and 152) [386]. Thus, the stereochemical integrity of the ( E ) - or (Z)-dienophiles was highly preserved in the products. A polymer-supported substrate has also been used in the hetero-Diels-Alder reaction. Aromatic imines are generated in situ on the polymer, and a Lewis acid-mediated [4 + 21 addition was conducted with an electron-rich olefin (cyclopentadiene) (Eq. 153) [387]. Further examples of hetero-Diels-Alder reactions are shown in Table 14.

2

+

l)

OEt

Ph

Ti(O-i-Pr)2C12 *

EPh"" t o T S 0 2 p h

(151 )

97%

Me

SOpPh

+

i(OEt Ph

Ti(O-i-Pr)2C12

EtoTso (152)

97%

*

Ph

718

Urabe/Sato

Table 14. Titanium-promoted hetero-Diels-Alder reactions. (Hetero)diene

(Hetero)dienophile

Titanium salt

Yield (“A) Ref.

Product

OMe TiCI4

Me< Me3Si0

BnO

O w M e

87

382, 383

74

388, 389

“ ‘ P H Me Me single isomer (after desilylation) Ph

Me

Ph TiCI4

0 (after desilylation)

B 384

(after desilylation) Me 386

SOzPh

Ti(O-i-Pr)2C12

EtoTso Ph

97

386

Me

Ti(O-i-Pr)2CIp “Me

43

390

97

391

85:15

NHBZ Ph -

TiCI4

Ph’

M e R q

0

0

\k K

de >99%, endolexo = 85:i 5

Ti(O-i-Pr)2CI2

85-88

385, 392-394

87-97

385, 395, 396

Me

R

Ti(O-CPr)2C12

c;”i

% de

TitaniumfW)Lewis Acids

719

Cationic hetero [4 + 21 cyclization has been performed with TiC14-PPh3 as Lewis acid. Equations (154) and (155) show that the process probably proceeds in a concerted path to give the corresponding products with excellent stereospecificity [397]. Ph

7 O

NI -SPh Me

Me

154)

Me

Ph

* TiCI4*PPh3

Me

67%

&qey

( 155 )

99:l

Me

The exolendo selectivity of the 1,3-dipolar addition of nitrones was regulated by the titanium salt as shown in Eq. (156) [398,399]. Aza-Cope rearrangement of a sugarderived substrate initiated by the acetal cleavage with TiCI4 proceeded diastereoselectively to give the open-chain product (Eq. 157) [400].

11:l

’

Titanium Lewis acids effect formal [2 + 21 cycloaddition as shown in Eqs (158) [401] and (159) [402,403]. Subtly changing the reaction conditions and substrates alters the product of Eq. (159) from the cyclobutane to a dihydrobenzofuran derivative, as will be described below. The analogous hetero [2 + 21 addition of a chiral aldehyde to a silylketene proceeded stereoselectively in the presence of titanium tetrachloride to give the propiolactone, as shown in Eq. (160) [404]. The silyl group was removed by the treatment with KF.

720

Urabe/Sato

SePh

Jr

i-Pr3Si

t-BuO2CTCO2Bu-I

+

TiC14-Ti(O-i-Pr)4 PhSe+:u l -t (2:l) t

PhSei-Pr3Si&C02Bu-t

+

C02Bi.1-t

( 158 )

I

57%

i-Pr3Si'

\

\

X

OMe Me

0

U

H

1 : l

T ~ c M~ ~e

e

w

76%

ph""

M

e

(159)

Me

-

0 single regioisomer

Ene reactions are promoted by titanium compounds as Lewis acids [405-4091. The carbonyl ene reaction of methylenedihydrofuran with aldehyde (Eq. 161) [410] and intramolecular reaction of an unsaturated aldehyde (Eq. 162) [411] are illustrated below. The cyclization of a conjugated ketone in the presence of a mixture of TiQ and Ti(O-i-Pr)4, as shown in Eq. (163), cleanly afforded the bicyclic ketone; this might be considered as the product of a vinylogous ene reaction [412].

'"'3 TiC141:Fi-Pr)4 *

Titaniurn(IV) Lewis Acids

OBn

721

(163)

Imines behave like aldehydes. This imino-ene reaction has been reviewed [408,409]. The following examples (Eqs (164) [409] and (165) [413]) are intramolecular reactions of an aldimine and a ketimine. It should be noted that in the former reaction a small amount of the unusual product (benzimine, the right) was formed and that in the latter reaction the MOM ether was eliminated during the reaction.

single isomer

2-(A1koxy)allyl or 2-[(trialkylsilyl)methy1]allyl derivatives such as alcohols, ethers, or sulfones undergo [3 + 41 addition with dienes in the presence of a titanium Lewis acid as shown in Eq. (166) (R = O R or (R'$3)CH2; Y = OH or S 0 2 R ) [414418]. When the R group is an alkoxy group, a cycloheptanone derivative is formed as the final product. Similarly starting material with a (trialkylsi1yl)methyl group affords a methylenecycloheptane. The simple Friedel-Crafts-type reaction of the diene might become a side reaction.

-c concerted

TiX4

R

4$

stepwise

722

Urabe/Sato

A recent example of an intermolecular [3 + 41 cycloaddition starts with an allylic acetal, as shown in Eq. (167) [419,420]. Other Lewis acids, for example AIEt,C13-, (n = 0-3), TMSOTf, TfOH, SbC15, SnC14 were less effective. Although the exact nature of the transition state is still uncertain, the stereochemistry of the product might be explained on the basis of the rule of endo addition with the least hindered approach of the diene. The possibility of asymmetric synthesis starting with the same substrate with a chiral acetal moiety has been mentioned (see Table 15).

(167) 99%

-

EtO (1 equiv)

(1.5 equiv)

The intramolecular version of this reaction has many applications. The stereochemistry of the starting material shown in Eq. (168) seems to influence the efficiency of the reaction [421,422].The acceptor of the allylic cationic species is not limited to conjugated dienes. The following result shown in Eq. 169 indicates that a simple terminal olefin might serve as the reaction partner to give bicyclic cyclopentane skeleton [423]. In this formal [3 + 21 cyclization, the reaction should proceed stepwise. Other results of inter- or intramolecular [3 + 41 or [3 + 21 cyclizations are collected in Table 15. The stereochemistry of the reactions has been studied in detail and is the subject of more extensive reviews [418,424].

aSph

fiph

PhS02Me

Me

TiCI4 (1 equiv) PhNHMe * (1 equiv) 70%

( 169 1

Me Me& H

Titanium(ZV)Lewis Acids

723

Table 15. Titanium-mediated [3 + 41 or [3 + 21 cyclization. Substrate(s )

Product

SiMe3 E t O 4

+

6

,%OEt

Yield (%)

x=o

99 X = C H 2 62

Ref.

419, 420

EtO

I

ds = 9:l

TOlSO2Q - 5 - " e

EtfiMe

74

424

58

424

S02T0l

P h . Me S 0 2 ~ s p h

@!kSPh 67

418, 421, 422.

P h S 0Me 2fiph 12

78-81

phso@t

425

724

UrabdSato

Table 15. (Contnd.)

Substrate(s)

Yield (%)

Product

Ref.

SiMe3 Me Me&

(+ PhNHMe)

Me Me&

423

86

426

56

427

a?:: H

PhNHMe) Me0

70

P O M e

EIZ= 3:l

Me0

I

Me3si*Me

(+ PhNHMe) N SOpPh

N S02Ph

A related version of this cyclization is the reaction illustrated in Eqs (170) and (171) [428], in which methylenecyclopropane was cleaved with TiC14 to give the similar ally1 cationic intermediate which adds to the double bond of allylsilane to give the cyclopentane framework.

-SiMe3

+

f i M e

80%

SiMe3

56 : 44

35 : 65

(170)

Titaniurn(IV)Lewis Acids

725

15.6 Friedel-Crafts and Related Reactions Friedel-Crafts reactions of aromatic compounds with acyl chlorides, anhydrides, or related compounds in the presence of a Lewis acid have been reviewed [429,430]. Among a variety of Lewis acids, the most typical is AIC13, although there are reactions as shown in Eqs (172) [431], (173) [432], and (174) [433] in which TiC14 was used as the Lewis acid.

+

&Me

i-Pro

/CCOCl

Ti&

OPr-i

i-Pro

Me0

$

Me

+ AceO

TIC4 78%

OPr-i

Meo$ Me0

HO

Me

/

OMe

( 172)

71Yo

OH

( 173)

Ac OMe

71 :29

It is well known that Friedel-Crafts acylation of aromatic compounds requires more than one equivalent of a Lewis acid relative to the substrate to bring the reaction to the completion, because the ketone produced deactivates the Lewis acid by complexation. Despite this, only 1 mol % TiC1(OTf)3 and 10 mol % TfOH in dichloromethane or acetonitrile proved sufficient for the acylation shown in Eq. (175); this is, therefore, a catalytic Friedel-Crafts reaction [434]. The high regioselectivity obtained is also useful.

726

Urabe/Sato

61-98%

R’ = alkyl, Ph

R2, R3 = H, Me, OMe

Compared with the acylation described above, titanium compounds seem to find more distinctive utility in the Friedel-Crafts reaction of less reactive electrophiles such as acetals, aldehydes, or ketones, as illustrated in Eq. (176). Alkylation of a phenol with an aldehyde in the presence of Ti(O-i-Pr)4 (Eq. 177) [435] left the acetal moiety unattacked and, at the same time, resulted in high diastereoselectivity. Pyrroles generally act as go6d acceptors towards electrophiles and often suffer from di- or poly-alkylation. Even an (ethoxycarbony1)pyrrole afforded the bis-pyrrole derivative with o-nitrobenzaldehyde in the presence of TiCL (Eq. 178) [436]. A glycine cation equivalent has been devised on the basis of Friedel-Crafts-type alkylation of an (N,O)-acetal in the presence of TiC14, as shown in Eq. (179). Indoles with an electronwithdrawing group are good acceptors [437]. In addition to aldehydes and acetals, a benzylic or allylic cation generated from a benzyl ester (Eq. 180) [438,439] or an ally1 chloride (Eq. 181) 14401 underwent aromatic substitution under the influence of TiCI4.Further results from Friedel-Crafts alkylations are summarized in Table 16.

@

Me 63%

Me0 OH

H

MeAOEt

MeO

Me HO H ; b H single 1

(177)

Titanium(IV)Lewis Acids

Et02C

45%

Me02C Me02C

H

Me02C

H

727

728

Urabe/Sato

Table 16. Friedel-Crafts alkylation of aromatic compounds. Ar-H

Electrophile

WH

Me0

Titanium salt

OH

BnOCH2CHO

OMe (Ar-H)

@ Me0

OH

TiCI(O-i-Pr)3

Product

Yield (%)

Ref.

79

441

85

441

Ar Bno&OH H

Ar BnOCH2CHO

TiCI3(0-i-Pr) (under u. s.)

Bno'-&'Ar H

Me OXCHO /l.OEt

435

Ti(O-i-Pr)4 (under u. s.)

single

ArCHO

442

H A; C02Et

436

TiCI4-Ti(O-i-Pr)4

59

(23)

OMe

OMe OMe

443

729

TitaniumQV)Lewis Acids Table 16. (Contnd.) Ar-H

Electrophile

Titanium salt

Product

Yield (%)

Ref.

CF3

I-BuNHq:H 0

I

t-BuNH

CF3

Me

(cF3c0)20 then TiCI4

(cF3c0)20 then TiCI4

Me

90

444

92

444

57

446

Me

Me

0 OH Bn02C

1 \LMe

CF$H(OH)OEt

YH

H

TiCI4

a H

dPh O".("y"

&OAC

-

OH

1

wo

Qo H

a0

447

a3

447

3:l

/ \

Ph,,,,

H

3:2

730

UrabeISato

Table 16. (ContndiContnd.) Ar-H

Electrophile

Titanium salt

Product

Yield (%)

Ref.

C02Et

Ph2G=N FOAc EtO2C

Ti&

45

437

65

440

BnO

T

O OBn

B

n B

n

O

BnO

m

OBn

TiCI4

O<

0 OBn

v-cl

Tic14

Me

Me

Formylation of aromatic compounds with C12CH(OMe) in the presence of TiC14, Rieche-Gross formylation [448,449], i s represented by Eq. (182) and could be classified as Friedel-Crafts alkylation of aromatic nuclei. Electron-rich aromatic compounds are usually good substrates, and the position of introduction of the formyl group can be predicted on the basis of the usual positional selectivity found for the Friedel-Crafts reaction. This method is a convenient means of formylation; examples are summarized in Table 17. Preparation of poly-aromatics from diarylmethanes has been achieved with the same reagent, as shown in Eq. (183), in which the resulting polyaromatic compound was further formylated. When aromatic ring was sterically congested the second formylation was suppressed (Eq. 184) [450].

TiCI4

Ar-H

+

CH30CHC12

H30+

A+ ," OMe

ArCHO

(182)

731

Titanium(IV)Lewis Acids Table 17. Formylation of aromatic compounds with (MeO)CHC12and Tic&. Ar-H

Ar-CHO

Yield (%)

Ref.

45 1

CHO

87

Me

452

Me

&yJ

t-Bu

/

Bu-t

quant.

450

69

453

75

454

38

455

BU-t

t-Bu

CHO

Br

Br

OMe

OMe

OMe

OMe

CHO

CHO

+Me O CHO H Me ?Pr

&cHo R

456

R

OPr

BnO

R = Me H 79 66

OPr

a:)

74

457

52

450

BnO OMe MeO,

OMe MeO,

t - B u o C H 2 e B u - t t-Bu--&H2eBu-t

OHC'

CHO

732

Urabe/Sato

CH30CHC12 TiCI4 *

t-BudCI+&Bu-t

1

t

Me -

B

u

Me

qH 2 - & 3 u - t CI

Me0

. Bu-t

t-BU

t-Bu

Me0

CH3OCHCIz

BU-i

*Jw (183)

t-Bu

TiCI4

Bu-t

CHO

55%

Me

Me CH30CHC12 (184)

M e Me O v C H 2 e OMeM e

Tic14 40%

Me0

Me

Me

OMe

The formylation of metalated sp2 carbons, for example in a stannylbenzene (Eq. 185) [458] or in vinylsilanes [459,460] (Eq. 186), with C12CH(OMe) and TiC14, in which the ips0 carbon to the stannyl or silyl group is selectively formylated, has been reported. The formylation of a vinylsilane was used in the preparation of a terpene aldehyde, nuciferal, as shown in Eq. (186) [461]. SnMe3

+

CH30CHC12

-

( 185 1

41 Yo

+ Me

CHO

TiCI4

CH30CHC12

TiCI4 48%

(186)

Me M qe

M qe

nuciferal

Titanium(W)Lewis Acids

733

The intramolecular Friedel-Crafts reaction provides a convenient way of preparing cyclic compounds. Equation (187) illustrates a fundamental intramolecular FriedelCrafts reaction furnishing an aromatic cyclic ketone [462,463]. For this particular reaction, TiCI4 was reported to be much preferable to other routine reagents, e.g. A1Cl3 or SnCI4. Cyclization of an isocyanide dihalide with a structure similar to those of acyl halides was promoted by titanium halides (Eq. 188) [464]. The halide ligands of the titanium salt should be adjusted to that of the starting organic halide, otherwise scrambling of these halides is observed in the product (Eq. 189) [464]. Me0

OMe

Me0

OMe

Lewis acidMe0 Me0

/

Me

187 Me0

-

Me

Me0

Lewis acid = TiCI4 79% AIC13 no react. SnCI4 41%

2:l

In addition to acetals, 3-, 5-, or 6-membered cyclic ethers are also suitable precursors in the intramolecular alkylation of aromatic nuclei [465,466]. A noteworthy feature of this reaction is the high stereospecificity of the cyclization (Eqs 190 and 191) [466], which is useful for the stereoselective construction of a carbocyclic structure. Intramolecular aromatic substitution occurred preferentially at the 6 position of an a,P,y,b-dienone to give a 6/7/6-fused system rather than a 6/5/6-tricyclic counterpart resulting from alternative P-attack (Eq. 192) [467]. The product was accompanied by an unusual compound (Eq. 192, right), which became the main product when the reaction was performed with BF3. OEt, as the Lewis acid. Considering the distribution of these products, the authors proposed a common intermediate generated by attack of a cationic b-carbon of the dienone on the aromatic @so-position of the tether rather than the ortho position. Migration of bond b is favored not to change the stable titanium chelate in the reaction mediated by TiCI4, whereas rearrangement of

734

Urabe/Sato

bond a is preferred when the boron Lewis acid is used, to minimize the non-bonding steric interaction between the Lewis acid and the carbocyclic framework. Results from intramolecular Friedel-Crafts reactions are summarized in Table 18.

I

OMe

I

OMe

OMe Lewis acid = Tic14 90% BF3eOEtZ 90%

migration of bond b

migration of bond a

& '3'

\

5 :1 1 : 4.5

Titanium(IV)Lewis Acids

735

Table 18. Intramolecular cyclization via Friedel-Crafts alkylation. Ar-H Me0

Titanium salt

Product

TiCI4

Me0

Ref

79

462, 463

97

468

67

468

93-98

469

52-83

470

94

464

OMe 0

Me0

OMe

Yield (%)

Me

Me0 4:1

Me0

?Me TiCI4 -78 "C

Me

Me0

'"Me OH

1O:l TiCI4 0 "C

OH

Me0

Me

li;l.:p

p

0

Me

TiCI4

Me R = H, alkyl

TiCI4

X

& ' N

X = H, F

Y = p F , pBr, pP h: rn-MeO, @CI

TiCI4

R

Me

g /

TiX4

CI

736

Urabe/Sato

Table 18. (Contnd.) Ar-H

Titanium salt

Product

Yield (%)

Ref.

83

471

Ti&

93

472

Ticla

94

472

35

473

68 70

466

,C02Me

,C02Me HN I

TiCI4

$ H

0 0 e

NH O p

P

h

14:l

HO TiCI4 CI M &

CI

Me

p CI

Ti(O-i-Pr)&I OH

Ti(O-CPr)3CI

&"

@OH

n=l n=2

TiCI4

OH

Titanium(ZV)Lewis Acids

737

Table 18. (ContndJContnd.) Ar-H

Titanium salt

64 /

Yield (“A)

Ref.

53

466

68

466

X=H 73 X = O M e 86

474 467

65

467

Product

Tic14

OMe

OMe

& : moMe Tic14

/

0

0

X

TiCl4

Olefins and acetylenes are susceptible to attack of a cationic carbon generated by a variety of Lewis acids [230]. Although these reactions are often grouped together, under the heading Friedel-Crafts-type reactions, the product is sometimes a mixture of several constituents-chemo-, regio-, and stereoisomers -which detracts from the synthetic value of the olefin version of Friedel-Crafts reaction. The TiC14-mediated addition of iron-complexed dienoyl chloride to a terminal olefin resulted in the formation of a mixture of products, as described above (Eq. 193) [475]. The use of a cyclic olefin in place of the terminal one reduced the number of the products, but the stereoselectivity of the acylation is still moderate. In the presence of TiC14, a-chloro-a-phenylselenoacetates alkylate terminal olefins regioselectively, giving y,d-unsaturated esters in better yield than with the use of other Lewis acids involving SnC14, ZnC12, and A1C13 (Eq. 194) [476]. An aromatic olefin underwent regioselective alkylation with chloromethyl alkyl ether (Eq. 195) [477,478] and the resulting benzylic cation could be trapped stereoselectively with an external nucleophile such as an azide ion. This stereoselectivity might arise from the particular circumstance of this benzylic cation bearing the sterically demanding ferrocene moiety.

738

Urabe/Sato

68%

8Yo

n = 2,3,4,6

EIZ = ca. 3:l

-Tic14

LiN3

+ CICH~OR~

( 195 1

51-76% R' = Me, Pr R2 = Me, PhCH2-

Cyclization of a quinone and an (aryl) olefin promoted by a Lewis acid is a useful method for the preparation of dihydrobenzofurans [443,479482]. The reaction between diarylethylene and methoxyquinone in the presence of a titanium salt is formulated in Eq. (196). The electronic state of the aromatic ring determined the actual path, either simple Friedel-Crafts alkylation of the aromatic ring or the aforementioned quinone-olefin cyclization, which is exemplified in Eq. (197) [443]. As can be seen from this equation, if the aromatic ring is highly activated by two electron-donating groups at appropriate positions, formation of the first carbon-carbon bond takes place at the aromatic carbon, rather than the olefinic moiety, resulting in FriedelCrafts alkylation of the aromatic nucleus. When, however, the aromatic ring is not sufficiently electron-rich, the olefinic position is attacked first and quinone-olefin cyclization then proceeds. Quinone mono- or bis-imides can be used in place of quinones to give nitrogen heterocycles [479,480]. For the mono-imine of the quinone shown in Eq. (198), an interesting switch of the regiochemistry was observed depending on the Lewis acid used [480,481]. This was explained in terms of the chelation structure formed from the titanium compound, the ketone carbonyl, and the methoxy group which is not likely in the BF3. OEt2-mediated reaction. Thus, BF3.OEt2 was assumed to coordinate to the imine lone pair to activate the P-position to the imine group, whereas the titanium salt would complex firmly with the a-alkoxycarbonyl group to activate the P-position to the carbonyl group.

Titnnium(IV)Lewis Acids

'I

'rf 0

Me0

OMe

(2:l)

59%

OMe

(197)

(3:l)

83% OH OMe

739

740

UrabeISato

Bn~,5x,t;TiX4 TiC14-Ti(O-CPr)4 (1:2) (7.5 equiv)

-

Me Aro$w8

OBn

100%

S02Ph Ar

( 198 1 Me0 OMe

The double bond of methylenecyclopropanes is alkylated by carbonyl compounds in the presence of TiC14 [483]. While the bicyclic methylenecyclopropane in Eq. (199) suffered simple alkylation followed by chlorination to give the product as a single stereoisomer, monocyclic methylenecyclopropanes showed a quite different behavior, including a ring opening reaction to give alcohols with an ally1 chloride moiety (Eq. 200). H

single

Intramolecular alkylation of olefins has been investigated extensively, perhaps because it might be synthetically more useful than the intermolecular version, because the regiochemical issue of both reacting electrophile and accepting olefin should less frequently arise. Intramolecular acylation of carbon-carbon double bonds, which is still a convenient method for the preparation of carbocyclic skeletons, has been con-

Titanium(ZV)Lewis Acids

741

ducted with an unsaturated acyl halide and a titanium halide (Eq. 201) [484]. When TiC14 was used, much of the undesired unsaturated ketone with a tetra-substituted double bond was formed. The situation was, however, improved by use of TiBr4- the more nucleophilic bromide ion minimizes formation of the elimination product to increase the yield of the bromoketone; this eventually led to the desired ketone with a trisubstituted double bond via dehydrobromination with DBU. Intramolecular ‘atom transfer’ cationic alkylation of olefins has been reported (Eq. 202) [485]. The reaction seems to be of general applicability and the reaction path has been proposed as depicted. Cationic alkylation of an olefin accompanied by the rearrangement of the carbon skeleton [486-488] as shown in Eq. (203) [487] was used for stereoselective construction of bicyclic compounds. Of several Lewis acids (BF3. OEtz, EtzAlCl, Me3SiOTf, and EtAICl,), TiC14 was found to be the optimum promoter in this transformation.

,SePh

Acetylenes are also reported to undergo intramolecular Friedel-Crafts-like alkylation as shown in Eq. (204) [489]. The reaction occurred regioselectively with respect to both epoxide and acetylene moieties and this was rationalized by the chelation structure involving the titanium metal as depicted. The facile preparation of a func-

142

Urabe/Sato

tionalized fused seven-membered ring seems to find application in natural product synthesis. More examples of intramolecular Friedel-Crafts-like alkylation of olefins and acetylenes are shown in Table 19.

p-Cationic carbon of u&unsaturated ketones coordinating to a titanium halide have been alkylated with an intramolecular olefinic bond (Eqs (205) [496] and (206) [497]). The reaction was terminated by incorporation of a chlorine atom from the Lewis acid, TiC14. An u,/3,y,&dienoate underwent a similar cyclization to give different products, depending on the kind of Lewis acid used (Eq. 207) [498].

Titaniurn(IV) Lewis Acids

743

Table 19. The Friedel-Crafts type alkylation of olefins and acetylenes. Substrate

Titanium salt

Product

x = CI

Yield (%)

3 : 2 3 : l

Br

Ref.

73 (bromide)

71

490

70

490

61 n = 2 43

487

ca.50

491

90

488

94

488

ds = 98: 2

Tic14 ds = 67:33

n=l (

H BnO

BnO BnO..,,

BnO,, TiCI4

q

x N

y 0o

X = OH and CI

Ph

CI

744

Urahe/Sato

Table 19. (Contnd.) Substrate

p.,SePh/

Titanium salt

Yield (%)

Product

TiCI4

Ref.

R = H 77 R = M e 81

485

46

485

R = H 97:3 R = Me 96:4

n=l n=2

6 40

: :

8 5 : 46 :

9 14

TIC4

70 39

95

493

80

494

TL

Ticla

H (after decomplexation)

Titanium(IV)Lewis Acids

745

Table 19. (ContndiContnd.) Substrate

Titanium salt

TiBr4

Product

Yield (%)

Ref.

19

495

20

495

32

495

98

489

88

489

The Lewis acid-promoted alkylation of electron-rich olefins such as enol ethers or enol silyl ethers with SN1-activeelectrophiles occurs regioselectively and provides an efficient method of a-alkylation of carbonyl compounds. Suitable SN1-active electrophiles are allylic or benzylic halides, u-halo ethers and sulfides, and tert-alkyl halides, and their derivatives. These reactions have been reviewed [499,500]. Equation (208) illustrates alkylation with a benzylic cation [501,502]. The use of an a-amino, a-imino, or a-alkoxy cation generated from a heterocyclic epoxide, an u-acetoxyhydrazone, or an u-chloro ether with the aid of Tic&is exemplified in Eqs (209) [179],210 [503,504],and 211 [505]. Alkylation with a-chlorosulfides proceeds similarly [506]. An advantageous feature of this method is that it realizes u-tert- or a-sec-alkylation of ketones, which is usually impossible with enolate chemistry under basic conditions. These u-alkylations of enol silyl ethers are illustrated in Eqs (212) and (213) [499,500]. Equation (212) shows the compatibility of an ester group in this alkylation, and Eq. (213) shows the regiospecificity of the method. The successful combination of both tertiary alkyl fragments to yield a peralkylated carbon-carbon unit in the lower half of Eq. (213) is noteworthy. The a-alkylation of ketene silyl acetals by this method in the presence of Tic14 proved to be discouraged [499]. The alkylation of enol silyl ethers, which could be prepared by a variety of methods with compatibility of functional groups, could be extended to an intramolecular reaction. Alkylation of TBS-enol ethers with the Nicholas procedure was conducted to effect the construction of a 10-membered ring (Eq. 214) [256,507-5091. The choice of Lewis acid and

746

UrabdSato

the accompanying base was critical. As far as the Lewis acid is concerned, other Lewis and protic acids including BF3.OEt,, SnC14,Ti(O-i-Pr)4,NbCIS,CF3C02H,HBF4,and TsOH are less effective.

TiCI4

+

Ph2CHCI

OSiMe3

Me2N.N

+

( 208 ) 64%

:"OSiMe3 R', R2 = H, alkyl R3 = alkyl

+I

TiCI4

R3

75-86%

Me2N.

N

R2

R3

29-92% de

n OSiMt I A

0

(210)

Titanium(IV)Lewis Acids

747

79%

0

TBSO

15.7 Esterification, Acetalization, and Related Reactions A titanium triflate, TiC1(OTf)3, proved to be an excellent catalyst for equimolar esterification of a carboxylic acid and an alcohol in the presence of (Me2Si0)4 as a dehydrating agent (Eq. 21.5) [510]. The catalyst is required only in very small amounts (0.1 mol %) and a variety of combinations of carboxylic acids and alcohols enter this esterification.

Ph-C02H (1 equiv)

+

Ph-OH (1 equiv)

TiCI(OTf)3 (0.1 mol%) (Me2Si0)4*

PhdOwPh

(215 )

(2 equiv) 99%

Titanium alkoxide is quite effective, presumably as an acidtbase catalyst, at facilitating transesterification between esters and alcohols [511-5131. The reaction conditions are mild and relatively hindered alcohols can be used. Methyl phenylacetate has been transformed to other esters of relatively hindered alcohols under the influence of Ti(OEt), (Eq. 216) [.514]. Ethyl (or methyl) esters of a variety of functionalized carboxylic acids could be converted into menthyl esters in good yields under titanium catalysis (Eq. 217) [514].

748

Urabe/Sato

Ti(0Et)d

+

PhnC02Me

R-OH

80 "C

2

phAco2R

(216)

Me

Me

&,,\OH Me Me

OH

89%

94%

98%

93%

76%

91%

Ti(0Et)d

RC02Et(Me)

(10 mol%)

+

(217)

(1 equiv) (1.4 equiv)

RC02Et(Me) = EtO EtOhC02Et 86%

NHAc NC-COzEt 72%

Et02CAC02Et 58% (dimenthyl ester)

NC

k=yCozMe 74%

The following transformations demonstrate the characteristic feature of titanium alkoxide-catalyzed transesterification. The isolated double bond does not enter into conjugation with the active methylene moiety (Eq. 218) [SlS]. Removal of a sterically demanding chiral auxiliary was possible without affecting the ketoester moiety (Eq. 219) [S16,S17]. Preparation of an ally1 ester was achieved in good yield with retention of the nitrone moiety essential for subsequent cycloaddition (Eq. 220) [S18].

Titanium(lV)Lewis Acids

749

ao ao i-PrOH

C02Me

*

(218)

Ti(O-i-Pr)4 80 "C 77%

COnPr-i

. EtOH

Ti(OEt)4 75-90%

w

0

R = alkyl, vinyl, allyl, Ph

A notable application of this transesterification is the transposition of an acyl group from one hydroxy group to the other (Eq. 221) [519]. The mild reaction conditions enable an acid-sensitive vinyltin moiety to remain unaffected. The migration of an acyl group plays an important role in the synthesis of a large-membered lactone [520,521];this is illustrated by the synthesis of scytophycin C (Eq. 222) [520].

OMe

Ti(O-i-Pr)4 91%

750

Urabe/Sato

Polymerization of a diester and a diol has been achieved by transesterification in the presence of a titanium alkoxide (Eq. 223) [522]. A contrasting depolymerization of a polyester with an alcohol and a titanium catalyst is exemplified in Eq. (224) [523].

i0qfH n = 8000

Ho30Bn

Ti(OBn)[ BnOH 57%

( 224 )

Transesterification can be used to cleave the acyl group from an ester to release the alcohol. The mildness of the reaction conditions enables chemoselective transformation. A siloxy group p to a ketone group was not eliminated (Eq. 225) [524], and formation of an epoxide from the unprotected bromohydrin did not occur (Eq. 226) [525]. Similarly, in the synthesis of an avermectin derivative, delactonization was carried out by the titanium-based method as shown in Eq. (227) [526]. OTIPS

OTIPS i-PrOH

AcO

*

Ti(O-i-Pr)4 95%

( 225 )

HO

OH i-PrOH

( 226 )

*

Ti(O-i-Pr)4 92%

OH

5HooSiMe3 Ti(O-i-Pr)4 77%

Titanium(IV)Lewis Acids

751

The conversion of Boc groups protecting amino groups to other more appropriate carbamate derivatives can be achieved with Ti(O-i-Pr)4 as shown in Eqs (228) and (229) [527]. If there are two Boc-amino moieties in the same molecule, that which is less hindered can be selectively converted to another carbamate group, e.g. benzoyloxy, as exemplified in Eq. (229).

. R-OH

H

H

Ti(O-i-Pr)4 PhmN'foR 82-85%

KoBu-f 0

Phm

0

R = Bn, allyl, Me3Si(CH2)2-

Substrates analogous to carboxylates also participate in the transesterification. Carboxylic imides or sulfonimides are cleaved in the presence of alcohol to give esters with a sensitive functional group remaining intact, as shown in Eqs (230) [528] and (231) [529]. This transesterification can be used to effect ester exchange in phosphates. The exchange of phenoxy groups in sugar phosphonates is more rapid than removal of acetate groups, with the exception of that at the anomeric position (Eq. 232) [530]. Transetherification of some ethers, as shown in Eq. (233), has been performed under similar reaction conditions [531].

d'

89%

Meozcq

. MeOH

Ti(OEt)4

PO(OBn)2

PO(0Ph)Z

AAcO c

O

(231 )

a OAc OAc

BnOH t

Ti(O-i-Pr)4

35%

(232)

AcO OAc OH

152

UraheISato

.

M e 0?Hk Me0

Ti(OR)4 ROH

:

l MI e 0q

. o

H

*

-

OMe

C

( 233 )

0 OR

R = E t 62% Pr 25% i-Pr 85%

In addition to ordinary titanium alkoxides of the type Ti(OR)4, a heterogeneous catalyst, TS-1 treated with K2C03 before the reaction, proved effective in the transesterification of ethylene carbonate to dimethyl carbonate with methanol [532]. Titanium salts nicely promote acetalization, transacetalization, and deacetalization, etc. Acetals and related compounds are prepared from the parent carbonyl compounds or other acetals in the presence of a titanium salt. In addition to ordinary acetals, (N,O)- or (S,S)-acetals could be prepared by this method. Equation (234) illustrates the preparation of a mixed acetal with different alkoxide groups [533]. Table 20 shows the preparation of different acetals in the presence of titanium salts. / 97:3

An interesting application of this method is the preparation of ( 0 , P ) - and (N,P)acetals, not otherwise an easy process. Treatment of an aldehyde with diethyl hydrogen phosphite in the presence of Tic& affords the (a-hydroxy) phosphonate in good yield (Eq. 235) [539,540]. Alternatively, the methoxy group of an (N,O)-acetal was replaced with a phosphonate group via the reaction of triethyl phosphite and TiC14 (Eq. 236) [541]. In the latter reaction the resultant phosphonate was subsequently used as an olefination reagent.

R-CHO

+

HP(O)(OEt)*

Ti(O-i-Pr)4 *

OH RTdP(0)(OEt)*

( 235 )

Titanium(IV)Lewis Acids

do

Me

' X o

Me0

+

- (Eta)$ TiCI4

P(OEt)3

YPMB

753

Me

CF3COpH

83%

anisole *

0

~ M B

(E~O)ZF O

A

Me02C

*

( 236 1

t-BUOpC E *t

t-BUOKH H

0

Table 20. Preparation of acetals promoted by titanium salts. Substrates

Titanium salt

Yield (Yo)Ref.

Product

ejH OMe OPr-i

TiCI4

70

533

Me3SiN3

EtSH

TiCI4

98-99 536

R = alkyl, Ph

:r 1"' Me 0-sugar

SEt

n

HS S H 0-sugar

BzO M;y;.% Ph MesSiSPh "H

Ti(0-i-Pr)C13

Me

SiMezPh

E 100%

63

538

154

Urabe/Sato

In the synthesis of naturally occurring products involving a sugar moiety, glycosidation is often performed at a final stage, when stereochemical control is a serious issue [542,543]. Because control of the a- and P-selectivity of the glycosidation is a long-standing problem, many kinds of titanium reagent have been investigated as a Lewis acid to achieve stereocontrol, as shown in Table 21. Anomerization promoted by TiC14 is a very selective means of producing a-glycosides (Eq. 237) [544]. Comparison of other Group 4 metal chlorides, for example ZrC14 and HfC14, and other Lewis acids (SnC14, BF3. OEt,, SbC15, SiCI4, GeC14) revealed that TiC14 is the best choice. The proposed mechanism of the Tickmediated anomerization is shown in Eq. (237).

MC14 (1 equiv) CH2C12

1

( 237 )

BnO& BnO

Brio (%Me MCI4= TiCI4 97:13 85% ZrC14 8515 93% HfC14 89:11 86%

Bn

Bn BnO BnO

t

OMe

Bnb \

BnO

I BnO BnO BnO

BnO H

This method was applied to more complex substrates as shown in Eq. (238), for which only a catalytic amount of the titanium salt works quite well [544]. A ribonucleoside is stereoselectively prepared from a ribofuranoside by use of a catalytic amount of a new titanium-based reagent generated from Tic14 and AgC104 (Eq. 239) [545]. Other titanium-mediated glycosidation reactions are summarized in Table 21.

Titanium(IV)Lewis Acids

755

Table 21. Titanium-mediated glycosidation of sugars. Sugar

Alcohol derivative Titanium salt

Yield (%) Ref.

Product

[@I

do" Aco%ob

AcO*F

-AgC104 Cp2TiClz

90 [36:64]

546

Me0

Me0

4

,OAc in Et20 TiF4

AcO AcO

F

85 [83:17] 546 [40:60]

TiC142AgC104

AcNH

547

AcNH

[80:20]

OAc

OAc

0 BnO

Me ~

O

A

C

TiCI42AgC104 N

86 [3:97]

545

99

548, 549

OSiMea

OKNEtZ S OKNEt' S sugar,

sugar,

CIH2CC02 A c o g c o 2 M e

TiBr4

Aces

CQMe

CIH2CC02 OCOCH2CI

[--I

Br

Acob OAc

(F-) AcO OAc

CF3ZnBr*2CH3CN TiF4

AcO

F

OAc

83 [40:60]

550

756

Urabe/Sato

,OBn TiBr4 (20 mol%) MgBrp*OEt2(100 mol%) ( 238 )

86% OMe

1

S

OMe

-

86%

I

OKNEt2 S

Tantazole B is a member of a group of structurally unique polythiazoline alkaloids. The TiC14-mediated cyclodehydration of an appropriate tripeptide triamide shown in Eq. (240), developed by Heathcock [551], is a very efficient method for the synthesis of this type of compound [552,553]. Other members of the similar class, mirabazoles [551,554,555] and thiangazole [552,556],were prepared in the same manner.

I

SH

I

SH

tantazole B

Preparation of heterocyclic compounds by coupling two constituents with a titanium Lewis acid is shown in Eqs (241) and (242). A I3C-labeled nitrogen heterocycle was synthesized by condensation of a keto-oxime and a-aminonitrile in the presence

Titarziurn(IV)Lewis Acids

757

of Tic& (Eq. 241) [557]. Dimethylaminocyanamide and a-iminoketone were combined in the presence of TiC14 to give an imidazolinone derivative after migration of the phenyl group during the reaction (Eq. 242) [558]. 0

phx;

+

Ph

cNy e 2

Ph

TiCI4 70%

PhxNyNMeZ N O P>-i

Pr!i

( 242 )

t

I

The presence of a carbon nucleophile rather than a heteroatom nucleophile in the acetal exchange reaction led to alkylation of the acetal (Eqs 243 [559] and 244 [560]). In Eq. (244), the type of methylmetal species alters the stereochemical outcome.

( 243 ) Bu H

97:3

758

Urabe/Sato

OMe OMe

-

OMe OMe

Me3AI

Me0

TiCI4 67-71Yo

.

HO

OMe

Deacetalization, the reverse of acetalization, was similarly promoted by TiC14. The example shown in Eq. (245) [561] illustrates the compatibility of functional groups. Neither demethylation of anisole nor elimination of the benzylic thiol group occurred. Equation (246) shows the regeneration of the diol moiety from an acetal [562]. Ph Ph

OMe

OMe

Ph

Me

"Ijl;. -

oh,

MsO

4

OMS

PhSH Ti& 83%

Ph

I

wo

OH OH N A

(246)

MsO

OMS

15.8 Preparation of Imines and Enamines Preparation of imines and enamines from carbonyl compounds and amines can be achieved with a dehydrating agent under acid/base catalysis [563]. Basically, primary amines afford imines unless isomerization to an enamine is favored as a result of conjugation, etc (see Eq. 252), and secondary amines afford iminium salts or enamines. These transformations can be conducted efficiently with a catalytic or stoichiometric amount of a titanium salt such as TiC14 or Ti(O-i-Pr)4. Equation (247) illustrates an advantageous feature of this method in the imination of a hindered ketone. t-Butyl propyl ketone resisted the formation of the imine even by some methods reported useful for sterically hindered ketones [564,565]. The TiC14-based method works well, however, for this compound, giving the desired imine in high yield within a relatively short reaction period [566]. Imine derivatives such as N-sulfonylimines could be

Titanium(IV)Lewis Acids

759

directly prepared from the corresponding starting materials in the presence of stoichiometric amounts of TiC14, as shown in Eq. (248) [567]. The preparation of imines from a variety of starting materials is shown in Table 22. Table 22. TiCl,-mediated preparation of imines. Ketone

Arnine

Product

Yield (%)

Ref.

93

568

64-86

566

NH

0

NH3 I

Ph

Me

0

x

Ph

RiAR2

1

NAMe NH2

R' = i-Pr, t-Bu, t-C&l R2 = Me, Et, Pr

569

0

R~ NH~

M z F C O ~ R 1

__

570

86-90

566

79-82

571

73

567

R2 = Bn, i-Pr

\Cl R' = Me, Et

4)"x

Ph I

Me

Ph

NH2

n=1,2

NPr-i

i-PrNH2 I

0 R

R=H,Me

N-SOZPh

PhS02NH2

>r

0 C(=N-SiMe&

572

760

Urabe/Sato

Ph Me

TiCI4 ( 247 )

NEt3

80%

+ PhS02NH2

TiCI4 73%

i;so;pn

( 248 )

The imines thus formed are often not isolated but are, instead, reduced directly to amines. Although NaBH3(CN) is a very common reducing agent, NaBH4 or other reagents shown in Table 23 can also be used. When preparation and reduction of the imine are performed successively in the same apparatus, Ti(O-i-Pr)4 seems to be a more suitable reagent than TiC14 for imine formation (Eq. 249) [573].Preparation of several amines by use of this sequence is shown in Table 23. Table 23. Reductive amination of ketones. Ketone

Amine

Titanium salt (Reducing agent)

Product

Yield (“h) Ref.

R = H, alkyl

x

V &OH

PhANH2 ‘NHBn

Ti(O-i-Pr)4

p

(NaBH3(CN))

573

60

576

R= OMe H 71 83

577

OMe

OMe i-PrNH2

80-81

i-PrHN

TiCI4 (H2/PtO2) fNEt2

H2N NEt2

Tic14 (Zn, AcOH)

&R

--. N’

0

Titarzium(IV)Lewis Acids

A+

n> OMe

H2N

.

c(

or

Ti(O-i-Pr)4 NaBH3(CN)

p

*

(neat)

EtOH

OMe

761

ANDoMe (249)

OMe

80-81yo

Treatment of aldehydes or ketones with secondary amines in the presence of Ti(0-iPr)4 generates (N,O)-hemiacetals (or iminium salts) which can be reduced by NaBH4 [578] or NaBH3(CN) [S79] to give tertiary amines, as shown in Eq. (250) [578]. R'

)co +

x . .-

Ti(O-i-Pr)4 R' Me2NH*HCI

*

NEt3 EtOH

R2

RZ

NMe2

NaBH4

OTi(O-/-Pr)3 72-96%

R' H XNMe2 RZ

( 250 )

R', R2 = H, alkyl

Ketones and secondary amines furnish enamines in the presence of TiC14 [580,581]. The preparation of a functionalized enamine shown in Eq. (251), in which the acetal moiety is retained in the product, illustrates the applicability of this reaction [S82]. Enamines prepared by this method are summarized in Table 24. Application to an intramolecular reaction is also found in Table 24. If formation of the enamine is thermodynamically preferred to formation of the isomeric imine, the former becomes the product even in the reaction of a ketone, a primary amine, and TiC14, as shown in Eq. (252) [583], in which the resulting enamine was, after acetylation, isolated as the enamide. EtO OEt EtO OEt

0

TBSO.

refl. 65%

H

A

A

,OM€

TBSo-h+foMe M Me0

e

o

r

'

Ac ?Ph

M

e

(252)

762

Urabe/Sato

Table 24. TiCI4-mediated formation of enamines. Ketone

-

+

EtO OEt

0

:pelF: Bn

Arnine

Product

+

Yield (Yo) Ref.

EtO OEt

(OI

?J

65

582

250

584

H

tl F:

Bn

d

--

581, 585

OR

15.9 Epoxidation and Aziridination Epoxidation of allylic alcohols with peracids or hydroperoxide such as t-BuOzH in the presence of a transition metal catalyst is a useful procedure for the synthesis of epoxides, particularly stereoselective synthesis [.587-5901. As the transition metal catalyst, molybdenum and vanadium complexes are well studied and, accordingly, are the most popular [587-5901. (Achiral) titanium compounds are also known to effect this transformation, and result in stereoselectivity different from that of the aforementioned Mo- and V-derived catalysts. The stereochemistry of epoxidation by these methods has been compared for representative examples, including simple [591] and more complex trans-disubstituted, trans-trisubstituted, and cis-trisubstituted allyl alcohols (Eqs (253) [592], (254) [592-5941, and (255) [593]). In particular the epoxidation of trisubstituted allyl alcohols shown in Eqs (2.54) and (255) highlights the complementary use of the titanium-based method and other methods. More results from titanium-catalyzed diastereoselective epoxidation are summarized in Table 25.

Titanium(IV)Lewis Acids

[ol Ph

P h G d O H

OTBS

OH +

P

h

W

H ( 253 )

Me

Me

Me

Ti(O-i-Pr)4, f-Bu02H VO(acac)2, f-BuO2H m-CPBA

2.3: 1 2.5 1 >25 : <1

Table 25. Epoxidation of ally1 alcohols with t-Bu02H and Ti(O-i-Pr)+ Ally1 alcohol

Product

Ph

Yield (%)

OTBS

phGJH Mi

__

592, 594

82

594

88

593

90

592, 594

90

593

Me

TBSO

TBSO

OH

OH

TESO C3H7J-y++OMe H

Ref.

TESO

-

C 3 H 7 W o H 7:l Me Me

Me

TBSO

H*

OTBS Me

Me

TESO

TESO

c3H,%Me OH

u 6.5:l OH

763

764

lJrabe/Sato

TBSO

TBSO

OH

TBSO

( 254 ) Me

Me

Me

OMe R = AcO+

{

Me0 OMe

TESO 3

H Me

Me

Me

Ti(O-i-Pr)4, t-BuOzH 10 : 1 (90%) VO(acac)z, t-BuOzH 1.5 : 1 m-CPBA 1 :99

R = TBSO

C

Me

7

w

e

99 : 1

Ti(O-i-Pr)4,t-Bu0,H VO(acac)2, f-Bu02H m-CPBA

PI

--

1 :40

TESO

c

3

yo:

TESO

~

7

w

+

e C3H7

Me

OH

OH Ti(O-i-Ptj4, t-Bu02H m-CPBA

6.5 : 1 1 15

(255)

90%

83%

Titanium silicate 1 (TS-1) has been used instead of titanium alkoxides in the epoxidation of allylic alcohols with hydrogen peroxide. The stereochemistry was examined for various types of allyl alcohol and proved somewhat different from that of the aforementioned Ti(O-i-Pr)4-catalyzed protocol [591]. An example for the simplest allylic alcohol is shown in Eq. (256).

threo TS-1, urea/H202 Ti(O-i-Pr)4, t-BuOzH

erythro 65 : 35 (72-95Yo) 71 : 29

Ti(O-i-Pr)4-catalyzed epoxidation works for allyl alcohols with an electron-deficient olefin. The epoxidation of different allyl alcohols bearing an electron-withdrawing group has been attested [596-5991 and Eq. (257) compares the stereochemical outcome of a few methods of epoxidation [596]. The titanium-based method generally results in considerable improvement of syn selectivity. The stereoselectivity of the reaction depicted by Eq. (258) is the reverse of that afforded by alkaline peroxide epoxidation [599].

Titanium(IV)Lewis Acids

Ti(O-i-Pr)4,f-Bu02H f-Bu02H, NaOH H202, NaOH VO(acac)2, t-BuO2H

>99 : 1 1O:l 4: 1 299 : 1

Ti(O-i-Pr)4,f-Bu02H

82% 91% 70% 92%

299 : 1

H202, NaOH

765

78%

1 : 1.5 76%

Photooxygenation of olefins with singlet oxygen then intramolecular epoxidation of the resulting allylic hydroperoxides in the presence of Ti(O-i-Pr)4 is a concise method of preparation of epoxyalcohols directly from olefins, as shown in Eq. (259) [600-6021. This transformation can be denoted hydroxyepoxidation of olefins. Both stages of Eq. (259) can be conducted simultaneously in one pot, i.e. photooxygenation of the olefin can be conducted in the presence of the titanium catalyst. Fundamental examples of this reaction are shown in Eqs (260) and (261) [600,601]. Extension of this hydroxyepoxidation to more complex substrates, often with very high diastereoselectivity, has been surveyed in a review article [600]. Rearrangement of an allylic peroxide in the presence of TiC14 has been reported [603].

"k"' R3

CH3

R' = alkyl R2 = H, alkyl R3 = H, alkyl, C02R

'02

Ti(O-i-Pr)4 Y

(hv)

84%

O

H

Me Me

(260)

766

UrabdSato

U

Ti(O-i-Pr)4 70%

>97:<3

In contrast to the epoxidation of ally1 alcohols and their derivatives described above, that of simple olefins under titanium catalysis seems to be undeveloped [604,605]. Aziridination of an olefin has been performed with the reagent shown in Eq. (262) in the presence of Ti(O-i-Pr)4 [606,607]. Excellent diastereoselectivity was observed. Other methods of aziridination to a,D-unsaturated carbonyl compounds [608,609] or of imines [610-6121 in the presence of a titanium Lewis acids are also available.

,,r%b N

HO

86%

NHOAc

15.10 Ring-Opening of Epoxides Regio- and stereoselective opening of epoxides is facilitated by titanium Lewis acids, and leads to a potential method for construction of consecutive stereogenic centers [613,614]. Sharpless intensively investigated titanium-catalyzed opening of 2,3epoxyalcohols with heteroatom nucleophiles [615,616] and revealed that it occurs stereoselectively with good to excellent regioselectivity. This transformation, and his asymmetric epoxidation [617-6191 are versatile means of preparation of optically active compounds. Titanium-mediated ring opening of truns-2,3-epoxyhexanol with dialkylamines exemplifies the selectivity of this method (Eq. 263) [615]. The importance of the hydroxy group is clearly apparent-the corresponding methyl ether shown in Eq. (264) did not react. Other nucleophiles and selectivities are summarized in Eq. (265), in which the oxirane ring is preferably cleaved at the C3 position. Except when a benzenethiolate was used as the nucleophile, the ring-opened products were not obtained in the absence of the titanium alkoxide. 0 &OH

R2N

Ti(O-i-Pr)4 +

RPNH (excess)

(1.5 equiv)

R = Et

+ &OH

O -H

OH

without Ti(O-i-Pr)4,refl. 3.7 : 1 with Ti(O-i-Pr)4, r.t. 20 : 1 ally1 100: 1 8'

(263) NR2

4% 90% 96%

Titanium(IV)Lewis Acids

Nu

Ti(O-i-Pr)4 2

OH

+

Nu-

Nu i-Pro CH2=CHCH20 PhS PhS PhSe N3 CN CN CI Br SCN PhC02 PhC02 AcO t-BUCO2 TsO

32-95%

*

767

+ &OH

-OH OH A

(265) NU B

A/ B Nui-PrOH 1OO:l CH2=CHCHpOH 1OO:l 6.4:l PhSH 9.O:l PhSNa PhSeH 6.4:l Me3SiN3 14:l Me3SiCN 4.9:l KCN 1.3:1-2.4:1 NH4CI 2.8:1-3.0:1 NH4Br 3.0:l 5.6:l NH4SCN 1OO:l PhC02NH4 1OO:l PhCO2H 65:l AcONH4 t-BuC02H 1OO:l TsO-l(CsNH7Me7)Hfl 1OO:l

Many applications of this transformation are listed in Table 26. The rule of C3 opening of 2,3-epoxy alcohols discussed above is not followed when particular substituents are placed proximate to the epoxide group. The reaction of Eq. (266) seems to be an example in which regioselection is probably controlled by a polar phosphine oxide group rather than the hydroxy group [620]. Another diastereoisomer, shown in Eq. (267), did not afford the corresponding product, suggesting the importance of proper alignment of the functional groups and the metal center [620]. Intramolecular attack of a nucleophile might not obey the aforementioned C3 opening, either, as shown in Eq. (268) [621].

OH

Phz(0)P

Ti(O-i-Pr)4

+ Me3SiN3

*

No reaction

( 267 )

168

UrabdSato

0

t-BUO Ti(O-i-Pr)4

H .N K O . ( 268 )

63% EEO

The regioselective ring opening of 2,3-epoxy acids can also be achieved (Eqs 269 and 270) [616]. The titanium-promoted reaction always favors C3 opening of the epoxides whereas in the absence of Ti(O-i-Pr)4 the same reaction proceeds with much lower or even reversed regioselectivity. The same tendency was observed for the reaction of 2,3-epoxy amides [616].

R’ = C7H15 R’= H C-C6H11 TBDPSOCH2 H

71-87% H C7H15 H H TBDPSOCH2 without Ti(O-i-Pr)4

84-95%

10 : 1 - >20 : <1

-

1 . 3 : l - < 1 :>20

Titanium(W)Lewis Acids

769

Table 26. Ring-opening of 2,3-epoxy alcohols. Epoxide

Nucleophile

BnOH OH

0

Titanium salt

Product

Ti(O-i-Pr)4

Yield (“A) Ref.

/ + + o B n

60

622

82

623

69

624

78

625

19

622

OH

O ,H

BnO&OH

Ti(0-i- Pr)4

B

n

O

OMPM y O

H

OH

OMe Ti[OCH2(C6H40Me-p)l4

0 k

OH O

H

TrS(CH2)5C02H

PhC02H

Ti(O-i-Pr)dHTrS(CH O , , 2)5C02 ) - ,

Ti(O-i-Pr)4

/ L o H

OH

OBZ

+ / L O B 2

32

OH

PhC02H

Ti(O-i-Pr)4

THPO

x ; THPO HO‘‘”

H

80

626

7

regioselectivity= 1OO:l

OBn HO

OH OBn

PhC02H

Ti(O-i-Pr)d

Ho 80 627 k .

-

OBz

Ti(O-i-Pr)3(0Ac)

&OH

90

628

770

Urahe/Sato

Table 26. (Contnd.) Epoxide

Nucleophile

NH40Ac

Titanium salt

Ti(04-Pr)4

Product

Yield (Yo) Ref.

+= +* 50

HO

+

629

23

AcO

NHCHPh2 Ph2CHNH2 Ti(O-CPr)4

68-74 630

/\(\OH

&OH

OH Ph2CHNH2 Ti(O-i-Pr)4

R2NH

&OH

Ti(O-i-Pr)4

61

14-91 633

&OH

Ti(O-i-Pr)2(N3)2

>46

634

Ti(O-i-Pr)2(N3)2

quant

634

99

632, 630

PH OPMB

631, 632

OPMB

l a H

65

OH

H N3

+

635

OPMB

1p:; OH

30

771

Titunium(IV)Lewis Acids

R'

R' A C O z H

+

PhS R2 /kC02H R' OH

Ti(O-i-Pr)4 PhSNa * (2 equiv) (1.5 equiv)

...

R2 OH Ri&COzH

+

(270)

SPh

20 : 1

without Ti(O-i-Pr)4 7744%

-

1 . 7 : l - 1 :13

Opening of an enyne monoepoxide with an amine took place regio- and stereoselectively (Eq. 271) [636], showing that the rule of C3 opening of 2,3-epoxyalcohols is still valid for substrates of this type.

t

n"T'

(271 )

Me

I

I,

H

Titanium-promoted epoxide opening is not limited to epoxyalcohols, but works for ordinary epoxides also. Terminal and internal epoxides with an acrylate moiety undergo ring-opening with the thiocyanate anion in the presence of TiC13, without complication (Eq. 272) [637]. It is interesting to note that a low-valent titanium chloride, TiC13, rather than the much more common TiC14 was used in this reaction. The incoming nucleophile tends to attack the less substituted terminus of the epoxide. Analogously, a gem-disubstituted epoxide was cleaved with chloride anion from the less hindered side, as shown in Eq. (273) [638].

:z regioseiecrive

3l

0 95% R=Me R' = Me

1 373

0

SCN

MeeO+Me

IMefO+Me OH

SCN 65 : 35

n=l

,

OMe

I

Ti(O-i-Pr)4

,

.-

. .. .

79%

A

OH

ii"( C

N

H

~

772

Urabe/Sato

An epoxide involving an anomeric carbon undergoes scission of the carbon-oxygen bond selectively at this position in the presence of silica-supported titanium oxide (TiOz. SiOz like TS-l), but the stereochemical integrity of the anomeric carbon is lost (Eq. 274) [639]. The ring opening of a cyclic diene monoepoxide with an amine was regio- and stereoselective (Eq. 275) [281]. Scrambling of the stereo- and regioisomers has, however, been reported in the substitution of an open-chain diene monoepoxide with silyl azide to afford at least three isomeric components (Eq. 276) [640].

PivO

:::0

PivO

rxH

6

PivO 71%

1 1 Yo

(i-Pr0)3Ti ,, .Ti(O-i-Pr)s

0

0

+

Bn2NH

0 (10rnol%)

*

0 1 ;

(275)

73%

Tic&plays a dual role in effecting epoxide opening and subsequent deoxygenation with allylsilane as depicted in Eq. (277) [641]. The reaction is highly stereospecific.

ox TiCI4

* H11C5+pC

5Hll

(277)

trans >99% Cis

92%

Epoxide opening accompanied by the pinacol-type rearrangement of a carbon framework in the presence of a titanium Lewis acid has been used for the stereoselective synthesis of acyclic compounds [642,643].Equations (278) and (279) illustrate this transformation and exemplify the dependence of stereospecificityon the geometry of the epoxide

Titanium(N)Lewis Acids

773

moiety [643]. The stereochemical integrity of the migrating alkenyl group is also retained in the products [643]. Stereoselective construction of a quaternary chiral carbon center, starting from an optically active epoxide prepared by the Sharpless epoxidation, is also viable (Eq. 280) [644]. Interception of the cationic intermediate formed after rearrangement proved possible with some carbon nucleophiles (Eq. 281) [645]. CI4TiOH 0

TiCI4

C3H7&ph

98%

(278) ~

&SiMe3

OH 0

TiCI4 C

3

H

7

y Ph

( 279 )

51me3

Me3Si, *OTIPS Me Me

TiCI4 77%

OTBS

W O OHC

T l P OTBS

S

(280)

\ySiMe3

Bn03siph +

TiCI4

NU-

B n O V N U

(281)

SiMe3

Nu-=

/mSiMe3

Me2Zn Et3SiD

Ho rOSiPh3 88% Me 22:l 60% D single 85%

Nu = ally1 33:l

The methylenecyclopropane oxide + cyclobutanone rearrangement has been coupled with asymmetric epoxidation to give optically active cyclobutanones, a versatile synthetic intermediate, without loss of the original enantiopurity of the epoxides (Eq. 282) [646]. Both processes occurring in this transformation are promoted by the same titanium species. Representative results are shown in Eqs 283 [646] and 284 [647]. The versatility of these transformations obviously relies on the facile accessibility of optically active epoxides. Sharpless

R

OH

Asymmetric* Epoxidation (Ti cat.)

kOH 5 OH

(282)

774

Urabe/Sato

Et

\

f-BUOzH

OH

96% ee

80%

(+)-DIPT Ti(O-i-Pr)4 t-Bu02H

Meo*oH Me0

OMe OMe X=H 82% 63%ee Me3Si 65% 92% ee

A relevant extension of the ring opening of epoxides with a titanium salt can be seen in the concomitant scission of the C-C bond of cyclobutane illustrated in Eqs (285) and (286) [648]. Choice of each diastereoisomer enables highly selective construction of the trisubstituted double bond; which finds application in terpene synthesis. The tandem cleavage of the c-0 and c-C bonds was similarly feasible in the combination of oxetane and cyclobutane as illustrated in the stereoselective synthesis of a homoallyl alcohol (Eq. 287) [648]. 0

TiC12(0-i-Pr)2 *

+ Me3SiSPh

Mee:e

77%

PhS SPh O -H Me

Me

(285)

EIZ = 97:3

TiC12(0-i-Pr)2 P

Me$~e

"

H

+

Me3SiSPh

62%

P

h

S

m

o

Me

H

( 286 1

Me

EIz=5:95

0 7 +

Me3SiSPh

t

88%

OH

Me

( 287 1

El2 = 99.5:0.5

An oxetane ring in a taxane skeleton was successfully opened with TiC14, despite the presence of many functional groups in the same molecule (Eq. 288) [649].

Titanium(IV)Lewis Acids

775

TiCI4 v

CH&I, 0 "C quant.

8 : 2

0

Intramolecular opening of epoxides with a hetero-atom nucleophile promoted by a titanium salt is shown in Table 27. Intramolecular alkylation of an epoxide with a metalated sulfone enhanced by Ti(O-i-Pr)4 has also been reported to give a single cyclization product, as shown in Eq. (289) [650]. Table 27. Intramolecular ring opening of epoxides. Epoxide

Titanium salt

Product

TS-1

O

O

O

H

Yield (%)

Ref.

92

651

34

652

76

653

Me 99% regioselective

TiCI4

single isomer

Ti(O-i-Pr)4

"'0PMB

HO HO

Me

, not assigned I

C

single isomer

An intramolecular reaction of epoxides promoted by a titanium halide which is somewhat different from simple opening of an epoxide with a nucleophile is shown in Eq. (290) [654]. The starting epoxide was first attacked by a bromide ligand of TiBr,, in an intermolecular manner, and this was followed by the intramolecular attack of

776

Urahe/Sato

the resulting alkoxide on the ally1 bromide moiety in the same molecule to give a tetrahydrofuran derivative. If this titanium bromide is replaced with a Brmnsted acid such as HBr, bromohydrins only were obtained as products, which is consistent with the above rationalization. Other Lewis acids such as MgBr2 and ZnBr2 afforded the same tetrahydrofuran derivative, but with inferior diastereoselectivity. In contrast, AgN03 afforded a tetrahydropyran derivative, most probably through a different path involving an oxonium ion intermediate generated by the first abstraction of the allylic bromine atom with Ag+. The resulting oxonium intermediate collapsed to the tetrahydropyran as a result of the nucleophilic attack of a nitrate anion. A

46%

C02Me

56%

C02Me

-

C02Me

-

15.11 Deprotection of Functional Groups Dealkylation of certain ethers occurs when they are treated with a titanium halide. This reaction has been applied to the removal of protective groups from alcohols and phenols [65.5,656]. Demethylation of the permethylated tetraphenol shown in Eq. (291) with TiBr4 could be performed stepwise. The second demethylation occurred specifically at the position indicated to give the bis-phenol with C, symmetry and a chiral plane (Eq. 291) [657]. Removal of a t-butyl group from an ether or ester has been readily effected by TiC14. This method is applicable to seemingly fragile molecules such as those shown in Eqs (292) [658] and (293) [659,660]. Although SnC14 is as effective a reagent as Tic& in the latter transformation, the titanium reagent was finally adopted, because it is environmentally preferable to tin reagents. Ethers bearing an SN1 active alkyl group, for example benzyl (Eqs (294) [661], (295) [662], (296) [663], and (297) [664]), methoxymethyl (MOM) (Eqs (298) [66.5] and (299) [666]), and (methoxyethoxy)methyl (MEM) (Eqs (300) [667] and (301) [668]) are selectively deprotected by TiC14 whereas other sensitive functional groups including TBS ether (Eqs 29.5 and 299), acetal (Eq. 295), ,8-alkoxy (Eq. 298), allylic ether (Eq. 299), and Cbz (Eq. 300) remain unattacked. It has, however, been reported that exposure of a TBS group to TiC14 can cleave its 0-Si bond [669]. Occasionally a liberated hydroxy group induced spontaneous cyclization or acylation under the reaction conditions used (Eqs 296 and 297).

Titarzium(IV) Lewis Acids

H

R' = Bn, PhOCHP R2 = functionalized alkyl, alkenyl

>65%

777

778

Urabe/Sato

TiC14 91Yo BnO

N3

TiCI4 BnO

9-

ffH

TiCI4

0

( 297 )

79%

O

0

O H”Me

TiCI4

(298)

80%

OH

OMOM

OTBS

OTBS

TBSO ,,,J

TBSO .,,J I

Me

-

s’

TiCI4

woM woH 79%

Me

( 300 1

Me

54%

Me Cbz OH

Cbz OMEM

TiCI4

RCo2h (301 )

RC02

OH

OMEM

R = Br(CH2)15CI4H2&H(Br)-

80% 57%

Titanium(IV)Lewis Acids

779

15.12 Titanium Lewis Acids in Radical Reactions The use of Lewis acids to impart chemoselectivity and stereoselectivity to free-radical polymerization and copolymerization is well documented [670]. Recent progress in radical reactions in organic synthesis has revealed the importance of Lewis acids in selective transformations [671,672]. Lewis acids have also been found to enhance the reactivity both of radical acceptors [673-6751 and of radicals themselves [676], thus increasing the efficiency of radical reactions. Titanium compounds are frequently investigated as Lewis acids in radical reactions [677-6801. When addition of an alkyl radical to a chiral vinylsulfoxide was conducted in the absence or presence of Ti(O-i-Pr)2C12,the stereochemistry of the product was reversed, very high diastereoselectivity being observed in the presence of the titanium salt (Eq. 302) [681,682]. The stereochemistry and high selectivity in the presence of the titanium salt were readily rationalized on the basis of a chelation intermediate between the titanium metal and the carbonyl and sulfoxide oxygens, as shown inEq. (302).

I

Bu-t

I

91%

38 : 62

Ti(O-i-Pr)&I2

98 : 2

In addition to the control of the stereochemistry of the reaction, enhancement of the efficiency of radical reactions is another important role of Lewis acids, as described above. It has been reported that the radical cyclization of y- or 8-cyanoketones is facilitated by coordination of their nitrile groups to a titanium species (Cp2TiPh) (Eq. 303) [683], with the coordinating nitrile group becoming more susceptible to radical addition. This was further evidenced by the observation that under the same treatment a y-ketoester cyclized to give the hydroxyketone, but the corresponding olefinic ketone did not, emphasizing the importance of the activation of cyano- or ester group by coordination, which is not likely for the olefinic substrate.

780

Urabe/Sato

LmTi(IV)O

p ,Ti(lll)Ln

L C CpnTiPh d m

(+

P

c-hl

J(

_I

In contrast with the above discussion, a radical itself (rather than a radical acceptor) can be activated by complexation with a Lewis acid. The aminyl radical cyclization shown in Eq. (304) is a slow process and yields of the cyclic product are often low. It is, however, known that a Brmsted acid promotes this cyclization [676], and by analogy the reaction proved to be promoted by the addition of a Lewis acid, which should coordinate with the nitrogen atom to increase the reactivity of the nitrogen radical. The effect of a series of titanium salts, Ti(O-i-Pr),C14,, at a concentration of 0.025 M, is shown in Eq. (304). It is apparent that use of Ti(O-i-Pr)CI3 resulted in significantly improved yield.

Bu,

1’9

c”’

Additive

X = H+ or Ti salt

U

Additive:

0.025 M Ti(O-i-Pr)d Ti(O-i-Pr)3CI Ti(O-i-Pr)*CIP Ti(O-i-Pr)CI3 Ti&

10% 31% 75% 99% 50%

15.13 Miscellaneous There are many examples of the stereoselective addition of nucleophiles to carbonyl groups in which chelation to the titanium center should be critical-reported examples include the stereoselective hydride reduction of a- or P-hydroxyketones (Eq. 305) [684-6861, of a-phosphino ketones [687], of a-sulfonylketones [688], and of an a,P-unsaturated carbonyl compound in a 1,4-fashion [689]. The stereoselective addition of organometallic compounds such as Grignard [669,690], zinc [691,692], copper [693], and other reagents [ l l ] to carbonyl and related compounds by taking advantage of titanium chelation is a well established method in the stereoselective

Titanium(N) Lewis Acids

781

synthesis. Equation (306) illustrates that the bulky TBS protective group prevents the oxy group from forming an intermediate chelate to reduce diastereoselectivity in the Grignard addition [669]. When, however, the silyl group was been replaced by the titanium at a higher temperature, the highly selective reaction proved possible, consistent with the many precedents.

305 H

R = Ph, f-Bu

[H-] = Et4NBH4,etc. Dibal

TBS

TiCI4 *

-78 "C

) TiCi4

'q Ph

S7:3 93:7-91:9

MeMgBr

Y -78OC 90% *

Me

Me

HO Me

TBSO

P Me

h

51:49

/Tp3

. -+ TiCI4

r.t. (-TBSCI)

' q p h Me

Ho Ho Me

MeMgBr

-78"C 92%

*

Y

P Me 98:2

h

The formation of a titanium chelate enables regiochemical control of the conjugate addition of a thiol to an a,P,y,d-dienone, as shown in Eq. (307) [694]. Simple base-catalyzed reaction occurred selectively at the terminal (6) position of the substrate. When, however, a similar reaction was performed in the presence of TiC14, addition occurred exclusively at the position fi to the carbonyl group, where the intermediate can take the chelate form, as depicted. The same observation was also noted for the corresponding conjugated trienone. A similar reaction has been applied to the cis + trans isomerization of conjugated dienoates [695].

182

Urabe/Sato

OH

NO2

+

( 307 1

H S m O H -

N(i-Pr)2Et

1

&ellent

yield

The reactions of organometallic reagents such as organolithium [696], -zinc [6977001, -magnesium 17011, and -aluminum species [702] are facilitated by the presence of TiC14 [9] as exemplified in Eq. (308) [703]. Even addition of a titanium compound to aldehydes was promoted in the presence of an extra amount of a titanium salt (Eq. 309) [704,705]. Titanium Lewis acids increase the reactivity of the a-position of a ketone (Eq. 310) [706] and the P-position of an a$-unsaturated carbonyl compound towards nucleophiles (Eq. 311) 1608,707-7091. The positive role of TiQ in the photohydroxymethylation of ketones and aldimines is ascribed to activation of methanol by the titanium salt (Eq. 312) [710].

Meopph 3 +

Me2Zn

284% Tic14

OMe

( 308 1

Meo*ph

OMe

(CHO

Additive

Ti(O-i-Pr)z +

( 309 )

MeoH Additive: none 7% Ti(O-i-Pr)zC12 50%

Titanium(IV)Lewis Acids

0

Additive

+NPh2 Br

+

0 d N p h ,

Ph3P

Additive: none TiCI4

783

(310)

(sluggish) 92%

Additive:

none Tic14

no reaction 89%

Intramolecular carbotitanation of acetylenes with active methylene compounds, which presumably involves activation of the triple bond by coordination of the titanium species, has been reported (Eq. 313) [711]. The resulting alkenyltitanium species reacted with iodine to give the vinylic iodide with high stereoselectivity.

C02Me

Tic14

Tic13 &C02Me C02Me

79%

only Z

The Schmidt reaction has been promoted by TiC14 (Eq. 314) [712].

784

Urabe/Sato

An interesting application of a titanium compound is the blocking of a carbonyl group against unfavorable chelation. Macrocyclization, via ruthenium-catalyzed metathesis, of the functionalized diene shown in Eq. (315) proceeds sluggishly, presumably because of the formation of an unproductive chelate involving the neighboring carbonyl group and the ruthenium metal. Addition of Ti(O-i-Pr)4, however, enables the reaction to proceed with improved yield [713]. Competitive or preferred coordination of the titanium to the ester group, resulting in regeneration of the ruthenium-carbene complex active in the metathesis reaction, might account for this observation.

I

If

(5 mol%)

*

Additive

Additive: none 22% Ti(O-CPr)4 (5 mol%) 55%

Endnote Abbreviations appearing in this chapter are explained in: J. Org. Chem. 1999,64(1),21A.

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Titanium(IV)Lewis Acids

785

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786 62. 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. 92. 93. 94. 95. 96. 97. 98.

99. 100. 101.

102. 103. 104. 105.

106. 107. 108. 109. 110.

111. 112. 113. 114. 115. 116. 117.

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Titanium(IV)Lewis Acids 118.

119. 120. 121. 122. 123. 124. 125. 126. 127. 128. 129. 130. 131. 132. 133. 134. 135. 136. 137. 138. 139. 140. 141. 142. 143. 144. 145. 146. 147. 148. 149. 1.50. 151. 152. 153. 154.

155. 156. 1.57. 158. 159. 160. 161 162. 163. 164. 16.5. 166.

787

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788

Urabe/Sato

167. Hayashi, T.; Kabeta, K.; Yamamoto, T.; Tamao, K.; Kumada, M. Tetrahedron Lett. 1983, 24, 5661-5664. 168. Nakamura, H.; Aoyagi, K.; Yamamoto, Y. J. Org. Chem. 1997,62,780-781. 169. Hon, Y.-S.; Yan, J.-L. Tetrahedron 1998,54,8525-8542. 170. Dombrowski, G. W.; Gassman, P G.; Kass, S. R. Tetrahedron Lett. 1997,38,7819-7822. 171. Bonini, B. F.; Comes-Franchini, M.; Mazzanti, G.; Ricci, A.; Sala, M. J. Org. Chem. 1996, 61, 7242-7243. 172. Horiuchi, Y.; Oshima, K.; Utimoto, K. J. Org. Chem. 1996,61,4483-4486. 173. Barrett, A. G. M.; Doubleday, W. W.; Hamprecht, D.; Kasdorf, K.; Tustin, G. J.; White, A. J. P.; Williams, D. J. Chem. Commun. 1997,1693-1700. 174. Mead, K. T.; Zemribo, R. Synlett 1996,1063-1064. 175. Pellissier, H.; Santelli, M. J. Chem. SOC.,Chem. Commun. 1995,607-608. 176. Wu, H.-J.; Chern, J.-H. J. Org. Chem. 1997,62,3208-3214. 177. Shinokubo, H.; Oshima, K.; Utimoto, K. Chem. Lett. 1995,461462. 178. Maeda, K.; Shinokubo, H.; Oshima, K. J. Org. Chem. 1997,62,64294431. 179. Burgess, L. E.; Gross, E. K. M.; Jurka, J. Tetrahedron Lett. 1996,37,3255-3258. 180. Stojanovic, A,; Renaud, P.; Schenk, K. Helv. Chim. Acta 1998,81,268-284. 181. Sato, T.; Kugo, Y.; Nakaumi, E.; Ishibashi, H.; Ikeda, M. J. Chem. SOC.Perkin Trans. 1 1995,18011809. 182. Tsirk, A.; Gronowitz, S.; Hornfeldt, A.-B. Tetrahedron 1997,53,771-784. 183. Sadakane, M.; Vahle, R.; Schierle, K.; Kolter, D.; Steckhan, E. Synlett 1997,9596. 184. Yamada, H.; Aoyagi, S.; Kibayashi, C. Tetrahedron Lett. 1996,37,8787-8790. 185. Ponzo, V. L.; Kaufman, T. S. Synlett 1995,1149-1150. 186. Lazareva, M. I.; Kryschenko, Y. K.; Hayford, A,; Lovdahl, M.; Caple, R.; Smit, W. A. Tetrahedron Lett. 1998,39,1083-1086. 187. Hermans, B.; Hevesi, L. J. Org. Chem. 1995,60,6141-6147. 188. Marko, I. E.; ChellC, F. Tetrahedron Lett. 1997,38,2895-2898. 189. Oriyama, T.; Ishiwata, A,; Sano, T.; Matsuda, T.; Takahashi, M.; Koga, G. Tetrahedron Lett. 1995, 36,5581-5584. 190. Ward, D. E.; Gai, Y.; Kaller, B. F. J. Org. Chem. 199.5,60,7830-7836. 191. Schuster, M.; Lucas, N.; Blechert, S. Chem. Commun. 1997,823-824. 192. Springer, J. B.; DeBoard, J.; Corcoran, R. C. Tetrahedron Lett. 199.5,36,8733-8736. 193. Liu, P.; Panek, J. S. Tetrahedron Lett. 1998,39,61474150. 194. Jain, N. F.; Cirillo, P. F.; Pelletier, R.; Panek, J. S. Tetrahedron Lett. 1995,36,8727-8730. 195. LongCpC, J.; Prandi, J.; Beau, J.-M. Angew. Chem. Int. Ed. Engl. 1997,36,72-75. 196. Jain, N. F.; Panek, J. S. Tetrahedron Lett. 1997,38,1349-1352. 197. Kalesse, M.; Eh, M. Tetrahedron Lett. 1996,37,1767-1770. 198. Panek, J. S.; Beresis, R. T.; Celatka, C. A. J. Org. Chem. 1996,61,6494-6495. 199. Paterson, I.; Bower, S.; McLeod, M. D. Tetrahedron Lett. 1995,36,175-178. 200. Roush, W. R.; Marron, T. G.; Pfeifer, L. A. J. Org. Chem. 1997,62,474478. 201. Panek, J. S.; Jain, N. F. J. Org. Chem. 1998,63,4572-4573. 202. Jain, N. F.; Takenaka, N.; Panek, J. S. J. Am. Chem. SOC.1996,118,12475-12476. 203. Masse, C. E.; Yang, M.; Solomon, J.; Panek, J. S. J. Am. Chem. SOC.1998,120,4123-4134. 204. Panek, J. S.; Masse, C. E. J. Org. Chem. 1997,62,8290-8291. 205. Panek, J. S.; Yang, M.; Solomon, J. Tetrahedron Lett. 1995,36,1003-1006. 206. Jain, N. F.; Panek, J. S. Tetrahedron Lett. 1997,38,1345-1348. 207. Liu, P.; Panek, J. S. Tetrahedron Lett. 1998,39,6143-6146. 208. Kim, Y. H.; Kim, S. H. Tetrahedron Lett. 1995,36,6895-6898. 209. Pandey, G.; Reddy, P. Y.; Das, €? Tetrahedron Lett. 1996,37,3175-3178. 210. Adinolfi, M.; Barone, G.; Iadonisi, A.; Mangoni, L.; Manna, R. Tetrahedron 1997,53,11767-11780. 211. Maezaki, N.; Matsumori, Y.; Shogaki, T.; Soejima, M.; Tanaka, T.; Ohishi, H.; Iwata, C. Chem. Commun. 1997,1755-1756. 212. Maeda, K.; Shinokubo, H.; Oshima, K. J. Org. Chem. 1998,63,45584560. 213. Beal, L. M.; Moeller, K. D. Tetrahedron Lett. 1998,39,4639-4642. 214. Allin, S. M.; Northfield, C. J.; Page, M. I.; Slawin, A. M. Z. Tetrahedron Lett. 1997,38,3627-3630. 215. Schierle, K.; Vahle, R.; Steckhan, E. Eur. J. Org. Chem. 1998,509-514. 216. Pansare, S. V.; Ravi, R. G.; Jain, R. P. J. Org .Chem. 1998,63,4120-4124. 217. Panek, J. S.; Schaus, J. V. Tetrahedron Lett. 1997,53,10971-10982. 218. Pandey, G.; Das, P. Tetrahedron Lett. 1997,38,9073-9076. 219. Kardassis, G.;Brungs, P.; Nothhelfer, C.; Steckhan, E. Tetrahedron 1998,54,3479-3488. 220. Kardassis, G.; Brungs, P.; Steckhan, E. Tetrahedron 1998,54,3471-3478. 221. David, M.; Dhimane, H.; Vanucci-BacquC, C.; Lhommet, G. Synlett 1998,206-208.

Titaniurn(IV)Lewis Acids 222. 223. 224. 225. 226. 227. 228. 229. 230. 231. 232. 233. 234. 235. 236. 237. 238. 239. 240. 241. 242. 243. 244. 245. 246. 247. 248. 249. 250. 251. 252. 253. 254. 255. 256. 257. 258. 259. 260. 261. 262. 263. 264. 265. 266. 267 268. 269. 270. 271. 272. 273. 274. 275.

789

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Titanium(IV)Lewis Acids 334. 335. 336. 337. 338. 339. 340. 341. 342. 343. 344. 345. 346. 347. 348. 349. 350. 351. 352. 353. 354. 355. 356. 357.

358. 359. 360. 361. 362. 363. 364. 365. 366. 367. 368. 369. 370. 371. 372. 373. 374. 375. 376. 377. 378. 379. 380. 381.

382.

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792 383. 384. 385. 386. 387. 388. 389. 390. 391. 392. 393. 394. 395. 396. 397. 398. 399. 400. 401. 402. 403. 404. 405. 406. 407. 408. 409. 410. 41 1 , 412. 413. 414. 415. 416. 417. 418. 419. 420. 421. 422. 423. 424. 425. 426. 427. 428. 429. 430. 431. 432. 433. 434. 435. 436. 437.

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Titanium(IV)Lewis Acids 438. 439. 440. 441. 442. 443. 444. 445. 446. 447. 448. 449. 450. 451. 452. 453. 454. 4.55. 456. 457. 458. 459. 460. 461. 462. 463. 464. 465. 466. 467. 468. 469. 470. 471. 472. 473. 474. 475. 476. 477. 478. 479. 480. 481. 482. 483. 484. 485. 486. 487. 488. 489. 490. 491.

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794 492. 493. 494. 495. 496. 497. 498. 499. 500. 501. 502. 503. 504. 50s.

506. 507. 508. 509. 510. 512.

512. 513. 514. 515. 516. 517. 518. 519. 520. 521.

522. 523. 524. 525. 526. 527. 528. 529. 530. 531. 532. 533. 534. 535. 536. 537.

538. 539. 540. 541. 542.

Urabe/Sato

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795

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796 599. 600. 601. 602. 603. 604. 605. 606. 607. 608. 609. 610. 611. 612. 613. 614. 615. 616. 617. 618.

619. 620. 621. 622. 623. 624. 625. 626. 627. 628. 629. 630. 631. 632. 633. 634. 635. 636. 637. 638. 639. 640. 641. 642. 643. 644. 645. 646. 647. 648. 649. 650. 651. 652. 653. 654.

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Titanium(N)Lewis Acids 655. 656. 657. 658. 659. 660. 661. 662. 663. 664. 665. 666. 667. 668. 669. 670. 671. 672. 673. 674. 675. 676. 677. 678. 679. 680. 681. 682. 683. 684. 685. 686. 687. 688. 689. 690. 691. 692. 693. 694. 695. 696. 697. 698. 699. 700. 701. 702. 703. 704. 705. 706. 707. 708.

797

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798 709. 710. 711. 712. 713.

Urabe/Sato Kataoka, T.; Iwama, T.; Tsujiyama, S. Chem. Commun. 1998,197-198. Griesbeck, A. G.; Buhr, S.; Lex, J. Tetrahedron Lett. 1998,39,2535-2536. Kitagawa, 0.:Suzuki, T.; Inoue, T.;Watanabe, Y.; Taguchi, T. J. Org. Chem. 1998,63,9470-9475. Wendt, J. A,: Aube, J. Tetrahedron Lett. 1996,37,1531-1534. Furstner, A.; Langemann. K. J. Am. Chem. SOC. 1997,119,9130-9136.

Lewis Acids in Organic Synthesis Edited bv Hisashi Yamarnoto Copyright 0WILEY-VCH Verlaa GmbH.2000

16 Chiral Ti(1V) Lewis Acids Koichi Mikami and Masahiro Terada

16.1 Introduction Enantioselective catalysis is an economical and environmentally benign process which affords a large amount of an enantio-enriched product while producing a small amount of waste material, because of the very small amount of chiral catalyst employed [l].The development of enantioselective catalysts is, therefore, a most challenging problem for synthetic organic chemists [2,3].Highly promising candidates for such enantioselective catalysts are metal complexes bearing chiral organic ligands. Among the Lewis acidic metal complexes, titanium(1V) is the central metal of choice, because of their high Lewis acidity [4] and relatively short metal-ligand bond lengths 151. In principle, more effective asymmetric environment could be constructed by use of chiral ligands with shorter bond lengths to the central metals. Chiral titanium complexes so far reported as Lewis acidic catalysts can be divided into two classes according to the type of chiral ligand-chiral titanocene derivatives and chiral titanium alkoxides (and/or amides). The former are used extensively as catalysts for stereoregular polymerization [6], and rarely as chiral Lewis acids 171. In contrast, the latter group has been widely explored as a chiral Lewis acidic catalysts. General procedures for the preparation of chiral titanium alkoxides are classified in Sch. 1 181. In Eq. (1)halide is replaced by a metalated ligand by transmetalation. In Eq. (2) a halide is replaced by metathesis of a silylated ligand with accompanying generation of a silylhalide. In Eq. (3) HCl is evolved with protic ligands, and hence must be removed by evaporation or neutralized with a base. In Eq. (4) ligand redistribution results in disproportionation. In Eq. ( 5 ) a chiral titanate ester is prepared by use of an alkoxy exchange reaction (transesterification) with a free chiral alcohol. The equilibrium is shifted towards the chiral titanium complex by azeotropic removal of the volatile achiral alcohol. In Eq. (6) alkyl (methyl, in particular) titanium complexes are used for deprotonation of the chiral ligands along with generation of alkane (methane). The chiral titanium alkoxide complexes thus obtained are usually bridged dimers, or, in extreme cases, trimers. Such aggregates are the favored form even in solution. As shown above, there are many ways of preparing chiral titanium alkoxides; these can be used as the enantioselective catalysts in carbon-carbon bond-forming reactions.

800 TiC14

TiCI4

Mikami/Terada

+

n NaOR

+

SiCI(OR)3

+

4 ROH

+ nROH + nNR3 4-nTiCI4

+

nTi(OR)4

(R0)3TiCI

+

3 R'OH

CH3TiCI3

+

ROH

+

+

n NaCl

(RO)TiCI3

+

SiC12(0R)2

(R0)2TiC12

+

2 HCI

+

n NR3HCI

(RO),TiC14.,

(RO),TiClc,

4 (RO),TiCL., (R'0)3TiCI

+

3 ROH

ROTiCI3

+

CH4

Scheme 1

16.2 Carbonyl Addition Reaction Alkyltitanium complexes can be obtained from metal carbanions via titanation. Introduction of chirality at the titanium center or on the ligand (or a combination of both) (Sch. 2) enables the possibility of asymmetric induction in the carbonyl addition reaction.

Scheme 2

Use of titanium complexes that are chiral at the titanium center closest to the reacting carbonyl group generally affords only low enantioselectivity, however, because of the configurational lability of chiral titanium center [9]. The use of a C, symmetric l,l'-bi-2-naphthol (BIN0L)-derived titanium complex [ 101 has been unsuccessful so far in allylation or methylation reactions [5].In one exception high enantioselectivity has been obtained with a BINOL-modified phenyltitanium reagent. Chiral titanium 'ate' complexes formed from BINOL-Ti(OPr')* [ll] and arylmagnesium halides could also be used in this reaction [12]. Allylation of aromatic and aliphatic aldehydes by use of cr,a,a',cr'-(4R, 5R)-tetraaryl-1,3-dioxolane-4,5-dimethanol (TADDOL [13])derived cyclopentadienyltitanium complexes has been found to give homoallyl alcohols with high enantioselectivity [14]. Enantioselective carbonyl addition of dialkylzinc reagents to aldehydes is one of the most important and fundamental asymmetric reactions [2,15]. Several chiral titanium complexes have been developed to accelerate this type of reaction (Sch. 3) [16,18-261 since Ohno and Kobayashi achieved high enantioselectivity in the presence of Ti(OPr'), and chiral disulfonylamide [16,17]. Seebach has also demonstrated that TADDOL-derived titanium complexes function as efficient asymmetric catalysts [MI.

Chiral Ti(ZV)Lewis Acids chiral ligand or chiral titanium complex /Ti(OPr')d

0 t

EtpZn

Ph

PhKH

NHSOpC F3

0

"'NHsoPcF~

Ref. 16: 99% ee (S) (0.5 mol%)

F'

TADDOL Ref. 18: 98% ee (S) (20 mol%) (R, R' = Me, Ar = Ph)

Ref. 18: 99% ee (S) (10 mol%) (R, R' = Me, Ar = Ph)

8:; &OH SOpNHBn

\

CI Ref. 19: 99% ee (S) (10 mol%)

/

Ref. 20: 85% ee (S) (10 mol%)

Ref. 21 : 71% ee (S) (20 mol%)

OMe

Ref. 22: 81% ee (S) (20 mol%)

Ref. 23: 85% ee (S) (5 mol%)

Ref. 24: 92% ee (S) (10 mol%)

HO OH

HO OH

Ar = polystyrene supported dendritic TADDOL with aromatic tether Ref. 25: 96% ee (S) (20 mol%)

Scheme 3

HO OH

HO OH

Ref. 26: 86% ee (R) (5 mol%)

801

802

MikarnUTerada

Practical access to functionalized dialkylzinc reagents, developed independently by Seebach [27] and Knochel [29,29] has opened the way to expansion of the synthetic utility of this addition reaction (Sch. 4). Seebach reported that exploitation of the Schlenk equilibrium of a mixture of a Grignard reagent, FG (functional group)RMgX, and 0.5 equiv. ZnC12 with dioxane enabled the in situ generation of a functionalized dialkylzinc reagent and the MgX2-dioxane complex (Sch. 4a) [27]. Knochel provided access to a range of functionalized dialkylzinc compounds by means of an iodide-zinc exchange reaction catalyzed by CuI (Sch. 4b) [28]. 1,4-dioxane

2 FG-RMgX

+

ZnC12

2 FG-R'CH21

+

Et2Zn

*

- MgX2*l,4-dioxane Cul (0.3 mol%)

-

t

(FG-R)2Zn

(a)

(FG-R'CH&Zn

(b)

-2 Etl Scheme 4

In our research on the asymmetric catalysis of the carbonyl-ene reaction, we found that the BINOL-Ti complexes (1) [30], prepared in situ, in the presence of 4-w molecular sieves, from diisopropoxytitanium dihalides (X2Ti(OPri)2:X = Br [31] or C1 [32]) and optically pure BINOL (vide infra), catalyze [33], rather than promote stoichiometrically, the carbonyl addition reaction of allylic silanes and stannanes [34]. The addition to glyoxylate of (E)-2-butenylsilane and -stannane proceed smoothly to afford the syn product in high enantiomeric excess (Sch. 5). The syn-product thus obtained could be readily converted to the lactone portion of verrucaline A [35]. (S)-BINOL (10 mol%) / CI2Ti(OPrj2 (10 mol%) I MS4A

(S)-BINOL

Scheme 5

OH

Chiral Ti(IV)Lewis Acids

803

We have also found that BINOL-Ti (1) catalyzes the Sakurai-Hosomi reaction of methallylsilanes with glyoxylates (Sch. 6) [36]. Surprisingly, however, the products were obtained in the allylic silane (ene product) form (vide infra), with high enantioselectivity. II

OH

Ph3si&c02CH3 95% ee

Ph3Si&

+

Hlcoz

Scheme 6

Asymmetric catalysis by BINOL-Ti complexes of the reaction of aliphatic and aromatic aldehydes with allylstannanes has been reported independently by Tagliavini/ Umani-Ronchi [37] and Keck [38]. Tagliavini/Umani-Ronchi [37] suggested that a new complex generated by the reaction of the BINOL-Ti complex with allylstannane was the catalytic species furnishing the remarkably high enantioselectivity (Sch. 7). Interestingly enough, no reaction occurred if 4-A molecular sieves (MS 4A) were not present during the preparation stage of the chiral catalys!. The authors reported that the sieves affected the subsequent allylation reaction. 4-A Molecular sieves dried for 12 h at 250 "C and 0.1 Torr were recommended. Keck reported that addition of CF3C02H or CF3S03H strongly accelerated reactions catalyzed by BINOL-Ti(OPr')2 complex (2) [38]. Briickner pointed out the undesirable effect of MS 4A in the methallylation reaction [39]. The BINOL-Ti catalyst prepared from Ti(OEt), (10 mol Yo) and (R)-BINOL (20 mol YO)in the absence of MS 4A achieved high enantioselectivity whereas the use of MS 4A at the catalyst-preparation stage resulted in quite low enantioselectivity. Chiral titanium complexes derived from optically active dendritic BINOLs are also effective in this allylation reaction [40].

Bun3Sn-

\

+

(S)-BINOL / CI2Ti(OPr92 (20 mol% each) t

dried MS 4A CH2C12, -20 "C rt

-

OH

wR

R = n-C5HIT 98% ee (75%) PhCH=CH 94% ee (38%) Ph 82% ee (96%)

Scheme 7

To construct an effective catalytic cycle in the allylation reaction of aldehydes with allylic stannanes catalyzed by BINOL-Ti, Yu used RSMR, (MR', = SiMe3 [41], BEt, [42], and AIEt, [42a]) as synergetic reagents (Sch. 8). They proposed that the synergetic effect arose from the Sn-S and M-0 bond-forming steps which reinforced regeneration of the BINOL-Ti catalyst in terms of producing strong Sn-S and M-0 bonds rather than weaker M-S bonds.

804

Mikurni/Terudu

(9-BINOL (20 rnol%) / Ti(OPr?4 (10 mol%) B u n 3 S n d \

0

+

/ Pr'SBEt2 (120 mol%)

OH

1 ,

H

MS 4A CH2C12, -20 "C

R"

R = PhCH2CH2 97% ee (93%) c - C ~ H I ~ 93%ee (77%)

Ph

+ U'

B u n 3 S \ n d

(S)-BINOL-Ti

96% ee (89%)

OMR', + Bun3SnSR

R -

R"CH0

RSMR',

(MR', = SiMe3, BEt2, AIEt2)

Scheme 8

The BINOL-Ti complex-catalyzed addition of allylsilane to aliphatic and aromatic aldehydes has been reported by Carreira [43]. The catalyst is prepared from BINOL and polymeric TiF4 (Sch. 9). The presence of a small amount of CH3CN is crucial to achieving not only high catalytic activity but also high enantioselectivity.

Me&-

(S)-BINOL /TiF4 (10 rnol% each)

+

*

-

OSiMe3

CH2C12, CH3CN R 0 "C R = t-Bu 94% ee (91%) Ph 80% ee (85%) CH2CH2Ph 61% ee (69%)

Scheme 9

Faller demonstrated the enantiomer-selective deactivation of racemic BINOL-Ti complex by using DIPT-derived titanium complex as a chiral poison (vide infra) (Sch. 10) [44]. The enantiomeric excess (ee) of the allylation product increased as the amount of DIPT employed was increased.

Chiral Ti(IV)Lewis Acids

805

Ti(OPrj4 (30 mol%) / (+)-BINOL (20 mol%)

B u n 3 S n e

+

0

/ (-)-DIPT (X mol%) MS 4A, CHzCIz (-)-DIPT 15 mol% 20 mol% 30 mol%

*

OH

w

Ph

39% ee (40%) 81% ee (47%) 91% ee (63%)

Scheme 10

16.3 Carbonyl-Ene Reaction The class of ene reactions with carbonyl compounds as the enophile, which we denote the ‘carbonyl-ene reaction’ [45], is an efficient alternative to the carbonyl addition reaction of allylic metals (Sch. 11).

Scheme 11

We have been investigating the possibility of stereocontrol in carbonyl-ene reactions promoted by a stoichiometric or catalytic amounts of different Lewis acids [45b,46]. In particular, we have developed a chiral titanium catalyst for the glyoxylate-ene reaction which furnishes a-hydroxy esters of biological and synthetic importance [47] in an enantioselective fashion (Sch. 12) [48-501. When different chiral titanium catalysts were screened [51] the best result was obtained with the titanium catalyst (1) prepared in situ, in the presence of MS 4A, from diisopropoxytitanium dihalides (XzTi(OPrz)z: X = Br or Cl) and optically pure BINOL or 6,6‘dibromo-l,l’-bi-2-naphthol (6-Br-BINOL) [52] (this ligand is now available commercially in the (R)-and (S)-forms). The remarkable levels of enantioselectivity and rate acceleration observed with these BINOL-Ti catalysts (1) stem from the favorable influence of the inherent C2 symmetry and the higher acidity of BINOLs compared with aliphatic diols. The reaction is applicable to a variety of 1,l-disubstituted olefins and furnishes the ene products with extremely high ee (Table 1). In reactions with mono- and 1,Zdisubstituted olefins, however, no ene product was obtained.

806

Mikami/Terada

I

(10 mol% each)

X = H 97% ee (R) (82%) X = Br >99% ee (R) (82%)

OH

OH

Br (R)-6-Br-BINOL

(R)-BINOL Scheme 12

Table 1. Asymmetric catalytic glyoxylate-ene reactions with different olefins." Run

A

Olefin

A

Xin Catalyst Time XZTi(0Pr') (mol YO) (h) CI

10 10

CI

1.0

8

Br

10

3

Product

8 flC02CH3

Yield (%)

ee

72 68

95 ( R ) 95 (S)"

78

93 ( R )

87

94 ( R )

(%)

Reactions were conducted with 1.0 mmol methyl glyoxylate, 2.0 mmol olefin, and the indicated amount of BINOL-Ti complex at -30 "C. (S)-BINOL was used instead of the ( R )counterpart.

a

This limitation has been overcome by the use of vinylic sulfides and selenides instead of mono- and 1,2-disubstituted olefins. With these substrates, the ene products are formed with almost complete enantioselectivity and high diastereoselectivity [53].

Chiral Ti(IV)Lewis Acids

807

The synthetic utility of the vinylic sulfide and selenide approach is exemplified by the synthesis of enantio-pure (R)-(-)-ipsdienol, an insect aggregation pheromone (Sch. 13) [S4]. Kabat and Uskokovic have demonstrated the asymmetric catalytic synthesis of lu,25-dihydroxyvitamin D3 ( ~ G ~ , ~ S ( O HA-ring ) ~ D ~synthon ) by means of a glyoxylate-ene reaction catalyzed by BINOL-Ti complex (1) (Sch. 14) [SS].

I

II

+

PhX-

(R)-BINOL-Ti (1) (0.5 mol%)

0

II

b

HAC0pCH3

CHpClp, MS 4A -30 "C

?H

PhXWCOpCH3

R

R R=H

[

X = S 94% (>99% ee) X = Se 95% (>99% ee)

q But

P

(R)-(-)-ipsdienol (>99% ee)

Scheme 13

0

+

(R)-BINOL-Ti (1) (10 mol%)

H ~ C O ~ C HMS4A, ~ CHpCIp, -23°C (75%)

*

HO'"" 94% ee

t -

OTBDMS

The synthetic potential of the asymmetric catalytic carbonyl-ene reaction depends greatly on the functionality possible in the carbonyl enophile. The types of enophile that can be employed in the asymmetric catalytic ene reaction have, however, previously been limited to aldehydes such as glyoxylate [49,51-53,55,56] and chloral [SO,57]. It is, therefore, highly desirable to develop other types of carbonyl enophile to provide enantio-enriched molecules with a wider range of functionality. We have thus developed an asymmetric catalytic fluoral-ene reaction [%I, which is

808

Mikami/Terada

an efficient approach to the asymmetric synthesis of some fluorine-containing compounds of biological and synthetic importance [59]. The reaction of fluoral with 1,ldisubstituted and trisubstituted olefins proceeds quite smoothly under catalysis by the BINOL-Ti complex (1) to provide the corresponding homoallylic alcohol with extremely high enantioselectivity (> 95 % ee) and syn-diastereoselectivity (> 90 %) (Sch. 15). The sense of asymmetric induction in the fluoral-ene reaction is exactly the same as observed for the glyoxylate-ene reaction; (R)-BINOL-Ti (1) provides the (R)-a-CF3 alcohol. The syn diastereomers of a-trifluoromethyl-P-methyl-substituted compounds thus synthesized with double stereogenic centers are more pronounced anti-ferroelectric properties than the anti diastereomers [60]. (R)-BINOL-Ti (1) (10 mol%) MS 4A CHzCI2, 0 ° C

-q CF3

R R=H >95% ee R = Me 96% ee (98% syn)

antiferroelectric liquid crystalline molecule

Scheme 15

BINOL-Ti catalysis can also be used for the carbonyl-ene reaction with formaldehyde or vinyl and alkynyl analogs of glyoxylates in an asymmetric catalytic desymmetrization (vide infra) approach to the asymmetric synthesis of isocarbacycline analogs (Sch. 16) [61].

(R)-BINOL-Ti (1) (20 mol%) w

CH2CI2 -30 "C or 0 "C OTBDMS

R=

Scheme 16

H

OTBDMS

OTBDMS

A6(9a)-isomer

A6-isomer

90

: 10 (61%)

{-cO&H3

92 (94%4R) :

8

(81%)

'!CO,CH,

92 (92%4R) :

8

(72%)

Chiral Ti(IV) Lewis Acids

809

16.4 Asymmetric Catalytic Desymmetrization Desymmetrization of an achiral, symmetrical molecule by a catalytic process is a potentially powerful but relatively unexplored concept in asymmetric synthesis. Although the capacity of enzymes to differentiate between enantiotopic functional groups is well known [62], there has been little investigation of non-enzymatic catalysts with similar capacity, particularly for carbon-carbon bond forming processes. The desymmetrization by the catalytic glyoxylate-ene reaction of prochiral ene substrates with planar symmetry provides efficient access to remote [63] and internal [64] asymmetric induction which is otherwise difficult to achieve (Sch. 17) [65]. The (2R,SS)-synproduct is obtained in > 99 YOee with more than 99 YOdiastereoselectivity. The diene thus obtained can be transformed to a more functionalized compound both regioselectively and diastereoselectively. (R)-BINOL-Ti (1)

0

(10 mol%) *

0si-H \

+

HKC02CH3

MS 4A CH2C12,rt

(53%)

w

C

O

2

C

H

3

os<+ 99% ee (> 99% syn)

J

1) 9-BBN 2) H202/NaOH

Scheme 17

16.5 Kinetic Optical Resolution On the basis of the desymmetrization concept, the kinetic optical resolution of a racemic substrate [66] can be recognized as an intermolecular version of desymmetrization. The kinetic resolution of a racemic allylic ether by the glyoxylate-ene reaction also provides efficient access to remote but relative [64] asymmetric induction. The reaction of allylic ethers catalyzed by the (R)-BINOL-derived complex (1) provides the (2R,SS)-synproducts with > 99 YOdiastereoselectivity and > 95 YOee (Sch. IS). The high diastereoselectivity, coupled with the high ee, strongly suggests that the catalyst/glyoxylate complex efficiently discriminates between the two enantiomeric substrates to accomplish the effective kinetic resolution. In fact, the relative rates of the reactions of the enantiomers, calculated by use of the equation: (ln[(l - c)(l - eerecov)] x {ln[(l - c)(l + eerecov)lI-I where c, the fraction consumed, = (eerecov)x (eerecov+ eeprod)-l, 0 < c, and ee < 1, were ca. 700 for R = i-Pr and 65 for R = Me. As expected, the double asymmetric induction [67] in the reaction of the (R)-ene component using the catalyst (S)-1

810

MikamUTerada

(‘matched’ catalytic system) led to complete (> 99 YO)2,5-syn-diastereoselectivity in high chemical yield, whereas reaction of (R)-ene using (R)-1 (‘mismatched’ catalytic system) produced a diastereomeric mixture in quite low yield (Sch. 19).

’*

(R)-BINOL-Ti (1) (10 mol%)

I

osi+

0

+

MS 4A CH2C12, rt

HKC02CH3

\

’@

2 C02CH3

os<+ R i-Pr Me

*

+

2,5-syn

ene-product

‘ 2,s-anti

+

R”C02CH3

OS;’s(

recovered ene

OS;’s( \

relative rate (kR/ks)

99.6% ee (>99% syn)

37.8% ee

720

96.2% ee (>99% syn)

22.0% ee

64

Scheme 18

BINOL-Ti (1) (10 mol%) +

dC02CH3

OS;’s( \

\

( R)

(S)-BINOL-Ti (1)

>99

:

<1

(R)-BINOL-Ti (1)

50

:

50

2,s-anti

Scheme 19

16.6 Positive Non-Linear Effect of Non-racemic Catalysts Deviation from the linear relationship, namely a ‘non-linear effect’ (NLE) is sometimes observed between the enantiomeric purity of chiral catalysts and the optical yields of the products [15a,68,69]. Amongst these deviations the convex deviation, which Kagan [70] and Mikami [71] independently refer to as positive non-linear effect, (abbreviation (+)-NLE (asymmetric amplification [72])) is currently attracting attention in attempts to achieve higher levels of asymmetric induction than the enantio-purity afforded by non-racemic (partially resolved) catalysts. In turn, (-)-NLE stands for the opposite phenomenon, concave deviation, namely a negative non-linear effect. We have observed a remarkable level of (+)-NLE in the catalytic ene reaction. For instance, in the glyoxylate-ene reaction, the use of a catalyst prepared from BINOL of 33.0 Yo ee provides the ene product with 91.4 YOee in 92 YO chemical yield (Sch. 20) [17a,b]. The ee thus obtained is not only much higher than that of the BINOL employed, but also very close to the value (94.6 % ee) obtained by use of enantiomerically pure BINOL (Fig. 1).

Chiral Ti(1V)Lewis Acids

811

BINOL (33.0%ee) / Br2Ti(OPri), (1.O mol% each) C02CH3

Ph

*

MS 4A

PhuC0,CH3 91.4% ee

(92%)

Scheme 20

" 0 d

Q

. -

0

$ * 2 a U

0 BINOL / C12Ti(OPri)2 (1 mol% each) 0 BINOL / Br,Ti(OPr'),

0 N

0

1

I

0

20

40

(1 mol% each)

-

60

1

80

'

1

100

BINOL / % ee (X% ee)

Figure 1. (+)-NLE in the asymmetric glyoxalate-ene reaction catalyzed by the BINOL-Ti complex.

16.7 Enantiomer-Selective Activation of Racemic Catalysts Whereas non-racemic catalysts can generate non-racemic products with or without NLE, racemic catalysts inherently produce only racemic products. A strategy whereby a racemic catalyst is enantiomer-selectively deactivated by a chiral molecule has been shown to yield non-racemic products [73,74],although the level of asymmetric induction does not exceed that attained by use of the enantiopure catalyst (Sch. 21a). Recently, the term 'chiral poisoning' [44,57,75] has been given to this deactivating strategy. In contrast, we have reported an alternative but conceptually opposite strategy to asymmetric catalysis by racemic catalysts. A chiral activator selectively activates one enantiomer of a racemic chiral catalyst. Greater enantioselectivity might be attained than that achieved by use of an enantio-pure catalyst (% eeact >> % eeenantlo.pure), in addition to greater catalytic efficiency (kaCt>> kcnantlo.pure) (Sch. 21b).

812

Mikami/Terada

Substrate I I )Product k (x% ee)

chiral deactivator ("poison")

(a)

Substrate

I,,,) k,,t.....@ Product

activated

(xact%

(k,,t >> k,

eel

XaCt >> x)

(b)

(animator, booster)

Scheme 21

Catalysis with racemic BINOL-Ti(OPr')Z ( 2 ) results in extremely high enantioselectivity by adding another diol for the enantiomer-selective activation (Sch. 22, Table 2) [76]. Significantly, remarkably high enantioselectivity (89.8 YO ee, R ) was achieved by use of just a half-molar amount ( 5 mol %) of (R)-BINOL activator added to a racemic (*)-BINOL-Ti(OPr2)2 complex (2) (10 mol Yo). Table 2. Enantiomer-selective activation of racemic BINOL-Ti(OPr')2 (2). Run

Chiral activator

Yield (%)

ee (%)

1

None

5.9

0

20

0

38

80.8

52

89.8

35

80.0

3

5" a

2.5 mol % (R)-BINOL was used as chiral activator.

Chiral T i 0 Lewis Acids

I

chiral activator (5 rnol%)

813

0

P h A , HKC02Bu"

*

toluene 0°C. 1 h

* PhIc"i,,,Bu" (R)

(_+)-BINOL-Ti(OPrjp (2) (10 rnol%)

Scheme 22

Activation of the enantiopure (R)-BINOL-Ti(OPr')2 catalyst (2) was investigated by further addition of (R)-BINOL (Sch. 23, Table 3). The reaction proceeded quite smoothly to provide the carbonyl-ene product in higher chemical yield (82.1 Y ) and enantioselectivity (96.8 YOee) than without additional BINOL (94.5 YO ee, 19.8 YO) (Run 2 compared with Run 1). Comparison of results from enantiomer-selective activation of the racemic catalyst (89.8 YOee, R ) (Table 2, Run 4) with those from use of the enantio-pure catalyst (with (96.8 YO ee, R) or without (94.5 YO ee, R ) activator) enabled calculation that that the reaction catalyzed by the (R)-BINOL-Ti(OPr'),/(R)BINOL complex ((R,R)-2')would be 26.3 times faster than that catalyzed by the (S)BINOL-Ti(OPri)z (2) in the racemic case (Sch. 24a). Indeed, kinetic studies show that the reaction catalyzed by the (R)-BINOL-Ti(OPr')21(R)-BINOL complex ((R,R)-2')is 25.6 times faster than that catalyzed by (R)-BINOL-Ti(OPr')2 (2). These results imply that the racemic (+)-BINOL-Ti(OPr')Z (2) and the half-molar amount of (R)-BINOL assemble preferentially into the (R)-BINOL-Ti(OPr~)21(R)-BINOL complex ((R,R)-2')and unchanged (S)-BINOL-Ti(OPr2)2 (2). In contrast, the enantiomeric form of the additional chiral ligand ((S)-BINOL) activates the (R)-BINOLTi(OPr')2 (2) to a lesser extent (Run 3), thus providing the carbonyl-ene product in lower optical (86.0 YOee, R ) and chemical (48.0 YO)yields than does (R)-BINOL.

BINOL P h A , H'COZB~" toluene 0 "C

* Phf l C O z B u "

(R)-BINOL-Ti(OPr?z (2) (10 rnol%)

Scheme 23

Table 3. Asymmetric activation of enantio-pure (R)-BINOL-Ti(OPr')2 (2). Run

BINOL

Yield (YO)

ee (a)

1

None

19.8

94.5

2

(R)-BINOL

82.1

96.8

3

(5')-BINOL

48.0

86.0

4

(*)-BINOL

69.2

95.1

(R)

814

Mikami/Terudu

(R)-2 / (R)-BINOL (R)-BINOL (5 mol%)

((R,R)-2')

* (R)-Product (96.8% ee) kact

kactl

-

(1 0 mol%)

-

89.8% ee (R) (x 26.3)

(a)

95.7% ee (R) (x 8.8)

(b)

k

(S)-2

'

(+)-BINOL (10 mol%)

k = 25.6

(R)-2 (R)-BINOL ((R,R)-2')

kact

+ (R)-Product (96.8% ee)

k a c t l k&t

(10 mol%)

(R)-2 (5')-BINOL ((R,S)-2')

(S)-Product (94.5% ee)

= 9.2

Fact

(R)-Product (86.0% ee)

Scheme 24

The great advantage of asymmetric activation of the racemic BINOL-Ti(OPr')2 complex (2) is highlighted in a catalytic version of the reaction (Table 2, Run 5). High enantioselectivity (80.0 YOee) is obtained by adding less than the stoichiometric amount (0.25 molar amount per (*)-2) of additional (R)-BINOL. A similar phenomenon on enantiomer-selective activation has been observed in aldol [77] and (hetero) Diels-Alder [78] reactions catalyzed by a racemic BINOL-Ti(OPrL)2 catalyst (2) (vide infra). Another possibility was explored by using racemic BINOL as an activator. When racemic BINOL was added to the (R)-BINOL-T~(OPI-')~ (2) yield and enantioselectivity were higher (95.7 YOee, 69.2 YO) than those obtained by use of the original catalyst (R)-BINOL-Ti(OPr')* (2) without additional BINOL (94.5 YOee, 19.8 YO)(Run 4 compared with Run 1).Comparison of the results obtained by use of the racemic activator (95.7 YOee, R) with those obtained by use of enantio-pure catalyst, (R)BINOL-Ti(OPr')2/(R)-BINOL ((R,R)-2')(96.8 YOee, R ) or (R)-BINOL-Ti(OPr'),I (S)-BINOL ((R,S)-2')(86.0 Y ee, R) (Run 4 compared with Runs 2 and 3), enabled calculation that that the reaction catalyzed by the (R)-BINOL-Ti(OPr')2/(R)-BINOL complex ((R,R)-2') would be 8.8 times faster than that catalyzed by (R)-BINOLTi(OPrL)2/(S)-BINOL((R,S)-2') (Sch. 24b). Kinetic studies showed the reaction catalyzed by the (R)-BINOL-Ti(OPrL)21(R)-BINOLcomplex ((R,R)-2')to be 9.2 times faster than that catalyzed by (R)-BINOL-Ti(OPr')2/(S)-BINOL ((R,S)-2).

16.8 Ene Cyclization Conceptually, intramolecular ene reactions [79] (ene cyclizations) can be classified into six different groups (Sch. 25) [45b,80]. In the ene cyclizations, the carbon numbers where the tether connects the [l,S]-hydrogen shift system are shown by the notation (m,n). A numerical prefix stands for the size of the ring being formed.

Chiral Ti(W)Lewis Acids

-

exo', ex0

2

815

exo', endo

-

endo, endo

endo, ex0

1

1

Scheme 25

Asymmetric catalysis of ene reactions was initially investigated for the intramolecular examples, because intramolecular versions are much more facile than their intermolecular counterparts. The first reported example of an enantioselective 6-(3,4) carbonyl-ene cyclization employed a BINOL-derived zinc reagent [81]. This, however, was successful only when excess zinc reagent (at least 3 equiv.) was used. An enantioselective 6-(3,4) olefin-ene cyclization has also been developed which uses a stoichiometric amount of a TADDOL-derived c h i d titanium complex (Sch. 26) [82]. In this ene reaction, a hetero Diels-Alder product was also obtained, the periselectivity depending critically on the solvent system employed. In both cases, geminal disubstitution is required of high ee are to be obtained. Neither reaction, however, constitutes an example of a truly catalytic asymmetric ene cyclization. Ph Ph

(1.1 eq.)

toluene

R=H R=Me

mesitylene

17% 39% (82% ee) 32% (86% ee)

37% 36% (92% ee) 37% (>98% ee)

CFC12CF2CI

63% (>98% ee)

25%

20days 4days

(-)

Scheme 26

We reported the first examples of asymmetric catalysis of intramolecular carbonylene reactions of types (3,4) and (2,4) using the BINOL-derived titanium complex (1) [80,83]. The catalytic 7-(2,4) carbonyl-ene cyclization gives the oxepane with high ee, and gem-dimethyl groups are not required (Sch. 27). In a similar catalytic 6-(3,4) ene cyclization, the truns-tetrahydropyran is preferentially produced, with high ee (Sch. 28). The sense of asymmetric induction is exactly the same as observed for the glyoxylate-ene reaction- the (R)-BINOL-Ti catalyst provides the (R)-cyclic alcohol.

816

MikamUTerada

Thus the chiral BlNOL-Ti catalyst effects efficient chiral recognition of the enantioface of the aldehyde and discrimination between the diastereotopic protons of the ene component in a truly catalytic fashion. PH

-

(i-Pr0)2TiC12/ (R)-BINOL(20 mol% each) AgX (40 rnol%) MS 4A CH2CI 2 1 day

R=H

R

I

R=H

R=Me R=Me

AgC104

91% ee

(43%)

AgOTf

92% ee

(40%)

AgC104

82Y0ee

(40%)

Scheme 27 (R)-BINOL (20 rnol%)

* MS 4A CH2C12, O’C, 1 day (50%)

$+GJ( ,..+

/ CI2Ti(OPrj2 / AgC104 (40(20 rnol%) rnol%)

(3R,4R)-trans 80 (84% ee)

(3R,4S)-cis 20 (74% ee)

Scheme 28

Basic research on the synthesis of analogs of the biologically active form of vitamin D3, la,2S-dihydroxyvitamin D3 (la,2S(OH)zD3) has led to the development of an important new field in medicinal chemistry [84]. We have also reported ‘symmetry’assisted enantiospecific synthesis of the A-ring of the vitamin D hybrid analogs, 19nor-22-oxa-la,25(OH)2D3 (Sch. 29) [85]. It should be noted here that extremely high 1,3-truns selectivity was achieved by combining the (R)-BINOL-Ti catalyst and the (R)-ene substrate without geminal disubstitution.

Chiral Ti(IV)Lewis Acids

OBn

817

(R)-BINOL-Ti (1)

* (R)

MS 4A CH2C12 rt, 38 h (65%)

HO"'3

1

OMPM

trans,Z 77

OMPM

trans,E 23 Y

19-nor-22-oxa-1~ x , 2 5 ( 0 H ) ~ D ~

Scheme 29

16.9 Aldol Reaction Because the aldol reaction is one of the most fundamental bond-construction processes in organic synthesis [86], much attention has been focused on the development of asymmetric catalysts for aldol reactions, using silyl enol ethers of ketones or esters as storable enolate components (the Mukaiyama aldol condensation) [87]. Reetz reported the catalysis by BINOL-TiCI2 of aldol reactions with aliphatic aldehydes [88]. BINOL-TiCI2 was prepared by treatment of the lithium salt of BINOL with Tic& in ether. After removal of the ether the residue was treated with dry benzene and the solid was separated under nitrogen. Removal of the solvent provided the red-brown complex, which was used as the catalyst for the aldol reaction to give 8 YO ee. Later, Mukaiyama reported that use of BINOL-Ti oxide prepared from (i-PrO)2. Ti=O and BINOL resulted in moderate to high enantioselectivity (Sch. 30) [89].

818

Mikami/Terada

(4-BINOL-Ti=O (20 mol%)

* Buts

toluene -78 "C - -43 "C, 16 h R = Ph a-naphthyl CH=CHPh

60% ee (91%) 80% ee (98%) 85%ee (98%)

Scheme 30

We have found that the BINOL-derived titanium complex serves as an efficient catalyst for the Mukaiyama-type aldol reaction of ketone silyl enol ethers with good control of both absolute and relative stereochemistry (Sch. 31) [90]. Surprisingly, however, the aldol products were obtained in the silyl enol ether (ene product) form, with high syn diastereoselectivity from either geometrical isomer of the starting silyl enol ethers.

OSiMe,

0

+

HKC02R

(R)-BINOL-Ti (1) (5 moloh)

73% E

Me3Si0

0 "C c30 min (54% - 63%)

86% Z

-+ COzR

SYn

R=Me

99% ee (98% syn, 94% 2)

R = n-Bu

99% ee (99% syn, 99% Z)

R=Me

99% ee (98% syn, 96% Z)

Scheme 31

It seems likely that the reaction proceeds through a prototropic ene reaction pathway, a pathway that has not been previously recognized as a possible mechanism in the Mukaiyama aldol condensation. Usually an acyclic antiperiplanar transition-state model has been used to explain the formation of the syn diastereomer from either ( E ) - or (Z)-silyl enol ethers [91]. The cyclic ene mechanism, however, now provides another rationale for the syn diastereoselectivity irrespective of enol silyl ether geometry (Sch. 32).

Chiral Ti(ZVjLewis Acids

819

i ?SiR13

Tz-ax.

t

Z,syn

r

A 0SR3

TE-eq.

I

I

E Scheme 32

The aldol reaction of a silyl enol ether proceeds in a double and two-directional fashion, upon addition of an excess amount of an aldehyde, to give the silyl enol ether in 77 % isolated yield and more than 99 % ee and 99 % de (Sch. 33) [92]. This asymmetric catalytic aldol reaction is characterized by kinetic amplification of product chirality on going from the one-directional aldol intermediate to the two-directional product. Further transformation of the pseudo C, symmetric product still protected as the silyl enol ether leads to a potent analog of an HIV protease inhibitor. Kinetic resolution of racemic silyl enol ethers by the BINOL-Ti catalyst (1) has been reported by French chemists [93].

820

Mikami/Terada

+

0 HKC0ZCH3

(R)-BINOL-Ti (1) (10 rnol%) O”C, 3 h CH302C (77%)

b’ >99% ee (>99% ant,)

Scheme 33

The silatropic ene pathway, i.e. direct silyl transfer from an enol silyl ether to an aldehyde, might be a possible mechanism in the Mukaiyama aldol-type reaction. Indeed, ab initio calculations show the silatropic ene pathway, involving the cyclic (boat and chair) transition states for the BH3-promoted aldol reaction of the trihydrosilyl enol ether derived from acetaldehyde with formaldehyde, to be favored [94]. We recently reported the possible intervention of a silatropic ene pathway in the asymmetric catalytic aldol-type reaction of silyl enol ethers of thioesters [95]. The chloro and amino compounds thus obtained are useful intermediates in the synthesis of carnitine and GABOB (Sch. 34) [96].

Chiral Ti(IV)Lewis Acids (4-BINOL-Ti (1) (5 mol%)

* RS

toluene 0 “C, 2 h

RS

821

96%ee (80%) R = B ~ X~= O B n x=cI 91%ee (61%) R=Bu’ X=NHBoc 88%ee (64%) R=Et

0

-0 U

OH N H

0 3

-0u

carnitine

N

OH M

e

3

GABOB

Scheme 34

There is a dichotomy in the sense of syn-anti diastereofacial preference, dictated by the bulkiness of the migrating group [94]. The sterically demanding silyl group results in syn diastereofacial preference but the less demanding proton leads to anti preference (Sch. 35). The anti diastereoselectivity in carbonyl-ene reactions can be explained by the Felkin-Anh-like cyclic transition-state model (TI) (Sch. 36). In the aldol reaction, by contrast, the now inside-crowded transition state (TI’) is less favorable than T i , because of steric repulsion between the trimethylsilyl group and the inside methyl group of aldehyde (TI’). The syn-diastereofacial selectivity is, therefore, visualized in terms of the anti-Felkin-like cyclic transition-state model (Tz’). OSiMe3 EtO 97% syn

6Bn

OBn >99% anti

Scheme 35

T1

Scheme 36

T1‘

T2‘

822

Mikarni/Terada

An aldol reaction with chiral P-benzyloxy aldehyde provides a method for the stereodivergent synthesis of both syn and anti diastereomers [97] with high diastereoselectivity dictated primarily by the chirality of the BINOL-Ti catalyst (1) rather than the P-benzyloxy aldehyde (Sch. 37) [98]. The aldol products can be used as useful key intermediates for p-lactone synthesis [99].

OBn

BINOL-Ti (1) (10 mol%)

0

EtS

giMe3 0 OBn

SiMe3

SYn

O"C, 1 8 h

anti

(R)-BINOL-Ti (1)

96

:

4

(S)-BINOL-Ti (1)

8

:

92

Scheme 37

Carreira employed a chiral BINOL-derived Schiff base-titanium complex as a catalyst for aldol reactions with acetate-derived ketene silyl acetals (Sch. 38) [loo]. The catalyst was prepared in toluene in the presence of salicylic acid, which was reported to be crucial to achieving high enantioselectivity. A similar Schiff base-titanium complex is also applicable to the carbonyl-ene type reaction with 2-methoxypropene (Sch. 39) [loll. Although conducting the reaction in toluene or ether solution provided no addition product, excellent chemical yield and enantioselectivity were attained by the use of 2-methoxypropene as a solvent.

Schiff base-Ti (2mol%) w

Me0

RH '

Me0

EtnO -10 "c,4 h

R = ph c-C6H11 CH=CHPh

Scheme 38

96% ee 95% ee 97% ee

Chiral Ti(ZV)Lewis Acids

823

Schiff base (20 mol%) Ti(OP& (10 mol%) 2,6-di-ferf-butyl-4-methylpyridine

(40 mol%) Me0

*

2-methoxypropene -10 "C, 4 h

Me0

R = C=C(CH2)3Ph 98% ee

(99%)

C=CPh

91% ee

(99%)

(CH2)ZPh

90% ee

(98%)

Scheme 39

Keck also investigated asymmetric catalysis with a BINOL-derived titanium complex [102,103] for the Mukaiyama aldol reaction. The reaction of a-benzyloxyaldehyde with Danishefsky's dienes as functionalized silyl enol ethers gave aldol products instead of hetero Diels-Alder cycloadducts (Sch. 40) [103]. The aldol product can be transformed into hetero Diels-Alder type adducts by acid-catalyzed cyclization. The catalyst was prepared from BINOL and Ti(OPrL)4,in 1:1 or 2:l stoichiometry, and oven-dried MS 4A, in ether under reflux. They reported the catalyst to be of BINOLTi(OPri)2 structure.

OMe

TMSO

(R)-BINOL (20 mol%) / Ti(OPrj4 (10 mol%) / CF3C02H (0.3mol%)

OTMS

*

ether -20 "C, 4 10-72 h

Me0

1

R = BnOCH2 n-C8Hj7 CH3CH=CH

CF3C02H

97Y0ee (60%) 97% ee (88%) 86% ee (50%)

Scheme 40

Sato/Kaneko [lo41 and Carreira [105] have independently employed acetoacetatederived 0-silyl dienolates as Si-substituted nucleophiles in asymmetric catalytic aldol reactions. The aldol products, d-hydroxy-/%ketoesters, and the derived syn- and antiP,d-diol esters are ubiquitous structural subunits in biologically active natural products such as the polyene macrolide antibiotics. These structural subunits are also found in chemotherapeutics, most notably compactin analogs [lo61 that have been studied as

824

MikamUTerada

cholesterol-reducing agents. Carreira transformed the aldol adducts to the medicinally important HMG-CoA reductase inhibitor [105a]. They also demonstrated the asymmetric synthesis of macrolactin A on the basis of the catalytic dienolate aldol reaction [lo%], which can be used to synthesize two key fragments, C3-C9 and Cll-C17 subunits (Sch. 41).

Br

(R)-Schiff base-Ti (2 mol%) Et20, 0 ° C

92%ee (R) (80%) Me H

(S)-Schiff base-Ti (2 rnol%)

.....................

*

Me

oxo

OSIMe3

92% ee (S) (80%)

Macrolactin A

Scheme 41

2-(Trimethylsilyloxy)furan can also be used as a functionalized silyl enol ether for the asymmetric catalytic aldol-type reaction. Figadere has reported that the reaction of aliphatic aldehydes with the siloxyfuran catalyzed by BINOL-derived titanium complex provides the diastereomeric mixtures with high enantioselectivity (Sch. 42) [107]. The addition reaction proceeds at the y position of the siloxyfuran to give butenolides of biological and synthetic importance.

Chiral Ti(IV)Lewis Acids

P

Me3Si0

0

+ 0

825

OH

(4-BINOL (10rnol%)

I Ti(OPrj4 (10 rnol%)* @CnHpn+i MS 4A Et20, -20°C (4s,5~)-syn

+

Y C n b n + i

O

anti

H K c n H2n+l n=7

n = 12

53 (87%ee) 70 (90%ee)

: :

47 30

(50%) (20%)

Scheme 42

16.10 Michael Reaction The Lewis acid-catalyzed conjugate addition of silyl enol ethers to a,P-unsaturated carbonyl derivatives, the Mukaiyama Michael reaction, is known to be a mild, versatile method for carbon-cabon bond formation. Although the development of catalytic asymmetric variants of this process provides access to optically active 1,5-dicarbonyl synthons, few such applications have yet been reported [log]. Mukiyama demonstrated asymmetric catalysis with BINOL-Ti oxide prepared from (i-Pr0)2Ti=0 and BINOL and obtained a 1,4-adduct in high % ee (Sch. 43) [109]. The enantioselectivity was highly dependent on the ester substituent of the silyl enol ether employed. Thus the reaction of cyclopentenone with the sterically hindered silyl enol ether derived from S-diphenylmethyl ethanethioate proceeds highly enantioselectively. Scolastico also reported that reactions promoted by TADDOL-derived titanium complexes gave the syn product exclusively, although with only moderate enantioselectivity (Sch. 44) [110].

(R)-BINOL-Ti=O (20 rnol%) Ph

Scheme 43

toluene -78 "C, 16 h (75%)

*90% ee

826

MikarnUTerada

B (1 00 mol%) M

e

O

q MS 4A toluene

Bub

-78 "C, 5 h (50%)

.

-

i H

47% ee (98% syn)

Scheme 44

16.11 (Hetero) Diels-Alder Reactions The (hetero) Diels-Alder reaction also is one of the most efficient carbon-carbon bond-forming processes in the construction of six-membered rings, by virtue of the high regioselectivity and stereoselectivity obtained at up to four newly created chiral centers 11111. Narasaka has demonstrated that TADDOL-Ti dichloride prepared from TADDOL and C12Ti(OPr')2 in the presence of MS 4A acts as an efficient catalyst in asymmetric catalytic Diels-Alder reactions with oxazolidinone derivatives of acrylates, a results in extremely high enantioselectivity (Sch. 45) [112]. Narasaka reported an intramolecular version of the Diels-Alder reaction, the product of which can be transformed into key intermediates for the syntheses of dihydrocompactin and dihydromevinolin (Sch. 46) 11131. Seebach and Chapuis/Jurczak 11141 independently reported asymmetric Diels-Alder reactions promoted by chiral TADDOL- and 3,3'-diphenyl BINOL-derived titanium alkoxides. Other types of chiral diol ligands were also explored by Hermann [115]and Oh [116]. 0 4 N ' O

0

LA

'

0

TADDOL-TIC1 toluene

*

q

100 mol% 200 mol% 10 mol%, MS 4A

TADDOL-TiCI2

Scheme 45

N 0

'

P

75% ee

91% ee 92% ee

Chiral Ti(IV)Lewis Acids

827

TADDOL-TiCI (30 mol%)

'd

U

toluene / petroleum ether rt, 150 h (70%) >95% ee

(R = H or Me) H R = H: dihydrocompactin Me: dihydromevinolin

Scheme 46

Several researchers have reported synthetic approaches based on asymmctric DielsAlder reactions catalyzed by TADDOL-Ti complexes 1117-1201. Dendritic [121] and polymer-supported TADDOL-Ti complexes [1221 have also been employed as recoverable and reusable catalysts to give comparatively high enantioselectivity. Transition-state models have been proposed independently by several groups for TADDOL-type titanium catalysis [121,123]. The TADDOL-derived titanium catalyst has also been used for inverse electrondemand Diels-Alder reactions [124-1271, although Posner favored the use of a BINOL-derived titanium catalyst in his inverse electron-demand Diels-Alder reactions for the synthesis of lc(,25(OH)zD3 (Sch. 47) [125,126].

828

Mikami/Terada

(R)-BINOL-Ti (1) (130 molo/o) toluene 96

-30 "C, 24 h

PO = TBDMSO

cf. PO = BnO

Ti,

- 98% ee (90%) 55% ee (63%)

TBDMSO"'" TBDMSO'""

OTBDMS

1a,25(OH)&

Scheme 47

We have previously reported that the hetero Diels-Alder reactions of glyoxylates with l-methoxy-1,3-butadienes proceed smoothly under catalysis by BINOL-Ti complex to give the cis product with high ee (Sch. 48) 11281.The hetero Diels-Alder products thus obtained can be transformed into monosaccharides [129]. The hetero DielsAlder product can, furthermore, readily be converted into the lactone portion of HMG-Co A inhibitors such as mevinolin or compactin [lo61 in few steps. (S)-BINOL-Ti (1) (10 mol%) CH2C12 -30 "C, 1 h (78%)

y

3

"'C02CH3 96%ee 6 s (88% 2,6-cis)

mevinolin

Scheme 48

Chirul Ti(1V)Lewis Acids

829

Interestingly, the chiral titanium complex derived from 6-Br-BINOL affords higher cis selectivity, enantioselectivity, and catalytic activity than the parent BINOL-Ti cat-

alyst in the hetero Diels-Alder reactions of 1-methoxydienes with glyoxylate, but not with bromoacrolein (Sch. 49) [130]. (R)-BINOL-Ti or (q-6-Br-BINOL-Ti (10 rnol%)

OCH3

(=

0

'

HKC02CH3

CH2C12 -30 "C, 1 h

C02CH3 cis

(R)-6-Br-BINOL-Ti 97% ee (86% yield, 8l%cis) 96% ee (78% yield, 88%cis) (4-BINOL-Ti

R '

B r V H

(5 mol%)

*

toluene -30"C, 1 h

endo

(R)-6-Br-BINOL-Ti 60% ee (71% yield, 95%endo) 81% ee (70% yield, 97%endo) (R)-BINOL-Ti

Scheme 49

The Diels-Alder reaction of methacrolein with 1,3-dienol derivatives can also be catalyzed by the BINOL-derived titanium complex, although the catalyst must be freed from molecular sieves (MS) to give the endo adduct with high enantioselectivity (Sch. 50) [131], because MS act as achiral catalysts in the Diels-Alder reaction. The asymmetric Diels-Alder reaction catalyzed by the MS-free (MS-(-)) BINOL-Ti complex (1')can be applied naphthoquinone derivatives as dienophiles to provide entry to the asymmetric synthesis of tetra- and anthracyclinone [132] aglycones (Sch. 51). The sense of asymmetric induction is exactly the same as that observed in the presence of MS in the asymmetric catalytic reactions described above. AcO

(R)-BINOL-Ti (10 rnol%)

MS 4A toluene, rt, 18 h

AcO

*

dS""" endo

MS-free (R)-BINOL-Ti ( 1 ' ) 94% ee (63% yield, 99%endo) cf. (4-BINOL-Ti (1) 80% ee (81% yield, 98%endo) MS 4A in the absence of 1 -(20% yield)

Scheme 50

830

Mikarni/Terada

MS-free (S)-BINOL-Ti (1') (1 0 CHzCIz rnol%) I

OAc

+$ H

rt, 6 h (-86%)

OH

0

I

OAc

- 96% ee

Scheme 51

The mode of preparz ion of the MS-free BINOL-Ti catalyst (1')de xmines the presence or absenceof a non-linear effect (NLE) (Sch. 52, Table 4, Fig. 2). When the MS-free catalyst (1') was prepared from partially resolved BINOL, a (+)-NLE was observed (Run 1). The combined use of enantio-pure (R)-1' and (*)-l' catalysts in the ratio 1:l resulted in a similar (+)-NLE (Run 2). By contrast, mixing enantio-pure (R)and (S)-1' catalysts in the ratio 3:l led to a linearity (no NLE) (Run 3), although an MS-free catalyst obtained by mixing ( R ) -and (S)-1' catalysts in the same 3:l ratio in the presence of M S , which was removed by filtration before the reaction, resulted in a (+)-NLE (Run 4). These experimental facts can be explained if the complex consists of oligomers which do not interconvert in the absence of M S in toluene but do interconvert in dichloromethane (See Run 7 for the (+)-NLE in CH2C12).When the reaction was conducted in the presence of MS, however, a (-)-NLE was observed (Run 5), because MS acts as an achiral catalyst for the Diels-Alder reaction (Run 6). In dichloromethane, moreover, the combined use of ( R ) -and (S)-l' catalysts (3:1), even without prior treatment with MS, resulted in a (+)-NLE (Run 7). Table 4. NLE in the asymmetric Diels-Alder reaction of l-acetoxy-l,3-butadiene and methacrolein catalyzed by MS-free BINOL-Ti (l'). Run

MS-free BINOL-Ti Yield ( O h ) (1')(YOee)

endo (YO)

ee (YO)

1"

52

41

98

76

2b

50

50

99

74

3"

50

62

99

40

4d

50

67

99

60

5'

50

62

95

29

6'

-

20

-

-

7s

50

52

99

53

Prepared from partially resolved BINOL (52% ee) and ClzTi(OPr')2. MS-free (R)-1' and MS-free (%)-l' (1:l). MS-free (R)-1' and MS-free (S)-1' (3:l). Prepared from MS-free (R)-1' and MS-free (S)-1' (3:l) in the presence of MS which was removed by filtration before the reaction. MS-free (R)-1' and MS-free (+)-l' (1:l) in the presence of MS 4A. No MS-free catalyst (1')in the presence of MS 4A. MS-free (R)-1' and MS-free (S)-1' (3:l) in CHzC12.

'

Chiral Ti(ZV)Lewis Acids

MS-free BINOL-Ti (1') (10 mol%)

AcO

831

AcO

i = + YCHO

d

-

toluene, rt, 18 h

CHo

endo

Scheme 52

0 MS-free (4-1'+ MS-free (k)-l' 0 MS-free (4-1'+ MS-free ( 9 - 1 '

m MS-free (4-1'+ MS-free (k)-l' in the presence of MS 4A 0

I

0

20

40 60 BINOL / % ee

.

80

I

100

Figure 2. (+)- and (-)-NLE, and the linear relationship, depending on the mode of preparation of the catalyst.

In the Diels-Alder reaction of glyoxylates with the Danishefsky diene (Sch. 53), asymmetric activation of (R)-BINOL-Ti(OPr')2 (2) by (R)-BINOL is essential if enantioselectivity is to be higher than that achieved by use of the enantio-pure BINOL-Ti catalyst ( 5 % ee) [78]. Effects of the torsional angles of 2,2'-biaryldiol ligands have been examined in the asymmetric Diels-Alder reaction of acrylate catalyzed by titanium complexes [133]. OMe

(R)-BINOL-Ti(OPrjp (2) (10 mol%)

Scheme 53

4h-8h without (4-BINOL

84% ee (50%) 5% ee (40%)

832

Mikami/Terada

As shown above, asymmetric catalysis of Diels-Alder reactions has been achieved by use of chiral titanium complexes bearing chiral diol ligands. Yamamoto has reported a chiral helical titanium complex derived from Ti(OPr’), and a BINOL-derived tetraol ligand (Sch. 54) [134]. The Diels-Alder products are obtained with uniformly high enantioselectivity, irrespective of the substituent pattern of cx&unsaturated aldehydes. Corey has also reported a new type of chiral titanium complex derived from an amino alcohol ligand (Sch. 55) [135]. The chiral titanium complex serves as an efficient asymmetric catalyst for the reaction of 2-bromoacrolein; the Diels-Alder product is obtained with high enantioselectivity.

azeotrope

+ Ti(OPrj4

I (10 mol%)

0 @l +

CHO

* CH2CI2 -78 - -40 “C

R’ = H, Rz = H R’ = Me, R2 = H R’ = H, R 2 = Me

CHO endo

k2

exo

96% ee (85% endo)

94% ee (99% e m ) 95% ee (70% endo)

Scheme 54

Scheme 55

Chiral titanocene derivatives can also be used as catalysts in asymmetric DielsAlder reactions (Sch. 56 and 57). Collins reported that the asymmetric Diels-Alder reaction of oxazolidine derivatives and cyclopentadiene was effectively catalyzed by

Chiral Ti(ZV)Lewis Acids

833

1,2-ethylenebi~tetrahydroindenyl-Ti(OTf)~ (Sch. 56) [136] and Bosnich demonstrated that the bistetrahydroindenyl-derived titanium complex with chiral biphenyl tether gave the Diels-Alder product with moderate ee (Sch. 57) [137].

'OTf

+

(5 mol%)

Q

CHsN02 -30 "C, 30 rnin (85%)

89% ee (88% endo)

Scheme 56

@zig ,

,,.:Ti(H20)2

I 2+ 2 TfO-

/

0

+

(2 CH2C12 mol%) -78 "C (>go%)

* 4 C H O

+

4

CHO

ex0 98 (75% ee)

endo :

2

Scheme 57

16.12 [2 + 21 and [2 + 31 Cycloaddition Reactions Asymmetric [2 + 21 cycloaddition reaction affords a practical means of synthesis of optically active cyclobutanes, which can be used as useful intermediates in organic synthesis [138]. Narasaka reported that asymmetric [2 + 21 cycloaddition between acryloyl oxazolidinone derivatives and bis(methy1thio)ethylene proceeded with high enantioselectivity when catalyzed by TADDOL-derived titanium complex (Sch. 58) [139]. The cyclobutane product was transformed into carbocyclic oxetanocin analogs or (+)-grandis01 [140]

834

Mikami/Terada

0

u

0

0

0

0

(10 mol%)

+

X i M e

toluene / petroleum ether O"C, 30min (96%)

SMe SMe 98% ee

Scheme 58

Engler reported [2 + 21 cycloaddition of 1,4-benzoquinones with styrenes using TADDOL-3 complex. The [2 + 21 cycloaddition products can, upon warming the reaction mixture, be transformed to the formal [2 + 51 cycloaddition products, dihydrobenzofurans, although with reduced %ee. The dihydrobenzofurans thus obtained are useful intermediates in the synthesis of biologically interesting natural products (Sch. 59) [141].

(5eq.)

/ Ti(OPrj4 (5 eq.) OMe

Me0 OMe

0

CH2C12, -78 "C (97%)

OMe 92% ee (88%)

41% ee (9%)

A

-78 "C to z -30 "C

Scheme 59

The [2 + 21 reaction of a ketene and a carbonyl compound has been well recognized as a general synthetic route to oxetanones, specifically p-lactones [142], the structural features of which are found in many biologically active natural products.

Chiral Ti(IV)Lewis Acids

835

The use of silylketenes as much more stable ketene analogs is, however, the key in the catalytic asymmetric [2 + 21 reaction used to provide cis adducts exclusively, with up to 80 % ee, by use of TADDOL-TiC12 (Sch. 60) [143]. Ph Ph

>95% cis

80%ee (66%)

Scheme 60

[2 + 31 Cycloaddition reactions between nitrones and alkenes furnish isoxazolidines, useful five membered heterocycles containing a nitrogen-oxygen bond [144]. Because of the labile nature of N-0 bond, isoxazolidines have long been widely used as 1,3-amino alcohol equivalents and as a variety of synthetic intermediates of natural products and related molecules, such as alkaloids, amino acids, and amino sugars. Asymmetric catalysis of [2 + 31 cycloaddition reactions of nitrones and oxazolidinone-derived acrylates was reported by Jorgensen, who used the TADDOL-Ti tosylate complex bearing the sterically more demanding achiral ligand to give exclusively the endo adduct with up to 93 % ee (Sch. 61) [145]. Ph Ph

0P h , N +Ph yH

0

+

0

d Nu K O 0

t

MS 4A toluene, 0 "C - rt, 48 h (298%)

0

0

endo X = CI (10 mol%) Br (10 mol%) OTs (50 mol%)

Scheme 61

10 (62% ee) 64 (76% ee) >95 (93% ee)

ex0 : : :

90 (60% ee) 36 (64% ee) <5 (-)

0

836

MikamUTerada

16.13 Cyanohydrin Formation Optically active cyanohydrins are synthetic precursors of a-hydroxy carboxylic acids, a-amino carboxylic acids, P-hydroxy amines, and several other classes of organic compound of biological importance [146]. Several efficient catalysts have been developed by using titanium as the central metal. In the addition reaction of cyanotrimethylsilane [1471 to aliphatic aldehydes, another synthetic application of a BINOL-Ti catalyst was reported by Reetz [88]. In this instance, however, BINOL-TiQ was prepared by treatment of the lithium salt of BINOL with Tic&in ether (vide supra). The BINOL-TiC12 thus obtained was used as a catalyst for the cyanosilylationreaction to give the cyanohydrins in up to 82 % ee (Sch. 62).

uH +

\

/

(20 mol%)

TMSCN

toluene -78 "C to rt, 10 h

*

flCN

182% ee

(85%) Scheme 62

Narasaka has reported that TADDOL-Ti dichloride catalyzes the asymmetric addition of trimethylsilylcyanide to aromatic and aliphatic aldehydes (Sch. 63) [148]. The reactions proceed only in the presence of MS 4A. In reactions with aliphatic aldehydes a chiral cyanotitanium species obtained by mixing of the TADDOL-Ti dichloride and trimethylsilylcyanide before addition of the aldehydes acts as a better chiral cyanating agent and affords higher enantiomeric excesses. Chiral titanium complexes obtained from an alcohol ligand and salicylaldehyde-type Schiff bases and a salen ligand have been reported to catalyze the asymmetric addition of hydrogen cyanide or

Ph Ph

Ph Ph

OH PhCHO

Scheme 63

+

TMSCN

* MS4A -65 "C

PhXCN

96% ee

Chiral Ti(ZV)Lewis Acids

chiral titanium alkoxides

Ref. 149: 91% ee (R) (20mol%)

Ref. 150: 76% ee (SJ (20mol%)


Ref. 151: 91% ee (S)(100mol%)

Ref. 153: 94% ee (S)(15mol%)

1 Bu'

Ph,,,

N

'H Ph"" O

(40mol%) Ref. 154: 85% ee (R) (20mol%)

Ref. 155: 90% ee (R) (10mol%)

MeO-

Ref. 158: 76% ee (S)(20mol%)

cs Ref. 159: 86% ee (S)(0.1mol%)

Scheme 64

I Ti(OPrl), (20mol%)

Ref. 156: 92% ee (S)(20mol%)

I chiral salen-titanium complexes 1

Ref. 157: 87% ee (R) (10mol%)

OH

Ref. 160: 68% ee (R) (20 mol%)

837

838

MikarnUTerada

trimethylsilylcyanide to aromatic and aliphatic aldehydes with high enantioselectivity [149-1601. Representative results from the reaction between benzaldehyde and trimethylsilylcyanide (or hydrogen cyanide) are listed in Sch. 64. Strecker-type addition of cyanide to imines has been reported to be catalyzed by chiral Ti Schiff base-tripeptide complexes (Sch. 65) [161]. The reaction is efficient (> 93 % conversion) and proceeds with excellent enantioselectivity (85-97 YOee) in the presence of 1.5 equiv. 2-propanol. Hoveyda and Snapper pointed out that catalyst turnover is significantly facilitated by the presence of 2-propanol. Optically pure products are usually isolated in > 80 % yields.

H (10 mol%)

Ph

/ Ti(OPrj4 (10 mol%) / i-PrOH (150 mol%)

NAPh

+ PhK

O

TMSCN

H

*

toluene, 4 "C, 20 h

PhnCN

97%ee (99%) cf. without i-PrOH 97'10 ee (30%)

Scheme 65

16.14 Miscellaneous Reactions Chiral titanium complexes are also employed as effective asymmetric catalysts for other carbon-carbon bond-forming reactions, for example addition of diketene (Sch. 66) [154c,l62], Friedel-Crafts reaction (Sch. 67) [163] (Sch. 68) [164], iodocarbocyclization (Sch. 69) [165], Torgov cyclization (Sch. 70) [166], and [2 + 11 cycloaddition (Sch. 71) [167]. Asymmetric functional group transformations can also be catalyzed by chiral titanium complexes. These transformations, for example the Sharpless oxidation [168] or hydride reduction [16Y] are, however, beyond the scope of this review because of space limitations. Representative results are, therefore, covered by the reference list.

%..

0 PhKH

Scheme 66

+

yo

0

c>T(OPr), 0 (100 mol%)

1) i-PrOH 2) HCI

*-

CH2CI2, -20 "C, 48 h (85%)

OH PhU

0 o P 84% ee

r

!

Chiral Ti(IV)Lewis Acids

&

(8-BINOL-Ti (1) (2 rnol%)

0

+

HKC02CH3

*

MS 4A toluene, -30 "C, 1 h (88%)

35-ycoZcH3 +

+

&CO&H3

otherisomers

OH (4-(11R)

( 4 4 1 1R)

51

45

4

Scheme 67

(R)-BINOL-Ti (1) (5 rnol%) TBDMSO

TBDMSO

A

Ph

+

*

H C 'F3

CHzC12 0 "C, 15 rnin (67%)

TBDMSO

OH

Ph

83 (98%ee)

:

17

Scheme 68 (TADDOL) 2-Ti (10 rnol%)

l2 (400 rnol%) CH2Clz /THF -78 "C (98%) Ph Ph

Ph Ph

(TADDOL)2-Ti

Scheme 69

14OoC*

$: H 98% ee

839

840

MikamUTerada

0

(72%)

70% ee

Scheme 70 (R)-BINOL (110 mol%) / Ti(OPrj4 (73 mol%) / TiCI4 (109 mol%)

MeaSi

CH2C12 -78 "C to -30 "C, -5.5 h (12%)

SiMe3

57% ee

Scheme 71

From a practical standpoint the development of more active and efficient catalysts is important, and structure-catalytic activity relationships will probably be the basis of the molecular design of asymmetric catalysts. Although determination of the structures of active titanium species has so far been quite limited [170], any progress in this field is likely to be worth the effort.

Acknowledgments We thank our past and present students and coworkers listed in the references, particularly Drs Yukihiro Motoyama and Satoru Matsukawa, now in Toyohashi University of Technology and Science and Chiba University, respectively, and would-be D r Yousuke Matsumoto, now in our graduate course, for their hard work.

References and Notes 1. Noyori, R. (1990) Science 248,1194-1199. 2. Noyori, R. (1994) Asymmetric Catalysis in Organic Synthesis. Wiley, New York. 3. Kagan, H. B. (1997) Asymmetric Synthesis. Georg Thieme Verlag, Stuttgart. 4. a) Childs, R. F., Mulholland, D. L., Nixon, A. (1982) Can. J. Chem. 60, 801-808; b) Laszlo, P., Teston, M. (1991) J. Am. Chem. Soc. 112,8750-8754. 5. a) Reetz, M. T. (1986) Organotitanium Reagents in Organic Synthesis. Springer-Verlag, Berlin; b) Seebach, D. (1990) Angew. Chem. Int. Ed. Engl. 29,1320-1367. 6. Reviews: a) Okamoto, Y., Nakano. T. (1994) Chem. Rev. 94, 349-372; b) Brintzinger, H.-H., Fischer, D., Mulhaupt, R., Rieger, B., Waymouth, R. M. (1995) Angew. Chem. Znt. Ed. EngI. 34,

Chiral Ti(1V)Lewis Acids

7. 8.

9. 10. 11. 12. 13.

14. 15. 16.

17.

18.

19. 20. 21. 22. 23. 24. 25. 26. 27. 28.

841

1143-1170; c) Hoveyda, A. H., Morken, J. P. (1996) Angew. Chem. Znt. Ed. Engl. 35, 1262-1284; d) Mikami, K., Tcrada, M., Osawa, A. (1997) KobunshUHigh Polymers Jpn. 46,72-76. a) Hollis, T. K., Robinson, N. P., Bosnich, B. (1992) J. A m . Chem. Soc. 114,5464-5466; b) Hollis, T. K., Bosnich, €3. (1995)J. Am. Chem. Soc. 117,4570-1581. a) Mikami, K., Terada, M., Nakai, T. (1993) Kikan Kagaku Sosetsu No. 17: Organic Chemistry of the Early Transition Metals. Gakkai Shuppan Center, Tokyo, p 87-98; b) Mikami, K., Nakai, T. (1995) Kagaku Zoukann No. 124. Kagaku Doujinn, Kyoto, p 177-192; c) Duthaler, R. O., Hafner, A. (1992) Chem. Rev. 92, 807-832; d) Bradley, D. C., Mehrotra, R. C., Gaur, D. P. (1978) Metal Alkoxide. Academic Press, New York; e) Feld, R., Cowe, P. L. (1965) The Organic Chemistry of Titanium. Butterworths, London; f) Mikami, K., Terada, M., Nakai, T. (1991) J. Synth. Org. Chem. Jpn. 49,566574. Reetz, M. T., Kyung, S.-H.,Westermann, J. (1984) Organometallics 3,1716-1717. Mikami, K., Motoyama, Y. (1995) in Encyclopedia of Reagents for Organic Synthesis. Paquette, L. A. ed., Wiley, Chichester, Vol. 1,p 395408. Mikami, K. (1995) in Encyclopedia of Reagents for Organic Synthesis. Paquette, L. A. ed., Wiley, Chichester, Vol. 1, p 407408. Wang, J.-T., Fan, X., Feng, X., Qian, Y.-M. (1989) Synthesis 291-292. Also see: Olivero, A. G., Weidmann, B., Seebach, D. (1981) Helv. Chim. Acta 64,2485-2488. Reviews: Braun, M. (1996) Angew. Chem., Int. Ed. Engl. 35,519-522; Dahinden, R.. Beck, A. K., Seebach, D. (1995) in Encyclopedia of Reagents for Organic Synthesis. Paquette, L. A. ed., Wiley, Chichester, Vol. 3, p 2167-2170; Narasaka, K., Iwasawa, N., Inoue, M., Yamada, T., Nakashima, M., Sugimori, J. (1989) J. Am. Chem. Soc. 111, 5340-5344; Beck, A. K., Bastani, B., Plattner, D. A,, Petter, W., Seebach, D. (1991) Chirnia 45,238-244. For aldol and allylmetal addition reactions with carbonyl compounds: Hafner, A., Duthaler, R. O., Marti,R., Rihs, G., Rothe-Streit,P., Schwarzenbach,F. (1992)J. Am. Chem. Soc. 114,2321-2336. a) Noyori, R., Kitamura, M. (1991) Angew. Chem. Znt. Ed. Engl. 30,49-69; b) Soai, K., Niwa, S. (1992) Chem. Rev. 92,833-856. a) Takahashi, H., Kawakita, T., Ohno, M., Yoshioka, M., Kobayashi, S. (1992) Tetrahedron 48,56915700; b) Yoshioka, M., Kawakita, T., Ohno, M. (1989) Tetrahedron Lett. 30,1657-1660; c) Takahashi, H., Kawakita, T., Yoshioka, M., Kobayashi, S., Ohno, M. (1989) Tetrahedron Lett. 30,7095-7098. For X-ray analysis of the titanium disulfonylamide complex: a) Pritchett, S., Woodmansee, D. H., Gantzel, P., Walsh, P.J. (1998) J. A m . Chem. Soc. 120, 642341424.Also see: b) Armistead, L. T., White, P. S., Gagne, M. R. (1998) Organonzetallics 17, 216-220; c ) Denmark, S. E., O’Connor, S. P., Wilson, S. R. (1998)Angew. Chem. Znt. Ed. Engl. 37,1149-1151. a) Schmidt, B., Seebach, D. (1991) Angew. Chenz.Znt. Ed. Engl. 30,99-101; b) Schmidt, B., Seebach, D. (1991) Angew. Chem. Int. Ed. Engl. 30,1321-1323; c) Seebach, D., Plattner, D. A,, Beck, A. K., Wang, Y. M. Hunziker, D. (1992) Helv. Chim. Acta 75,2171-2209 d) Seebach, D., Beck, A. K., Schmidt, B., Wang, Y. M. (1994) Tetrahedron 50, 43634384; e) Ito, Y. N., Ariza, X., Beck, A. K., Bohac, A,, Granter, C., Gawley, R. E., Kuhnle, F. N. M., Tuleja, J., Wang, Y. M., Seebach, D. (1994) Helv. Chim. Acta 77, 2071-2110. Also see: f) Shao, M-Y., Gau, H.-M. (1998) Organometallics 17, 48224827. a) Zhang, X., Guo, C. (1995) Tetrahedron Lett. 36, 49474950; b) Qiu, J., Guo, C., Zhang, X. (1997) J. Org. Chem. 62, 2665-2668; c) Guo, C., Qiu, J., Zhang, X., Verdugo, D., Larter, M. L., Christie, R., Kenney, P., Walsh, P. J. (1997) Tetrahedron 53,4145-4158. Mori, M., Nakai, T. (1997) Tetrahedron Lett. 38,6233-6236. a) Ramon, D. J., Yus, M. (1997) Tetrahedron Asymm.8, 2479-2496; b) Ramon, D. J., Yus, M. (1998) Tetrahedron 54, 5651-5666. Also see: c) Armistead, L. T., White, P. S., Gagne, M. R. (1998) Organometallics 17,42324239, Hwang, C.-D., Uang, B.-J. (1 998) Tetrahedron Asymm. 9,3979-3984. Mino, T., Oishi, K., Yamashita, M. (1998) Synlett 965-966. Fieischer, R., Braun, M. (1998) Synletr 1441-1443. a) Rheiner, P. B., Sellner, H., Seebach, D. (1997) Helv. Chim. Acta 80,2027-2032; b) Sellner, H.. Seebach, D. (1999) Angew. Chem. Znt. Ed. 38,1918-1920. a) Yu, H.-B., Zheng, X.-F., Hu, Q.-S., Pu, L. (1999) Polym. P r e p 40, 546-.; b) Pu, L. (1999) Chem. Eux J. 5,2227-2232. Also see: c) Hu, Q.-S., Huang, W.-S., Vitharana, D., Zheng, X.-F., Pu, L. (1997) J. Am. Chem. Soc. 119,12454-12464. a) Seebach, D., Behrendt, L.. Felix. D. (1991) Angew. Chem., Znt. Ed. Engl. 30, 1008-1009; b) Bussche-Hunnefeid, J. L., Seebach, D. (1992) Tetrahedron 48,5719-5730. Reviews: a) Knochel, P., Singer, R. D. (1993) Chem. Rev. 93, 2117-2188; b) Knochel, P. (1995) Synlett 393403; c) Knochel, P. (1991) in Comprehensive Organic Synthesis. Trost, B. M., Fleming, I. ed., Pergamon, London, Vol. 1, p 211-229.

842 28.

30. 31. 32. 33. 34. 35. 36. 37. 38.

39. 40. 41. 42.

43. 44. 45.

46. 47.

48. 49. 50.

51. 52.

53. 54.

Mikami/Terada a) Rozema, M. J., Sidduri, A,, Knochel, P. (1992) J. Org. Chem. 57, 1956-1958; b) Brieden, W., Ostwald, R., Knochel, P. (1993) Angew. Chenz. Znt. Ed. Engl. 32,582-584; c) Eisenberg, C., Knochel, P. (1994) J. Org. Chem. 59,3760-3761; d) Ostwald, R., Chavant, P.-Y., Stadtmuller, H., Knochel, P. (1994) J. Org. Chem. 59, 41434153; e) Langer, F., Schwink, L., Devasagayaraj, A,, Chavant, P.-Y., Knochel, P. (1996) J. Org. Chem. 61,8229-8243. Mikami, K. (1995) in Encyclopedia of Reagents for Organic Synthesis. Paquette, L. A. ed., Wiley, Chichester, , Vol. 1,p 403406. For the experimental details of the glyoxylate-ene reaction including the preparation of BrzTi (OPr‘)2: Mikami, K., Terada, M., Narisawa, S., Nakai, T. (1992) Org. Synth. 71,1421. Dijkgraff, C., Rousseau, J. €? G. (1968) Spectrochim. Acta 2,1213-1217. Review: Cozzi, P. G., Tagliavini, E., Umani-Ronchi, A. (1997) Gazz. Chim. It. 127,247-254. Aoki, S., Mikami, K., Terada, M., Nakai, T. (1Y93) Tetrahedron 49, 1783-1792. For the synthesis, see: a) Roush, W. R., Blizzad, T. A. (1982) Tetrahedron Lett. 23,2331-2334; b) Still, W. C., Ohmizu, H. (1981) J. Org. Chem. 46,5242-5244. Mikami, K., Matsukawa, S. (1994) Tetrahedron Lett. 35, 3133-3166. Costa, A. L., Piazza, M. G., Tagliavini, E., Trombini, C., Umani-Ronchi, A. (1993) J. A m . Chem. Soc. 115,7001-7002. a) Keck, G. E., Tarbet, K. H., Geraci, L. S. (1993) J. Am. Chern. Soc. 115,846778468;b) Keck, G. E., Krishnamurthy, D., Crier, M. C. (1993) J. Org. Chem. 58, 65434544; c) Keck, G. E., Geaci, L. S. (1993) Tetrahedron Lett. 34,7827-7828; d) Keck, G. E., Krishnamurthy, D., Chen, X. (1994) Tetrahedron Lett. 35,83234324, Weigand, S., Briickner, R. (1996) Chem. Eur. J. 2,1077-1084. Yamago, S., Furukawa, M., Azuma, A., Yoshida, J. (1998) Tetrahedron Lett. 39,3783-3786. Yu, C.-M., Choi, H.-S., Jung, W.-H., Lee, S.-S. (1996) Tetrahedron Lett. 37,7095-7098. a) Yu, C.-H., Choi, H.-S., Jung, W.-H., Kim, H.-J., Shin, J. (1997) J. Chem. Soc. Chem. Commun. 761-762 b) Yu, C.-M., Yoon, S.-K., Choi, H.-S., Baek, K. (1997) J. Chem. Soc. Chem. Commun. 763-764; c) Yu, C.-M., Yoon, S.-K., Baek, K., Lee, J.-Y. (1998) Angew. Chem. Ed. Znt. 37, 23922395. Also see: d) B(OMe)3 as a synergetic reagent: Yu, C.-M., Choi, H.-S., Yoon, S.-K., Jung, W.H. (1997) Synlett 889-890. Gauthier, Jr., D. R., Carreira, E. M. (1996) Angew. Chem., Int. Ed. Engl. 35,2363-2365. Faller, J. W., Sams, D. W. I., Liu, X. (1996) J. Am. Chenz. SOC. 118,1217-1218. Comprehensive reviews on carbonyl-ene reactions: a) Mikami, K., Terada, M. in Comprehensive Asymmetric Catalysis, Jacobsen, E. N., Pfaltz, A,, Yamamoto, H. eds., Springer, Heidelberg, in press; b) Mikami, K., Shimizu, M. (1992) Chem. Rev. 92, 1021-1050; c) Snider, B. B. (1991) in Comprehensive Organic Synthesis. Trost, B. M., Fleming, I. ed., Pergamon, London, , Vol. 2, p 527-561 and Vol. 5 , p 1-27; d) Mikami, K., Terada, M., Shimizu, M., Nakai, T. (1990) .I. Synth. Org. Chem. Jpn. 48,292-303. Review: Mikami, K. (1995) in Advances in Asymmetric Synthesis. JAI Press, Greenwich, Connecticut, Vol. 1, p 1 4 4 . a) Omura, S. (1986) J. Synth. Org. Chem. Jpn., 44,127; b) Hanessian, S. (1983) Total Synthesis ofNatural Products: The ‘Chiron’ Approach. Pergamon, Oxford; d) Mori, K. (1981) The Total Synthesis of Natural Products. Wiley, New York, Vol. 4; e) Seebach, D., Hungerbuhler, E. (1980) Modern Synthetic Methods. Scheffold, R. ed., Otto Salle Verlag, Frankfurt am Main, Vol. 2, p 91-172. a) Mikami, K. (1996) Pure Appl. Chem. 68,639-644; b) Mikami, K., Terada, M., Nakai, T. (1995) in Advances in Catalytic Processes. Doyle, M. P. ed., JAI Press, London, Vol. 1, p 123-149; c) Mikami, K., Terada, M., Narisawa, S., Nakai, T. (1992) Synlett 255-265. a) Mikami, K., Terada, M., Nakai, T. Annual Meeting of the Chemical Society of Japan, Tokyo, April 14,1988; Abstract No. 1XIB43; Mikami, K., Terada, M., Nakai, T. (1989) J. Am. Chem. Soc. 111, 194C1941; b) Mikami, K., Terada, M., Nakai, T. (1990)J. Am.Chem. Soc. ll2,3949-3954. Yamamoto et al. have also reported an asymmetric catalytic ene reaction, which employs chloral as the enophile using the 3,3’-bissilylated BINOL aluminum catalyst: Maruoka, K., Hoshino, Y., Shirasaka, T., Yamamoto, H. Annual Meeting of the Chemical Society of Japan, Tokyo, April 14, 1988; Abstract No. 1XIIB27; Maruoka, K., Hoshino, Y., Shirasaka, T., Yamamoto, H. (1988) Tetrahedron Lett. 29,3967-3970. Mikami, K., Terada, M., Nakai, T. (1989) Chern. Express 4,589-592. 6-Br-BINOL-Ti catalyst: a) Mikami, K., Motoyama, Y., Terada, M. (1994) Znorg. Chim. Acta 222, 71-75; b) Terada, M., Motoyama, Y., Mikami, K. (1994) Tetrahedron Lett. 35,6693-6696; c) Terada, M., Mikami, K. (1995)J. Chem. Soc., Chem. Commun. 2391-2392. Chem. Commun. 327-328. Terada, M., Matsukawa, S., Mikami, K. (1993).1. Chem. SOC., For syntheses of enantiomerically enriched ipsdienol a) >96 YO ee: Mori, K., Takigawa, H. (1991) Tetrahedron 47, 2163-2168; b) 96 % ee: Brown, H. C., Randad, R. S. (1990) Tetrahedron 46, 44634472; c) 91 % ee: Ohloff, G., Giersch, W. (1977) Helv. Chim. Acta 60,1496-1500.

Chiral Ti(ZV)Lewis Acids 55. 56.

57. 58.

59. 60.

61. 62. 63. 64. 65. 66. 67. 68.

69.

70. 71

72. 73. 74. 75.

76. 77. 78. 79.

843

Kabat, M. M., Lange, M., Wovkulich, P. M., Uskokovic, M. R. (1992) Tetrahedron Lett. 33, 77017704. a) van der Meer, F. T., Feringa, B. L. (1992) Tetrahedron Lett. 33, 66954696; b) Kitamoto, D., Imma, H., Nakai, T. (1995) Tetrahedron Lett. 36, 1861-1864; c) Corey, E. J., Barnes-Seeman, D., Lee, T. W., Goodman, S. N. (1997) Tetrahedron Lett. 38,6513-6516; d) Chavarot, M., Byrne, J. J., Chavant, P. Y., Pardillos-Guindet, J., Vallee, Y. (1 998) Tetrahedron Asymm.9,3889-3894. Faller, J. W., Liu, X. (1996) Tetrahedron Lett. 37,3449-3452; a) Mikami, K., Yajima, T., Terada, M., Uchimaru, T. (1993) Tetrahedron Lett. 34, 7591-7594; b) Mikami, K., Yajima, T., Terada, M., Kato, E., Maruta, M. (1994) Tetrahedron Asymm. 5, 10871090; c) Mikami, K., Yajima, T., Takasaki, T., Matsukawa, S., Terada, M., Uchimaru, T., Maruta, M. (1996) Tetrahedron 52,85-98. Review: Welch, J. T., Eswarakrishnan, S. (1990) Fluorine in Bioorganic Chemistry. Wiley, New York, NY. a) Mikami, K., Siree, N., Yajima, T., Terada, M., Suzuki, Y. Annual Meeting of the Chemical Society of Japan, Tokyo, March 28-31,1995; Abstract No. 3H218;b) Mikami, K., Yajima, T., Siree, N., Terada, M., Suzuki, Y.. Kobayashi. I. (1996) Synlett837-838;c) Mikami, K., Yajima, T., Terada, M., Kawauchi. S., Suzuki, Y., Kobayashi, I. (1996) Chem. Lett. 861-862; d) Mikami, K., Yajima, T., Terada, M., Suzuki, Y., Kobayashi, I. (1997) Chem. Commun. 57-58; e) Takanishi, Y., Takezoe, H.; Suzuki, Y., Kobayashi, I., Yajima, T., Terada, M., Mikami, K. (1999) Angew. Chem., Int. Ed. 38,2354-2357. a) Mikami, K., Yoshida, A. (1995) Synlett, 29-31; b) Mikami, K., Yoshida, A., Matsumoto, Y. (1996) Tetrahedron Lett. 37,8515-8518. Ward, R. S. (1990) Chem. Soc. Rev. 19, 1-19. Review: Mikami, K., Shimizu, M. (1993) J. Synth. Urg. Chem. Jpn. 51,1-31. Bartlett, P. A. (1980) Tetrahedron 36,2-72. Mikami, K., Narisawa, S., Shimizu, M., Terada, M. (1992) J. Am. Chem. Soc. 114, 6566-6568; (1992) J. A m . Chem. SOC.114,9242-9242. a) Kagan, H. B., Fiaud, J. C. (1988) Topics in Stereochemistry Interscience, New York, Vol. 18; b) Brown, J. M. (1988) Chem. Ind. (London) 612-617. a) Masamune, S., Choy, W., Peterson, J., Sita, L. R. (1985) Angew. Chem., Int. Ed. Engl. 24, 1-30; b) Heathcock, C. H. (1985) in Asymmetric Synthesis Morrison, J. D. ed., Academic Press: New York, Vol. 3, p 111-212. Excellent reviews: a) Girard, C., Kagan, H. B. (1998) Angew. Chem. Znf. Ed. 37, 2923-2959; b) Avalos, M., Babiano, R., Cintas, P., Jimenez, J. L., Palacios, J. C. (1997) Tetrahedron Asymm. 8, 2997-3017; c) Kagan, H. B., Girard. C., Guillaneux, D., Rainford, D., Samuel, O., Zhang, S. Y., Zhao, S. H. (1996) Acta Chem. Scand. 50, 345-352; d) C. Bolm (1996) in Advanced Asymmetric Synthesis (Ed.: G. R. Stephenson), Blackie Academic and Professional, New York, pp. 9-26; Excellent mechanistic investigations: a) Kitamura, M., Okada, S., Suga, S., Noyori, R. (1989) L Am. Chem. Soc. 111,40284036; b) Kitamura, M., Suga, S., Niwa, M., Noyori, R. (1995) J. A m . Chem. SOC.117,4832-4842; c) Kitamura, M., Yamakawa, M., Oka, H., Suga, S., Noyori, R. (1996) Chem. Eur. J. 2, 1173-1181; d) Kitamura, M., Suga, S., Oka, H., Noyori, R. (1998) J. Am. Chem. Soc. 120,9800-9809; e) Kitamura, M., Oka. H., Noyori, R. (1999) Tetrahedron 55,3605-3614. a) Guillaneux, D., Zhao, S.-H., Samuel, O., Rainford, D., Kagan, H. B. J. Am. Chem. Soc. 1994, 116, 9430-9439; Puchot, C., Samuel, O., Dunach, E., Zhao, S., Agami, C., Kagan, H. B. J. Am. Chem. SOC.1986,108,2353-2357. a) Terada, M., Mikami, K., Nakai, T. (1990) .I. Chem. SOC., Chem. Commun. 1623-1624; b) Mikami, K., Terada, M. (1992) Tetrahedron 48, 5671-5680; c) Terada, M., Mikami, K. (1994) J. Chem. Soc. Chem. Cummun. 833-834; d) Mikami, K., Motoyama, Y., Terada, M. (1994) Inorg. Chim. Acta 222,71-75. Oguni, N., Matsuda, Y., Kaneko, T. (1988) J. A m . Chem. Soc. 110,7877-7877. Alcock, N. W., Brown, J. M., Maddox, P. J. (1986) J. Chem. Soc., Chem. Commun. 1532-1533. Maruoka, K., Yamamoto, H. (1988) J. A m . Chem. Soc. 111,789-790. a) Faller, J. W., Parr, J. (1993) J. Am. Chem. Soc. 115, 804405; b) Faller, J. W., Mazzieri, M. R., Nguyen, J. T., Parr, J., Tokunaga, M. (1994) Pure Appl. Chem. 66, 1463-1469; c) Faller, J. W., Tokunaga, M. (1993) Tetrahedron Lett. 34,7359-7362; d) Sablong, R., Osborn, J. A., Faller, J. W. (1997) J. Urganomet. Chem. 527,65-70. a) Mikami, K., Matsukawa, S. (1997) Nature 385, 613-615; b) Matsukawa, S., Mikami, K. (1995) Tetrahedron Asymm.6, 2571-2574. Also see: Volk, T., Korenaga, T., Matsukawa, S., Terada, M., Mikami, K. (1998) Chirality, 10, 717-721. Matsukawa, S., Mikami, K. (1996) Enantiomer 1,69-73. Matsukawa, S., Mikami, K. (1997) Tetrahedron Asymm. 8, 815-816. a) Taber, D. F. (1984) Intramolecular Diels-Alder and Alder Ene Reactions. Springer Verlag, Berlin; b) Fujita, Y., Suzuki, S., Kanehira. K. (1983) L Synth. Urg. Chem. Jpn. 41, 1152-1167: c)

844

80. 81. 82. 83. 84.

85.

86. 87. 88. 89. 90. 91.

92. 93. 94. 95. 96. 97.

98. 99. 100. 101. 102. 103. 104. 105. 106. 107. 108.

109. 110.

Mikami/Terada Oppolzer, W., Snieckus, V. (1978) Angew. Chem., Int. Ed. Engl. 17, 476486; d) Conia, J. M., Le Perchec, P. (1975) Synthesis 1-19. Mikami, K., Sawa, E., Terada, M. (1991) Tetrahedron Asymm.2,1403-1412. a) Sakane, S., Maruoka, K., Yamamoto, H. (1986) Tetrahedron 42,2203-2209; b) Sakane, S., Maruoka, K., Yamamoto, H. (1985) Tetrahedron Lett. 26,5535-5538. a) Narasaka, K., Hayashi, Y., Shimada, S. (1988) Chem. Lett. 1609-1612; b) Narasaka, K., Hayashi, Y., Shimada, S., Yamada, J. (1991) Isr. J. Chem. 31,261-271. Mikami, K., Terada, M., Sawa, E., Nakai, T. (1991) Tetrahedron Lett. 3 2 ,6 5 7 1 4 7 4 . Reviews: a) Bouillon, R., Okamura, W. H., Norman, A. W. (1995) Endocrine Reviews 16, 200257; b) Dai, H., Posner, G. H. (1994) Synthesis 1383-1398. Special issue: c) Uskokovic, M. ed. (1993) Biomed. Chem. Lett. 3, No. 9. a) Mikami, K., Osawa, A,, Isaka, A,, Sawa, E., Shimizu, M., Terada, M., Kubodera, N., Nakagawa, K., Tsugawa, N., Okano. T. (1998) Tetrahedron Lett. 39,3359-3362; b) Okano. T., Nakagawa, K., Tsugawa, N., Ozono, K., Kubodera, N., Osawa, A,, Terada, M., Mikami, K. (1998) Biol. Pharm. Bull. 21, 1300-1305; c) Mikami, K., Koizumi, Y., Osawa, A,, Terada, M., Takayama, H., Nakagawa, K., Okano, T. (1999) Synlett, 1899-1902. a) Evans, D. A,, Nelson, J. V., Taber, T. R. (1982) Topics in Stereochemistry. Vol. 13, Interscience, New York; b) Mukaiyama, T. (1982) Org. React. 28,203-331. Reviews: a) Bach, T. (1994) Angew. Chem. Int. Ed. Engl. 33,417419; b) Groger, H., Vogl, E. M., Shibasaki, M. (1998) Chem. Eur. J. 4, 1137-1141; c) Nelson, S. G. (1998) Tetrahedron Asymm. 9, 357-389. Reetz, M. T., Kyung, S.-H.,Bolm, C., Zierke, T. (1986) Chem. Ind. (London)824-824. Mukaiyama, T., Inubushi, A,, Suda, S., Hara, R., Kobayashi, S. (1990) Chem. Lett. 1015-1018. Also see ref. 54b. Mikami, K., Matsukawa, S. (1993) J. A m . Chem. Soc. 115,7039-7040. a) Murata, S., Suzuki, M., Noyori, R. (1980) J. A m . Chem. Soc. 102,3248-3249: b) Yamamoto, Y., Maruyama, K. (1980) Tetrahedron Lett. 21,46074610. Mikami, K., Matsukawa, S., Nagashima, M., Funabashi, H., Morishima, H. (1997) Tetrahedron Lett. 38,579-582. Delas, C., Szymoniak, J., Lefranc, H., Moise, C . (1999) Telrahedron Lett. 40, 1121-1122. Mikami,K.,Matsukawa,S., Sawa,E., Harada, A,, Koga,N. (1997) Tetrahedron Lett. 38,1951-1954. Mikami, K., Matsukawa, S. (1994) J. A m . Chem. SOC.116, 40774078. a) Kolb, H. C., Bennari, Y. L., Sharpless, K. B. (1993) Tetrahedron Asymm. 4,133-141; b) Larcheveque, M., Henrot, s. (1990) Tetrahedron 46,42774282. a) Reetz, M. T., Jung, A. (1983) J. Am. Chem. SOC.105,48334835; b) Evans, D. A., Duffy, J. L., Dart, M. J. (1994) Tetrahedron Lett. 35,8537-8540; c) Evans, D. A., Dart, M. J., Duffy, J. L., Yang, M. G., Livingston, A. B. (1995) J. A m . Chem. Soc. 117, 6619-6620; d) Evans, D. A., Dart, M. J., Duffy, J. L., Yang, M. G. (1996) J. A m . Chem. Soc. 118,43224343. Matsukawa, S., Mikami, K. Annual Meeting of the Chemical Society of Japan, Kyoto, March 2831,1995, Abstract No. 3H106. Review on natural p-lactones and unnatural derivatives. Pommier, A, Pons, J.-M. (1995) Synthesis 729-744, a) Carreira, E. M., Singer, R. A,, Lee, W. (1994) J. A m . Chem. Soc. 116,8837-8838; b) Singer, R. A., Carreira, E. M. (1997) Tetrahedron Lett. 38,927-930. Carreira, E. M., Lee, W., Singer, R. A. (1995) J. Am. Chem. SOC.117,3649-3650 Keck, G. E., Krishnamurthy, D. (1995) J. Am. Chem. Soc. 117,2363-2364. Keck, G. E., Li, X.-Y., Krishnamurthy, D. (1995) J. Org. Chem. 60,5998-5999. a) Sato, M., Sunami, S., Sugita, Y., Kaneko, C. (1994) Chem. Pharm. Bull. 42, 839-845; b) Sato, M., Sunami, S., Sugita, Y., Kaneko, C. (1995) Heterocycles 41,1435-1444. a) Singer, R. A,, Carreira, E. M. (1995) J. Am. Chem. Soc. 117, 12360-12361; b) Kim, Y, Singer, R. A., Carreira, E. M. (1998) Angew. Chem. Znt. Ed. Engl. 37,1261-1263. Review on asymmetric synthesis: Rosen, T., Heathcock, C. H. (1986) Tetrahedron 42,49094951. Szlosek, M., Franck, X., Figadere, B., Cave, A. (1998)J. Org. Chem. 63,5169-5172. Sn complexes: a) Yura, T., Iwasawa, N., Narasaka, K., Mukaiyama, T. (1988) Chem. Lett. 10251026; b) Iwasawa, N., Yura, T., Mukaiyama, T. (1989) Tetrahedron 45, 1197-1207; Cu complexes: c) Bernardi, A,, Colombo, G., Scolastico, C. (1996) Tetrahedron Lett. 37,8921-8924; d) Evans, D. A,, Rovis, T., Kozlowski, M. C., Tedrow, J. S. (1999) J. Am. Chem. SOC. 121, 1994-1995; e) Kitajima, H., Katsuki, T. (1997) Synlett 568-570. Kobayashi, S., Suda, S., Yamada, M., Mukaiyama, T. (1994) Chem. Lett. 97-100. a) Bernardi, A,, Karamfilova, K., Boschin, G., Scolastico, C. (1995) Tetrahedron Lett. 36,1363-1364: b) Bernardi, A,, Karamfilova, K., Sanguinetti, S., Scolastico, C. (1997) Tetrahedron 53,13009-13026.

Chiral Ti(IV) Lewis Acids

845

111. Review: a) Dias, L. C. (1997) J. Braz. Chem. Soc. 8, 289-332; b) Oh, T., Reilly, M. (1994) Org. Prep. Proced. Int. 26, 129-158; c) Deloux, L., Srebnik, M. (1993) Chem. Rev. 93, 763-784; d) Kagan, H. B., Riant. 0. (1992) Chem. Rev. 92,1007-1019; e) Narasaka. K. (1991) Synthesis 1-11. 112. a) Narasaka, K., Iwasawa, N., Inoue, M., Yamada, T., Nakashima, M., Sugimori, J. (1989) J. Am. Chem. Soc. 111,5340-5345; b) Narasaka, K., Inoue, M., Okada, N. (1986) Chem. Lett. 1109-1112; c) Narasaka, K., Tnoue, M., Yamada, T. (1986) Chem. Lett. 1967-1968; d) Narasaka, K., Inoue, M., Yamada, T. (1987) Chem. Lett. 2409-2412; e) Iwasawa, N., Hayasahi, Y., Sakurai, H., Narasaka, K. (1989) Chem. Lett. 1581-1584; f) Narasaka, K., Tanaka, H., Kanai, F. (1991) Bull. Chem. SOC.Jpn. 64,387-391; g) Narasaka, K., Yamamoto, I. (1992) Tetrahedron 48,5743-5754. 113. a) Iwasawa, N., Sugimori, J., Kawase, Y., Narasaka, K. (1989) Chem. Lett. 1947-1950; b) Narasaka, K., Saitou, M., Iwasawa, N. (1991) Tetrahedron Asymm.2,1305-1318. 114. a) Chapuis, C., Jurczak, J. (1987) Helv. Chim. Acta 70, 436440; b) Seebach, D., Beck, A. K., Imwinkelried, R., Roggo, S., Wonnacott, A. (1987) Helv. Chirn. Acta 70,954975, 115. Ketter, A,, Glahsl, G., Herrmann, R. (1990) J. Chem. Research (S), 278-279; (1990) J. Chem. Research ( M ) ,2118-2156. 116. a) Devine, P. N., Oh, T. (1991) Tetrahedron Lett. 32, 883-886; b) Devine, P. N., Oh, T. (1992) J. Org. Chem. 57,396-399; 117. Braun, M. (1996) Angew. Chem. Int. Ed. Engl. 35,519-522. 118. a) Quinkert, G., del Grosso, M., Bucher, A,, Bauch, M., Doring, W., Bats, J. W., Durner, G. (1992) Tetrahedron Lett. 33,3617-3620; b) Quinkert, G., del Grosso, M., Doring, A., Doring, W., Schenkel, R. I., Bauch, M., Dambacher, G. T., Bats, J. W., Zimmermann, G., Durner, G. (1995) Helv. Chim. Acta 78,1345-1391. 119. a) Engler, T. A,, Letavic, M. A,, Takusagawa, F. (1992) Tetrahedron Lett. 33, 6731-6734; b) Engler, T. A., Letavic, M. A., Lynch, K. O., Takusagawa, F. (1994) J. Org. Chem. 59,1179-1183. 120. Bienayme, H. (1997) Angew. Chem. Int. Ed. Engl. 36,2670-2673. 121. Seebach, D., Marti, R. E., Hintermann, T. (1996) Helv. Chim. Acta 79,1710-1740. 122. a) Altava, B., Burguete, M. I., Escuder, B., Luis, S. V., Salvador, R. V., Fraile, J. M., Mayoral, J. A., Royo, A. J. (1997) J. Org. Chem. 62,3126-3134; b) Irurre, J., Fernandez-Serrat, A,, Rosanas F. (1997) Chirality 9,191-197. 123. a) Corey, E. J., Matsumura, Y. (1991) Tetrahedron Lett. 32, 62894292; b) Haase, C., Sarko, C. R., DiMare, M. (1995) J. Org. Chem. 60, 1777-1787; c ) Seebach, D., Dahinden, R., Marti, R. E., Beck, A. K., Plattner, D. A., Kuhnle, N. M. (1 995) J. Org. Chem. 60,1788-1799; d) Gothelf. K. V., Hazell, R. G., Jergensen, K. A. (1995) J. A m . Chem. Soc. 117,44354436; e) Gothelf. K. V., J0rgensen, K. A. (1995) J. Org. Chem. 60,6847-6851; f) Garcia, J. I., Martinez-Merino, V., Mayoral, J. A. (1998) J. Org. Chem. 63,2321-2324. 124. a) Tietze, L. F., Ott, C., Gerke, K., Buback, M. (1993) Angew. Chem. Int. Ed. Engl. 32,1485-1486; b) Tietze, L. F., Ott, C., Frey, U. (1996) Liehigs Ann. 63-67. Also see: c) Tietze, L. F., Saling, P. (1992) Synlett 281-282. 125. Posner, G. H., Carry, J.-C., Lee, J. K., Bull, D. S., Dai, H. (1994) Tetrahedron Lett. 35,1321-1324. 126. a) Posner, G. H., Eydoux, F., Lee, J. K., Bull, D. S. (1994) Tetrahedron Lett. 35, 7541-7544; b) Posner, G. H., Dai, H., Bull, D. S., Lee, J. K., Eydoux. F., Ishihara, Y., Welsh, W., Pryor, N., Petr, Jr., S. (1996) J. Org. Chem. 61,671-676. 127. a) Wada, E., Yasuoka, H., Kanemasa, S. (1994) Chem. Lett. 1637-1640. Also see: b) Wada, E., Pei, W., Kanemasa, S. (1994) Chem. Lett. 2345-2348. 128. Terada, M., Mikami, K., Nakai, T. (1991) Tetrahedron Lett. 32,935-938. 129. a) Konowal, A,, Jurczak, J., Zamojski, A. (1976) Tetrahedron 32,2957-2959; b) Danishefsky, S. J., DeNinno, M. P. (1987) Angew. Chem., Int. Ed. Engl. 26,15-23. 130. Motoyama, Y., Terada, M., Mikami, K. (1995) Synlett 967-968. 131. a) Mikami, K., Motoyama, Y., Terada, M. (1994) J. Am. Chem. Soc. 116,2812-2820; b) Mikami, K., Terada, M., Motoyama, Y., Nakai, T. (1991) Tetrahedron Asymm. 2,643-646. 132. a) Krohn, K. (1990) Tetrahedron 46,291-318; b) Krohn, K. (1986) Angew. Chem., Int. Ed. Engl. 25, 790-807; c) Broadhurst, M. J., Hassall, C. H., Thomas, G. J. (1985) Chem. Ind. (London) 18,10&112. 133. Harada, T., Takeuchi, M., Hatsuda, M., Ueda, S., Oku, A. (1996) Tetrahedron Asymm. 7, 24792482; Also see: ref. 52a. 134. Maruoka, K., Murase, N., Yamamoto, H. (1993) J. Org. Chem. 58,2938-2939. 135. Corey, E. J., Roper, T. D., Ishihara, K., Sarakinos, G. (1993) Tetrahedron Lett. 34,8399-8402. 136. a) Jaquith, J. B., Gu m , J., Wang, S., Collins, S. (1995) Organometallics 14, 1079-1081. Also see: b) Hong, Y., Kuntz, B. A., Collins, S. (1993) Organometallics 12, 964-969; c) Jaquith, J. B., Levy, C. J., Bodar, G. V., Wang, S., Collins, S. (1998) Organometallics 17,914-925. 137. Odenkirk, W., Bosnich, B. (1995) J. Chem. SOC. Chem. Commun. 1181-1182 138. Bellus, D., Ernst, B. (1988) Angew. Chem. Int. Ed. Engl. 27,797-827.

846

Mikami/Terada

139. a) Narasaka, K., Hayashi. Y., Shimadzu, H., Niihata, S. (1992) J. A m . Chem. Soc. 114, 8869-8885; b) Hayashi. Y., Narasaka, K. (1989) Chem. Lett. 793-796; c) Hayashi, Y., Narasaka, K. (1990) Chem. Lett. 1295-1298; d) Hayashi, Y., Niihata, S., Narasaka, K. (1990) Chem. Lett. 2091-2094. 140. a) Ichikawa, Y., Narita, A,, Shiozawa, A,, Hayashi, Y., Narasaka, K. (1989) J. Chem. Soc. Chem. Commun. 1919-1921; b) Narasaka, K., Kusama, H., Hayashi, Y. (1991) Bull. Chem. Soc. Jpn. 64, 1471-1478; c) Narasaka, K., Hayashi, K., Hayashi, Y. (1994) Tetrahedron 50,45294542. 141. Engler, T. A,, Letavic, M. A,, Reddy, J. P. (1991) J. A m . Chem. Soc. 113,5068-5070. 142. a) Pommier, A., Pons, J.-M., (1993) Synthesis 441449; b) Hyatt, J. A,, Raynolds, P. W. (1994) Org. React. 45,159-646. 143. Yang, H. W., Romo, D. (1998) Tetrahedron Lett. 39,2877-2880. 144. Reviews: a) Gothelf, K. V., J@rgcnsen,K. A. (1998) Chem. Rev. 98,863-909; b) Frederickson, M. (1997) Tetrahedron 53,403425. 145. a) Gothelf, K. V., Jergensen, K. A. (1994)J. Org. Chem. 59,5687-5691; b) Gothelf, K. V.,Thomsen, I., Jergensen, K. A. (1996) J. Am. Chem. Soc. 118,59-64; c ) Gothelf, K. V., Hazel, R. G., Jergensen, K. A. (1996) J. Org. Chem. 61,346-35s; d) Gothelf, K. V., J@rgensen,K. A. (1996) Acta Chem. Scand. 50, 652460 e ) Jensen, K. B., Gothelf, K. V., Hazell, R. G., Jergensen, K. A. (1997) J. Org. Chern. 62, 2471-2477; f) Jensen, K. B., Gothelf, K. V., Jergensen, K. A. (1997) Helv. Chim. Acta 80,2039-2046; g) Gothelf, K. V., Jergensen, K. A. (1997) J. Chem. Soc. Perkin Trans. 2 111-115. 146. Reviews: a) North, M. (1993) Synlett 807-820; b) Effenberger, F. (1994) Angew. Chem. Int. Ed. Engl. 33,1555-1564. 147. Rasmussen, J. K., Heilmann, S. M., Krepski, L. R. (1991) " The Chemistry of Cyunotrimethylsilane", Advances in Silicon Chemistry JAI Press. Greenwich, , Vol. 1. 148. a) Narasaka, K., Yamada, T., Minamikawa, H. (1987) Chem. Lett. 2073-2076; b) Minamikawa, H., Hayakawa, S., Yamada, T., lwasawa, N.. Narasaka, K. (1988) Bull. Chem. Soc. Jpn. 61,43794383. 149. a) Hayashi, M., Matsuda, T., Oguni, N. (1990) J. Chem. Soc. Chem. Commun. 1364-1365; b) Hayashi, M., Matsuda. T., Oguni, N. (1992) J. Chem. Soc., Perkin Trans. 1 3135-3140. 150. Callant, D., Stanssens, D., de Vries, J. G. (1993) Tetrahedron Asymm.4,185-188. 151. a) Bolm, C., Miiller, P. (1995) Tetrahedron Lett. 36, 1625-1628; b) Bolm, C., Miiller, P., Harms, K. (1996) Acta Chem. Scand. 50,305-315. 152. Mori, M., Imma, H., Nakai, T. (1997) Tetrahedron Lett. 38,6229-6232. 153. Hwang, C.-D., Hwang, D.-R., Uang, B.-J. (1998)J. Org. Chem. 63,6762-6763. 154. a) Hayashi, M., Miyamoto, Y., Inoue, T., Oguni, N. (1991) J. Chem. SOC.Chem. Commun. 17521753; b) Hayashi, M., Miyamoto, Y,, Inoue, T., Oguni, N. (1993) J. Org. Chem. 58, 1515-1522: c ) Hayashi, M., Inoue, T., Miyamoto, Y., Oguni, N. (1994) Tetrahedron 50,43854398. 155. a) Mori, A., Nitta, H., Kudo, M.. Inoue, S. (1991) Tetrahedron Lett. 32, 43334336; b) Nitta, H., Yu, D., Kudo, M., Mori, A,, Inoue, S. J. Am. Chem. Soc. 1992,114,7969-7975. Also see: c) Mori, A,, Ohno, H., Nitta, H., Tanaka, K., Irioue, S. (1991) Synlett 563-564. 156. a) Jiang, Y., Zhou, X., Hu, W., Wu, L., Mi, A. (1995) Tetrahedron Asymm. 6, 405408; b) Jiang, Y., Zhou, X., Hu, W., Li, Z., Mi, A. (1995) Tetrahedron Asymm.6,2915-2916. 157. a) Pan, W., Feng, X., Gong, L., Hu, W., Li, Z.. Mi, A,. Jiang, Y. (1996) Synlett 337-338; b) Jiang, Y., Gong, L., Feng, X., Hu, W.. Pan, W.. Li, Z., Mi, A. (1997) Tetrahedron 53,14327-14338. 158. a) Belokon, Y. N., Ikonnikov, N. S., Moscalenko, M. A,, North, M., Orlova, S., Tararov, V. I., Yashkina, L. (1996) Tetrahedron Asymm. 7,851-855; b) Belokon, Y. N., Flego, M., Ikonnikov, N. S., Moscalenko, M. A,, North, M., Orizu, C., Tararov, V. I., Tasinazzo, M. (1997) J. Chem. Soc. Perkin Trans. I 1293-1295; c) Belokon, Y., Moscalenko, M. A., Ikonnikov, N. S., Yashkina, L. V., Antonov, D., Vorontsov, E., Rozenberg, V. (1997) Tetrahedron Asymm.8,3245-3250. 159. a) Tararov, V. I., Hibb$ D. E., Hursthouse, M. B., Ikonnikov, N. S., Malik, K. M. A,, North, M., Orizu, C., Belokon, Y. N. (1998) Chem. Commun.387-388; b) Belokon, Y. N., Caveda-Cepas, S., Green, B., Ikonnikov, N. S., Khrustalev, V. N., Larichev, V. S., Moscalenko, M. A,, North, M., Onm, C., Tararov, V. I., Tasinazzo, M., Timofeeva, G. I., Yashkina, L. V. (1999)J. Am. Chem. Soc. 121,3968-3973. 160. Zi, G.-F., Yin, C.-L. (1998)J. Mol. Cat. A 132, LI-L4. 161. a) Krueger, C. A., Kuntz, K. W., Dzierba, C. D., Wirschun, W. G., Gleason, J. D., Snapper, M. L., Hoveyda, A. H. (1999) J. Am. Chem. Soc. 121, 4284-4285. Also see: b) Cole, B. M., Shimizu, K. D., Krueger, C. A,, Harrity, J. P. A,, Snapper, M. L., Hoveyda, A. H. (1996) Angew. Chem. Int. Ed. Engl. 35,1668-1671. 162. Hayashi, M., Inoue, T., Oguni, N. (1994) J. Chern. Soc., Chem. Commun.341-342. 163. Terada, M., Sayo, N., Mikami, K. (1995) Synlett 411415. 164. Ishii, A,, Kojima, J., Mikami, K. (1999) Org. hett. I , 2013-2016; Also see: a. Ichii, V. A. Soloshonok, K. Mikami, (1999) J. Org. Chem. 65,1597-1599. 165. a) Inoue, T.; Kitagawa, 0, Kurumizawa, S., Ochiai, O., Taguchi, T. (1995) Tetrahedron Lett. 36, 1479-1482; b) Inoue, T.; Kitagawa, O., Ochiai, O., Shiro, M., Taguchi, T. (1995) Tetrahedron Lett.

Chiral Ti(ZV)Lewis Acids

166. 167. 168.

169.

170.

847

36, 9333-9336; c) Inoue, T., Kitagawa, O., Oda, Y., Taguchi, T. (1996) J. Urg. Chem. 61, 82568263; d) Inoue, T., Kitagawa, O., Saito, A,, Taguchi, T. (1997) J. Org. Chem. 62,7384-7389. Enev, V. S., Mohr, J., Harre, M., Nickisch, K. (1998) Tetrahedron Asymm.9,2693-2699. Yamazaki, S., Tanaka, M., Yamabe, S. (1996) J. Org. Chem. 61,40464050. a) Johnson, R. A,, Sharpless, K. B. (2000) Catalytic Asymmetric Synthesis, Second Edition, Eds: Ojima I, VCH, New York. b) Katsuki, T.; Martin, V. S. (1996) Org. React. 48, 1-299; c) Johnson, R. A,, Sharpless, K. B. (1991) in Comprehemive Organic Synthesis. Trost, B. M., Fleming, I. ed., Pergamon Press, Oxford, Vol. 7, p 389-436; d) Finn, M. G., Sharpless, K. B. (1985) in AsymmetricSynthesis. Morrison, J. D. ed., Academic Press, New York, Vol. 5, p 247-308: e) Rossiter, B. E. (1985) in Asymmetric Synthesis.Morrison, J. D. ed., Academic Press, New York, Vol. 5, p 193-246. For review on catalytic enantioselective reduction with chiral titanocene complexes: a) Halterman, R. L. (1992) Chem. Rev. 92, 965-994. For a recent example of catalytic asymmetric reduction of ketones: b) Carter, M. B., Schiott, B., Gutierrez, A., Buchwald, S . L. (1994) J. Am. Chem. SOC.116,11667-11670. For an imine version, see: c) Willoughby, C. A,, Buchwald, S. L. (1994) J. A m . Chem. SOC.116, 11703-11714; d) Verdaguer, X., Lange, U. E. W., Buchwald, S. L. (1998) Angew. Ckem. Int. Ed. 37, 1103-1107. For the use of chiral alkoxy titanium complexes, see: e) Almqvist, F., Torsyensson, L., Gudmundsson, A,, Frejd, T. (1997) Angew. Chem., Int. Ed. Engl. 36,376-377; f) Lindsley, C. W., DiMare, M. (1994) Tetrahedron Lett. 35,5141-5144; g) Giffels, G., Dreisbach, C., Kragl, U., Wegerding, M., Waldmann, H., Wandrey, C. (1995) Angew. Chem., Int. Ed. Engl. 34,2005-2006. a) Williams, I. D., Pedersen, S. F., Sharpless, K. B., Lippard, S. L. (1984) J. Am. Chem. Soc. 106, 6430-6431; b) Bachand, B. Wuest, J. D. (1991) Organometallics 10, 2015-2025, c) Boyle, T. J., Eilerts, N. W., Heppert, J. A,, Takusagawa, F. (1994) Organometallics 13, 2218-2229; d) Corey, E. J., Letavic, M. A., Noe, M. C., Sarshar, S. (1994) Tetrahedron Lett. 35,7553-7556; Nugent, W. A,, Harlow, R. L. (1994) J. A m . Chem. Soc. 116, 6142-6148; e) Terada, M., Matsumoto, Y., Nakamura, Y., Mikami, K. (1997) Chem. Commun. 281-282: f) Terada, M., Matsumoto, Y., Nakamura, Y., Mikami, K. (1999) Inorg. Chim. Acta 296,267-272.

Lewis Acids in Organic Synthesis Edited bv Hisashi Yamarnoto Copyright 0WILEY-VCH Verlaa GmbH.2000

17 Hf-Centered Lewis Acids in Organic Chemistry Keisuke Suzuki and Shigeo Yamanoi

17.1 Introduction This chapter describes the use of Hf-centered Lewis acids in organic synthesis. Although the last two decades have witnessed an explosive growth of the use of titanium-centered Lewis acids [la] and then their zirconium counterparts [lb], the corresponding status of the hafnium derivatives remains limited, presumably because of less ready availability, and also the well-known similarity to Zr because of the lanthanide contraction [2]. Increasing data on the uniqueness of hafnium-centered Lewis acids are, however, becoming available. Some commercially available hafnium derivatives are listed in Table 1. HfC14 is the major starting material for the different hafnium derivatives. CpzHfClz is the hafnium complex that has found most widespread utility in carbohydrate synthesis [3] and, to some extent, in polymerization chemistry [4].The corresponding Cp* (CsMes) complex is also available. Hf(OTf)4 was recently prepared from HfC14 and CF3S03H [5]. Table 1. Some commercially available Hf derivatives. FW

m.p. ("C)

1 g price (US$)"

HfC14

320.30

432434

1.2 (0.16)

Cp2HfClz

379.59

230-233

13 (2.6)

Cp*zHfCl~

519.86

> 300

45 (46)

Hf(0Tf)d

714.76

> 350

23(-)

a

Numbers in parentheses are the price of Zr derivatives

17.2 Use of

C p Z H f C 1 2 in

Carbohydrate Synthesis

Glycosyl fluorides are glycosyl donors characterized by shelf stability and the capacity to be specifically activated by certain Lewis acids, e.g. SnC12-AgC104, Me3SiOTf, SiF4, and BF3. OEt2 [6]. Among the activators, the combination of Cp2HfC12 and AgC104 has particularly high reactivity in this context (Eq. 1) [7]. Although originally developed for the synthesis of the mycinamicin macrolide antibiotics (Fig. 1) [7c], the Hf-based activator quickly became popular in the synthesis of a variety of bioactive glycoconjugates.

850

Suzuki/Yarnanoi

CppHfCI2.2AgC104 B BnO n

OBnOF G

MS4A I CH2C12

+

+

BnO

BnO

(1)

93%

Figure 1. Mycinamicin IV.

The high activation of the C-F bond is attributed to the high fluorophilicity of the electron-deficient hafnocene perchlorate complex (Eq. 2) [7b]. Double ligand exchange, by use of CpzHfClz and AgC104 in 1:2 ratio, leads to an even higher reactivity. Although perchlorate is an excellent non-coordinating anion in terms of reactivity, great attention should be given to the potential hazard of AgC104 [8]. For most purposes, silver triflate (AgOTf) serves as a good substitute.

CP, CP’

,CI Hf+

clod-

cp.Hf,cI Cp’

*F

The high reactivity persists even for the assembly of large oligosaccharides of high molecular weight. The synthesis of trimeric LeX glycosphingolipid is a good example (Fig. 2) [9]; even more impressive is Fig. 3, the synthesis of an oligosaccharide composed of 25 sugars [lo]. Taking advantage of its shelf stability and the specific activation conditions, glycosyl fluoride is used as one of the donors in the orthogonal glycosylation strategy (Fig. 4) [lla]; thioglycosides and glycosyl fluorides can also be used as the donor. The specific activators are NIS-AgOTf for thio donors, and Cp2HfC12-AgC104 (1:2) for fluoro donors. The strategy eliminates some otherwise necessary reaction steps, including temporary protection/deprotection of the anomeric position and subsequent conversion into the donor.

Hf-Centered Lewis Acids in Organic Chemistry

HO OPiv H Aco@OA; O Pth -

OAc HO

OBz

$ plvo~

k

pivo & PlVOo

~

N3~

~ I)-C13H27 o ~ BZ = CBHSCO

OAc OAc

I

1) A, Cp2HfCI2, AgOTf, MS 4A 2,6-di-t-butyl-4-methylpyridine, 84% 2) thiourea, 2,6-lutidine, 90%

n-C13H27

I

1) A, Cp2HfClp, AgOTf, MS 4A 2.6-di-t-butyC4-methylpyridine, 79% 2) thiourea, 2,6-lutidine. 90%

HO

n-C13H27

I

I

Trimeric LeX

A

Figure 2. Synthesis of trimeric LeX sphingolipid.

851

852

Suzuki/Yamanoi

Figure 3. Synthesis of a 25-sugar oligosaccharide (deprotection stages are omitted).

A BnO c O G s p h

H

PhthN

&

G

F

PhthN NIS, AgOTf

05% SPh SPh

CppHfClz 2ASC104 72%

65% PhthN

PhthN

F

Figure 4. Orthogonal glycosylation.

This strategy has been further extended to polymer-supported glycoside synthesis [llb]. A diglycosyl fluoride attached to a PEG polymer is connected to a disaccharide by use of CpzHfC12and AgOTf (Fig. 5).

Hf-Centered Lewis Acids in Organic Chemistry

CpzHfCI,,

853

AgOTf

MS 4A, benzene 86%

0 NPhth

I

QOMe Figure 5. Polymer-supported glycoside synthesis #1.

In another report of polymer-supported synthesis of an oligosaccharide Cp2HfC12AgOTf was used for activation of glycosyl fluoride on a resin (Fig. 6) [12a]. DES-0

B BnBnO 0-0 BnO B n BnO

O0 BnO G 0 OBz

+

& OBz

n BnO

BnO Bno@o&Sph BnO

~

o

~

o

OBz

OBz

CpzHfCIzlAgOTf DTBP, MS 4A CHzCiz

DES-0

DTBP =

t-BU

BnO

OBz Figure 6. Polymer-supported glycoside synthesis #2.

OBz

854

SLizuki/Yarnanoi

Along similar lines is a report of ‘one-pot glycosylation’ which enables rapid assembly of oligosaccharide structures. The orthogonally activatable donors are sequentially introduced to the central acceptor that has three distinct hydroxyl groups. Hf-activation of the glycosyl fluoride is again a key element of the reaction (Fig. 7) [12b]. OMBz

1) Cp,HfClp, AgOTf

MBzO MBzO

I -

Me OTf

2) MeOTf

OMBz

MS 4A, CH2CI2 one-pot yield

MBzO MBzO

39%

AcO AcO

Figure 7. One-pot glycosylation.

Combination of CpzHfC12 and AgC104 in the ratio 1:2 catalyzes the decarboxylation of glycosyl carbonates, thereby giving rise to glycosides (Eq. 3 ) . The stereochemical outcome is solvent-dependent -a-selectivity is obtained in Et,O, ,&selectivity in CH2C12 [13]. cat. Cp2HfCl2, AgC104

BBnOn

+

BnO O G OCO2R

R = Cyc/eC&,CH2-

BnO BnO&

BnO

OR

80% (a/ p = 95 / 5, in Et20) 73% (a/ = 34 / 66,in CH2C12)

(3)

855

Hf-Centered Lewis Acids in Organic Chemistry

Epimerization of ,8-glucosides to the corresponding a anomers is promoted by the group IV metal halides (MX4, M = Ti, Zr, Hf; Eq. 4). The proposed mechanism for this anomerization includes the Lewis acid-mediated fission of the endo-cyclic C-0 bond (Fig. 8). The rate and extent of the anomerization are in the order Ti > Zr > Hf. and the best result is obtained by use of TiBr4 (20 mol %) and MgBrz.OEt, (100 mol %) [14].

B n 0 G o M e BnO BnO

P HfC14

B BnO n

O

6

(4)

CH2C12 BnoOMe

86%, a /B = 89 / 11

BnO.,,, BnO BnO

BnO.,,, OMe

+

BnO

BnO

BnO

Figure 8. Mechanism proposed for

+

a anomerization.

Aryl C-glycoside antibiotics, as exemplified by vineomycinone B2 and gilvocarcin V (Fig. 9) are an emerging class of natural products [1S]. During their synthesis the '0 -+ C glycoside rearrangement' (Eq. 5 ) [16] is used for regioselective installation of a phenol into a sugar at its anomeric position. When the glycosyl donor (X = F or OAc) and a phenol derivative are treated with a Lewis acid at low temperature, an 0glycoside is rapidly formed. Upon warming to 0 "C or higher the 0-glycoside is converted to the C-glycoside, C-C bond-formation occurring at the position ortho to the phenol hydroxyl.

0

HO

OH

0

Vineomycinone B2

Figure 9. Aryl C-glycosides.

OH Gilvocarcin V

856

Suzuki/Yamanoi Me

The cationic Hf reagent plays two critical roles. The conversion of the 0-glycoside to the C-glycoside proceeds via oxonium-phenolate ion pair I generated by the Lewis acid (Fig. 10) [16f]. The efficiency of CpzHfClz-AgC104 in this context is clearly seen if the result is compared with those obtained from other Lewis acids, e.g. BF3. OEt,under otherwise similar conditions, the '0 + C rearrangement' goes cleanly to completion with the Hf reagent but remains incomplete if BF3.OEt, is used (Eq. 6). The stereoselectivities are also markedly different; this is ascribed to the extent of equilibration-the more stable anomer accumulates if the Lewis-acid used is strong enough to enable the repeated generation of o-quinone methide species I1 (Fig. 10) [16f].

I

II

Figure 10. Reactive species in the 0 + C glycoside rearrangement.

Promoter

+

CH2CI2 -78 -+ 0 "C

"

O

m

(6)

BzO

OBz /

BF3oOEt2

70% yielda)

alP=3.411

Cp2HfC12,AgC104

98% yield

u/P=11>99

a) O-Glycoside was obtained in 28% yield.

Another stereochemically interesting feature was observed in the synthesis of the gilvocarcins [17]. The alb preference is not obvious for the furanoside-series, and indeed the outcome depends heavily on the metal center of the Lewis acid-a-selectivity is obtained with Hf, P-selectivity with Sn (Eq. 7). Although the difference might reflect the behavior of the coordinated species, many factors inhibit understanding of the true origin of the stereoselectivity.

Hf-Centered Lewis Acids in Organic Chemistry

'6 +

A

H O ,. Bn Me c O

Lewis acid ~

HO

I CH&Ip -78 - + 2 0 ° C

OBn

HO

-

/

857

(7)

+

OBn OBn

SnCI4, AgC104 CppHfClp, AgC104

OBn

69%

a f P = 7158

86%

a l p = 8.211

One interesting reaction between glycosyl fluorides and phenol or naphthol was reported by using Cp2HfC12and AgOTf to give benzo- or naphthodihydrofurans. The process includes a glycosylation sequence, a 1,2-shift, and intramolecular cyclization (Eq. 8) [18a]. An isochroman was obtained upon reaction with benzyl alcohol

(Eq. 9) [18b].

@PF

%

CppHfClp, AgOTf

OMe

+

+

CHpCIp

Br

Br

21% (R = 6-bromo-2-naphthyl)

44%

HF

%

+

BnOH

- U P

CppHfCIp, CH2C12, -50 2 AgC104 "C -+ r.t.

OMe

o*''

)r" "

(9)

82% (R = Me, Bn)

Cp2HfC12and AgOTf have been used in nucleoside synthesis starting from a bisfluorinated sugar and a bis-silylated pyrimidine (Eq. 10). Interestingly, the fluoride at the anomeric center was selectively activated [18c].

0

OSiMe3

3

N \

CpZHfCIz, AgOTf

ANN benzene,85%

* 87: 13

858

Suzuki/Yamanoi

17.3 Use of HfC14 and Hf(OTf)4 The Friedel-Crafts acylation has long been believed to be a stoichiometric process, because the carbonyl product coordinates with the conventional Lewis acid, e.g. A1C13. A catalytic version of this reaction has, however, been reported [19]. In the presence of HfC14 and AgC104, both used in catalytic amounts, a carboxylic acid is treated withp-trifluoromcthylbenzoic anhydride, thereby generating the corresponding mixed anhydride in situ; this reacts smoothly with the coexisting arene to give the aromatic ketone. A trimethylsilyl ester is also employed as the starting material (Eq. ll).

20 mol% HfCI4 40 mol% AgCI04

0

ICOSiMe3

OMe

*

(11)

(CF3OCO)zO

OMe

53%

CHZCI2,r.t.

When, later, Hf(OTf)4 was prepared it was found to be a more effective catalyst, enlarging the scope of the reaction in terms of yield, applicability, and turnover number (Eq. 12) [5]. 0

(RCO)ZO +

o\

5 mol% Hf(OTf), OMe

OMe

R = Me (95%), Et (93%) CPr (quart), f-Bu (91%)

In the Friedel-Crafts acylation of benzene, the above procedure gave only poor yield, whereas a new catalyst system, Hf(OTf)4 and CF3S03H, was found to catalyze the reaction of even deactivated benzenes, e.g. chlorobenzene and fluorobenzene (Eq. 13) [20]. 10 mol% Hf(OTf)4 10 mol% TfOH

F

100 "C

83%

The ulkylution of aromatic compounds with alkyl chlorides is also possible by use of a combination of the catalysts Hf(OTf)4 and LiC104 (Eq. 14). A high LiC104/RC1 ratio was found to be crucial for generating the active species, and slow addition was used to meet this requirement [5].

Hf-Centered Lewis Acids ifit Organic Chemistry

RCI

-+

0,

5 mot% Hf(OTf)4 50 mol% LiC104

*

859

(14)

MeN02

R = Bn (82%, d p = 41/59), t-Bu (71%) 1-adamantyl (75%,m/p = 7/93)

A new acidic esterification has been reported in which a carboxylic silyl ester is condensed with an alcohol under the action of p-trifluoromethylbenzoic anhydride and a combination of HfC14 and AgOTf as catalyst (Eq. 15).The esters are obtained in high yields even if almost equimolar amounts of substrates are employed. The method is applicable to the esterification of a,/3-enoic acids, such as crotonic acid, which is often hampered by side reactions, e.g. EIZ isomerization, deconjugation, and the Michael reaction [21a,b].

+ n O S i M e 3

20 mol% HfCI4 40 mol% AgOTf

*

Ph-f

OSiMe3

-

(C F3+CO),0 CHzCI,

phy

no

(15)

86%

The esterification was used in the preparation of an eight-membered lactone in the total synthesis of a new natural product, cephalosporolide Dl (Eq. 16) [21c].

OH O -H

QBn 0

cat. Hf(OTf)4 (CF3oCO),O

(16)

*

CH3CN, THF, reflux

67%

Hf(OTf)4 catalyzes the Fries rearrangement (Eq. 17) [22]. Direct acylation of phenols is also possible by treatment with acid chloride to give ortho-acylated product (Eq. IS). A crossover experiment showed that the reaction involves direct C-acylation and the rearrangement of the in situ-formed ester [22].

10 mol% Hf(OTf)4 toluene, 100 "C

76%

860

Suzuki/Yamanoi

+ CH3COCI

&

*

10 LiCI04, mol%MeN02 Hf(OTf)4 50 "C

(18)

90%

Hf(OTf)4 [or Zr(OTf)4] also acts as a catalyst in the allylation of imines with allyltributylstannane (Eq. 19) [23]. Extension to the three-component condensation of aldehyde, amine, and allyltin was made possible by use of these catalysts in the presence of a dehydrating agent, MgS04 (Eq. 20). Other Lewis acids were ineffective, because they decompose or become deactivated by the amine andlor the water produced during imine formation.

N/PCIPh

K,

+

e S n B u 3

10 mol% Hf(OTf)*

*

CH3CN. r.t., 16 h

Ph

OCH0 +

PhNH2

+

Ph

cat. MgS04, Hf(OTf)4 C2HsCN

e S n B u 3

-78

(+

+

(20)

o c

83%

The Hf(OTf)4-catalyzed Mannich-type reaction of imine with enol silyl ethers has been used as a means of access to p-amino carbonyl compounds (Eq. 21) [23]; this also was extended to a three-component reaction (Eq. 22). N/Ph

AH

Ph

+

OSiMe3

cat. Hf(OTf)4

Y O M e

CH3CN, 0 "C

PhNH 0

+:.r

P h v O M e

(21)

92%

OCH0+ +

OSiMe3

PhNH2

A S E t

PhNH 0

cat. Hf(OTf)4

MgSO4, C2HsCN -78 "C

*

d-"

SEt

95%

(22)

HfCentered Lewis Acids in Organic Chemistry

861

17.4 Hydro- and Carbometalation and Polymerization Hydro- and carbometalation reactions are gaining increasing importance in organic synthesis [24]. HfC14 (or ZrC14) catalyzes the hydrostannation of alkyne, thereby effecting the regio- and stereoselective anti-addition of tributyltin hydride to give cisvinylstannane (Eq. 23) [25a]. The corresponding hydrosilylation was unfruitful with HfCI4, but was found to proceed if A1C13 or EtAIC1, was employed [25b].

R3M = Bu3Sn Et3Si

86% 28%

z.95: <5 :~95: <5

A new example of carbornetalation is the HfC14-catalyzed trans-addition of allylsilane to unactivated alkynes (Eq. 24) [26]. The mechanism proposed for this regioand stereoselective formation of silylated 1,4-dienes is illustrated in Fig. 11.

C6H5*H

+

-SiMe3

/

50 mol% HfC14

(24) CH2C12.O "C

Figure 11. Mechanism proposed for the HfCL-catalyzed allylsilylation of alkynes.

Resurgent interest in Ziegler-Natta polymerization was triggered by Kaminsky's report of the high catalytic activity of Cp2ZrX2 and, to a lesser extent, the Hf counterpart coupled with methylaluminoxane (MAO) in a-olefin polymerizations [4]. There is evidence that the cationic complexes play an active role; stereoregulation, isotactic or syndiotactic, became possible with the advent of structurally tailored metallocenes (Fig. 12) [27].

862

Suzuki/Yamanoi

ML*-MA0

n d

* isotactic polypropylene

ML"-MA0 n &

* syndiotactic polypropylene

Figure 12. Metallocene-catalyzed polymerization.

17.5 Miscellaneous Reactions Homologation of ketones into their a-methoxylated hornologs was originally reported by Trost [28a]. HfCI4 (or ZrC14) proved effective as a Lewis acid for the rearrangement step, giving good yields of the corresponding products (Eq. 25) [28b].

&

S02Ph

PhSOpCH(Li)OMe THF, -78 "C, 83%

6 equiv. HfCI4

CH2C12,r.t. 80%

The hydrate of Hf(OTf)4 [or Zr(OTf)4] serves as an excellent catalyst for the mono-nitration of o-nitrotoluene by use of a single equivalent of concentrated nitric acid (Eq. 26). The only side-product is water, and the catalyst is readily recycled from the aqueous phase [29].

Hf-Centered Lewis Acids in Organic Chemistry

NO2

863

63 : 27

2,6-Dialkylphenols, which are difficult to prepare by conventional methods, are synthesized in one step by the Cp2HfC12-catalyzedcross-aromatization of cyclohexanone with aldehydes (Eq. 27) [30].

References 1. (a) Mikami, K. this book, Chap. 16. (b) Takahashi, T. this book, Chap. 18. 2. (a) Cardin, D. J.; Lappert, M. F.; Raston, C. L.; Riley, P. I. In Comprehensive Organometallic Chemistry, Wilkinson, G.; Gordon, F.; Stone, A,; Abel, E. W., Eds.; Pergamon: Oxford, 1982; Vol. 3, p. 559. (b) Cardin, D. J.; Lappert, M. F.; Raston, C. L. In Chemistry of Organo-Zirconium and -Hafnium Compounds; Ellis Horwood: New York, 1986; Chap. I. 3. Suzuki, K. Pure & Appl. Chem. 1994,66, 1557. 4. (a) Mohring, P. C.; C o d e , N. J. J. Organomet. Chem. 1994, 479, 1. (b) Bochmann, M. J. J. Chem. Soc., Dalton Trans. 1996,255. (c) Kaminsky, W.; Amdt, M. Adv. Polym. Sci. 1997,127,144. 5. (a) Hachiya, I.; Moriwaki, M.; Kobayashi, S. Tetrahedron Lett. 1995,36,409. (b) Hachiya, I.; Moriwaki, M.; Kobayashi, S. Bull. Chem. Soc. Jpn. 1995,68,2053. 6. See the references cited in ref. 7. 7. (a) Suzuki, K.; Maeta, H.; Matsumoto, T.; Tsuchihashi, G. Tetrahedron. Lett. 1988, 29, 3571. (b) Suzuki, K.; Maeta, H.; Matsumoto, T. Tetrahedron. Lett. 1989,30,4853. (c) Matsumoto, T.; Maeta, H.; Suzuki, K.; Tsuchihashi, G. Tetrahedron. Lett. 1988,29, 3575. For the corresponding reaction by Cp2ZrCI2-AgC1O4, see Matsumoto, T.; Maeta, H.; Suzuki, K.; Tsuchihashi, G. Tetrahedron. Lett. 1988,29, 3567. 8. Brinkley, Jr., S. R. J. Am. Chem. Soc. 1940,62,3524. 9. Nicolaou, K. C.; Caulfield, T. J.; Kataoka, H.; Stylianides, N. A. J. Am. Chem. Soc. 1990,112,3693. 10. Matsuzaki, Y.; Ito, Y.; Nakahara, Y.; Ogawa, T. Tetruhedron Lett. 1993,34, 1061. 11. (a) Kanie, 0.;Ito, Y.; Ogawa, T. .I. Am. Chem. Soc. 1994,126, 12073. (b) Ito, Y.; Kanie, 0.;Ogawa, T. Angew. Chem., Int. Ed. Engl. 1996,35,2510. 12. (a) Doi, T.; Sugiki, M.; Yamada, H.; Takahashi, T.; Porco, Jr., J. A. Tetrahedron Lett. 1999,40,2141. See, also Yamada, H.; Sugiki, M. Takahashi, T. the Annual Meeting of the Chemical Society of Japan 1999, 2A1 28. (b) Yamada, H.; Harada, T.; Miyazaki, H.; Takahashi, T. Tetrahedron Lett. 1994,35, 3979. See, also Tukamoto, Y.; Ikeda, T.; Yamada, H.; Takahashi, T. the Annual Meeting of the Chemical Society of Japan 1999,2A1 34. 13. Iimori, T.; Azumaya, I.; Shibazaki, T.; Ikegami, S. Heterocycles 1997,46, 221. 14. Mukaiyama, T.; Takeuchi, K.; Uchiro, H. Chem. Lett. 1997,625. 15. (a) Suzuki, K. Matsumoto, T. In Recent Progress in the Chemical Synthesis of Antibiotics and Related Microbial Products, Lukacs, G. Ed.; Springer: Berlin, 1993 Vol. 2, p. 353. (b) Suzuki, K.; Matsumoto, T. In Preparative Carbohydrate Chemistry, Hanessian, S. Ed.; Marcel Dekker: New York, 1997 p. 527. 16. (a) Matsumoto, T.; Katsuki, M.; Suzuki, K. Tetrahedron. Lett. 1988, 29, 6935. (b) Matsumoto, T.; Katsuki, M.; Jona, H.; Suzuki, K. Tetrahedron, Lett. 1989,30, 6185. (c) Matsumoto, T.; Hosoya, T.;

864

17.

18. 19. 20. 21. 22. 23. 24.

25. 26. 27.

28. 29.

30.

Suzuki/Yamanoi

Suzuki, K. Tetrahedron. Lett. 1990, 31, 4629. (d) Matsumoto, T.; Hosoya, T.; Suzuki, K. Synlett 1991, 709. (e) Matsumoto, T.; Hosoya, T.; Suzuki, K. Tetrahedron. Lett. 1991,32, 6735. (f) Matsumoto, T.; Katsuki, M.; Jona, H.; Suzuki, K. J. Am. Chem. Soc. 1991,113, 6982. (a) Matsumoto, T.;Hosoya, T.; Suzuki, K. J. Am. Chem. SOC.1992,114,3568. (b) Hosoya, T.; Takashiro, E.; Matsumoto, T.; Suzuki, K. J. Am. Chem. SOC.1994,116,1004. (a) Matheu, M. I.; Echarri, R.; Domenkch, C.; Castillon, S. Tetrahedron 1996,52,7797. (b) Matheu, M. I.; Echarri, R.; Castillon, S. Tetrahedron. Lett. 1993, 34, 2361. ( c ) Matbeu, M. I.; Echarri, R.; Castillon, S. Tetrahedron. Lett. 1992,33, 1093. (a) Mukaiyama, T.; Ohno, T.; Nishimura, T.; Suda, S.; Kobayashi, S. Chem. Lett. 1991, 1059. (b) Harada, T.; Ohno, T.; Kobayashi, S.; Mukaiyama, T. Synthesis 1991,1216. (c) Suzuki, K.; Kitagawa, H.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 1993,66,3729. Kobayashi, S.; Iwamoto, S. Tetrahedron Lett. 1998,39,4697. (a) Mukaiyama, T.; Shiina, I.; Miyashita, M. Chem. Lett. 1992, 625. (b) Miyashita, M.; Shiina, I.; Miyoshi, S.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 1993,66, 1516. (c) Shiina, I.; Fukuda, Y.; Ishii, T.; Fujisawa, H.; Mukaiyama, T. Chem. Lett. 1998,831. (a) Kobayashi, S.; Moriwaki, M.; Hachiya, I. Tetrahedron Lett. 1996, 37, 2053. (b) Kobayashi, S.; Moriwaki, M.; Hachiya, I. Bull. Chem. SOC.Jpn. 1997, 70,267. Kobayashi, S.; Iwamoto, S.; Nagayama, S. Synlett 1997,1099. (a) Knochel, P. In Comprehensive Organic Synthesis, Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991 Vol. 4, p 865. (b) Negishi, E.; Takahashi, T. Synthesis 1988, 1. (c) Negishi, E. Acc. Chem. Res. 1987,20, 65. (d) Zweifel, G.; Miller, J. A. Org. React. 1984,32,375. (e) Normant, J.-F.; Alexakis, A. Synthesis 1981,841. (a) Asao, N.; Liu, J.-X.;Sudoh, T.; Yamamoto, Y. J. Org. Chem. 1996, 61,4568. (b) Asao, N.; Sudo, T.; Yamamoto, Y. J. Org. Chem. 1996,61,7654. Yoshikawa, E.; Gevorgyan, V.; Asao, N.: Yamamoto, Y. J. Am. Chem. Soc. 1997, I Z Y , 6781. (a) Ewen, J. A.; Haspeslagh, L.; Atwood, J. L.; Zhang, H. J. Am. Chem. SOC.1987,109, 6544. (b) Herrmann, W. A.; Rohrmann, J.; Herdtweck, E.; Spaleck, W.; Winter, A. Angew. Chem., Int. Ed. Engl. 1989,28, 1511. (c) Mise, T.; Miya, S.; Yamazaki, H. Chem. Lett. 1989, 1853. (d) Spaleck, W.; Antberg, M.; Rohrmann, J.; Winter, A.; Bachmann, B.; Kiprof, P.; Behm, J.; Herrmann, W. A. Angew. Chem., Int. Ed. Engl. 1992,31,1147. ( e ) Kawarnura-Kuribayashi, H.; Koga, N.; Morokuma, K. J. Am. Chem. Soc. 1992,114,8687. (a) Trost, B. M.; Mikhail, G. K. J. Am. Chem. SOC.1987,109,4124. (b) Phillipson, N.; Anson, M. S.; Montana, J. G.; Taylor, R. J. K. J. Chem.Soc., Perkin Trans. I , 1997,2821. Waller, F. J.; Barrett, A. G. M.; Braddock, D. C.; Ramprasad, D. Tetrahedron Lett. 1998,39,1641. Nakano, T.; Shirai, H.; Tamagawa, H.; Tshii, Y.; Ogawa, M. J. Org Chem.1988,53, 5181.

Lewis Acids in Organic Synthesis Edited bv Hisashi Yamarnoto Copyright 0WILEY-VCH Verlaa GmbH.2000

18 Zirconium Lewis Acids Ryuichiro Hara and Tamotsu Takahashi

18.1 Introduction The number of articles on zirconium Lewis acids is much smaller than that on titanium, an element in the same group. Basically, the mechanism of reaction using zirconium Lewis acids is the same as that with other Lewis acids. Often the stereoselectivity or enantioselectivity of the reaction is emphasized. Hitherto few results have shown zirconium Lewis acids to be superior to other Lewis acids such as TiC14, SnC14,AlC13, etc. Zirconium Lewis acids are often mild, which enables reaction with moderate to good selectivity. Recently, zirconium cation compounds have attracted attention because they are extremely reactive in olefin polymerization. The Kaminsky-type polymerization of olefins with zirconium compounds is interesting, but beyond the scope of this review.

18.2 Zirconium Enolates and Aldol Reactions [l] 18.2.1 Diastereoselective Aldol Reactions via Zirconium Enolates Zirconium enolates are prepared by the reaction of lithium enolates with Cp2ZrC12. Aldol reactions mediated by zirconium enolates are characterized by high syn selectivity and good yields as a result of stereo control of the ligands on the metal (Eq. 1) [2]. Even at -78 "C zirconium enolates are reactive in addition to aldehydes because of the high Lewis acidity of the metal. The reaction of (Z)-enolates with aldehydes proceeds via chair-like conformation; the conformation is boat-like for (E)-enolates [2a]. Thus both ( E ) -and (2)-enolates (2) prepared from ketone 1 give predominantly syn aldols syn-3.

1

syn-3

unti -3

866

Hara/Takahashi

Zirconium enolates can also be derived from amides. It is of particular interest that diastereoselective functionalization of /3-lactams has been performed in high yields (Eq. 2) P I . i) LDA, THF, HMPA

n-C4H9

ii) C ~ ~ Z C I ~

b

H o ~ - . FNTBDPS a-C4H9

ii) MeCHO, -78 "C, 1 rnin

0GBDps

H o ~ nNTBDPS - c d - b

(2)

0

8oo/6

4

+

anti-5 9%

syn-5 87%

Zirconium enolates and the reaction products have been structurally characterized [2i-2k].

18.2.2 Asymmetric Aldol Reactions via Zirconium Enolates [3] Zirconium enolates of chiral amido derivatives (6) have been were employed to achieve an asymmetric aldol reaction. Hydrolysis of the aldol products (7) gave phydroxycarboxylic acids (8) with high enantioselectivity (Eq. 3). 0

OH

OH

Hoot*

Ph

A u x N * v Ph PhCHO

R' ~

or

-b

R' or OH H O O C G : Ph

6 Rl

El

7

MEMO AUXN' =

A

N

O N

v

8

r,

MOMO

MOMO

TBSO$ TBSO

(3)

867

Zirconium Lewis Acids

18.2.3 Cross-Aldol Reactions Mediated by Zr(O-t-Bu)4 Zr(O-t-Bu)d is a mild reagent that can be used in cross-aldol reactions and intramolecular aldol reactions without the basic treatment of the starting ketones, whereas the use of Cp2ZrCl enolate gave unsatisfactory results. For example; treatment of bromoketone (9) with Zr(O-t-Bu)4 followed by the addition of aldehyde (10) gave a-bromoP-hydroxyketone (11) in 56 % yield (Eq. 4) [4].

Q

Br3y

J:Me

TH ~

d'

(?-A?

b

Zr(O-t-Bu)4 (2.5 eq)

CHO

-30 "C

:Je (4)

TH pd"

OH 0

56% 10

I1

18.2.4 Zirconium-Catalyzed Mukaiyama Aldol Reactions Zirconocene triflates ( C ~ ~ z r ( 0 Torf )C~P ~ Z ~ ( O T THF) € ) ~ . and the titanocene analogs are highly cationic Lewis acids. Thus, Cp2Zr(OTf)z catalyzes Mukaiyama cross-aldol reactions between silyl enol ethers and aldehydes [5].For example, enolate (12)reacted with an aldehyde within a short period to give silylaldol(13) in high yield (Eq. 5).

re3OCH0 > Cp2Zr(OTf)2 (0.5 mol%) inCH3N02

Ph

12

25 "C, <5 min.

(5)

ph%

90%

13

A cationic zirconocene complex, [Cp2Zr(O-t-Bu) .THF](BPh4) has also been investigated and found to catalyze Mukaiyama aldol reactions [6]. The regioselectivity of the catalytic reaction was not as high as that of stoichiometric reactions.

868

Hara/Takahashi OTMS ph+C02M Me

PhCHO

>

MewoTMS OMe

in CH2C12, -78"C

14

+ QTMS p&C02Me

Cp2Zrf(O-t-Bu)THF][BPh4] (10 mol%)

Me 15

98% (1.28:l)

18.2.5 Ring-Opening Aldol-Type Reaction of 2,2-Dialkoxycyclopropane-

carboxylic Ester [7] Cyclopropane rings of 2,2-dialkoxycyclopropanecarboxylicesters are opened by a variety of Lewis acids, for example SnBr4, TiC14, TiBr4, A1C13, GaC13, ZrC14, and HfC14. When the 3,3-dialkyl substrate (16) was employed for the reaction with an aldehyde in the presence of TiC14 and ZrC14, it was found that the &:trans ratio was reversed as shown in Eq. (7). For the reaction of cyclopropanecarboxylic ester (18) which has one substituent at the C-3 position, the best yield and diastereoselectivity of lactone (20) were obtained when ZrC14 was used as the Lewis acid. The transition state after ring-opening is shown as 19; this explains the stereochemistry of product 20, formed by a route which avoids steric hindrance (Eq. 8). i)R2CH0, L. A.(1.1 eq) C02Et

M

ii) CH2C12, pTsOH,-78 toluene, "C 80 "C

+ 0 3 ; ? t (7)

0+2Et

hnan

-9

lYlG"

16

K-

K-

&-I 7

trans-I 7

R2 = PhCH2CH2, L. A. =TiCI4, 1 h ; 88% ZrCl , 2 2 h; 60%

18

19

78:22 32:68

R = c-Hex; 89%

20

Zirconium Lewis Acids

869

18.2.6 Aldol Reactions of a-Naphthol [8] a-Naphthol reacts with achiral pyruvates to give the aldol-type C-C coupling product 22 (Eq. 9) in the presence of a chiral cyclopentadienyl zirconium catalyst [Sd].

0

(9)

&

Cp'ZrC13 (5 mol%), CH2C12, H20 (25 mol%) -60 to -1 0 "C. 24 h

21 (Cpl=

22

*)

18.2.7 Mannich-Type Reactions The chiral-modified binaphthol complex (23) has been prepared (Eq. 10) and shown to be an efficient catalyst for enantioselective Mannich-type reactions [9]. The reaction of imine (24) with ketene silyl acetal in the presence of the catalyst 23 with NMI afforded p-amino acid derivatives 25 and 26 in high enantioselectivity (Eq. 11).

2

(10)

OH

Br

Br

23

23 (5-10 rnol%) OSiMe3 NMI (5-30 rnol%) OMe

C02Me

CHzClz, -45 "C

(1 1)

70% 24

25

26

83% (87% ee)

18.2.8 Robinson Annelation Reaction An intramolecular bicyclization reaction of the Robinson annelation-type has been reported as an extension of the aldol-type reaction (Eq. 12) [lo]. The success of this multi-step reaction might be attributable to both the basicity and acidity of zirconium alkoxide.

870

Hara/Takahashi

Zr(O-n-Pr)4 b

80% 27

28

18.3 Friedel-Crafts Type Reactions 18.3.1 Acylation and Alkytation Reactions The catalytic activity of ZrC14 in acylation [111 and alkylation reactions [12] has been studied for more than half a century and compared with that of A1Cl3. More recently it has been found that Zr(OTf)4 and Hf(OTf)4 is sometimes an efficient catalyst in Friedel-Crafts acylation reactions [13], although the characteristics of the zirconium Lewis acid in this classical reaction, and the scope of the reaction, have not yet been extensively studied. One outstanding reaction related to Friedel-Crafts alkylation is the sliding cyclohexane rearrangement mediated by ZrC14 as shown in Eq. (13) [14]. When tetralin 29 was stirred with ZrC& at ambient temperature for 2 days isomerized product 32 was obtained in high yield. The mechanism in which intermediates 30 and 31 are proposed involves the ambivalent. hard and soft Lewis acidic character of zirconium.

-

OMe

a,]

Z C l4

+ r.

MeO

t., 2 days

?Me

zrc 13

29 30

31

32 76%

18.3.2 Fries Rearrangement ZrCI4 as a stoichiometric reagent [15a] and Zr(OTf), as a catalyst [15b], and other group 3 and 4 metal compounds, have been found to be efficient mediators of the Fries rearrangement. 0-Acetylnaphthol(33) was converted to C-acetylnaphthol(34) in 76 % yield by use of the best catalyst so far, Hf(OTf)4. The use of Zr(OTf), resulted in 71 % yield (Eq. 14).

k

Zr(OTf)4 (10 mol%)

OH 0

toluene, 100 "C, 6 h

71 %

33

34

Zirconium Lewis Acids

871

18.4 Allylation Reactions Using Allylsilanes and Allylstannanes Allylsilanes and allylstannanes are known to undergo the allylation reactions of aldehydes and ketones in the presence of Lewis acids (the most commonly used are Tic& and SnCI4). Zirconium Lewis acids have often been compared with the titanium analogs. For most allylation reactions using allylsilanes the best results were obtained when TiC14 or SnQ was used. For allylation reactions using allylstannanes, as illustrated in Eq. (15), however, ZrC14 was used as the Lewis acid to obtain the bicyclic compound 36 via the intramolecular allylation of stannylaldehyde (35) [16].

&

L.A. CH2C12

b

SnBu3

Hq"4 +

sjn-36

35

(15)

unti-36

Table (Conversion of 35 to 36)

temp i"C, time imin

L. A. zrc14 ~

1

~

SnC14 ALCl3 CF3C02H -

(C6H6)

4

-70 -85 -70

-89 -70 90

10 10 5 10 10 480

Yield 1% (syi : an@ 95 84 89 85 95 85

(90:lO) (82:18) (89:11) (93:7) (99:l) (100:O)

Although various Lewis acid-catalyzed or -mediated reactions of aldehydes have been developed, less progress has been made in the reactions of imines using Lewis acids, probably because Lewis acids are often deactivated or decomposed by basic imines. Imines (37) have, however, been efficiently allylated by Zr(OTf)4 or Hf(OTf)4 catalyst in CH3CN to give homoallylamines (38) (Eq. 16); under similar conditions with using AIC13 or SnCI4 as catalyst low yields of allylated products were obtained ~71. ,R2 N R ' KH

37

+ &

Zr(0Tf)d (15 mol%)

+

p../SnBus CH3CN, r.t.

(16)

R1

313

Asymmetric intramolecular allylation of imine 39, with a chiral auxiliary on the imino nitrogen, was attempted with 2 equiv. Lewis acids (Eq. 17) [MI. When ZrCI4 was employed as a Lewis acid, of four possible diastereomers of P-aminotetrahydrofuran (40), the only isomer obtained was that with trans substituents on the tetrahydropyran ring.

872

Hara/ Takahashi

\Nr\Ph -

B u 3 S U -

CHpClp, -78

"C,3 h 97%

39

40 trans 100% (91% de)

cis 0%

When catalytic asymmetric allylation was attempted with a catalytic amount of chiral titanium complexes, BINOL-TiC12 or BINOL-Ti(O-i-Pr)2 the reaction was found to be slow. The reaction was performed satisfactorily when BINOL-Zr(0-iPr)z was employed as catalyst in the presence of molecular sieves (Eq. 18) [19a]. 20% (S)-BINOL-Zr(O-i-Pr)2 RCHO

+

w S n B u 3

b

R

(18)

L

MS /CH2C12 41 Xelds 34-84%, ee 87-93%

This asymmetric reaction was recently improved by using a Lewis acid system of BINOL, ZrC14(THF)2 and 4-tert-calix[4]arene prepared in situ [ 19b]. The modified method required only 2 'YO BINOL and zirconium to obtain up to 96 YO ee of the homoallylalcohols.

18.5 Open-Ring Addition to Oxiranes and Aziridines Along with the development of chiral Lewis acid catalysts, a chiral trialkanolamine (42) has been used to prepare the catalyst (43) (Eq. 19). By use of this zirconium complex as a catalyst, enantioselective addition of the azide to rneso epoxides was achieved [20a]. Thus, the oxirane ring was opened by i-PrMe2SiNs to give the adduct (44) with high enantioselectivity (Eq. 20). In another example, a diamide ligand (45), which behaves as a tetradentate ligand, was used to achieve a similar reaction (Eqs 21 and 22) [20b].

N k ) 3

+

Zr(O-t-Bu)4

H20

-*

(L-Zr-0-t-Bu),

THF

42

b

(L-Zr-OH)yt-BuOH

43

oo

i-PrMezSiN3,43 (10 rnol%)

o;hMe2i-Pr

1,2dichlorobutane, 0 "C, 48 h 44 86%, 93%ee

(19)

Zirconium Lewis Acids

873

46

TMSN3,Zr(O-t-Bu), (0.1 eq),45 (0.01 eq.)

aEQMe3

(22)

EtzNH (0.1 eq.), CH2C12, 0 "C, 5 d 47

Oxophilic early transition metal Lewis acids were shown to react differently from azaphilic Lewis acids when ring-opening of acylaziridines was attempted [21]. When N-acyl aziridine 48 was treated with trimethylsilylazide in the presence of a catalytic amount of C P * Z ~ ( S ~ Fthe ~ )product ~, was azide-amide 49, whereas in the presence of Cu(OTf)* the ring-expansion product, oxazoline 51, was formed (Sch. 1). TMSN3

0

Cp2Zr(SbF& (10 rnol%)

.R

/

b

THF

,TMS

.'I5 "'5 -t

57-58%

Another example of ring-opening of the oxirane ring is the kinetic resolution of racemic oxiranes by use of chiral Lewis acid catalysts, including Zr(O-t-Bu)4, with (R)-(+)&naphthol [22].

18.6 Diels-Alder and Hetero-Diels-Alder Reactions The first successful asymmetric Diels-Alder reaction was the reaction of cyclopentadiene with a chiral a,p-unsaturated amide with Evans' auxiliary by use of different Lewis acids [23]. The highest endolexo selectivity was observed when ZrCI4 was used, although the enantioselectivity when ZrC14 was employed was lower, in the ratio 7.2:1, whereas use of Et2AlCl under similar conditions gave a ratio of 17:l (Eq. 23).

874

Hara/Takahashi

J. J,

M e \

N

0

Q ZC14(1.4 eq)

*

+

&Me

CH2CI2, -78 "C, 3 h

i

COX"

+

M &e ,

em-54

X"0C

(23)

(2 isomem)

99%

53 Lewis acid (equiv)

SnCI4 (1 . l ) Tic14 (1.1) ZCI4 (1.4) EQAlCl (1.4)

conditions

endo- 54a

endo-54 b

yield 1%

ZendoErxo endo-dendo-b

-78 "C, 3 h -78 "C, 3 h -78 "C, 3 h -78 "C, 2.5 h

14.9 9.9 99 50

70 100

100 100

3.1 2.7 7.2

17.0

A cationic zirconocene complex formed by treatment of Cp2ZrC12 with AgC104 has been found to catalyze Diels-Alder reactions [24]. For example, reaction of epoxy ester 55 with isoprene presumably proceeds via the formation of dioxolenium ion 56 then cyclization (Eq. 24). Hydrolysis gave cyclohexenecarboxylic acid 57.

ii) H20

d o - &

JyC0'"124,

b

0

CppZrC12 (10 mol%) AgCIO, (2 mol%) CHzCl2, 0 "C,7 h

55

iii) LiOH, THF/H20

iv) H30+

57

83%

56

A chiral zirconium bis(triflate) complex has been found to catalyze asymmetric Diels-Alder reactions (Eq. 25) [25].

r,

,OTf

(5 mol%)

OTf 0

0

M e d N K O

u

58

+

Q

b

i-PrNOn, -78 "C 84%

&"" +

cox endo- 59

9 5 8 e.e.

(25)

&O 'x Me exo -59

(15:l)

As for the 0x0-Diels-Alder reaction, not much has been reported; other Lewis acids are usually superior [26]. As for the aza-Diels-Alder reaction, enantioselective reactions between imino dienophiles 60 and diene 61, using a chiral binaphtholzirconium catalyst 23, are known (Eq. 26) [27].

Zirconium Lewis Acids

875

OH

HO

23 (5-20 mol%) (L = NMI)

(26)

toluene, 4 5 "C R1

60

61

Yield: 47-96%. ee: 64-93%

62

18.7 [2 + 21 Cycloaddition Reactions The [2 + 21 cycloaddition reaction of 1-(trimethylsily1oxy)cyclopentene (63) and acetylenecarboxylate, in the presence of ZrC14, was accompanied with desilylation to afford bicyclo[3.2.0]heptene carboxylate 64 (Eq. 27) [28].

bw

C02Et

(-JoSiMe3

+

OH C02Et

ZCI4 (1 eq)

11,

Et20/CHzCI2, 25 "C

90%

63

(27)

H 64

Allyltritylsilane 65 reacted with aldehydes in different ways depending on the nature of the Lewis acid employed [29]. The intermediate drawn as 66 is plausible (Sch. 2). When Z r C 4 was employed as the Lewis acid, ring closure occurred through path h to give oxetane derivative 67, whereas BF3. OEt, gave tetrahydrofuran derivative 68 through path a.

7

R+SiMe2CPh3

a

-? SiMezCPh3

MXiMepCPh3

-b

R 65

66

67

\

BF3-0Et;

'q 68

S iMe2CPh3

Scheme 2

18.8 Zirconium-Catalyzed and -Mediated Oxidation and Reduction Reactions [30] The first zirconium-catalyzed oxidation reaction was reported by Kaneda, in which a zirconium oxide complex or zirconium alkoxide as the catalyst and t-BuOOH as an oxidant were employed to oxidize primary and allylic alcohols into aldehydes in high yields without formation of carboxylic acids [31].

876

Hara/Takahashi

Meerwein-Ponndorf-Verley-type reduction of carbonyl compounds and Oppenauer-type oxidation of allylic alcohols 69 proceed simultaneously under the influence of a catalytic amount of Cp2ZrH2(Eq. 28) [32a]. CpzZrH2 orCpZZr(O-i-Pr)p (2 rnol%) -OH

+

PhCHO

b

R

toluene, reflux, 8 h

@fo

(28)

R

70

69

Meerwein-Ponndorf-Verley reduction was efficiently and selectively achieved by use of l-(4-dimethylaminophenyl)ethanolas the reducing alcohol (2-4 equiv.) and Z r ( 0 t-Bu)4 (0.2 equiv.) as the catalyst [32b]. Oppenauer oxidation was selectively achieved by using chloral (1.2-3 equiv.) as the hydrogen acceptor and Zr(O-t-Bu)4 (0.2 equiv.) as the catalyst [32c]. Krohn showed that the oxidation of phenols by TBHP was mediated by zirconium y. or C1Ti(O-i-Pr)3was found acetylacetonate (Eq. 29), although [ M 0 ( 0 ~ ) ~ O ] pHMPT to be superior [33]. Zr(acac)4 (1 eq) TBHP (3 eq) CHzCIz, 20 "C, 12 h OMe 71

57%

OMe 72

An interesting tandem ortho-phenol oxygenation and oxy-Cope rearrangement of 74 was recently published (Eq. 30) [34].

73

74

75

18.9 Hydrometalation Reactions Catalyzed by Zirconium Complexes Because zirconium complexes are also ?t-base accepting Lewis acids, a variety of reactions based on interactions of carbon-carbon x-bonds with zirconium have been investigated.

Zirconium Lewis Acids

877

18.9.1 Hydroalumination of Olefins (Eq. 31) [35]

LiA H4, cafdlyst THF, 30 "C 76

77

catalysts

ZCId (whenR2 = H) Cp2ZrC12 (when R2 = akyl or phenyl)

18.9.2 Hydrostannation of alkyne (Eq. 32) [36]

18.9.3 Carbometalation of alkynes Carboal~mination[~~' and c a r b o ~ i n c a t i o n 'reactions ~~~ of alkynes with CpzZrCl2 as a catalyst have been reported (Eqs 33 and 34). R

MedI

RCECH

t

cat Cp;, ZC12

HAlMe H

Me

(33)

79

R

R'ZnX RCECH

H

t

cat. Cp2Zrl2

R'j=(ZnX 80

(34)

18.10 Miscellaneous Reactions Acylation of primary amines and stereodiscrimination has been described (Eq. 35) [39], P-hydroxysulfone rearrangement has been reported for homologation of ketones (Eq. 36) [40], and glycosylation mediated by glycosyl fluoride has also been reported (Eq. 37) [41].

878

Ar

HnrdTnkahashi

8,8, LI

+ NH2-R

Cp2ZrCI2 (20 mol%)

0

THF, 25 "C, 18 h

A r A N eR H

81

82

6:

...

ACO \,,

(35)

.*F

stero14SiMe3, ZrCI4 (1 eq)

"OAc OAC

~~0 ,,.' b - s t e r o l

(37)

t

AcO"

CH2CI2/MeCN,0 "C

"'OAc

ACO"

OAC

86

87

The addition of ethyl diazoacetate to aldehydes is promoted by Lewis acids. Although TiC14 and SnC14 are superior to ZrCI4; occasionally ZrC14 resulted in better selectivity (Eq. 38) [42]. N2@C02Et

(6 eq)

The cationic zirconocene species which result from the hydrozirconation of alkynes or alkenes then treatment with AgC104 or AgAsFh are sufficiently Lewis acidic to form new carbon-carbon bonds with aldehydes [43]. Two-carbon and four-carbon homologation reactions have been reported as an extension of this reaction (Eqs 3941).

-

R~CHO

,dR cut. 1 AgC104 or AgAsFG

Cp2Zr(H)C I

R'

+

CH2C12

cP2q

CI 90

t

R 2 p R ' OH 91

(39)

879

Zirconium Lewis Acids

CHO

i) -OEt,

0""""

CmZr(H)CI /CH2C12

ii) cut. AgAsFG

(40)

92

IDMe,

0"""

Cp2Zr(H)CI /CH2C12

0"'""""

(41)

i' 89 ii) cut. AgASF6

93

iii) H3O+

A bisallylically activated ether bridge 94 has been opened by ZrC& (Eq. 42) [44]. OSi Me3

ZCI4 (3 eq) CH2C12, -78 "C, 30 rnin.

&OH

93% 95

94

Zirconocene complexes, denoted Cp2ZrH2,are efficient catalysts in the Tischenkotype dimerization of aldehydes to esters 96 (Eq. 43) [45a], and the reaction has been modified to enable the stereoselective reduction of P-hydroxyketones with aldehydes (Eq. 44) [45b].

Lo,

Cp2ZrH2 orCp2Zr(H)CI (5% rnol)

L

+ RCHO

J

(43)

R

THF, r.L, 5 h 96

bL L

mCHo , car. Cp2ZrH2

(4.4)

THE r.t., 5 h

97 >99% (antvsyn = 84/16)

A binuclear zirconium catalyst, prepared in situ from Zr(O-t-Bu)4, (R)-6-BrBINOL, and (R)-3-Br-BINOL has been used in catalytic and enantioselective synthesis of a-aminonitriles 98 as shown in Eq. (45) [46].

880

HaraITakahashi

catalyst (0.1 eq) toluendbenzene (l/l),

HN

(45)

-&toO”C, 12h

98 55-97%, e.e. 7492%

References 1. For a comprehensive review, see: Paterson, I. “The Aldol Reaction: Transition Metal Enolates”, 2. (a) Evans, D. A.; McGee, L. R. Tetrahedron Lett. 1980,21,3975. (b) Yamamoto, Y.; Maruyama, K. Tetrahedron Lett. 1980,21,4607. ( c ) Masamune, S.; Imperiali, B.; Garvey, D. S. J. Am. Chem. Soc. 1982, 104,5528. (d) d’Angelo, J.; Pecquet-Dumas, F. Tetrahedron Lett. 1983,24,1403. (e) Bernet, B.; Bishop, P. M.; Caron, M.; Kawamata, T.; Roy, B. L.; Ruest, L.; Sauve, G.; Soucy, P.: Deslongchamps, l? Can. J. Chem. 1985,63,2810. (f) Brown, D. W.; Campbell, M. M.; Taylor, A. P.; Zhang, X.-A. Tetrahedron Lett. 1987,28,985. (g) Panek, J. S.;Bula, 0.A. Tetrahedron Lett. 1988,29, 1661. (h) Yamago, S.; Machii, D.; Nakamura, E. J. Org. Chem. 1991,56, 2098. (i) Cozzi, l? G.; Veya, P.; Floriani, C.; Rotzinger, F. €?; Chiesi-Villa,A,; Rizzoli, C. Organometullics1995, 14,4092. (j)Veya, €?; Cozzi, P. G.; Floriani, C.; Rotzinger, F. P.; Chiesi-Villa,A,; Rizzoli, C. Organometullics 1995,14,4101. (k) Solari, G.; Solari, E.; Floriani, C.; Vhiesi-Villa,A,; Rizzoli, C. Organometallics 1997,16,508. 3. (a) Evans, D. A.; McGee, L. R. J. Am. Chem. Soc. 1981,103,2876.(b) Katsuki, T.; Yamaguchi, M. Tetrahedron Lett. 1985,47,5807. 4. Sasai, H.; Kirio, Y.; Shibasaki, M. J. Org. Chem. 1990,55,5306. 5. (a) Bosnich, B.; Robinson, N. P.; Hollis, ‘I. K. Tetrahedron Lett. 1992,43,6423. (b) Lin, S.: Rondar, G. V.; Levy, C. J.; Collins, S. J. Org. Chem. 1998,63, 1885. 6. (a) Hong, Y.; Norris, D. J.; Collins, S. J. Org. Chem. 1993,58, 3591. (b) Cozzi. P. G.; Floriani, C.; Chiesi-Villa, A,; Rizzoli, C. Synlett 1994, 857. 7. (a) Shimada, S.; Hashimoto, Y.; Sudo, A.; Hasegawa, M.; Saigo, K. J. Org. Chem. 1992,57,7126.(b) Shimada, S.; Hashimoto, Y.; Sudo, A,; Hasegawa, M.; Saigo, K. Tetrahedron 1993, 49,1589. ( c ) Shimada, S.; Hashimoto, Y.; Saigo, K. J. Org. Chem. 1993,58,5226. 8. (a) Erker, G.; Berg, K.; Treschanke, L.; Engel, K. Inorg. Chem. 1982,21,1277. (b) Piccolo, 0.;Filippini, L.; Tinucci, L.; Valoti, E.; Citterio, A. Helv. Chim.Acta 1984,67,739. ( c ) Erker, G.; Berg, K.; Sarter, C. Organomet. Synth. 1987,3,29. (d) Erker, G.; van der Zeiden, A. A. H. Angew. Chem. Int. Ed. Engl. 1990,29,512. 9. Ishitani, H.; Ueno, M.; Kobayashi, S. J. Am. Chem. Soc. 1997,119,7153. 10. Attah-Poku, S. K.; Chau, F.; Yadav, V. K.; Fallis, A. G. J. Org. Chem. 1985, 50, 3418. 11. (a) Heine, H. W.; Cottle, D. L.; van Matter, H. L. J. Am. Chem. Soc. 1946, 68,524. (b) Gore, P. H.; Hoskins, J. A. J. Chem. Soc. 1964, 5666. ( c ) Pivsa-Art, S.; Okuro, K.; Miura, M.; Murata, S.; Nomura, M. J. Chem. Soc., Perkin Trans I 1994,1703. 12. Segi, M.; Nakajima, T.; Suga, S. Bull. Chem. Soc. Jpn. 1980,53,1465. 13. (a) Hachiya, I.; Moriwaki, M.; Kobayashi, S. Tetrahedron Lett. 1995, 36, 409. (b) Hachiya, I.; Moriwaki, M.; Kobayashi, S. Bull. Chem. Soc. Jpn. 1995,2053. 14. Harrowven, D. C.; Dainty, R. F. Tetrahedron Lett. 1996,37,3607. 15. (a) Harrowven, D. C.; Dainty, R. F. Tetrahedron Lett. 1996,37, 7659. (b) Kobayashi, S.; Moriwaki, M.; Hachiya, I. Bull. Chem. Soc. Jpn. 1997, 70,267. 16. (a) Denmark, S. E.; Weber, E. J.; Wilson, T. M.; Willson, T. M. Tetrahedron 1989, 45, 1053. (b) Kunz, T.; Janowitz, A, ReiBig, H.-U. Chem. Ber. 1989,122,2165. 17. Kobayashi, S.; Iwamoto, S.; Nagayama, S. Synlett 1997,1099. 18. Park, J.-Y.;Park, C.-H.; Kadota, I.; Yamamoto, Y. Tetrahedron Lett. 1998,.39, 1791. 19. (a) Bedeschi, P.; Casolari, S.; Costa, A. L.; Tagliavini,E.; Umani-Ronchi, A. Tetrahedron Lett. 1995,36, 7897. (b) Casolari, S.; Cozzi, P. G.; Orioli, €?; Tagliavini, E.; Umani-Ronchi, A. Chem. Commun. 1997, 2123. 20. (a) Nugent, W. A. J. Am. Chcm. Soc. 1992, 114, 2768. (b) Adolfsson, H.; Moberg, C. Tetrahedron Asymmetry1995,6,2023. 21. Ferraris, D.; Drury 111, W. J.; Cox, C.; Lectka, T. J. Org. Chem. 1998,63,4568.

Zirconium Lewis Acids

881

22. (A) Brunner, M.; MuRmann, L.; Vogt, D. Synlett 1993, 893. (b) Brunner, M.; MuRrnann, L.; Vogt, D. Synlett 1994, 69. 23. Evans, D. A,; Chapman, K. T.; Basaha, J. J. A m . Chem. Soc. 1988,110,1238. 24. Wipf, P.; Xu, W. Tetrahedron 1995,51,4551. 25. Jaquith, J. B.; Guan, J.; Wang, S.; Collins, S. Organometallics 1995,14,1079. 26. Tietze, L. F.; Schneider, C. Synlett 1992,755. 27. Kobayashi, S.; Komiyama, S.; Ishitani, H. Angew. Chem. Int. Ed. Engl. 1998,37,979. 28. (a) Franck-Neumann, M.; Miesch, M.; Gross, L. Tetrahedron Lett. 1990,31,5027. (b) Franck-Neumann, M.; Miesch, M.; Gross, L. Tetrahedron Lelt. 1992,33,3879. 29. Groaning, M. D.; Brengel, G. P.; Meyers, A. I. J. Org. Chem. 1998,63,5517. 30. For a general review on the zirconium alkoxide catalyzed oxidation reactions, see: Krohn, K. Synthesis 1997,1115, and references therein. 31. (a) Kaneda, K.; Kawanishi, Y.; Teranishi, S. Chem. Lett. 1984, 1481. (b) Krohn, K.; Vinke, I.; Adam, H. J. Org. Chem. 1996,61,1467. 32. (a) Nakano, T.; Ishii, Y.; Ogawa, M. J. Org. Chem. 1987,52,4855.(b) Knauer, B.; Krohn, K. Liebigs Ann. 1995,677. (c) Krohn, K.; Knauer, B.; Kupke, J.; Seebach, D.; Beck, A. K.; Hayakawa, M. Synthesis 1996, 1341. 33. (a) Krohn, K.; Rieger, H.; Khanbabaee, K. Chem. Ber. 1989,122,2323. (b) Krohn, K.; Rieger, H.; Briiggrnann, K. Synthesis 1990,1141. (c) Krohn, K.; Briiggmann, K.; Doring, D.; Jones, P. G. Chem. Ber. 1992,125,2439. 34. Krohn, K.; Bernhard, S. Synthesis 1996,699. 35. (a) Sato, F.; Sato, S.; Sato, M. J. Organomet. Chem. 1976, 122, C25. (b) Sato, F.; Tomuro, Y.; Ishikawa, H.; Sato, M. Chem. Lett. 1980,99. 36. (a) Asao, N.; Liu, J.-X.; Sudoh, T.; Yamamoto, Y. J. Chem. Soc., Chem. Comrnun. 1995, 2405. (b) Asao, N.; Liu, J.-X.; Sudoh, T.; Yamamoto, Y. J. Org. Chem. 1996,6/, 4568. 37. (a) Van Horn, D. E.; Negishi, E. J. Am. Chem. Soc. 1978,100,2252.(b) Rand, C. L.; Van Horn, D. E.; Moore, M. W.; Negishi, E. J. Org. Chem. 1981, 22, 2715. (c) Negishi, E.; Yoshida, T. J. A m . Chem. Soc. 1981,103,4985. (d) Miller, J. A,; Negishi, E. Tetrahedron Lett. 1984,25,5863. (e) Miller, J. A,; Negishi, E. Isr. J. Chem. 1984, 24, 76. (f) Negishi, E.; Van Horn, D. E.; Yoshida, T. J. Am. Chem. Soc. 1985,107,6639, (8) Negishi, E.; Van Horn, D. E. Organomet. Synth. 1986,3,467. 38. (a) Negishi, E.; Van Horn, D. E.; Yoshida, T.; Rand, C. L. Organometallics 1983,2,563. (b) Negishi, E.; Miller, J. A. J. Am. Chem. SOC.1983,105,6761. 39. Yokomatsu, T.; Arakawa, A,; Shibuya, S. J. Org. Chem. 1994,59,3506. 40. Phillipson, N.; Anson, M. S.;Montana, J. G.;Taylor, R. J. K. J. Chem. Soc., Perkin Trans. 11997,2821. 41. Pikul, S.; Switzer, A. G. Tetrahedron: Assymetry 1997.8, 1165. 42. Angle, S. R.; Wei, G. P.; KO,Y. K.; Kubo, K. J. Am. Chem. Soc. 1995,117,8041. 43. (a) Maeta, H.; Hashimoto, T.; Hasegawa, T.; Suzuki, K. Tetrahedron Len. 1992,33,5965. (b) Maeta, H.; Suzuki, K. Tetrahedron Lett. 1992,33,5969. (c) Maeta, H.; Suzuki, K. Tetrahedron Lett. 1993,34,341. (d) Maeta, H.; Hasegawa. T.; Suzuki, K. Synlett 1993,341. (e) Suzuki, K. Pure Appl. Chem. 1994,66, 1557.(f) Suzuki, K.; Hasegawa, T.; Imai, T.; Maeta, H.; Ohba, S. Tetrahedron 1995,51,4483. 44. Stohrer, I.; Hoffmann, H. M. letrahedron 1992,48,6021. 45. (a) Morita, K.-I.; Nishiyama, Y.; Ishii, Y. Organometallics 1993,12, 3748. (b) Umekawa, Y.; Sakaguchi, S.; Nishiyama, Y.; Ishii, Y. J. Org. Chem. 1997,62, 3409. 46. Ishitani, H.; Komiyama, S.; Kobayashi, S. Angew. Chem. Int. Ed. 1998,37,3186.

Lewis Acids in Organic Synthesis Edited bv Hisashi Yamarnoto Copyright 0WILEY-VCH Verlaa GmbH.2000

19 Sc(II1) Lewis Acids Shu Kobayashi

19.1 Introduction The element scandium (Sc) is in group 3 (above La and Y), and its radius is appreciably smaller than those of any other rare earth elements. Scandium is uncommon probably because of the lack of rich sources and difficulties of separation. Its chemical behavior is known to be intermediate between that of aluminum and lanthanides [l].Use of scandium in organic synthesis was rather limited before scandium trifluoromethanesulfonate (Sc(OTf)3) was first introduces as a promising Lewis acid in 1993 [2]. Although Lewis acid-catalyzed carbon-carbon bond-forming reactions are now of great interest in organic synthesis, these reactions must be conducted under strictly anhydrous conditions, because most Lewis acids react immediately with water rather than the substrates, and are decomposed or deactivated. Sc(OTf)3, however, was found to be stable in water, and effectively activated carbonyl and related compounds as a Lewis acid in water. Although it had already been found that lanthanide triflates (Ln(OTf)3; Ln = La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu) and yttrium triflate (Y(OTf)3) are stable in water and can act as Lewis acid catalysts in aqueous media [3], Sc(OTf), occasionally has even better properties even than Ln(OTf)3. Sc(OTf)3, moreover, worked well as a Lewis acid catalyst in several organic solvents, and chiral scandium triflates have also been developed. Although other scandium salts have recently been reported in the literature, their properties are similar to Sc(OTf), in many respects, and so this article surveys useful synthetic reactions which employ Sc(OTf), as a catalyst, focusing in particular on carboncarbon bond-forming reactions in organic solvents, aqueous media, and the solid phase.

19.2 Reactions in Organic Solvents Although Sc(OTf)3 and other scandium salts are water-stable and used in aqueous media, they are also successfully employed in organic media. They are used catalytically in many reactions and can often be recovered and reused because they are stable under usual water-quenching conditions.

19.2.1 Aldol Reactions Sc(OTf), is an effective catalyst in aldol reactions of silyl enol ethers with aldehydes [4,5]. The activities of typical rare earth triflates [Sc, Y, Yb(OTf)3] were evaluated in the reaction of 1-trimethylsiloxycyclohexenewith benzaldehyde in dichloromethane (Table 1). Although the reaction scarcely proceeded at -78 "C in the presence of Yb(OTf)3 or Y(OTf)3 [3b], the aldol adduct was obtained in 81 % yield in the presence of Sc(OTf),. Obviously, Sc(OTf), was more active than Y(OTf)3 or Yb(OTf)3 in this reaction.

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Kobayashi

Catalyst (5 mol%) * CHICHI, -78 "C, 15 h

PhCHO

Ph%

Table 1. Effects of catalysts. Entry

Catalyst

Yield (YO) 81 Trace Trace

Several examples of S~(OTf)~-catalyzed aldol reactions of silyl enolates with aldehydes were been examined. Silyl enolates derived from ketones, thioesters, and esters reacted smoothly with different types of aldehyde in the presence of 5 mol % Sc(OTf), to afford the aldol adducts in high yields. Sc(OTf), was also found to be an effective catalyst in aldol-type reactions of silyl enolates with acetals. The reactions proceeded smoothly at -78 "C or room temperature to give the corresponding aldoltypc adducts in high yields without side-reaction products. It should be noted that aldehydes were more reactive than acetals. For example, while 3-phenylpropionaldehyde reacted with the ketene silyl acetal of methyl isobutyrate at -78 "C to give the aldol adduct in 80 % yield, no aldol-type adduct was obtained at -78 "C in the reaction of the same ketene silyl acetal with 3-phenylpropionaldehyde dimethyl acetal. The acetal reacted with the ketene silyl acetal at 0 "Cto room temperature to give the adduct in 97 740 yield (Sch. 1).

Ph

Sc(OT03(5 mol%) CH2C12 -78°C; 0%* 0°C tort: 97%

P

h

q

O

M

e

Scheme 1. Sc(OTf)3-catalyzed aldol reactions.

19.2.1.1 Recovery and Re-Use of the Catalysts S C ( O T ~is) ~more soluble in water than in organic solvents such as dichloromethane. The catalyst can be recovered almost quantitatively from the aqueous layer by simple extraction after the reaction was complete (Sch. 2), and it could be re-used. The recovered catalyst is also effective in the 2nd reaction, and the yield of the 2nd run is comparable with that of the 1st run (Eq. 1) [4].Because Sc(OTf)3 can be successfully recovered and re-used in many other reactions, it is expected to solve severe environmental problems caused by mineral acid- or Lewis acid-promoted reactions in the chemical industry.

Sc(II1) Lewis Acids

885

water (quench) I

I

I

(extraction)

1

I

I

I

(purification)

(removal of water)

Scheme 2. Recovery of the catalyst.

Sc(0TO3(5 mol%) PhCHO

-

CH2C12, -78 "C, 1 h 88% (1st run) 89% (2nd run)

+

P h V O M e

(1)

19.2.2 Michael Reactions Michael reactions of silyl enolates or ketene silyl acetals with a,p-unsaturated carbonyl compounds are among the most important carbon-carbon bond-forming processes in organic synthesis. Sc(OTf)3 was found to be effective [4], and the reactions proceeded smoothly in the presence of a catalytic amount of Sc(OTf)3, under extremely mild conditions, to give the corresponding 1,5dicarbonyl compounds in high yields after acid work-up (Eq. 2). Silyl enolates derived from ketones, thioesters, and esters were applicable, and no 1,2-addition products were obtained. The products could, furthermore, be isolated as synthetically valuable silyl enol ethers (I) when acid-free work-up was performed. The catalyst could be recovered almost quantitatively and could be re-used.

+

Sc(0TO3(10 mol%)

VSiMe3

R4

R5

CH2C12, tt

*

R2

H+

___)

0

R 1 k $ R 5 R3 R4

I

19.2.3 Mannich-Type Reactions Mannich and related reactions are among the most fundamental and useful methods for the synthesis of p-amino ketones or ,&amino esters, leading to p-lactam derivatives [6]. In the classical Mannich routes to p-amino ketones and esters yields are

886

Kohnyashi

sometimes low, because significant side-reactions such as deamination occur under the rather drastic reaction conditions. To enable the reactions to be performed under milder conditions, new modifications using preformed iminium salts [7] and imines [S] were introduced. These intermediates are, however, often hygroscopic and/or thermally unstable. As for the reactions using silyl enolates, use of a stoichiometric amount of TiC14 as a promoter was first reported in 1977 [Sa], since when some efficient catalysts have been developed [Sc-e,9]. It was first observed that reactions of imines with ketene silyl acetals proceeded smoothly in the presence of 5 mol % Yb(OTf)3 (a representative lanthanide triflate) to afford the corresponding ,&amino ester derivative in a moderate yield. The yield was improved when Sc(OTf)3, rather than Yb(OTf)3, was used as catalyst (Eq. 3) [lo]. Not only silyl enolates derived from esters, but also one derived from a thioester worked well to give the desired p-amino esters and thioester in high yield. In the reactions of the silyl enolate derived from benzyl propionate, anti adducts were obtained with good selectivity. In addition, the catalyst could be recovered when the reaction was complete, and could be re-used. N-Ph

+

PhKH

2s:

M(OT03 (5 rnol %) * CHzC12.0 "C

PhPhD

S

E

t

(3)

80% (M = Sc) 65% (M = Yb)

A novel Mannich-type reaction of N-@-aminoalky1)benzotriazoles with silyl enolates has also been developed [ll]. Four-component (silyl enolates, a$-unsaturated thioesters, amines, and aldehydes) coupling reactions have also been successfully conducted with Sc(OTf)3 as catalyst, to afford the corresponding amino thioester and y-acyl-d-lactam derivatives stereoselectively in high yields (Sch. 3) [12].

j y 3

+

/ajiSElSbC15-Sn(OTf)2 mol%) (5

CHZC12, -78 "C *

EtS

[ E t S U E ' ]

0

-

0

PhCHO, PhNH2, Sc(OTf),

-18"C

to

0 "C Ph

Ph

0

Hg(OCOCF&, CH,CN, 0 "C Scheme 3. One-pot synthesis of d-lactams.

Ph

Ph

Sc(III) Lewis Acids

887

19.2.4 Mannich-Type Reactions Using Hydrazones Acylhydrazones are aldehyde and ketone equivalents, and imine equivalents, and their stability is much higher than that of imines. Indeed, acylhydrazones derived from aliphatic aldehydes are often crystalline and can be stored, although their reactivity as electrophiles is known to be low. It was recently found that in the presence of a catalytic amount of Sc(OTf)3 benzoylhydrazones reacted with ketene silyl acetals to afford the corresponding adducts, /?-N'-benzoylhydrazino esters, in high yields (Eq. 4) [13]. Not only aromatic but also aliphatic, a$-unsaturated aldehydes, and glyoxylate benzoylhydrazones reacted smoothly. On the other hand, the catalytic activation of benzoylhydrazones by use of a typical Lewis acid such as TiCI4, SnC14, or BF3. OEt2, etc., was not effective in this reaction.

The /?-N'-benzoylhydrazino esters were readily converted into a variety of N-containing compounds. Reductive cleavage of the nitrogen-nitrogen bond of the hydrazino compounds was successfully conducted by use of Raney Ni under a H2 atmosphere [ 141 to afford the /?-amino esters. Cyclization of P-N'-benzoylhydrazino esters was conducted under basic conditions; p-lactams were obtained by treatment with nBuLi at -78 "C, whereas pyrazolones were produced in the presence of NaOMe in MeOH at room temperature or under reflux (Sch. 4).

, v R20R3R 4

A'

0

N-NH

NaOMe, O2 D

R

0

'

V

O

'R R3

Scheme 4. Conversion to p-amino esters, pyrazolones, and p-lactams.

It was also found that in the presence of a catalytic amount of Sc(OTf)3 benzoylhydrazones reacted with tetraallyltin to afford the corresponding homoallylic hydrazines; these were readily converted to homoallylic amines. Three-component reactions of aldehydes, benzoylhydrazine, and tetraallyltin also proceeded smoothly in the presence of a catalytic amount of Sc(OTf), [El.

19.2.5 Friedel-Crafts Acylation and Fries Rearrangement Friedel-Crafts acylation reactions are fundamental and important processes in organic synthesis and in the chemical industry [16]. In these reactions more than a stoichiometric amount of a Lewis acid such as AIC13 or BF3.OEt2 is needed, because

888

Kohayashi

of the consumption of the Lewis acid by coordination to products (aromatic ketones). It has been found that a small amount of Sc(OTf), catalyzed Friedel-Crafts acylation reactions effectively [17]. The catalytic activity of Sc(OTf)3 was found to be much greater than that of Ln(OTf), (Eq. 5). Although acylation of benzene or chlorobenzene did not occur, introduction of an electron-donating group effectively promoted the acylation. For example, in the acetylation of thioanisole, o- or m-dimethoxybenzene gave a single acetylated product in an excellent yield. Benzoylation of anisole also proceeded smoothly in the presence of a catalytic amount of Sc(OTf)3. Although both benzoic anhydride and benzoyl chloride were effective in the reactions, benzoic anhydride resulted in a slightly higher yield of 4-methoxybenzophenone. In each reaction formation of the other isomers was not detected by GLC. Also in this reaction, Sc(OTf), could be easily recovered from aqueous layers and re-used. It was also found that addition of lithium perchlorate (LiC104) as a co-catalyst improved yields dramatically [IS]. This novel Sc(OTf),-catalyzed Friedel-Crafts acylation reaction has advantages over the conventional AlC13-promoted reaction. cat. M(OT03

*

Ac~O

CH~NOI,50 "C,4 h

MeO+Ac

-

M = Sc : 89% Yb : 55% Y : 28%

The Fries rearrangement of acyloxybenzene or naphthalene derivatives proceeds smoothly in the presence of a catalytic amount of Sc(OTf), (Eq. 6) [19]. It has also been found that the triflate was an efficient catalyst in 2-acylation (direct acylation) reactions of phenol or naphthol derivatives with acid chlorides. Both reactions were successfully conducted by use of a small amount of Sc(OTf)3. +

RCOCl

or

cat. Sc(OTO1

0

{$ 19.2.6 Diels-Alder Reactions The Diels-Alder reaction is one of the most useful synthetic means of preparing cyclic compounds. Although many Diels-Alder reactions have been conducted at high reaction temperatures without catalysts, heat-sensitive compounds cannot be employed in complex multistep syntheses. The Diels-Alder reaction is, furthermore, reversible, and the lowest possible temperatures are generally used. Although Lewis acid catalysts enable the reactions to proceed at room temperature, or below, with satisfactory yields, they are often accompanied by diene polymerization and excess amounts of the catalyst are often needed for catalysis of reactions involving carbonyl-containing dienophiles [20].

Sc(III) Lewis Acids

889

Table 2. Sc(OTf)3-catalyzedDiels-Alder reactions.a

Entrv

Diene

Majorproduct

Yield/% b,

endo/exoC)

1

Q

95

87:13

2

0

89

1oo:o

3

h

90

-

4

H

86

-

97

84:16

96

89:ll

0

83

>95: 5

8

h

91

-

9

H

88

-

10

Q

83

1OO:O

11

0

89

94:6

12

H

92

-

5

6

7

a

DienoDhile

Q Q

Reaction conditions: 10 mol % Sc(OTf)3, CH2C12,0 "C. Isolated yield. Determined by 'H andlor I3C NMR.

Lanthanide triflates are also efficient catalysts in some Diels-Alder reactions, and Sc(OTf), is clearly more effective than Ln(OTf), as a catalyst [21]. In the presence of 10 mol YOY(OTf)3 or Yb(OTf)3, only a trace amount of the adduct was obtained in the Diels-Alder reaction of methyl vinyl ketone (MVK) with isoprene. The reaction proceeded smoothly, however, giving the adduct in 91 % yield in the presence of 10 mol YOSc(OTf)3 [21a]. Several examples of the Sc(OTf)3-catalyzed Diels-Alder reactions are shown in Table 2. The Diels-Alder adducts are always obtained in high yield with high endo selectivity.

890

Kobuyashi

19.2.7 Aza Diels-Alder Reactions The Diels-Alder reactions of imines (aza Diels-Alder reactions, imino Diels-Alder reactions) are recognized as being among the most useful synthetic tools for the preparation of nitrogen-containing six-membered heterocycles [22]. Although Lewis acids often promote these reactions, more than stoichiometric amounts of the acids are needed because of the strong coordination of the acids to nitrogen atoms [22]. Sc(OTf), has proved to be an efficient catalyst in these reactions. In the presence of 10 mol YOSc(OTf)3, N-benzylideneaniline reacts with 2-truns-lmethoxy-3-trimethylsiloxy-1,3-butadiene (Danishefsky’s diene) [23] to afford the corresponding aza Diels-Alder adduct, a tetrahydropyridine derivative, quantitatively (Eq. 7) [24]. In the reaction of N-benzylideneaniline with cyclopentadiene under the same conditions, on the other hand, the reaction course changed and a tetrahydroquinoline derivative was obtained (Eq. 8). In this reaction, the imine acted as an azadiene toward one of the double bonds of cyclopentadiene as a dienophile 1251. In the reaction with 2,3-dimethylbutadiene a mixture of tetrahydropyridine and tetrahydroquinoline derivatives was obtained. A vinyl sulfide, a vinyl ether, and a silyl enol ether worked well as dienophiles to afford the tetrahydroquinoline derivatives in high yields [26,27]. cat. Sc(OT03

(7)

CH3CN. rt Ph

One synthetic problem in aza Diels-Alder reactions is the stability of imines under the influence of Lewis acids. It is desirable that the Lewis acid-activated imines are immediately trapped by dienes or dienophiles. In 1989, Sisko and Weinreb reported a convenient procedure for the aza Diels-Alder reaction of an aldehyde, a Id-diene, and N-sulfinyl p-toluenesulfonamide via N-sulfonyl imine produced in situ- a stoichiometric amount of BF3. OEt, was used as a promoter [28a]. Sc(OTf),-catalyzed three-component coupling reactions of aldehydes, amines, and dienes have been examined. In the presence of 10 mol % Sc(OTf), and magnesium sulfate, benzaldehyde was treated with aniline and Danishefsky’s diene. The desired three-component reaction proceeded smoothly to afford the corresponding tetrahydropyridine derivative in 83 ‘TO yield (Eq. 9) [24b]. Under the same reaction conditions, cyclopentadiene was used instead of Danishefsky’s diene to afford the corresponding tetrahydroquinoline derivative (Eq. lo). Different combinations of aldehydes, amines, and alkenes are possible in these reactions, and afford diverse tetrahydroquinoline derivatives in high yields. OSiMe

PhCHO

+ H2N

cat. Sc(OTfl3, MgS04CHjCN, rt 83%

(9) Ph

0

Sc(lI1) Lewis Acids

PhCHO

891

cat. Sc(OTf),

+

CH,CN,

H2N

rt

H

The three component coupling reactions also proceed smoothly in aqueous solution, and commercial aqueous formaldehyde solution can also be used directly (Eq. 11).

HCHOaq.

+

0‘‘ 0

cat. Sc(OTQ3

+

(11)

H~OEtOWTol(1/9/4), rt

H2N

90%

H

A possible mechanism of these reactions is shown in Sch. 5 [24b]. It should be noted that a stepwise mechanism including intermediate I1 is suggested in these types of aza Diels-Alder reaction [28b].

Scheme 5. Possible mechanism of the three-component coupling reaction.

19.2.8 1,3-Dipolar Cycloadditions The 1,3-dipolar cycloaddition of nitrones to alkenes is a useful route to isoxazolidine derivatives, the reductive cleavage of which furnishes a range of compounds such as phydroxy ketones, p-amino alcohols, etc. [29]. Although Lewis acids are known to promote the cycloaddition [29,30], some nitrones, especially aliphatic nitrones, are unstable under these conditions and lower yields are sometimes obtained. The threecomponent coupling reaction of benzaldehyde, N-benzylhydroxylamine, and N-phenylmaleimide proceeded smoothly in the presence of a catalytic amount of Sc(OTf)3, to afford the corresponding isoxazolidine derivative in a good yield with high diastereoselectivity (Eq. 12) [31].

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Kobayashi

endo

ex0

52%- endolexo = >99/1

19.2.9 [2 + 21-Cycloaddition Reactions of Imines with Alkynyl Sulfides a,/?-Unsaturated thioimidates are useful intermediates in organic synthesis [32]. It has been found that a new reaction of imines with alkynyl sulfides proceeds smoothly in the presence of a catalytic amount of Sc(OTf)3, affording a,P-unsaturated thioimidates [33]. These reactions are assumed to proceed via [2 + 21-cycloaddition and successive fragmentation. Thus, the [2 + 21-cycloaddition of imines to alkynyl sulfides proceeds smoothly to form azetine intermediates, which are unstable and immediately fragment to the corresponding a,p-unsaturated thioimidates (Eq. 13).

19.2.10 Asymmetric Catalysis 19.2.1 0.1 Asymmetric Diels-Alder Reactions Efficient asymmetric Diels-Alder reactions catalyzed by chiral Lewis acids have recently been reported [34]. Although rare earth compounds were expected to be promising Lewis acid reagents, few asymmetric reactions catalyzed by chiral rare earth Lewis acids were reported [35], although rare earth triflates, especially Yb(OTf)3 and S C ( O T ~ are )~, good catalysts in the Diels-Alder reactions of a variety of dienophiles with cyclic and acyclic dienes (as mentioned in Section 19.2.6). It was first found that a chiral Yb catalyst, prepared in situ from Yb(OTf)3 , (R)(+)-1,l'-bi-2-naphthol [(R)-BINOL], and a tertiary amine, in dichloromethane, was quite effective in enantioselective Diels-Alder reactions [36]. Some additives were also found to be effective not only in stabilizing the catalyst but also in controlling enantiofacial selectivity in the Diels-Alder reaction. When 3-acetyl-1,3-oxazolidin-2one was combined with the chiral catalyst as an additive, the (2S,3R) form of the endo adduct was obtained in 93 YOee. When, on the other hand, 3-phenylacetylacetone was mixed with the catalyst as an additive, the (2R,3S) form of the endo adduct was obtained in 81 % ee [37]. The chiral Sc catalyst could be prepared similarly from Sc(OTf)3, (R)-BINOL, and a tertiary amine in dichloromethane (Eq. 14) [38]. The catalyst was also found to be effective in Diels-Alder reactions of an acrylic acid derivative with dienes (Table 3). The amines employed in the preparation of the catalyst had a large influence on enantioselectivity. The highest enantioselectivity was observed when cis-l,2,6-trimethylpiperidine was employed as the amine. It should be noted that even 3 mol %o of the catalyst was enough to complete the reaction yielding the endo adduct with 92 YOee.

Sc(IZI) Lewis Acids

1.2 eq

893

WOH (14) *

Sc(OT1)s

MS4A

2.4 eq. amine

+

"chiralSc triflate"

0 "C, 30 min

Table 3. Enantioselective Diels-Alder reactions with a chirai scandium catalyst.

R

Me

Catalyst/mol%

Yield/%

endo/exo

20

94

8911 1

eel% (endo) 92 (2S, 3 R )

10

84 84

86/14 87/13

96 (2S, 3R) 93 (2S, 3R)

5

It was found that 3-acetyl-l,3-oxazolin-2-one or 3-benzoyl-1,3-oxazolin-2-one was a good additive for stabilization of the chiral Sc catalyst, but that enantioselectivity could not be reversed by use of additives, behaviour different from that of the chiral Yb catalyst. This can be explained by the coordination number of Sc(II1) and Yb(II1) -whereas Sc(II1) has up to seven ligands, specific coordination numbers of Yb(II1) enable up to twelve [39]. The structure in Sch. 6 was postulated for the chiral Sc catalyst [40]. The unique structure was in accord with I3C NMR and IR spectra. The most characteristic aspect of the catalyst was the presence of hydrogen-bonds between the phenolic hydrogens of binaphthol and the nitrogens of the tertiary amines. The coordination of this catalyst might be similar to that of the lanthanide(II1)-water or -alcohol complex. It should be noted that the structure is quite different from those of conventional chiral Lewis acids based on aluminum [41], boron [42], or titanium [43].In this chiral catalyst, the axial chirality of (R)-BINOL is transferred through the hydrogen-bonds to the amine parts, which shield one side of the dienophile effectively. This is consistent with experimental results showing that amines employed in the preparation of the chiral catalysts strongly influence selectivity and that use of bulky amines results in better selectivity.

894

Kobayashi

Scheme 6. Chiral scandium catalysts.

The sense of asymmetric induction in chiral Sc(II1)-catalyzed reactions can be rationalized by assuming an intermediate octahedral Sc(II1)-dienophile complex (Sch. 7). The axial chirality of (R)-BINOL is transferred to the amine, the re face of the acyl-1,3-oxazolidin-2-one is effectively shielded by the amine part, and a diene approaches the dienophile from the si face to afford the adduct with a high enantioselectivity. A

@

diene Scheme 7. Assumed transition state.

Because the amine part can be freely selected, the design of efficient catalyst systems is easier than for catalysts based on (R)-BINOL.

19.2.10.2 AsymmetricA z a Diels-Alder Reactions Although asymmetric versions of aza Diels-Alder reactions using chiral auxiliaries have been reported, only one example uses a stoichiometric amount of a chiral Lewis acid [44]. The first reported example of a catalytic enantioselective aza Diels-Alder reaction employed a chiral lanthanide catalyst [45]. A chiral ytterbium or scandium catalyst, prepared from Yb(OTf), or Sc(OTf), , (R)-BINOL, and DBU, is effective in the enantioselective aza Diels-Alder reactions. The reaction of N-alkylidene- or N arylidene-2-hydroxyaniline with cyclopentadiene proceeded in the presence of the chiral catalyst and 2,6-di-tert-butyl-4-methylpyridine (DTBMP) to afford the corresponding 8-hydroxyquinoline derivatives in good to high yields with good to excellent diastereo- and enantioselectivity (Eq. 15).

Sc(I1I) Lewis Acids

dH

Q

cat. C h i d Sc Complex DTBMP * MS4A, CHzCIz, -15 "C

%

895

HO 58%

DTBMP = 2,6-Di-f-butyl-4-methylpifidine

cis/fruns>99/1 73% ee (cis)

19.2.10.3 Asymmetric 1,3-Dipolar Cycloaddition Reactions Catalytic asymmetric 1,3-dipolar cycloaddition of a nitrone with a dipolarophile has been performed using a chiral scandium catalyst [31]. The chiral catalyst, which was effective in asymmetric Diels-Alder reactions, was readily prepared from Sc(OTf)3, (R)-(+)-BINOL, and cis-1,2,6-trimethylpiperidine. The reaction of benzylbenzylideneamine N-oxide with 3-(2-butenoyl)-1,3-oxazolidin-2-one was performed in the presence of the chiral catalyst to yield the desired isoxazolidine in 69 % ee with perfect diastereoselectivity (endolexo = > 99:l) (Sch. 8) [31,46]. It was found that reverse enantioselectivity was observed when a chiral Yb catalyst, prepared from Yb(OTf)3, the same (R)-(+)-BINOL, and cis-1,2,6-trimethylpiperidine, was used instead of the Sc catalyst under the same reaction conditions. chiral Yb catalyst (20 mol%)

MS4A, CHIC12 ri, 20 h -O.N+Bn PhKH

0

+

OUN

78% ee (3s.4R,5.9

0

& A chiral (20Sc mol%) catalyst

MS4A. CHzCli rt, 20 h

chiral Ln catalyst: Ln(OTf),

+

-

B n N q N p pN.**

31: ,(&

O O 69% ee (SR,4S, 5R)

Scheme 8. Asymmetric 1,3-dipolar cycloaddition. Synthesis of both enantiomers by use of the same chiral source and a choice of lanthanides.

19.2.11 Miscellaneous Reactions Sc(OTf)3 also catalyzes acetalization reactions [47a,b],acylal formation [47c], p-selective glycosilation reactions with thioglycosides [48], and acylation reactions of alcohols [49]. Guanidium formation reactions of carbodiimide with benzylamine [SO], intermolecular stereoselective radical additions to N-enoyloxazolidinones [Sl], and rearrangement of

896

Kobayashi

epoxides [52] have also been reported. Some elimination reactions such as decarbonylation of aromatic aldehydes [53] and dehydration reactions of aldoximes to nitriles [54] proceed in the presence of Sc(OTf)3. Finally, nitration of simple aromatic compounds [55], alkylation of hydroquinone with allylic alcohols [56a] or 1,3-diene [56b], Friedel-Crafts alkylation reactions [57],and ene reaction [58], etc., are also recent topics investigated using Sc(OTf), as a Lewis acid catalyst.

19.3 Reactions in Aqueous Media 19.3.1 Aldol Reactions The importance of aqueous reactions is now generally recognized, and development of carbon-carbon bond-forming reactions that can be performed in aqueous media is now one of the most challenging topics in organic synthesis [59]. It has been found that Sc(OTf)3 was effective in aldol reactions of silyl enolates with aldehydes in aqueous media (water-THF; Eq. 16) [4]. Reaction between aromatic and aliphatic aldehydes such as benzaldehyde and 3-phenylpropionaldehyde and silyl enolates have been performed successfully in aqueous solvents. In addition, direct treatment of aqueous solutions of water-soluble formaldehyde and chloroacetaldehyde with silyl enolates affords the corresponding aldol adducts in good yields. Water-sensitive silyl enolates could be used in aqueous solutions with Sc(OTf), as catalyst.

Sc(OTf)3-catalyzed aldol reactions of silyl enol ethers with aldehydes have recently been successfully performed in micellar systems [60]. Although the reaction proceeded sluggishly in water (without organic solvents), reactivity was remarkably enhanced by the presence of a small amount of a surfactant. In these systems, versatile carbon-carbon bond-forming reactions proceeded smoothly in water without the use of organic solvents. Lewis acid catalysis in micellar systems was first observed in the model reaction of the silyl enol ether of propiophenone with benzaldehyde. Although the reaction proceeded sluggishly in the presence of 0.2 equiv. (OTf)3 in water, remarkable enhancement of reactivity was observed when the reaction was conducted in the presence of 0.2 equiv. Yb(OTf)3 in an aqueous solution of sodium dodecylsulfate (SDS, 0.2 equiv., 35 mM), and the corresponding aldol adduct was obtained in 50 % yield. The yield was improved to 88 % when Sc(OTf)3 (0.1 equiv.) was used as a Lewis acid catalyst. The critical micelle concentration would suggest that micelles would be formed in these reactions. It was also found that the surfactants influenced the yield, and that Triton X-100 was effective in the aldol reaction (although a longer reaction time was required), whereas only a trace amount of the adduct was detected when cetyltrimethylammonium bromide (CTAB) was used as the surfactant. Although several organic reactions in micelles have been reported [61], this was the first report of Lewis acid catalysis in micellar systems.

Sc(III) Lewis Acids

Sc(OTf), (0.1 eq.) R'CHO

SDS (0.2eq.) *

f

40,

R2

0

897

OH

d'+R1

R3

Table 4. Sc(OTf)3-catalyzed aldol reactions in micellar systems.

Aldehyde

Silyl Enolate

PhCHO

88

Ph

HCHO

1

86 [bl

1

88 IC1

1

82 Id]

88 Iel

PhCHO

2 PhCHO

Yield/%

re3

80 [4

75 I&hl

Ph

OSiMe, PhCHO

94

EtS *

OSiMe3 PhCHO

a

Me+

84 [hl

synlanti = 50:50. synianti = 4 5 : ~ ~ . synJanti = 4159.

Commercially available HCHO aq. (3 mL), 1 (0.5 mmol), Sc(OTf)3 (0.1 mmol), and SDS (0.1 mmol) were combined. ' synlanti = 51:43. synianti = 69:31. Sc(OTf)? (0.2 equiv.) was used. More silyl enolate (1 .5 equiv.) was added after 6 h.

'

Several examples of Sc(OTf)3-catalyzed aldol reactions in micellar systems are shown in Table 4. Not only aromatic, but also aliphatic and a,P-unsaturated aldehydes react with silyl enol ethers to afford the corresponding aldol adducts in high yields. Aqueous formaldehyde solution also worked well. Even the ketene silyl acetals, which readily hydrolyze in the presence of a small amount of water, reacted with aldehydes

898

Kobayashi

in the present micellar systems to afford the corresponding aldol adducts in high yields. It should be noted that work-up procedures including phase separation are easy because only a small amount of the surfactant was used.

19.3.2 Allylation Reactions Synthesis of homoallylic alcohols by reaction of ally1 organometallics with carbonyl compounds is one of the most important processes in organic synthesis [62]. Allylation reactions of carbonyl compounds with tetraallyltin [62,63] proceeded smoothly under the influence of a catalytic amount of Sc(OTf), [64] to afford the adducts, homoallylic alcohols, in high yields under extremely mild conditions [65]. The reactions were usually performed successfully in aqueous media (Eq. 17). It is noteworthy that unprotected sugars reacted directly to give the adducts in high yields (Eq. IS). The allylated adducts are intermediates in the synthesis of higher sugars [66]. The allylation reactions of aldehydes with tetraallyltin also proceeded smoothly in micellar systems with Sc(OTf), as a catalyst [67]. No organic solvents were used in these reactions.

Three-component reactions of aldehydes, amines, and allyltributyltin also proceeded smoothly in micellar systems with Sc(OTf), as Lewis acid catalyst, to afford the corresponding homoallylic amines in high yields (Eq. 19) [68]. Not only aromatic aldehydes but also aliphatic, unsaturated, and heterocyclic aldehydes worked well. The procedure is very simple-merely mixing an aldehyde, an amine, and allyltributyltin in the presence of Sc(OTf)3 and SDS in water; no homoallylic alcohol (an adduct between an aldehyde and allyltributyltin) was produced. It was suggested that imine formation from aldehydes and amines was very fast under these conditions, and that the selective activation of imines rather than aldehydes was achieved. N PhKH

DR

+

Q

cat. CH,CN, Sc(OTf), rt *

(19)

R&h; H

It is noteworthy that the use of the recoverable scandium catalyst and water as the solvent would result in clean and environmentally friendly systems.

&(Ill) Lewis Acids

899

19.3.3 Mannich-Type Reactions Mannich-type reactions of aldehydes, amines, and vinyl ethers proceeded smoothly in the presence of a catalytic amount of Sc(OTf)3 in aqueous media (Eq. 20) [69]. Commercially available aqueous solutions of formaldehyde and chloroacetaldehyde were used directly and the corresponding /3-amino ketones were obtained in good yields. Phenylglyoxal monohydrate, methyl glyoxylate, an aliphatic aldehyde, and an a$unsaturated aldehyde also worked well to give the corresponding p-amino esters in high yields. Sc(OTf), (0.2 eq.) SDS (0.2 eq.) R’CHO

+

R~NH~ +

(20)

*

/~SnBu3

HzO,rt, 20 h

R’

It was recently found that three-component coupling reactions of aldehydes, amines, and silyl enolates proceeded smoothly in micellar systems with Sc(OTf)3 as catalyst [70]. In a typical procedure, the amine and 1-phenyl-1-trimethylsiloxyethene were combined in the presence of Sc(OTf), (5 mol %) in 35 mM SDS, and the aldehyde was then added. The reaction proceeded smoothly at room temperature to afford the corresponding p-amino ketone derivative in 87 % yield. It is reported that the dehydration (imine formation) and the coupling of two water-unstable substrates, OSiMe3

Sc(OTf), (0.05 eq.)

R ~ C H O+ eMeOC6H4NH2 + R3+R2

H20, SDS (0.2 eq.) rt, 2-5 h

R4

-

eMeOC6H4.

NH 0

Table 5. Mannich-type reactions in water.

R‘ Ph Ph Ph 2-fury1 PhCO PhCH=CH i-Bu Ph(CH2)Z c-C6H I 1

Ph 2-fury1 PhCO PhCH=CH i-Bu Ph Ph

R2 Ph Ph Ph Ph Ph Ph Ph Ph Ph Me0 Me0 Me0 Me0 Me0 EtS EtS

R3

R4

Yield/%

H H H H H H

H H H H H H H H H Me Me Me Me Me H H

87 goa 8.9

H H H Me Me Me Me Me H Me

Yb(OTf)3 (0.05 equiv.) was used insted of Sc(OTf)3. Cu(OTf), (0.05 equiv.) was used instead of Sc(OTf)3. ‘ Catalyst (0.1 equiv.). a

8Y

83 74c 72 75

79C3d 73 80 67 64 68 85 0°C. synianti

=

3.0:1 [14].

900

Kobayashi

the imine and the silyl enol ether, occurred successfully in water. Only a trace amount of the product was obtained without SDS under the same reaction conditions. No side-reaction adducts, for example deamination and aldol products, were obtained. It is reported that similar reactions performed in organic solvents sometimes resulted in the formation of deamination products. Other examples, and the results obtained, are summarized in Table 5. Aromatic aldehydes and heterocyclic, a,/?-unsaturated, aliphatic aldehydes, and a glyoxal worked well, affording the desired adducts in high yields. It is worthy of note that different types of aliphatic aldehyde reacted smoothly to give the corresponding p-amino ketone derivatives in high yields. For silyl enolates, not only ketone-derived silyl enol ethers but also thioester- and ester-derived ketene silyl acetals worked well. The products were readily converted to free p-amino ketones and esters. Thus, treatment of the products with cerium ammonium nitrate in acetonitrile-water (9:l) at room temperature induced smooth deprotection of the 2-methoxyphenylamino group to give free p-amino carbonyl compounds [71,72].

19.3.4 Strecker Reactions Strecker reactions are among the most efficient methods of synthesis of a-amino nitriles, useful intermediates in the synthesis of amino acids [73] and nitrogen-containing heterocycles such as thiadiazoles, imidazoles, etc. [74]. Although classical Strecker reactions have some limitations, use of trimethylsilyl cyanide (TMSCN) as a source of cyano anion provides promising and safer routes to these compounds [73b,75]. TMSCN is, however, readily hydrolyzed in the presence of water, and it is necessary to perform the reactions under strictly anhydrous conditions. Bu3SnCN [76], on the other hand, is stable in water and a potential source of cyano anion, and it has been found that Strecker-type reactions of aldehydes, amines, and Bu3SnCN proceed smoothly in the presence of a catalytic amount of Sc(OTf)3 in water [77]. No surfactant was needed in this reaction. The reaction was assumed to proceed via imine formation and successive cyanation (it was confirmed that imine formation was much faster than cyanohydrin ether formation under these reaction conditions); again the dehydration process (imine formation) proceeded smoothly in water. Several examples of the Strecker-type reaction were tested. For all the compounds investigated, including aromatic, aliphatic, heterocyclic, and a$-unsaturated aldehydes, the reactions proceeded smoothly to afford the corresponding a-amino nitriles in high yield. The adducts, a-(N-benzhydry1)amino nitriles, were readily converted to a-amino acids [78], and Strecker-type reactions using other amines such as aniline and benzylamine also proceeded smoothly to afford the corresponding adducts in high yields. Although the Strecker reaction proceeded smoothly, it was thought that use of the toxic tin reagent might restrict the application of the reaction [79] and attempts were made to recover tin materials after the reaction (Sch. 9). The Strecker-type reaction was performed using equimolar amounts of an aldehyde and an amine, and a slight excess of Bu3SnCN. When the reaction was complete excess Bu3SnCN was treated with a weak acid to form bis(tributy1tin) oxide [SO] whereas the adduct a-(N-tributyltin)amino nitrile (111), was hydrolyzed by addition of water to produce a-amino nitrile IV and tributyltin hydroxide, that was readily converted to bis(tributy1tin) oxide [SO]. Thus, all the tin was converted to bis(tributy1tin) oxide, which could be recovered quantitatively by simple extraction. It has already been reported that bis(tributy1tin)

Sc(III) Lewis Acids

901

oxide can be converted to tributyltin chloride [81] and then to Bu3SnCN. Because the catalyst, Sc(OTf)3, is also recoverable and reusable, these Strecker-type reactions constitute a completely recyclable system. In addition to the excellent properties of Sc(OTf), as a catalyst, complete recovery of the tin materials in these reactions should be noted. Although many useful tin reagents have been developed, their toxicity has sometimes limited their use in organic synthesis. This present method provides a solution to this problem, resulting in an environmentally-friendly chemical processes.

n

reusable

R'CHO +

R~NH'

Sc(OTf),

*

+ Bu3SnCN

Bu3Sn,

NR'

R A N

111

\Ref. 76 Bu3SnCI

Scheme 9. Recycle system of the novel Strecker-type reaction.

19.3.5 Diels-Alder Reactions Even these proceeded in aqueous media [82]. Thus, naphthoquinone reacted with cyclopentadiene in THF-H20 (9:1) at room temperature to give the corresponding adduct in a 93 % yield (enddexo = lO0:O) (Eq. 21).

19.4 Reactions in the Solid Phase 19.4.1 Aldol Reactions Using Polymer-Supported Silyl Enol Ethers Silyl enol ethers are versatile reagents in organic synthesis [83].They are used as isolable enolate equivalents and many useful reactions have been developed using silyl enol ethers [83]. As a new approach to exploit an efficient method for combinatorial synthesis [84], silyl enol ethers were successfully immobilized on to a polymer. Polymer-supported silyl enol ethers (PSSEEs) were prepared according to Sch. 10 [85]. In aldol reactions of PSSEEs with aldehydes, it was again found that Sc(OTf), was an efficient catalyst [86]. An example of the preparation of a 1,3-diol library by use of PSSEEs is shown in Sch. 11. In all cases, the reactions proceeded smoothly to afford the corresponding 1,3-diols in good yields. 1,3-Diols are successfully cleaved from the

902

Kobayashi

support by treatment with LiBH4, and it is also possible to produce P-hydroxy aldehydes or P-hydroxy carboxylic acids directly by use of appropriate cleavage procedures (Sch. 12).

PC'

SH

Scheme 10. Synthesis of polymer-supported silyl enol ethers

Sc(ll1) Lewis Acids

PSH 4

I . R'COCI; 2. TMSOTf/Et3N S

I

c

J S

OSiMe3 &OBn

1 . R2CH0, Sc(OTf), (20 mol%) 2. LiBH4

&aI

1

a

PhCHO

82%

a

d ph&CHo

PhCHO

55 %

d ph&CHo

56 %

77%

Scheme 11. 1,3-Diol libraries based on aldol reactions.

/

DIBALH * -78 "C, 19 h

H

v

P

h

CH2C12,

\lN NaOH-Dioxane (1:4)* 100 "C,6 h

73% (based on 4)

H O v P h

59% (based on 4) Scheme 12. Conversion to /?I-hydroxy aldehyde or P-hydroxy carboxylic acid.

903

904

Kobayashi

19.4.2 Mannich-Type Reactions Using PSSEE PSSEEs react with imines in the presence of a Lewis acid to afford /3-amino thioesters, which can be reduced to give amino alcohols (Table 6) [%a]. In this reaction, although typical Lewis acids such as TiC14, SnC14, and BF3. OEt, gave poor results, a catalytic amount of Sc(OTf)3 or Hf(OTf)4 gave better results. This process provides a convenient method for the construction of an amino alcohol library.

N

S

PhK

Lewis acid H

S

L.

CH2C12, rt, 20 h

LiBH4 P

Et,O, rt

HO

Table 6. Effect of Lewis acids. Lewis acid (mol %)

Yield (%)

Lewis acid (mol %)

Yield (YO)

S K I 4 (100)

2

Zr(OTf)4 (10)

23

TiC1, (100)

3

Hf(OTf)4 (10)

70

BF3.OEt2 (100)

10

SII(OT~)~ (10)

40

Sc(OTf)3 (10)

65

TMSOTf (1 0)

47

In the solid phase, Sc(OTf)3 also effectively catalyzed Mannich-type three-component reactions of aldehydes, amines, and PSSEEs to afford polymer-supported pamino thioesters (Eq. 22). Reductive cleavage from the supports gave the amino alcohols in good to high yields [85b]. ,&Amino acid and p-lactam libraries are also constructed according by this method (Eq. 23).

Sc(OT03(10 mol%)

THF : HZO (9: 1) 0

93% yield, endolexo = 100/0

*

0

(22)

Sc(III) Lewis Acids

905

19.4.3 Michael Reactions Using PSSEE Whereas a stoichiometric amount of Tic14 was used in the original liquid-phase reactions [87], it was found that a catalytic amount of Sc(OTf)3 was effective in solidphase Michael reactions of PSSEEs with a,P-unsaturated ketones [@]. Whereas the 1,5-dicarbonyl compound was obtained in 38 YOyield in the model reaction of PSSEE 5 with chalcone and a stoichiometric amount of TiC14, the yield was improved to 93 YO by use of 20 mol YOSc(OTf)3 as a catalyst in the same reaction. In addition to improvement of the yield, it should be noted that after the reaction Sc(OTf)3 was readily removed from the product resins by filtration because it is soluble in water; the insoluble titanium residue which appeared after quenching the reaction by addition of water in the TiC14-mediated reaction was often difficult to remove and would contaminate the product resins. Several examples of the Michael reactions on solid phases are shown in Table 7. Not only acyclic but also cyclic a$-unsaturated ketones reacted smoothly with PSSEEs to afford the corresponding adducts in high yields.

19.4.4 Aldol-Type Reactions Using PSSEE Aldol-type reactions of PSSEEs with acetals have been successfully performed using S C ( O T ~as ) ~a catalyst (Eq. 24) [SS]. The reactions were performed at room temperature and the adducts were cleaved from the polymer supports by use of LiBH4 to give 1,3-diolmonoethers. The SR-MAS NMR technique was als$ usi&#h effect in the 1. NaOMeMeOH-THF development the reactions. 2. HZO

(24) PMP = p-MeOPh

CHzClz-acetone 74%

19.5 Conclusions Sc(III), especially Sc(OTf)3, is a new type of a Lewis acid that is different from typical Lewis acids such as A1C13, BF3, SnCI4, etc. Whereas most Lewis acids are decomposed or deactivated in the presence of water, Sc(OTf), is stable and works as a Lewis acid in aqueous solutions. S C ( O T ~is) ~also an excellent Lewis acid catalyst in organic solvents. Many nitrogen-containing compounds such as imines and hydrazones are successfully activated by use of a small amount of Sc(OTf)3. A catalytic amount of Sc(OTf)3 is usually enough to complete reactions, and Sc(OTf)3 can be recovered for re-use when reactions are complete. Whereas lanthanide triflates [Lr1(0Tf)~]have similar properties, the catalytic activity of Sc(OTf), is occasionally greater than that of LII(OT~)~. Whereas Ln(OTf), can have nine to twelve ligands, Sc(OTf)3 can have up seven and its ionic radius is smaller than those of the lanthanides. Use of Sc(OTf)3 catalysis in micellar systems is a clean and environmentally friendly process, and will become more important in the future. Several solid-phase organic reactions have been successfully performed with S C ( O T ~as) ~catalyst.

906

Kobayashi

0

OSiR

S

+

$

d

R

3

Sc(OTf), (20 mol%)

>-

H20

CHzC12, -78 "C, 20 h

6

a l ) NaOMe (10 eq.),THF-MeOH (4: 1); 2) IRC-76; 3) Me3SiC1, MeOH Table 7. Michael reactions of PSSEE with aB-unsaturated ketones.

Entry

PSSEE

a,p-Unsaturated Ketone

S

XBuMe2 5ab

6a

Phdfh '

AA

5a

A

P

h

8

5a

8

5a OSiMe3

91

87

Ph

5a

Yield/%

6b

80

83

81

6a

60

6b

75

5cd

6a

64

5de

6a

48

5b OSiMe3

S

AN OSiMe3

S

0.94 mmol g-'. 0.88 mmol g-I. 0.96 mmol 8'. 0.76 mmol g-'.

A

Sc(1II) Lewis Acids

907

Acknowledgments Our work in this area was partially supported by CREST, Japan Science and Technology Corporation (JST), and a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture, Japan. The author thanks and expresses his deep gratitude to his coworkers whose names appear in the references. D r Hidekazu Oyamada and Yuri Nakasugi are also acknowledged for their contribution to the preparation of this article.

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908

22. 23. 24. 25. 26.

27.

28. 29. 30.

31. 32. 33. 34.

35.

36. 37.

38. 39. 40. 41. 42.

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Hagihara, Tetrahedron Lett. 1967, 41994200. (b) L. S. Povarov, Russian Chem. Rev. 1967, 36, 656; Usp. Khim. 1967, 36, 1533-1562. (c) D. F. Worth, S. C. Perricine, E. F. Elslager, J. Heterocycl. Chem. 1970, 7, 1353-1356. (d) T. Kametani, H. Takeda, Y. Suzuki, H. Kasai, T. Honda, Heterocycles 1986,24,3385-3395. (e) Y. S. Cheng, E. Ho, P. S. Mariano, H. L. Ammon, J. Org. Chem. 1985,50,5678-5686, and references cited therein. For the reactions of vinyl sulfides, see: (f) K. Narasaka, T. Shibata, Heterocycles 1993,35,1039-1053. Fujiwara et al. reported a similar type of reaction: Y. Makioka, T. Shindo, Y. Taniguchi, K. Takai, Y. Fujiwara, Synthesis 1995,801-804. (a) J. Sisko, S. M. Weinreb, Tetrahedron Lett. 1989, 30, 3037-3040. (b) Y. Nomura, M. Kimura, Y. Takeuchi, S. Tomoda, Chem. Lett. 1978,267-270. (a) R. Huisgen, R. Grashy, H. Hauck, H. Seidl, Chem. Ber. 1968,101,2043-2055. (b) J. J. Tufariello, 1,3Dipolar Cycloaddition Chemistry (Ed.: A. 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Sc(III) Lewis Acids

909

43. (a) M. T. Reetz, S. H. Kyung, C. Bolm, T. Zierke, Chem. lnd. 1986, 824825. (b) K. Mikami, M. Terada, T. Nakai,J. Am. Chem. Soc. 1990,112,3949-3954. 44. (a) K. Ishihara, M. Miyata, K. Hattori. T. Tada, H. Yamamoto, J. Am. Chem. Soc. 1994,116, 1052010524. (b) H. Waldmann, Synthesis 1994,535-551. (c) E. Borrione, M. Prato, G. Scorrano, M. Stivanello, J. Chem. Soc., Perkin Trans. 1 1989,2245-2250. 45. H. Ishitani, S. Kobayashi, Tetrahedron Left.1996,37,7357-7360. 46. S. Kobayashi, M. Kawamura, J. Am. Chem. Soc., 1998,120,5840-5841. 47. (a) K. Ishihara, Y. Karumi, M. Kubota, H. Yamamoto, Synlett 1996, 839-841. (b) S. Fukuzawa, T. Tsucihmoto, T. Hotaka, T. Hiyama, Synlett 1995, 1077-1078. (c) V. K. Aggarwal, S. Fonquerna, G. P. Vennall, Synlett 1998,849. 48. K. Fukase, I. Kinoshita, T. Kanoh, Y. Nakai, A. Hasuoka, S. Kusumoto, Tetrahedron 1996, 52, 3897-3904. 49. (a) K. Ishihara, M. Kubota, H. Kurihara, H. Yamamoto, J. Org. Chem. 1996,61,45604567. (b) A. G. M. Barrett, D. C. Braddock,% Chem. Soc. Chem. Commun. 1997,351-352. SO. N. Yamamoto, M. Isobe, Chem. Lett. 1994,2299-2302. 51. (a) M. P. Sibi, J. Ji, Angew. Chem. lnt. Ed. Engl. 1996,35, 190-192. (b) M. P. Sibi, C. P.Jasperse, J. Ji, J. A m Chem. Soc. 1995,117,10779-10780. 52. (a) M. Prein, A. Padwa, Tetrahedron Left. 1996, 37, 6981-6984. (b) H. G. Bazin, R. J. Kerns, R. J. Linhardt, Tetrahedron Lett. 1997, 38, 923-926. (c) M. Prein, P. J. Manley, A. Padwa, Tetrahedron 1997,53,7777-7794. 53. C. B. Castellani, 0. Carugo, M. Giusti, C. Leopizzi, A. Perotti, A. G. Invernizzi, G. Vidari, Tetrahedron 1996,52,11045-11052. 54. S. Fukuzawa, Y. Yamaishi, H. Furuya, K. Terao, F. Iwasaki, Tetrahedron Lett. 1997,38,7203-7206. 55. F. J. Waller, A. G. M. Barrett, D. C. Braddock, D. Ramprasad, J. Chem. Soc. Chem. Commun. 1997. 613-614. 56. (a) M. Matsui, N. Karibe, K. Hayashi, H. Yamamoto, Bull. Chem. Soc. Jpn. 1995, 68, 3569-3571. (b) M. Matsui, H. Yamamoto, Bull. Chem. Soc. Jpn. 1995,68,2663-2668. 57. (a) T. Tsuchimoto, K. Tobita, T. Hiyama, S. Fukuzawa, J. Org. Chem. 1997,62,6997-7005. (b) M. T. E. Gihani, H. Heaney, K. F. Shuhaibar, Synlett 1996,871-872. 58. V. K. Aggarwal, G. P. Vennall, P. N. Davey, C . Newman, Tetrahedron Lett. 1998,39,1997-2000. 59. (a) C. J. Li, Chem. Rev. 1993,93,2023-2035. (b) A. Lubineau, J. Ange, Y. Queneau, Synthesis 1994, 741-760. 60. S. Kobayashi, T. Wakabayashi, S. Nagayama, H. Oyamada, Tetrahedron Lett. 1997,38,45594562. 61. Judging from the amount of the surfactant used in the present case, the aldol reaction would not proceed only in micelles. (a) J. H. Fendler, E. J. Fendler, Catalysis in Micellar and Macromolecular Systems, Academic, London, 1975. (b) Mixed Surfactant Systems (Eds.: P. M. Holland, D. N. Rubingh), ACS, Washington, DC, 1992. (c) Structure and Reactivity in Aqueous Solution (Eds.: C. J. Cramer, D. G. Truhlar), ACS, Washington, DC, 1994. (d) Surfactant-Enhanced Subsurface Remediation (Eds.: D. A. Sabatini, R. C. Knox, J. H. Hanvell), ACS, Washington, DC, 1994. 62. Review: Y. Yamamoto, N. Asao, Chem. Rev. 1993,93,2207-2293. 63. For the reactions of carbonyl compounds with tetraallyltin, (a) W. G. Peet, W. Tam. J. Chem. Soc., Chem. Comrnun. 1983,853-854. (b) G. Daude, M. Pereyre, J. Organomet. Chem. 1980,190,43-52. (c) D. N. Harpp, M. Gingras, J. Am. Chem. Soc. 1988, ZIO,7737-7745. (d) S. Fukuzawa, K. Sato, T. Fujinami, S. Sakai, J. Chem. Soc., Chem. Commun. 1990,939-940. (e) A. Yanagisawa, H. Inoue, M. Morodorne, H. Yamarnoto, J. Am. Chem. Soc. 1993,115,10356-10357. 64. Sc(OTf), promoted allylation reactions of carbonyl compounds were reported. (a) Tetraallylgermanium: T. Akiyama, J. Twai, Tetrahedron Lett. 1997, 38, 853-856. (b) Allyltrimethylsilane: V. K. Aggarwal, G. P. Vennall, Tetrahedron Lett. 19%,37, 3745-3746. Sc(OTf), is also an effective catalyst for the allylation of imines with allyltributyltin. (c) C. Bellucci, P. G. Cozzi, A. Umani-Ronchi, Tetrahedron Lett. 1995,36,7289-7292. 65. I. Hachiya, S. Kobayashi, J. Org. Chem. 1993,58,6958-6960. 66. (a) W. Schmid, G. M. Whitesides, J. Am. Chem. Soc. 1991,113,66746675. (b) E. Kim, D. M. Gordon, W. Schmid, G. M. Whitesides, J. Org. Chem. 1993,58,5500-5507. 67. S. Kobayashi, T. Wakabayashi, H. Oyamada, Chem. Lett. 1997,831-832. 68. S. Kobayashi, T. Busujima, S. Nagayama,J. Chem. Soc., Chem. Commun. 1998,19-20. 69. S. Kobayashi, H. Ishitani, J. Chem. Soc., Chem. Commun. 1995,1379. 70. S. Kobayashi, T. Busujima, S. Nagayama, unpublished. 71. D. R. Kronenthal, C. Y. Han, M. K. Taylor,J. Org. Chem. 1982,47,2765-2768. 72. H. Ishitani, M. Ueno, S. Kobayashi, J. Am. Chem. Soc. 1997,119,7153-7154. 73. (a) A. Strecker,Ann. Chem. Pharm. 1850, 75,2745. (b) Y. M. Shafran, V. A. Bakulev, V. S. Mokrushin, Russian Chem. Rev. 1989,58, 148-162.

910 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84.

85. 86.

87. 88.

Kohayashi (a) L. M. Weinstock, P. Davis, B. Handelsman, R. Tull, J. Org. Chem. 1967,32,2823-2829. (b) W. L. Matier, D. A. Owens, W. T. Comer, D. Deitchman, H. C. Ferguson, R. J. Seidehamel, J. R. Young, 1 Med. Chem. 1973,16,901-908. (a) I. Ojima, S. Inaba, K. Nakatsugawa, Chem. Lett. 1975, 331-334. (b) K. Mai, G. Patil, Tetrahedron Lett. 1984,25,45834586. (c) S. Kobayashi, H. Ishitani, M. Ueno, Synlett 1997,115-116. (a) J. G. A. Luijten, G. J. M. van der Kerk, Investigations in the Field of Organotin Chemistry, Tin Research Institute, Greenford, 1955, p. 106; (b) M. Tanaka, Tetrahedron Lett. 1980,21,2959-2962; (c) S. Harusawa, R. Yoneda, Y. Omori, T. Kurihara, Tetrahedron Lett. 1987,28,41894190. S. Kobayashi, T. Busujima, S. Nagayama, J. Che. Soc., Chem. Commun. 1998,981-982. M. S. Iyer, K. M. Gigstad, N. D. Namdev, M. Lipt0n.J. Am. Chem. Soc. 1996,118.4910-4911. A. G. Davies, Organotin Chemistry, VCH, Weinheim (1997). J. M. Brown, A. C. Chapman, R. Harper, D. J. Mowthorpe, A. G. Davies, P. J. Smith,J. Chem. Soc., Dalton Trans. 1972,338-341. A. G. Davies, D. C. Kleinschmidt, P. R. Palan, S. C. Vasishtha,J. Chem. Soc. (C) 1971,3972-3976. Some Diels-Alder reactions in water without a catalyst were reported. For example, (a) D. C. Rideout, R. Breslow, J. Am. Chem. Soc. 1980, 102, 7816-7817. (b) P. A. Grieco, P. Garner, Z. He, Tetrahedron Lett. 1983,24, 1897-1900. Reviews: (a) J. K. Rasmussen, Synthesis 1977, 91-1 LO. (b) I. Fleming, Chimia, 1980, 34, 265-271. (c) P. Brownbridge, Synthesis 1983, 1-28; 85-104. (d) W. P. Weber, Silicon Reagents for Orgunic Synthesis, Springer, Berlin, 1983. (e) E. W. Colvin, Chem. Soc. Rev. 1978, 7,15-64. Reviews: (a) E. M. Gordon, R. W. Barrett, W. J. Dower, S. P. A. Fodor, M. A. Gallop, J. Med. Chent. 1994,37,1385-1401. (b) N. K. Terrett, M. Gardner, D. W. Gordon, R. J. Kobylecki, J. Steele, Tetrahedron 1995,51,8135-8173. (c) G. Lowe, Chem. Soc. Rev. 1995,37,309-317. (d) J. S. Fruchtel, G. Jung, Angew. Chem., Znt. Ed. Engl. 1996,35, 1 7 4 2 . (e) L. A. Thompson, J. A. Ellman, Chem. Rev. 1996, 96, 555-600. (f) F. Balkenhohl, C. von dem Bussche-Hiinnefeld, A. Lansky, C. Zechel, Angew. Chem., Int. Ed. Engl. 1996,35,2288-2337. (a) S. Kobayashi, I. Hachiya, S. Suzuki, M. Moriwaki, Tetrahedron Lett. 1996,37,2809-2812. (b) S. Kobayashi, M. Moriwaki, R. Akiyama, S. Suzuki, I. Hachiya, Tetrahedoon Lett. 1996,37, 77837786. S. Kobayashi, I. Hachiya, M. Yasuda, Tetrahedron Lett. 1996,37,5569-5572. K. Narasaka, K. Soai, T. Mukaiyama, Chem. Lett. 1974,1223-1224. S. Kobayashi, R. Akiyama, T. Furuta and M. Moriwaki, Molecules Online 1998,2,35-39.

Lewis Acids in Organic Synthesis Edited bv Hisashi Yamarnoto Copyright 0WILEY-VCH Verlaa GmbH.2000

20 Lanthanide Lewis Acids Catalysis Masakatsu Shibasaki, Ken-ichi Yamada, and Naoki Yoshikawa

20.1 Introduction The lanthanide group (57La-71L~)and the actinides (x9A~-1"3Lr)constitute inner transition elements. Because of their identical outer shell electron configuration (5s25p6except for La), the lanthanides often have similar properties. The stable oxidation state of lanthanides is trivalent and most lanthanide Lewis acids afford trivalent ions. It should be noted that lanthanide metals (Ln(O)), divalent ions (Ln(I1)) and tetravalent ions (Ln(1V)) are also used for organic reactions such as reduction and oxidation. Lanthanide ions are characterized by hard Lewis acidity and therefore have strong affinity toward hard Lewis bases such as nitrogen or oxygen containing ligands. In addition, lanthanide Lewis acids have several characteristic features which are not observed for traditional Lewis acids. Much attention has recently been devoted to this field. This review focuses on the use of achiral and chiral lanthanide Lewis acids in organic chemistry [11.

20.2 Achiral Catalysis by Lanthanide Lewis Acids 20.2.1 Lanthanide Triflate-Promoted Reactions in Aqueous Media [2] Lanthanide (Ln) catalysts are characterized by their tolerance to water. Generally, water is a poison for common Lewis acids. In 1991, Kobayashi et al. found that ytterbium(II1) triflate, Yb(OTf)3, was an efficient catalyst of Mukaiyama aldol reactions in aqueous tetrahydrofuran (THF) (Table 1) [3]. Neodymium triflate, Nd(OTf)3, gadolinium triflate, Gd(OTf)3 and lutetium triflate, Lu(OTf)3 also catalyzed the reaction efficiently, although yields were low for lanthanum (La), praseodyum (Pr) and thulium (Tm). The use of Ln catalysts enabled the use of aqueous solutions of aldehydes (e.g. formalin, entry 5 ) or hydrate of aldehydes (entry 9) for aldol reactions. The products were usually obtained in good yields, although the diastereoselectivities reported were modest. It is worthy of note that aldehydes containing a hydroxy group (entry 10) or pyridine ring (entry 11), which strongly coordinate to Lewis acids and thereby deactivate them, could be also used. The reaction is limited to silyl enol ethers derived from ketones and thioesters, and the desired products were not obtained from silyl enol ethers derived from esters, owing to hydrolysis of the enol ethers. Feringa et al. developed aqueous Michael reactions catalyzed by Yb(OTf)3 (Eq. 1) [4]. P-keto esters and a-nitro esters could be used as Michael donors for the reaction. a,/i?-Unsaturated ketones and a,/i?-unsaturated aldehydes without /i?-substituents were good Michael acceptors for the reaction but the reaction did not proceed with ethyl acrylate or acrylonitrile. The reported yields were excellent, though the reaction required prolonged reaction time (3-5 days).

912

Shibasaki/Yamada/Yoshikawa

Table 1

R’CHO

+

R2&R3

entry

OH 0

Ln(OTf), (10 rnol%)

OSiMe3

H20-THF, rt

* R ’ V R 2

R3

silyl enol ether

aldehyde

Ln

yield (%) (sydantq

Yb

91 (73/27)

Yb

89 (63/37)

OSiMe3

1

PhCHO 1

2

1

3

1

4

1

5

HCHO aq.

6

6

OSiMe3

qe3 Yb

93 (73/29)

Yb

81 (53147)

2

Yb

94

CH3CHO

2

Gd

93 (46/54)

7

+CHO

2

Gd

82 (60/40)

8

CI-CHO

2

Yb

95 (45/55)

2

Yb

67 (27/73)

2

Lu

81 (55/45)

2

Lu

87 (42/58)

OSiMe3

Ph&

2

0 9 PhKCHO.H

2 0

10

11 QCHO

EWG

”’

R202C

EWG = COR or NO2 R’ = H or alkyl

0 +

d

Yb(OTf)3 ~

R3 = H3Me,

Et or Ph

w

EWG R’

H 230 , n * R202C 3-5

excellent yield

R3

(1)

913

Lanthanide Lewis Acids Catalysis

Wang et al. reported that Ln(OTf), catalyzed aza-Diels-Alder reactions in water (Table 2) [5]. This reaction combined three components-an aldehyde, an amine and a diene -to give nitrogen-containing heterocycles in good yield. Yields were found to be low in the absence of the catalyst (3-37%). In the absence of dienes, dihydropyridine and/or pyridine were formed from an aldehyde and an amine (Eq. 2) [6]. Dysprosium triflate, Dy(OTf),-catalyzed electrophilic substitution reactions of indoles with aldehydes or ketones have also been reported (Eq. 3) [7].Nucleophilic attack occurred at the C3 position of the indole, giving diindolylalkanes in good yields. When C3 position of the indole was blocked by a substituent, the nucleophilic attack occurred at the C2 position to give the monoindolyl products in moderate yields (Eq. 4). Table 2

R'CHO

+ R2NH2+

"3 R3

R3

R4

Ln(OTf),

R5

H20

R1QR4 *

R''

R5 k3

entry

aldehyde

amine

i

n-C5H,qCHO

BnNH2.HCI 3

2

ECHO

3

3

PhCH2CHO

3

4

CH20 5

3

diene

5

4

Pr

64 (2.5/1)

Bn

Yb

4

yield (Yo) (exo/endo) 68 (2.9/1)

La

4

72 (4/1) 93

0

NH2 5

product(s)

Ln

Ph*C02Me 6

Nd Ph

1/3

Ph

Ph 6

R'-CHO

5

+ WNH*.HCI

6

Ln(OTf),

Nd

-

96

"eR'xR, \+

H20

n'C02Me

Y

R2

R'

Y

R2

(2)

914

Shibasaki/Yumada/Yoshikawa

R’

mR

+ mC5HllCHO

H

DY(OTf)3

*

EtOH-H20 moderate yield

n-C5H11

(4)

OEt

Kobayashi et al. studied the catalytic activity of many metal salts in Mukaiyamaaldol reactions in aqueous THE They came to the conclusion that the catalytic activity of a metal in aqueous media should be related both to the hydrolysis constant, Kh, and water exchange rate constant (WERC) of the metal [8]. All metals with good catalytic activity had pKh values ranging between 4.3 and 10.08 and WERC > 3.2 x lo6 M - ~C1.This was because when pKh for a metal is < 4.3, the metal cation is readily hydrolyzed to generate oxonium ion, which then helps the decomposition of the silyl enol ethers. When pKh > 10.08 the Lewis acidity of the metal is too low to promote the reaction. When the WERC is < 3.2 x lo6 M - ~ s-l, exchange of water molecules seldom occurred and aldehydes had a very little chance to coordinate to the metal to be activated. The metals which fulfill these criteria are Sc(III), Fe(II), Cu(II), Zn(II), Y(III), Cd(II), Ln(II1) and Pb(I1).

20.2.2 Selectivities Lanthanide Lewis acids sometimes have unique selectivity in reactions. Nakai et al. reported that europium(II1) efficiently catalyzed the Mukaiyama-aldol reactions (Eq. 5 ) and Mukaiyama-type Michael reactions (Eq. 6) [9]. Although enantioselectivity in these reactions was poor ( 6 1 0 % enantiomeric excess, ee), remarkable substrate selectivity was observed in Eu-catalyzed Mukaiyama-aldol reactions (Table 3). Mukaiyama-aldol reactions were also promoted by other usual Lewis acids, such as TiC14. Steric factors affected Eu-catalyzed Mukaiyama-aldol reactions more than TiC14-promoted reactions (entries 1, 2). An unusual order of reactivity was observed in such reactions i.c. o-methoxybenzaldehyde which contained an electron-donating group reacted faster than benzaldehyde (entry 3), and p-nitrobenzaldehyde which contained electron-withdrawing group reacted slower than benzaldehyde (entry 4). These results suggested that reactivity of aldehydes relied strongly on the ability of the aldehydes to coordinate to the Eu catalyst in this reaction. This rationalized the fact that the bidentate aldehyde, e.g. a-benzyloxypropanal reacted faster than the monodentate aldehydes (entries 5 , 6 ) .

Lanthanide Lewis Acids Catalysis

Eu(dppm)3 Me3Si0 (2.5 mol Yo) R ' G O M e CH2C12 * R'

OMe R'CHo

+ R*40SiMe3

0

+

(2.5 mol Yo)

OMe R'40SiMe3

CH2C12

-

OMe R'

n=1or2

Table 3 E ~ ( d p p m ) ~Me390

R'CHO R%HO

OMe

+

(2.5 mol Yo)

AOSiMe3

CH2C12

0

Ri-0~~ Me3Si0

R2-OMe aldhydes

entry

1

products ratio

YHO

\CHO

299 : 1 (77 : 23)a

aCHO YCH0

>99 : 1 (45 : 5 q a

2

>99 : 1 (68 : 32)a

3 OMe

a

5

YCH0 \CHO OBn

199 : 1

6

yCHo YH0 OSiBuMep OBn

97 : 3

Products ratio in the reaction with TiC14 (100 mol %) at-78 "C

(5)

915

916

Shibasaki/Yamada/Yoshikawa

The high sensitivity of lanthanide reagents to steric factors is also observed in the cyanosilylation reaction of ketones catalyzed by ytterbium cyanide, Yb(CN)3 (Eq. 7) [lo]. Other reactions, for example epoxide and the aziridine opening by trimethylsilyl cyanide, TMSCN, are also efficiently catalyzed by Yb(CN)3 [ll].This Yb reagent is not regarded as a Lewis acid but as the active species in these reactions.

U

>99:1

Kobayashi et al. also reported interesting chemoselectivity of aldehydes and imines in the Yb(OTf)3-catalyzed addition reactions of silyl enol ether, allylstannane or trimethylsilyl cyanide [12]. In the competitive reactions between aldehydes and imines, the imines reacted faster than the aldehydes (Tables 4-6). This tendency is not unique to Yb as catalyst; selectivity is similar for other Lr1(0Tf)~.Nuclear magnetic resonance (NMR) studies revealed selective formation of an imine-Yb(OTf)3 complex in the presence of an aldehyde. This preference was reversed when conventional Lewis acids (SnCI4, TiC14, TMSOTf, and BF3.OEt,) were used. Table 4

A3

entry

~1

1 2

Ph Ph

3 4 5 6

Ph Ph Ph Ph

R2

product

R3

R4

Ph Me pMeO-Ph Me

Ph Ph

299 : 1 299 : 1

Ph Ph t-Bu Et

>99 : 1 >99 : 1 >99: 1 >99 : 1

Me Ph Me Ph -(CH2)4Me SEt

>99 : 1 >99 : 1 >99 : 1 >99:1

Me Me2

>99: 1 299: 1

7 8 9 10

2-fury1 C-C~HI~ Ph Ph

11 12

Ph f%H17

gCI-Ph Ph Ph Ph Ph Ph Ph Ph PhCHp Ph2CH

Me H H Me

SEt OMe

(amine/alcohol)

Lanthanide Lewis Acids Catalysis

917

Table 5 N, R2

Yb(OTf)3

entry

HNxR2

product

RI R2

(arnine/alcohol)

1 2

Ph Ph

Ph pMeO-Ph

>99 : 1 >99: 1

3

Ph Ph 2-fury1 2-thiophenyl C-c~Hii

pCI-Ph PhCH2 Ph Ph Ph

>99: 1 >99 : 1 >99 : 1 >99 : 1 >99 : 1

4

5

6 7

Table 6

product

entry

~1

1 2

Ph Ph

Ph pMeO-Ph

>99: 1 >99: 1

3 5

Ph Ph n-CaH17

pCI-Ph Ph2CH Ph2CH

>99: 1 299: 1 >99: 1

6

C-C~HII

Ph

>99 : 1

4

(arnine/alcohol)

Ln(II1) have large ionic radii, which enables Ln(II1) to have a larger coordination number than typical Lewis acids. This capacity of Ln(II1) to complex many ligands sometimes affects the stereoselectivity of reactions and makes them different from those of typical Lewis acids, for example TiC14. Nakai et al. discovered that the Mukaiyama-aldol reactions of a-benzyloxypropanal and (2)-ketene silyl acetals afforded products with unusual stereochemistry (Eq. 8) [13]. This selectivity can be explained via a chelation-antiperiplanar transition state. In the transition state the aldehyde formed a chelate with the Eu catalyst by means both of the oxygen atoms of benzyloxy group and the ester carbonyl, whereas the keten silyl acetal coordinated to the metal through the oxygen atom of the

918

Shihasaki/Yarnada/Yoshikawa

methoxy group (Fig. 1, left). The same reaction promoted by TiC14 generally gave syn product via a chelation-synperiplanar transition state in which the ketene silyl acetal did not coordinate to the Ti catalyst (Fig. 1,right).

yCHO + OBn

R = Me, Et, OBn, OMe, OSiMe3

Hgd &COzMe

(&COzMj

CHzCIz OBn R major product

OBn R major product of the TiCI4 promoting reaction

Ti ..

Figure 1

20.2.3 Other Reactions Catalyzed by Lanthanide Lewis Acids Lanthanide Lewis acids catalyze many of the reactions catalyzed by other Lewis acids, for example, the Mukaiyama-aldol reaction [14], Diels-Alder reactions [15], epoxide opening by TMSCN and thiols [14,10], and the cyanosilylation of aldehydes and ketones [17]. For most of these reactions, however, lanthanide Lewis acids have no advantages over other Lewis acids. The enantioselective hetero Diels-Alder reactions reported by Danishefsky et al. exploited one of the characteristic properties of lanthanides -mild Lewis acidity. This mildness enables the use of substrates unstable to common Lewis acids, for example Danishefsky's diene. It was recently reported by Shull and Koreeda that Eu(fod)s catalyzed the allylic 1,3-transposition of methoxyacetates (Table 7) [MI. This rearrangement did not proceed with acetates or benzoates, and seemed selective to a-alkoxyacetates. This suggested that the methoxy group could act as an additional coordination site for the Eu catalyst, and that this stabilized the complex of the Eu catalyst and the ester. The reaction proceeded even when the substrate contained an alkynyl group (entry 7), or when proximal alkenyl carbons of the allylic acetate were fully substituted (entries 10, 11 and 13). In these cases, the Pd(I1) catalyzed allylic 1,3-transposition of allylic acetates was not efficient.

Lanthanide Lewis Acids Catalysis

919

Table 7 entry

allylic methoxyacetate

product

yield (%)

80

R' 3

4

73

Ro""T 81

R'

5

68

98

Ph

7 7

99

87

88

9

87 ( Z E = 1.4/1)

10

84 (9/8 = 4.6/1)

11

12

c,,,,,,

%,,,,,,

82 ( a l p = 6.6/1)

37

68 + 8

920

Shihasaki/Yamada/Yoshikawa

Ciufolini et al. developed carbonyl-ene reactions catalyzed by the 1:l complex of Yb(fod)3 and acetic acid [19]. 2-Methoxypropene reacted with a variety of aldehydes under the conditions used, providing the protected alcohols in good yields (Eq. 9). Addition of acetic acid was essential-the reaction did not proceed with Y b ( f ~ d ) ~ alone. Addition of silica gel to the reaction mixture was found to enhance the rate of the reaction and to make the reaction clean, although the use of silica gel was not mandatory. Double activation of the aldehydes as a result of coordination to the Yb Lewis acid and hydrogen-bonding with the acidic hydrogen of the acetic acid was proposed for the reaction (Fig. 2).

OMe

Yb(fod)3, ACOH

(9)

H

Yb--0 y - 4 3 H-0

)==o

R

(fod ligands omitted for clarity) Figure 2

Another characteristic property of lanthanide Lewis acids is their tolerance of Lewis bases. As discussed above, lanthanide triflates retain Lewis acidity in the presence of water. In 1986, Forsberg et al. found that lanthanide triflates activated nitriles even in the presence of amines, which were more basic than water. La(OTf)3 catalyzed the aminolysis of nitriles, giving amidines in good yields (Eq. 10) [20]. This was the pioneering work that showed the capacity of lanthanide to activate substrates in the presence of strong Lewis bases, for example amines and water. Utimoto et al. showed that 1P-addition of benzylamine to crotonate was catalyzed by LII(OT~)~, affording the p-amino ester in excellent yield (Eq. 11) [21]. Yamamoto et al. used Yb(OTf)3 as catalyst in aziridine opening by benzylamine (Eq. 12) [22]. Aggarwal et al. reported that lanthanide triflates accelerated Baylis-Hillman reactions catalyzed by 1,4-diazabicyclo[2.2.2]octane(DABCO) (Eq. 13) [23]. The lanthanide triflates acted as Lewis acids, activating the carbonyls and the aziridines in the presence of amines, whereas standard Lewis acids formed complexes with amines and were deactivated. The Baylis-Hillman reaction was accelerated further by addition of multidentate ligands, for example l,l’-bi-2-naphthol (BINOL) or triethanolamine. It was proposed that the ligands should form chelates with lanthanide, preventing complexation of DABCO with the lanthanide.

R ’ N H ~+ R ~ C N R’ = alkyl

R2 = Me, Et or Ph

La(OTf)3

R’\N

* RZAN,R’

Lanthanide Lewis Acids Catalysis

921

95%

DABCO b E W G +R'CHO EWG = C02R or CN

Ln(OTf)3 ' R ,&EWG

II

Kobayashi et al. found that lanthanide triflates were excellent catalysts for activation of C-N double bonds-activation by other Lewis acids required more than stoichiometric amounts of the acids. Examples were aza Diels-Alder reactions, the Mannich-type reaction of N-(a-aminoa1kyl)benzotriazoles with silyl enol ethers, the 1,3dipolar cycloaddition of nitrones to alkenes, the 12-cycloaddition of diazoesters to imines, and the nucleophilic addition reactions to imines [24]. These reactions are efficiently catalyzed by Yb(OTf)3. The arylimines reacted with Danishefsky's diene to give the dihydropyridones (Eq. 14) [25,26]. The arylimines acted as the azadienes when reacted with cyclopentadiene, vinyl ethers or vinyl thioethers, providing the tetrahydroquinolines (Eq. 15). Silyl enol ethers derived from esters, ketones, and thioesters reacted with N-(a-aminoalky1)benzotriazoles to give the ,&amino carbonyl compounds (Eq. 16) [27]. The diastereoselectivity was independent of the geometry of the silyl enol ethers, and favored the anti products. Nitrones, prepared in situ from aldehydes and N-substituted hydroxylamines, added to alkenes to afford isoxazolidines (Eq. 17) [28]. Addition of diazoesters to imines afforded cis-aziridines as the major products (Eq. 18) [29]. In all the reactions the imines could be generated in situ and the three-component coupling reactions proceeded smoothly in one pot.

922

R'CHO

Shibasaki/Yarnada/Yoshikawa

+ ArNH2 +

or

*

or MgS04, CHSCN,rt

R5

R'CHO + R30C&R4 + R~NHOH

Yb(OTf)3

R2

RZlNaR' + R 2 1 N a R4 R 5

R4

(1 7)

MS4A, toluene, rt *

COR~

R;

endo

COW

~1

ex0 endolexo

>77/23

RCHO + Ph2CHNH2 + N2CHC02Et

Yb(OTf)3 MS4A, hexane, rt *

YHPh2 N

(1 8)

R/IC02

20.3 Chiral Lanthanide Lewis Acid Catalysis 20.3.1 Introduction Lanthanides have strong affinity for heteroatoms such as nitrogen and oxygen in organic molecules, as described above, thus enabling strong activation of functional groups such as carbonyl. In addition, the coordination number of lanthanides is normally nine to twelve, larger than that of other Lewis acidic metals such as Ti, Al, B, and Sn. It is, therefore, expected that the behavior of lanthanides toward ligands would be different from that of other Lewis acids in general. This indicates that a lanthanide would maintain its Lewis acidity even after being coordinated by chiral ligands, whereas conventional Lewis acids often lose their activity as a result of coordinative saturation. Briefly, lanthanides have attractive features for the development of

Lanthanide Lewis Acids Catalysis

923

chiral Lewis acids. Despite this, few examples of asymmetric reactions using lanthanide catalysts have appeared until recently. After advances in achiral reactions using lanthanide reagents, however, the number of reports on asymmetric reactions promoted by lanthanide catalysts has increasing in the last decade.

20.3.2 Catalytic Asymmetric Diels-Alder Reactions and H e t e r o Diels-Alder Reactions Promoted by Chiral Lanthanide Catalysts Danishefsky and co-workers pioneered the use of chiral lanthanide complexes as catalysts in organic reactions. They found out that Eu(hfc)3, which is used as an NMR shift reagent, promoted hetero Diels-Alder reactions [30] of aldehydes with siloxydienes and induced enantiomeric enrichment (Sch. 1) [31]. Suitable substituents on the dienes were introduced to improve the extent of asymmetric induction. The best result was obtained in the reaction of benzaldehyde with l-methoxy-2-methyl-3-(trimethylsiloxy)-l,3-butadiene using 1 mol % Eu(hfc)3; the enantiomeric excess was, however, moderate (58%). The authors maintained that the major advantage of lanthanide catalysis lay in the survival of othcrwise labilc systems used as adducts. OMe

i) Eu(hfc)3 (1 mol %), -10 "C 'Ph

ii) CF3COOH

*

0nPh OMe OH

Scheme 1

Kobayashi and co-workers exploited the use of lanthanide in a variety of achiral reactions and extended them into several catalytic asymmetric reactions. Their work commenced with catalytic asymmetric Diels-Alder reactions [32]. The reaction was performed with a chiral ytterbium catalyst prepared from Yb(OTf)3, binaphthol and a tertiary amine. The amine significantly influenced reaction selectivity. When triethylamine was used in the preparation of the catalyst, the desired product was obtained in moderate ee (33%) (Table 8, entry 1). After screening several reaction conditions, they found that, in general, bulky amines gave better results (entries 2-6). They suggested interesting explanations of this experimental result on the basis of investigations into catalyst structure. Consequently, the use of cis-1,2,6-trimethylpiperidine combined with 4 A molecular sieves (4A MS) was found to produce the best result (yield 77%, endolexo = 89/11, endo = 95% ee) (entry 6 ) . During the course of their studies, Kobayashi's group noticed that stirring the catalyst solution at 0 "C or at room temperature led to deactivation of the catalyst. They speculated that the catalyst should be stabilized by the substrate or the product during the reaction and sought additives such as dicarbonyl compounds to stabilize the catalyst. The results are summarized in Table 9. Unexpectedly, addition of 13-diketones such as acetylacetone resulted in the formation of the opposite enantiomer of the product (entries 35), whereas addition of oxazolidinone had no effect on the configuration of the product (entries 1and 2). When 3-phenyl-2,4-pentanedionewas used as additive the product was

924

Shibasaki/Yamada/Yoshikawa

obtained in 81% ee and the configuration was opposite to that in the absence of the additive (entry 5). In other words, both enantiomers of the product can be synthesized by use of the same chiral source simply by changing the additive [33].

.rs-

Table 8 0

AdNKO

0

chiral Yb catalyst (20 rnol Yo)

0

+

U

*

u0

CH2C12,amine

CON

ee (%) of endo adduct

entry

amine

MS

temp. (iC)

1

Et3N

-

23

87

76/24

33

2

n-Bu3N

-

23

quant.

83117

68

3

i-Pr2NEt

-

23

82

85115

70

4

i-Pr2NEt

MS 4A

23

88

87113

83

MS4A

23

91

86114

90

I

MS 4A

0

77

89111

95

a

5 6

chiral Yb catalyst = Yb(OTf), (20 rnol O h )

+ (17)-BINOL (24 rnol %) + amine (48 rnol %)

*.+

Table 9

0

0

-dNA0

u

yield (YO)

chiral Yb catalysta) +additive (20 rnol Yo)

+

CH2C12, MS 4A, 0 iC

K

CON

0

U

(2S, 3R) entry

additive 0

1

CON

(2R, 3s)

ee (Yo)

yield (%)

endolexo

25, 3 R I 2R, 3 5

66

87113

94.016.0

88

96.513.5

93

0

u

3

80

88112

22.5l77.5

55

4

69

88112

15.5184.5

69

83

9317

9.5190.5

5

Ph

0

U

a) Chiral Yb catalyst = Yb(OTf)3 (20 rnol %) + (R)-BINOL (24 rnol YO) + cis-l,2,6-trimethylpiperidine (48 rnol Yo). b) 1,2,2,6,6-PentamethyIpiperidinewas used instead of cis-l,2,6-trimetylpiperidine.

81b,

Lanthanide Lewis Acids Catalysis

925

These workers also investigated the structure of the catalyst [34]. On the basis of 13CNMR and IR spectroscopic studies they suggested a structure in which the tertiary amine coordinated to phenolic protons of binaphthol (Sch. 2). According to their description, high enantioselectivity could be achieved by transferring the axial chirality of binaphthol via a hydrogen-bond to the amine part, which shielded one side of the dienophile. This explanation was consistent with the observation that use of bulky amines led to better selectivity. The catalyst seemed, moreover, to have two binding sites for ligands. The interesting phenomena described above, namely inversion of the configuration of the product, could be explained by this characteristic nature of the coordination. The dienophile coordinates to site A more favorably than to site B; hence, cyclopentadiene attacks from the si face of the dienophile to afford the (2S, 3R) adduct. When, on the other hand, 3-phenyl-2,4-pentanedione was added, it coordinates strongly to site A. The dienophile, therefore, coordinates to site B and cyclopentadiene attacks from the re face of the dienophile, giving rise to the opposite enantiomer, (2R,3s).They also prepared the same type of catalyst from other lanthanides (Lu, Tm, Er, Ho, Y, and Gd). These catalysts also had the same characteristic lanthanide properties as that prepared with ytterbium, although the ee obtained depended strongly on the ionic radii of lanthanides.

Q t

site A

0

R’

,JI,K,

0 or

Mark6 and co-workers applied chiral Yb catalysts to enantioselective Diels-Alder reactions of electron-deficient dienes (Table 10) [35]. When the reaction of 3-carbomethoxy-Zpyrone with phenyl vinyl sulfide was conducted in the presence of THF ( 5 mol equiv. to Yb), the bicyclic lactone was obtained in 92% yield and in more than 95% ee (entry 5). Vinyl ethers could also be used as dienophiles, affording the corresponding products with excellent selectivities.

926

Shibasakd Yarnada/ Yoshikawa

Table 10

COOMe

entry

XR

Yb(OTf)3, (17)-BINOLM e:&* i-Pr2NEt,CH2C12,THF

dienophile

THF

yield (%)

ee (%)"I

5 eq

81

65 (30)

1

BuO-

2

BUS%

10 eq

85

74 (42)

3

cyo-

10 eq

90

96 (80)

4

cys%

10 eq

67

>95(92)

5

PhS-

5 eq

92

> 9 5 (88)

a)The numbers in parentheses refer to ees obtained without added THF.

Inanaga and co-workers developed another type of lanthanide catalyst for asymmetric hetero Diels-Alder reaction (Sch. 3) [36]. Benzaldehyde reacted with l-methoxy-3-(trimethylsiloxy)-1,3-butadienein the presence of chiral Yb(II1) phosphate to afford the corresponding adduct in 77% yield and in 70% ee. Because the reaction mixture was heterogeneous, they tried to make a clear solution by addition of ligands and examined their effects on the reactions. Pyridine and pyridine derivatives dissolved the catalyst and chemical yields and ee were usually improved. The best result (93'Yo ee) was obtained in the reaction of p-anisaldehyde with 2,6-lutidine as additive. M e oi

i) Yb[(R)-(-)-BNPI3 additive, rt

RCHO +

*

ii) H+ TMSO

0

additive

: y. 77%, 70% ee (R = Ph) 2,6-lutidine : y. 94%, 89% ee (R = Ph) 2,6-lutidine : y. 86%, 93% ee (R = pMeO-C6H4)

Yb[(R)-(-)-BNP]s :

Scheme 3

Lanthanide Lewis Acids Catalysis

927

Mikami and co-workers reported a hetero Diels-Alder reaction of butyl glyoxylate using a chiral lanthanide catalyst reported by Shibasaki's group in 1994 (Sch. 4) [37]. They found that addition of water (11 mol equiv. to catalyst) resulted in the formation of the product in higher yield and ee. Such tolerance of water is never encountered in conventional Lewis acid catalysis. The catalyst (10 mol YO)promoted the reaction of Danishefsky's diene with butyl glyoxylate in the presence of water to afford the corresponding product in up to 88% yield and 66% ee. i) lanthanide bis-triflylarnides (10 rnol %) PhCHdH20, -78 "C ii) CF~COOH 0

-n

"zBu

TBDMSO

Tf

Ph catalyst =

--

Qn Ph

,

Tf

PTf)

'"CO~BU

OMe

txcH20H

up to y. 88%, 66% ee

Scheme 4

20.3.3 Catalytic Asymmetric Aza Diels-Alder Reactions Promoted by Chiral Ytterbium Catalysts Kobayashi and co-workers had revealed that lanthanide triflates were excellent catalysts for aza Diels-Alder reactions and successfully developed these into catalytic asymmetric reactions [38]. Initially the reaction of N-benzylideneaniline with cyclopentadiene was performed in the presence of a catalyst prepared from Yb(OTf)3, binaphthol and 1,3,5-trimethylpiperidine. Although the reaction proceeded smoothly, no asymmetric induction was obtained. Believing that bidentate coordination of the substrate might be necessary for chiral induction, they tried N-benzylidene-2-hydroxyaniline rather than N-benzylideneaniline as a substrate. Although the catalyst prepared from 1,3,5-trimethylpiperidine gave only low enantiomeric excess (6%), contrary to their expectation, the selectivity was greatly improved by use of DBU instead of 1,3,5trimethylpiperidine. After screening several additives, they found that the enantiomeric excess was further improved by addition of 2,6-di-t-butylpyridine (DTBP). Thus, the reaction of N-benzylidene-2-hydroxyaniline and cyclopentadiene was found to proceed in the presence of the chiral Yb catalyst (prepared from Yb(OTf)3, binaphthol and DBU) combined with DTBP to give the corresponding tetrahydroquinoline derivative in 92% yield with high selectivity (cisltrans = >99/1, 71% ee) (Table 11, entry 10). Vinyl ethers could also be used as dienophiles; the substrates tested are summarized in Table 11.

928

Shihasaki/Yamada/Yoshikawa

Table 11

+

f‘~3

R2

chiral Yb catalysta (10-20 mol %) additive (100 mol %) CH2C12, MS 4A

R’ OH

a

catalyst (mol %)

yield

ee of cis

entry

R’

1

Ph

20

58

9416

61

2

Ph

10

52

9416

77

3

a-Naph

20

69

>99/1

86

4

a-Naph

DPPC

20

65

9911

91

5

a-Naph

DTBMP~

20

74

>99/1

91

6

a-Naph

DTBMP

10

62

9812

82

7

a-Naph

DTBMP

20

80

66134

70

8

a-Naph

DTBMP

20

90

9119

78

9

a-Naph

DPP

20

67

9317

86

10

Ph

20

92

>99/1

71

11

a-Naph

DTBMP

20

69

29911

68

12

C-CBHll

DTBMP

20

58

>99/1

73

alkene

/’oB~

0 0

additive

(Yo)

cidfrans

(“w

Chiral Yb catalyst = Yb(OTf)3 + (17)-BINOL + DBU. DTBP: 2,6-Di-f-butyC4-methylpyridine. DPP: 2,6-Dimethylpyridine. DTBMP: 2,6-Di-f-butyl-4-methylpyridine.

The authors assumed the transition state of the reaction was that shown in Sch. 5 , in which the imine was fixed by bidentate coordination to Yb and the additive (DTBP) interacted with the phenolic hydrogen of the imine. Because the top face of the imine was shielded by DBU, the dienophile would approach from the bottom face, affording high selectivity.

Lanthanide Lewis Acids Catalysis

929

Scheme 5

20.3.4 Catalytic Asymmetric 1,3-Dipolar Cycloaddition Reactions Promoted by Chiral Yb Catalysts 1,3-Dipolar cycloadditions between nitrones and alkenes to give isoxazolines are very important reactions in organic synthesis, because 1,3-amino alcohols can be synthesized from isoxazoline derivatives. Jorgensen and co-workers reported catalytic asymmetric 1,3-dipolar cycloaddition reaction by use of a Ln-PyBOX complex [39]. The catalyst was prepared from Yb(OTf)3, 4-A molecular sieves, and PyBOX, and the reaction was performed between alkenes and nitrones. Enantiomeric excesses were up to 73% (Sch. 6 ) ; combination of Yb(OTf)3 and binaphthol gave a racemic product.

fi

y. 54%, endolexo = 9614, 73% ee (endo)

;;2""'30,

catalyst = Yb(0Tf) .H20 +

iScheme 6

Kobayashi and co-workers obtained better selectivity with a chiral Yb catalyst (Table 12) [40]. When N-benzylidenebenzylamine N-oxide was reacted with 3-(2butenoyl)-1,3-oxazolidin-2-one in the presence of a catalyst prepared from Yb(OTf)3, binaphthol and cis-1,2,6-trimethylpiperidine, the corresponding isoxazoline was obtained in 78% ee (entry 3). Interestingly, the addition of N-methyl-bis[(R)-1-(1naphthy1)ethyllamine ((R)-MNEA) instead of cis-1,2,6-trimethylpiperidineresulted in increased ee (96% ee, entry 6 ) whereas addition of (S)-MNEA gave the adduct in only 62% ee (entry 7). When, moreover, the reaction was conducted in the absence of 4A MS or in the presence of other additives, inversion of the absolute configurations of the products was observed (Table 13, entries 2 and 3) [41], as had been observed

930

Shibasaki/Yamada/Yoshikawa

for catalytic asymmetric Diels-Alder reactions (Table 9) [32b]. Reactions with other substrates were performed with the same chiral catalyst; by suitable choice of additive it was possible to prepare either enantiomer of the corresponding isoxazolines with high selectivity. Several examples are shown in Table 13. Table 12 Bn,

0

0

chiral Yb catalysta

N+

L/

HKPh entry

amine

1 2 3

Et3N i-Pr2NEt cis-1 ,2,6-TMPC (R)-MPEA~ (9-MPEA ( R)-MNEAe (S)-MNEA

4 5 6 7

MS 4A, CH2C12, rt yield (YO)

endolexo

ee (%)b

9911 > 9911 9911 > 9911 9713 9911 9911

63 62 78 71 35 96 62

65 73 73 92 80 92 87

catalyst = Yb(0Tf) 3 + (S)-binaphthol + amine. Ee of the endo adducts. cis-l,2,6-Trimethylpiperidine. a Chiral Yb

d

I

Table 13 Bn,

(20 mol Yo)

N+

10

entrv 1

2 3

4 5 6 7 8 9 10

11

R’ Ph Ph Ph 2-fury1 1 -naphthyl Ph Ph Ph Ph C2H5

R’

12 (3R,4S,5R)

additive MS 4A none 10 MS 4A MS 4A 10 MS 4A 10 MS 4A MS 4A

yield (“10) endolexo 92 83 90 89 88 83 91 72 89 88

9911 9812 9911 9515 9812 9713 9911 9911 9812 53147

;

ChiralYb catalyst =Yb(OTf) + (S)-BINOL + (4-MNEA. Ee of the endo adducts. ‘The reverse enantiofacial selectivity (3 S,4R,5S) was obtained.

a

ee (“h)b 96 -50‘

-83‘ 89 85 -81C

79 -88‘ 93 96

Lanthanide Lewis Acids Catalysis

931

20.3.5 Enantioselective Mukaiyama Aldol Reaction Promoted by Chiral Lanthanide Complexes Mukaiyama aldol reactions are useful means of constructing complex molecules for the total synthesis of natural products. Although catalytic asymmetric Mukaiyama aldol reactions have been achieved by use of a variety of chiral Lewis acids [42],no report of the use of chiral lanthanide catalysts was available until recently, despite the potency of these catalysts. Shibasaki and co-workers reported the first examples of chiral induction with chiral lanthanide complexes (Sch. 7) [43]. Catalysts prepared from lanthanide triflates and a chiral sulfonamide ligand afforded the corresponding aldol products in moderate enantiomeric excess (up to 49% ee). OTMS

RCHO +

>=d,,

Ln-catalyst (20 mol %)

CH2C12, -40 "C

*-

R = Ph, PN02C6H4, phkOC6H4, PhCH2CH2 Ln = La, Eu, Yb

)f,oPh (n) ' 'L

H+

0

OH

E t O y R

up to 49% ee

Tf

Ln-catalyst =

Ph

I

Tf

Scheme 7

20.4 Lanthanides Containing Multifunctional Heterobimetallic and Heteropolymetallic Asymmetric Catalysis 20.4.1 Introduction Although the development of a variety of Lewis acids has enabled the realization of a wide range of catalytic asymmetric reactions, most of the catalysts have limited activity in terms of either enantioselectivity or chemical yields. The major difference between synthetic asymmetric catalysts and enzymes is that the former activates only one side of the substrate in an intermolecular reaction, whereas the latter not only can activate both sides of the substrate but also can control the orientation of the substrate. If this kind of synergistic cooperation could be realized in synthetic asymmetric catalysis, it would open up a new field in asymmetric synthesis, and a wide range of applications might well ensure. In this section we discuss asymmetric two-center catalysis promoted by chiral lanthanide complexes with Lewis acidity and Bronsted basicity [44,45].

932

Shibasaki/Yamada/Yoshikawa

20.4.2 Heterobimetallic Asymmetric Catalysis Our preliminary attempts to obtain a basic chiral rare earth complex led us to create several new chiral heterobimetallic complexes which catalyze different types of asymmetric reaction. The rare earth-alkali metal-tris(l,l'-bi-2-naphthoxide) complexes (LnMB, where Ln = rare earth, M = alkali metal, and B = l,l'-bi-2-naphthoxide) have been efficiently synthesized from the corresponding metal chloride or alkoxide [46-49], and the structures of the LnMB complexes have been unequivocally determined by a combination of X-ray crystallography and LDI-TOF-mass spectroscopy, as shown in Fig. 3 [50-531.

(R)-binaphthol

M

Ln = rare earth, M = alkali metal

\

(4-binaphthol

Figure 3

For example, an effective procedure for the synthesis of LLB (where LL = lanthanum and lithium) is treatment of LaC13.7 H 2 0 with 2.7 mol equiv. BINOL dilithium salt, and NaO-t-Bu (0.3 mol equiv.) in THF at 50 "C for 50 h. Another efficient procedure for the preparation of LLB starts from La(O-i-Pr)3 [54], the exposure of which to 3 mol equiv. BINOL in THF is followed by addition of butyllithium ( 3 mol equiv.) at 0 "C. It is worthy of note that heterobimetallic asymmetric complexes which include LLB are stable in organic solvents such as THF, CH2C12and toluene which contain small amounts of water, and are also insensitive to oxygen. These heterobimetallic complexes can, by choice of suitable rare earth and alkali metals, be used to promote a variety of efficient asymmetric reactions, for example nitroaldol, aldol, Michael, nitro-Mannich-type, hydrophosphonylation, hydrophosphination, protonation and Diels-Alder reactions. A catalytic asymmetric nitroaldol reaction, a direct catalytic asymmetric aldol reaction, and a catalytic asymmetric nitro-Mannich-type reaction are discussed in detail below. The nitroaldol (Henry) reaction has been recognized as a powerful synthetic tool and has been used in the construction of numerous natural products and other useful compounds. We succeeded in realizing the first example of a catalytic asymmetric nitroaldol reaction by the use of a catalytic amount of LLB.

Lanthanide Lewis Acids Catalysis

933

The rare earth metals are generally regarded as 17 elements with similar properties, especially in respect of their chemical reactivity. In the above-mentioned catalytic asymmetric nitroaldol reaction, however, we observed pronounced differences both in the reactivity and the enantioselectivity of the different rare earth metals used. For example, when benzaldehyde and nitromethane were used as starting materials, the corresponding Eu complex gave the nitroaldol in 72% ee (91%) in contrast to 37% ee (81%) when LLB was used (-40 "C, 40 h). These results suggest that small changes in the structure of the catalyst (ca 0.1 A in the ionic radius of the rare earth cation) can cause a drastic change in the optical purity of the nitroaldols produced. Although nitroaldol reactions are generally regarded as equilibrium processes, no detectable retroni troaldol reactions were observed in Ln-BINOL complex-catalyzed asymmetric nitroaldol reactions. Having succeeded in obtaining the first results from a catalytic asymmetric nitroaldo1 reaction, we attempted to apply the method to the catalytic asymmetric synthesis of biologically important compounds. The nitroaldol products were readily converted into fi-amino alcohols and/or a-hydroxy carbonyl compounds and convenient syntheses of three kinds of optically active P-blocker are presented in Sch. 8 [55-571. CH3N02 (10-50 equiv) (R)-LLB (3.3 mol %) Ar\ 0nCHO -50 "C, THF 13 16 19 H2, Pt02, CH30H " / \ / o*" A acetone, 50 "C

OH

H

A r \ O y N 0 2 OH 14: 90% (94% ee) 17: 80% (92% ee) 20: 76% (92% ee)

15: 80% (S)-metoprolol 18: 90% (S)-propranolol 21 : 88% (S)-pindolol

Scheme 8

Interestingly, the nitroaldol products 14,17 and 20 were found to have (S)-absolute configuration when (R)-LLB was used. The nitronates thus seem to react preferentially with the si face of the aldehydes, in contrast to the enantiofacial selectivity which might have been expected on the basis of results obtained from reaction of aldehydes such as hydrocinnamaldehyde. These results suggest that the presence of an oxygen atom at the fi-position greatly influences the enantiofacial selectivity. LLB-type catalysts could also be used to promote diastereoselective and enantioselective nitroaldol reactions starting from prochiral materials, although with limited enantioselectivity (< 78% ee) and diastereoselectivity (ca 2:l-3:l). To obtain high enantio- and diastereoselectivity we focused our attention on the preparation of a novel asymmetric cata-

934

Shibasaki/Yamada/Yoshikawa

lyst. Among many catalysts prepared, catalysts 22-28 (Fig. 4) were the first that were found to result in higher enantioselectivity in the catalytic asymmetric nitroaldol reaction of hydrocinnamaldehyde with nitromethane.

26: R = C S P h 27: R = C Z C S ~ ( C H ~ ) ~ 28: R = C&SiEt3 28a: R = C S T B S 28b: R = C E C S ~ ( C H ~ ) ~ P ~

LLB: R = H 22: R = Br 23: R = CH3 24: R = C=N 25: R = C=CH

Figure 4

With more effective asymmetric catalysts in hand, we next applied the most efficient catalysts 27 and 28 to diastereoselective nitroaldol reactions. We were very pleased to find that high syn selectivity and enantioselectivity were always obtained by use of 3.3 mol % catalyst [%I. Representative results are listed in Table 14. Table 14

OH

catalyst RCHO

+

29: R = PhCH2CH2 33: R = CHs(CH2)4

R'CH2N02

30: R' = CH3 34: R' = Et 37: R' = CH20H

Entry Aldehyde Nitroalkane Catalyst 1 2 3 4 5 6 7 8 9

29 29 29 29 29 29 29 33 33

30 30 30 34 34 37 37 37 37

R%R'

(3.3 mol %)* THF

LLB 27 28 LLB 28 LLB 28 LLB 28

f

syn No2 31 (syn),32 (anti): 35 (syn),36 (anti): 38 (syn), 39 (anti): 40 (syn),41 (anti):

OH R Y R '

anti NO2 R = PhCH2CH2, R' = CH3 R = PhCH2CH2, R' = Et R = PhCH2CH2,R' = CH20H R = CH3(CH2)4,R' = CH20H

Time (h)

Temp ("c)

Nitroaldols

Yield (%)

75 75 75 138 138 111 111 93 93

-20 -20 -20 -40 -40 -40 -40 -40 -40

31 + 3 2 31 + 3 2 31 + 3 2 35+36 35+36 38+39 38+39 40+41 40+41

79 72 70 89 85 62 97 79 96

OH Ph/\rCOOH NH2

42

ee of synlanti syn (YO) 74:26 85115 89111 85115 9317 84116 9218 87113 92:8

66 92 93 87 95 66 97 78 95

Lanthanide Lewis Acids Catalysis

935

It seems that the syn selectivity in the nitroaldol reaction can best be explained as arising from steric hindrance in the bicyclic transition state; it seems that the greater stereoselectivity obtained by use of catalysts 27 and 28 can be ascribed to increased catalyst stability, even in the presence of an excess of highly acidic nitroalkanes. The syn-selective asymmetric nitroaldol reaction was successfully applied to the catalytic asymmetric synthesis of threo-dihydrosphingosine 45, which elicits a variety of cellular responses by inhibiting protein kinase C. An efficient synthesis of erythro-AHPA 42 from L-phenylalanine was, moreover, achieved by using LLB (Sch. 9) [59].

CH3(CH,)14CHO 43

OH

46 (

+ anti-adduct )

+

catalyst (10 rnol %) O,”+.’/oH

r

37

-40 “C, 163 h OH

fhreo-dihydrosphingosine 45

catalyst 28: 78% (syn /anti = 91 :9), syn: 97% ee LLB catalyst: 31%(syn /anti =86: 14), syn: 83% ee

Scheme 9

Catalytic asymmetric nitroaldol reactions promoted by LLB or its derivatives require at least 3.3 mol YOasymmetric catalyst for efficient conversion, and even then the reactions are rather slow. To enhance the activity of the catalyst, consideration of the possible mechanism of catalytic asymmetric nitroaldol reactions is clearly a necessary prerequisite to formulation of an effective strategy. One possible mechanism of catalytic asymmetric nitroaldol reactions is shown at the top of Sch. 10. We strove to detect the postulated intermediate I by use of a variety of methods, but were unsuccessful, probably owing to the low concentrations of the intermediate, which we thought might be ascribed to the presence of an acidic OH group in close proximity. To remove a proton from I, we added almost 1 equiv. base to the LLB catalyst. After many attempts, we were finally pleased to find that 1 mol % second-generation LLB (LLB-11), prepared from LLB, 1 mol equiv. H20, and 0.9 mol equiv. butyllithium efficiently promoted catalytic asymmetric nitroaldol reactions. We also found that the use of LLB-IT (3.3 mol YO)accelerated these reactions. The use of other bases such as NaO-t-Bu, KO-t-Bu and Ca(O-i-Pr)2 gave less satisfactory results. The structure of LLB-I1 has not yet been unequivocally determined. We propose here, however, that it is a complex of LLB and LiOH. A proposed reaction course for its use in an improved catalytic asymmetric nitroaldol reaction is shown at the bottom of Sch. 10 [60]. Industrial application of a catalytic asymmetric nitroaldol reaction is being examined. Having developed an efficient catalytic asymmetric nitroaldol reaction, we next applied our attention to a direct catalytic asymmetric aldol reaction. The aldol reaction is generally regarded as one of the most powerful carbon-carbon bond-forming reactions. The development of a range of catalytic asymmetric aldol-type reactions has proven to be a valuable contribution to asymmetric synthesis. In all these catalytic asymmetric aldol-type reactions, however, preconversion of the ketone moiety to a more reactive species such as an enol silyl ether, enol methyl ether or ketene silyl

936

Shibasaki/Yarnada/Yoshikawa

acetal is an unavoidable necessity (Sch. 11).Development of a direct catalytic asymmetric aldol reaction, starting from aldehydes and unmodified ketones, is thus a noteworthy endeavor. Such reactions are known in enzyme chemistry [61]; the fructose1,6-bisphosphate and DHAP aldolases are characteristic examples. The mechanism of these enzyme-catalyzed aldol reactions is thought to involve co-catalysis by a Zn2+ cation and a basic functional group in the active site of the enzyme, with the latter abstracting a proton from a carbonyl compound while the former functions as a Lewis acid to activate the other carbonyl component.

1

-

LLB-II Scheme 10

(a) Mukaiyama-type Reactions

0

A: SiR, or CH3

o ' ~ chiral catalyst

*AR~ R'CHO (b) Direct Reactions 0 __

A0

0

* R'

chiral catalyst

R'CHO

R'

Scheme 11

We speculated that it might be possible to develop a direct catalytic asymmetric aldol reaction of aldehydes and unmodified ketones by employing heterobimetallic catalysts. Our initial concerns were dominated by the possibility that our heterobimetallic asymmetric catalysts would be ineffective at promoting aldol reactions because

Lanthanide Lewis Acids Catalysis

937

of their rather low Brgnsted basicity. We were thus pleased to discover that the desired aldol reactions of tertiary aldehydes proceeded smoothly in the presence of LLB as catalyst (up to 94% ee). Development of an efficient catalytic asymmetric aldol reaction using aldehydes with a-hydrogens is clearly a much greater challenge than the examples discussed above, because self-aldol products can readily be formed. We found, however, that the reaction of cyclohexanecarboxaldehyde with acetophenone, for example, proceeded smoothly without significant formation of the self-aldol product of cyclohexanecarboxaldehyde, giving the aldol product in 44% ee and 72% yield. The reaction between hydrocinnamaldehyde, with two u-hydrogens, and acetophenone proved more difficult, however. Although the aldol product was obtained in 52% ee, the yield was low (28%), because of the formation of self-condensation by-products (-20 "C). Thus, we have achieved success in performing direct catalytic asymmetric aldol reactions of aldehydes with unmodified ketones for the first time [62]. To make this methodology synthetically useful, however, the challenge remains to reduce the amounts of ketones and catalysts used, reduce reaction times, and increase enantioselectivity. As mentioned above, we observed for an asymmetric nitroaldol reaction that the LLB .LiOH tight complex enhanced the catalytic activity of LLB. Encouraged by this result, development of a new strategy to activate LLB for the direct catalytic asymmetric aldol reaction was attempted [63].As a result the catalyst generated from LLB, KHMDS (0.9 equiv. relative to LLB) and H20 (1 equiv. relative to LLB), which presumably forms a heteropolymetallic complex, was found to be a superior catalyst for the direct catalytic asymmetric aldol reaction giving 48 in 89% yield and 79% ee (8 mol % LLB were used). We employed this method to generate KOH in situ because of its insolubility in THE The use of KO-t-Bu instead of KHMDS gave a similar result, indicating that HMDS does not play a key role. Interestingly, further addition of H20 (1 equiv. relative to LLB) resulted in the formation of 48 in 83% yield and higher ee. A similar result was obtained by use of the powder obtained from the catalyst solution by evaporation of the solvent. This powder is easily handled without the need for an inert atmosphere. In addition, we were pleased to find that as little as 3 mol % catalyst promoted the reaction efficiently to give 48 in 71% yield and 85% ee. Moreover, in contrast to catalytic asymmetric nitroaldol reactions, the generation of LiOH or other bases was found to give less satisfactory results. The results are summarized in Table 15.

938

ShibasakilYarnada/Yoshikawa

Table 15

Ph.

Entry 1 2 3 4 5a 6 7

a 9 a

Base

H 2 0 (mol %) Time (h)

- (LLB itself) KHMDS KHMDS KHMDS KHMDS KHMDS LHMDS NHMDS KHMDS

-

ia

0

8

18 ia

16 6 32 16 16 16

33 18 5 5 5

ia

Yield (%) trace a3 a9 a3 71 67 22 28 74

ee (%)

58 79 a5 a5 89 80 86 a4 -

LLB (3 mol %), base (2.7 mol %), H20 (6 mot %).

This newly developed heteropolymetallic catalyst system was applied to a variety of direct catalytic asymmetric aldol reactions, giving aldol products 48-64 in modest to good ee, as shown in Table 16. It is worthy of note that even 62 can be produced from hexanal 54 in 55% yield and 42% ee without the formation of the corresponding self-aldol product (-50 "C). This result can be understood by considering that aldehyde enolates are not usually generated by the catalyst at low temperature, an assumption which was confirmed by several experimental results. It is also worthy of note that the direct catalytic asymmetric aldol reaction between 46 and cyclopentanone 55 also proceeded smoothly to afford 64 in 95% yield (synlanti = 93:7, syn = 76% ee, anti = 88% ee). Several of the aldol products obtained were readily converted to their corresponding esters by Baeyer-Villiger oxidation. These results also are summarized in Table 16. Ester 66 was further transformed into key epothilone A intermediate 69 and also a key synthetic intermediate 70 for bryostatin 7. What is the mechanism of these direct catalytic asymmetric aldol reactions using LLB-II? It is apparent that selfassembly of LLB and KOH occurs, because of the formation of a variety of aldol products in high ee and yields. In addition, the 13CNMR and LDI-TOF(+)MS spectra of LLB .KOH show the occurrence of rapid exchange between Li' and K'. We have already found that LPB[LaK3tris(binaphthoxide)] itself is not a useful catalyst for aldol reactions, and that the complexes LPB . KOH or LPB . LiOH give rise to much less satisfactory results. We thus believe that the BINOL core of the active complex is essentially LLB. Therefore, the heteropolymetallic complex of LLB and KOH, with KOH axially coordinated to La, among other possible complexes, would be the most effective catalyst for this reaction. To clarify the reaction mechanism, we conducted kinetic studies. As a result, significant isotope effects ( k H l k D - 5) were observed, and the reaction rate has been found to be independent of the concentration of the aldehyde. Both of these results indicate that the rate-determining step is deprotonation of the ketone; they also suggest that the catalyst readily forms a relatively tight complex with the aldehyde, thus activating it. This coordination of an aldehyde was supported by the 'H

Lanthanide Lewis Acids Catalysis

939

NMR spectrum. Although the precise role of HzO is not yet clear, we have suggested a working model of the catalytic cycle and a possible mechanism which enables us to explain the observed absolute configurations of the products (Sch. 12). Table 16

0

9

( 4 - L L B (8 rnol %) KHMDS (7.2 rnol %)

R'KH+P FH2 -R' , 9 0 (16 rnol %) I

10 Y1i M O R 265-67

46: R' = t-Bu 49: PhCH2C(CH3)2

47: 47a:R2 R2==Ph CH3

49: R' 29: R' 52: R' 53: R' 54: Ri

50: R' = Et 51: R2 = 3-NOz-CsHd 55: R2 = -(CH2)3R

= i-Pr = PhCH2CH2 = BnOCH2C(CH& = Et2CH = n-C5HI1

Aldehyde Ketonea

Entry

(R')

1 2 3 4d 5 6e

49 46 46 46

7s 8h

91 11' 12

52 52 49 49 53 54 29 46

Time Yield

(R2) (eq) Aldol 47 (5) 47(5) 47a (10) 50 (15) 47(5) 47(5) 47(5) 51 (3) 51 (3) 51 (5) 51 (3) 55 (5)

56 48 56 57 58 58 59 60 61 62

(h)

ee

(YO) ("10)

i

b

Yield of esterb

15 28 20 95 36 24 15 70 96 96 31 99

75 88 85 89 6580%' 62 76 72 88 91 90 66:73%' 70 93 90 33 68 70 67:80%' 60 80 55 42 50 30 63 95 76/88 68: 85%' 64 (synlanti = 9317) (synlantl)

Excess of ketone was recovered after reaction. bThe yield from aldol product. Conditions: SnC14 (cat.), (TMS0)2, trans-N,N'-bis(pto1uenesulfonyl)cyclohexane-l,2-diamine (cat.), MS 4A, CH2C12. 8 mol % of H20 was used. eThe reaction was carried out in 5.7 mmol (52) scale. Conditions: mCPBA, NaH2P04,DCE. gThe reaction was carried out at -30 "C. "he reaction was carried out at -50 "C. 'Conditions: i) Pt02, H2, MeOH; ii) ZCI, Na2C03,MeOH-H'O; iii) SnCI4 (cat.), (TMSO)2, hans-N,N'-bis(ptoluenesuIfonyl)cyclohexane-1,2-diamine(cat.), MS 4A, CH2C12. R' (67) = 3-ZNH-CsH4.1 Conditions: (R)-LLB (15 rnol %), KHMDS (13.5 rnol Yo),H2O (30 rnol Yo),-45 "C. Conditions: (R)-LLB (30 rnol YO),KHMDS (27 rnol YO),H20 (60 mol Yo).'The reaction was carried out at -40 "C. a

'

69

70

940

Shihasaki/Yarnada/Yoshikuwa

IV

111

Scheme 12

The stereoselectivities seem to be kinetically controlled. In fact, the ee of the aldol product was constant during the course of the reaction. Thus, we have succeeded in performing the first catalytic asymmetric aldol reaction between aldehydes and unmodified ketones by using heterobimetallic or heteropolymetallic catalysts. Several reactions have already been synthetically useful especially for tertiary aldehydes, leading to the catalytic asymmetric synthesis of key intermediates en route to natural products [63]. Further studies are currently in progress. These rare earth-containing heterobimetallic complexes can be utilized for a variety of efficient catalytic asymmetric reactions, as shown in Sch. 13, and quite recently we have succeeded in realizing the first example of a catalytic asymmetric nitro-Mannich-type reaction using the newly developed heterobimetallic complex 71 (Table 17) [72].

Lanthanide Lewis Acids Catalysis

EtS~SPh-4-t-Bu

up to 90% SCH2Ph ee70

P

t

up to 93% ee70 \

4

P

941

h

up to 97% ee7' 0

M = Na)

COOBn COOBn up to 92% ee5'

up to 93% ee69

(Ln = pr, M = K)

LSB(Ln = La, M = Na) M-0

0-M

0

hydrophosMichael LSB

\ up to 98% ee68

\

hydrophosphonylation /PB (Ln = La, M = K)

epoxidation La or Yb alkali metal free complex

H"CHPh2

up to 94% ee@ Scheme 13

COOEt

0 up to 93% ee64

942

Shibasaki/Yamadu/Yoshikawa

Table 17

” n

71 (20 mol Yo) : o + CH3N02 ArAN-PPh2 (5 equlv) toluene /THF (7:l) H

ll

Ar/+N,PPh2

72

-40 “C

Entrya

Ar

1

Ph 4-CI-Ph

2

3 4 5

ptolyl 2-fury1 2-thiophenyl

73

lmines Products Time (h) Yield (“A)ee (“YO)

72a 72b 72c 72d 72e

73a 73bb 73cb 73db 73eb

60 60 168 168 168

79 93 85 57 41

91 87 89 83

69

Nitromethane was added over 27 h. bThe absolute configuration was tentatively assigned. a

(R)-binaphthol

References 1. Recent reviews, (a) T. Nakai and K. Tomooka in Lewis Acid Reagents (Ed.: H. Yamamoto), Oxford University Press, New York, 1999, 203-223. (b) T. Nakai, S. Kobayashi, H. Ishitani, S. Matsubara, K. IJtimoto, M. Shibasaki, H. Sasai and T. Arai, Kikan Kagaku Sosetsu 1998,37,79-129. 2. For reviews, see a) S. Kobayashi, Synlett 1994,689-701; b) W. Xie, Y. Jin, P. G. Wang, CHEMTECII 1999,29, 23-29. 3. a) S. Kobayashi, Chem. Lett. 1991, 2087-2090; b) S. Kobayashi, I. Hachiya, Tetrahedron Lett. 1992, 33,1625-1628; c) S. Kobayashi, I. Hachiya, J. Org. Chem. 1994,59,3590-3596. 4. a) E. Keller, B. L. Feringa, Tetrahedron Lett. 1996,37, 1879-1882; b) E. Keller, B. L. Feringa, Synlett 1997,842-844. 5. a) L. -B. Yu, D.-P. Chen, P. G. Wang, Tetrahedron Lett. 1996, 37, 2169-2172; b) L. -B. Yu, J. Li, J. Ramirez, D.-P. Chen, P. G. Wang, J. Org. Chem. 1997,62,903-907. 6. L. -B. Yu, D. -P. Chen, J. Li, J. Ramirez, P. G. Wang, J. Org. Chem. 1997,62,208-211. 7. D. -P. Chen, L. -B. Yu, P. G. Wang, Tetrahedron Lett. 1996,37,44674470. 8. S. Kobayashi, S. Nagayama, T. Busujima, J. A m . Chem. Soc. 1998,120,8287-8288. 9. K. Mikami, M. Terada, ‘r.Nakai, J. Org. Chem. 1991,56,5456-5459. 10. a) K. Utimoto, T. Takai, Y. Kasuga, S. Matsunaga, Appl. Organomet. Chem. 1995, 9, 413419; b) S. Matsubara, T. Takai, K. Utimoto, Chem. Lett. 1991,1447-1450. 11. For the epoxide opening reactions, see a) S. Matsubara, H. Onishi, K. Utimoto, Tetrahedron Lea. 1990, 31, 6209-6212; for the aziridine opening reactions, see b) S. Matsubara, T. Kodama, K. Utimoto, Tetrahedron Lett. 1990,31,6379-6380. 12. a) S. Kobayashi, S. Nagayama, J. Org. Chem. 1997,62,232-233; b) S. Kobayashi, S. Nagayama, J. Am. Chem. Soc. 1997,119,10049-10053. 13. M. Terada. J. -H. Gu, D. C. Deka, K. Mikami, T. Nakai, Chem. Lett. 1992,29-32. 14. A. E. Vougioukas, H. B. Kagan, Tetrahedron Left.1987,28,5513-5516. 15. H. Kobayashi, J. Nie, T. Sonoda, Chem. Lett. 1995,307-308. 16. A. E. Vougioukas, H. B. Kagan, Tetrahedron Lett. 1987,28,6065-6068. 17. Y. Yang. D. Wang, Synlett 1997,1379-1380. 18. B. K. Shull, T. Sakai, M. Koreeda, J. Am. Chem. Soc. 1996,118,11690-11691.

Lanthanide Lewis Acids Catalysis

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19. a) M. V. Deaton, M. A. Ciufolini, Tetrahedron Lett. 1993, 34, 2409-2412; b) M. A. Ciufolini, M. V. Deaton, S. Zhu, M. Chen. Tetrahedron 1997,53,16299-16312. 20. a) J. H. Forsberg, T. M. Balasubramanian, V. T. Spaziano, J. Chem. Soc., Chem. Commun. 1976, 1060-1061; b) J. H. Forsberg, V. T. Spaziano, T. M. Balasubramanian, G. K. Liu, S. A. Kinsley, C. A. Duckworth, J. J. Poteruca, P. S. Brown, J. L. Miller,J. Org. Chem. 1987,52,1017-1021. 21. S. Matsubara, M. Yoshioka, K. Utimoto, Chem. Lett. 1994,827-830. 22. M. Meguro, N. Asao, Y. Yamamoto, Tetrahedron Lett. 1994,35,7395-7398. 23. a) V. K. Aggarwal, G. J. Tarver, R. McCague, Chem. Commun. 1996,2713-2714; b) V. K. Aggarwal, A. Mereu, G. J. Tarver, R. McCague,J. Org. Chem. 1998,63,7183-7189. 24. S. Kobayashi, H. Ishitani, M. Ueno, Synlett 1997,115-116. 25. S. Kobayashi, H. Ishitani, S. Nagayama, Chem. Lett. 1995,423. 26. S. Kobayashi, H. Ishitani, S. Nagayama, Synthesis 1995,1195-1202. 27. S. Kobayashi, H. Ishitani, S. Komiyama, D. C. Oniciu, A. R. Katritzky, Tetrahedron Lett. 1996,37, 3731-3734. 28. a) S. Kobayashi, R. Akiyama, M. Kawamura, H. Ishitani, Chem. Lett. 1997, 1039-1040; b) S. Kobayashi, R. Akiyama, Tetrahedron Lett. 1998,39,9211-9214. 29. S. Nagayama, S. Kobayashi, Chem. Lett. 1998,685-686. 30. For an excellent review of Diels-Alder reactions, see: H. B. Kagan, 0. Riant, Chem. Rev. 1992, 92, 1007-1 019. 31. M. Bednarski, C. Maring, S. Danishefsky, Tetrahedron Lett. 1983,24,34.5-3454. 32. a) S. Kobayashi, I. Hachiya, H. Ishitani, M. Araki, Tetrahedron Lett. 1993, 34, 45354538; b) S. Kobayashi, H. Ishitani, I. Hachiya, M. Araki, Tetrahedron 1994,50,11623-11636. 33. a) S. Kobayashi, H. Ishitani, J. A m . Chem. Soc. 1994,116,4083-4084. For other examples of syntheses of both enantiomers using same chiral source, see: b) T. Yamada, K. Imagawa, T. Nagata, T. Mukaiyama, Chem. Lett. 1992, 2231-2234; d) G. Desimoni, G. Faita, A. G. Ivernizzi, P. P. Righetti, Tetrahedron, 1997,53,7671-7688. 34. S. Kobayashi, H. Ishitani, M. Araki, I. Hachiya, Tetrahedron Lett. 1994,35,6325-6328. 35. I. E. Marko, I. ChellC-Regnaut, B. Leroy, S. L. Warriner, Tetrahedron Lett. 1997,38,4269-4272. 36. T. Hanamoto, H. Furuno, Y. Sugimoto, J. Inanaga, Synlett 1997,79-80. 37. K. Mikami, 0. Kotera, Y. Motoyama, H. Sakaguchi, Synlett 1995,975-977. 38. H. Ishitani, S. Kobayashi, Tetrahedron Lett. 1996,37,7357-7360. 39. A. I. Sanchez-Blanco, K. V. Gothelf, K. A. Jgrgensen, Tetrahedron Lett. 1997,38,7923-7926. 40. S. Kobayashi, M. Kawamura, J. A m . Chem. SOC.1998,120,5840-5841. 41. M. Kawamura, S. Kobayashi, Tetrahedron Lett. 1999,40,3213-3216. 42. For recent examples of catalytic asymmetric Mukaiyama-aldol reactions, see: a) S. E. Denmark, R. A. Stavenger, K. -T. Wong, X. Su, J. A m . Chem. Soc. 1999,121,4982-4991; b) A. Yanagisawa, Y. Malsumolo, K. Asakawa, H. Yamamolo, J. A m . Chem. Soc. 1999,121,892-893; c ) D. A. Evans, M. C. Kozlowski, J. A. Murry, C. S. Burgey, K. R. Campos, B. T. Connell, R. J. Staples, J. Am. Chem. Soc. 1999,121,669-685; d) D. A. Evans, C. S. Burgey, M. C. Kozlowski, S. W. Tregay, J. Am. Chem. Soc. 1999, 686-699; e) J. Kruger. E. M. Carreira, J. Am. Chem. Soc. 1998, 120, 837-838. For reviews, see: f) S. G. Nelson, Tetrahedron; Asymmetry 1998, 9, 357-389; g) H. Groger, E. M. Vogl, M. Shibasaki, Chem. - E m J. 1998,4,1137-1141. 43. K. Uotsu, H. Sasai, M. Shibasaki, Tetrahedron: Asymmetry 1995,6,71-74. 44. H. Steinhagen, G. Helmchen, Angew. Chem. Znt. Ed. Engl. 1996,35,2339-2342. 45. M. Shibasaki, H. Sasai, T. Arai, Angew. Chem. Int. Ed. Engl. 1997,36,1236-1256. 46. H. Sasai, T. Suzuki, S. Arai, T. Arai, M. Shibasaki,.l. Am. Chem. Soc. 1992,114,4418-4420. 47. H. Sasai, T. Suzuki, N. Itoh, M. Shibasaki, Tetrahedron Lett. 1993,34,851-854. 48. H. Sasai, T. Suzuki, N. Itoh, S. Arai, M. Shibasaki, Tetrahedron Lett. 1993,34,2657-2660. 49. H. Sasai, S. Watanabe, M. Shibasaki, Enantiomer 1997,2,267-271. 50. H. Sasai, T. Suzuki, N. Itoh, K. Tanaka, T. Date, K. Okamura, M. Shibasaki, J. A m . Chem. Soc. 1993,115,10372-10373. 51. H. Sasai, T. Arai, Y. Satow, K. N. Houk, M. Shibasaki, J. Am. Chem. Soc. 1995,117,6194-6198, 52. E. Takaoka, N. Yoshikawa, Y. M. A. Yamada, H. Sasai, M. Shibasaki, Heterocycbs 1997,415,157-163. 53. H. C. Aspinall, J. L. M. Dwyer, N. Greeves, A. Steiner, Organometallics 1999,18,1336. 54. Purchased from Kojundo Chemical Laboratory Co. Saitama, Japan. 55. H. Sasai, N. Itoh, T. Suzuki, M. Shibasaki, Tetrahedron Lett. 1993,34,855-858. 56. H. Sasai, Y. M. A. Yamada, T. Suzuki, M. Shibasaki, Tetrahedron 1994, 50, 12313-12318. 57. H. Sasai, T. Suzuki, N. Itoh, M. Shibasaki, Appl. Organomet. Chem. 1995,9,421-426. 58. H. Sasai, T. Tokunaga, S. Watanabe, T. Suzuki, N. Itoh, M. Shibasaki, J. Org. Chem. 1995,60,73887389. 59. H. Sasai, W.-S. Kim, T. Suzuki, M. Shibasaki, M. Mitsuda, J. Hasegawa, J. Ohashi, Tetrahedron Lett. 1994,35,6123-6126.

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60. T. Arai, Y. M. A. Yamada, N. Yamamoto, H. Sasai, M. Shibasaki, Chem. -EUKJ. 1996,2,1368-1372. 61. W.-D. Fessner, A. Schneider, H. Held, G. Sinerius, C. Walter, M. Hixon, J. V. Schloss, Angew. Chem. Int. Ed. Engl. 1996,35,2219-2221. 62. Y. M. A. Yamada, N. Yoshikawa, H. Sasai, M. Shibasaki, Angew. Chem. Int. Ed. Engl. 1997, 36, 1871-1873. 63. N. Yoshikawa, Y. M. A. Yamada, J. Das. H. Sasai, M. Shibasaki,J Am. Chrm. Soc. 1999,121,41684178. 64. H. Sasai, E. Emori, T. Arai, M. Shibasaki, Tetrahedron Lett. 1996,37,5.561-5.564. 6.5. H. Sasai, M. Bougauchi, T. Arai, M. Shibasaki, Tetrahedron Lett. 1997,38,2717-2720 66. a) M. Bougauchi, S. Watanabe, T. Arai, H. Sasai, M. Shibasaki, J. Am. Chem. Soc. 1997, 119, 23292330; b) S. Watanabe, Y. Kobayashi, T. Arai, H. Sasai, M. Bougauchi, M. Shibasaki, Tetrahedron Lett. 1998, 39, 7353-7356; c) S. Watanabe, T. Arai, H. Sasai, M. Bougauchi, M. Shibasaki, J. Org. Chem. 1998,63,8090-8091. 67. H. Sasai, S. Arai, Y. Tahara, M. Shibasaki, J. Org. Chem. 1995,60,6656-6657. 68. a) H. Groger, Y. Saida, S. Arai, J. Martens, H. Sasai, M. Shibasaki, Tdrahedron Lett. 1996, 37, 9291-9292; b) H. Groger, Y. Saida, H. Sasai, K. Yamaguchi, J. Martens, M. Shibasaki, J. Am. Chem. Soc. 1998,120,3089-3103. 69. K. Yamakoshi, S. J. Harwood, M. Kanai, M. Shibasaki, Tetrahedron Lett. 1999,40,2.56.5-2568. 70. E. Emori, T. Arai. H. Sasai, M. Shibasaki, J. Am. Chem. Soc. 1998,120,40434044. 71. K. Funabashi, Y. Saida, M. Kanai, T. Arai, H. Sasai, M. Shibasaki, Tetrahedron Lett. 1998, 39, 73.53-1356. 72. K. -i. Yamada, S. J. Harwood, H. Groger, M. Shibasaki, Angew. Chem. Int. Ed. 1999,38,3504-3506.

Lewis Acids in Organic Synthesis Edited bv Hisashi Yamarnoto Copyright 0WILEY-VCH Verlaa GmbH.2000

21 Polymer-Supported Metal Lewis Acids Shinichi Itsuno

21.1 Introduction After Merrifield’s pioneering work on solid-phase peptide synthesis [l],not only the construction of various new compounds on polymer supports, but also the application of polymer-supported reagents and catalysts in organic chemistry has also received much attention [2]. The use of polymer-supported catalysts and reagents as an aid to organic synthesis has stimulated significant interest and is becoming an increasing common feature in synthesis laboratories. Their importance has apparently increased as a result of rapid progress in combinatorial chemistry in pharmaceutical and agrochemical research. Recent interest in combinatorial synthetic methodology promoted a study of polymersupported reactions including the use of polymeric reagents and catalysts. Polymer-supported methodologies are now indispensable for satisfying the requirements of new environmental legislation and the drive towards clean technology. Polymeric catalysts are convenient to use, non-corrosive, non-toxic, and easy to separate from the reaction mixture; they can be reused many times without loss of their catalytic activity. The ease of removal of polymeric catalysts by filtration makes them an attractive alternative to conventional solution methods. Another expected advantage is the ‘polymer effect’ which might enhance the activity of the catalyst by site isolation or, in contrast, as a result of cooperative effects from neighboring groups. Suitable loading of the catalytic site and the amount of crosslinking should, therefore, be determined for each catalyst. The tendency of the crosslinked polymer to swell has a very large effect on catalytic activity. This can be controlled by the polymerization conditions. The structure of the crosslinking agent also has an important influence on catalytic activity. One drawback of crosslinked polystyrene is its low mechanical strength at the divinylbenzene concentrations used for the synthesis of porous polystyrenes. Recently divinyl monomers with a flexible structure have been introduced as alternatives to divinylbenzene. The major disadvantages of polymer-supported catalysts are the difficulty of analysis of polymeric species, the reduced reaction rates because of the heterogeneity of the reactions, and their greater expense because of extra synthetic steps required to prepare and use them. The most common polymeric supports are crosslinked polystyrene beads which are prepared by suspension polymerization. Two different types of polystyrene bead can be prepared. One is macroreticular (highly porous) and another is microporous (gel type) resins. Microporous resins have a large surface area and it is usually these which are used to prepare polymer-supported reagents or catalysts. Although soluble polymers also can be used as supports, separation of the supports usually requires precipitation or ultrafiltration. The structure and morphology of polymer supports and their physicochemical properties have recently been described by Sherrington [3]. Although Lewis acids are very useful in many organic reactions, they do have certain drawbacks. For example, A1C13 decomposes when exposed to moisture, tends to dimerize when dissolved, and often forms a suspension of Al(OH)3 during reaction work-up. Polymer-supported versions of metal Lewis acids have become important. If

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crosslinked polymers are to be used as polymer-supported Lewis acid catalysts, the polymers should be functionalized to enable attachment of the metal Lewis acid. A variety of reactive groups can be introduced to the crosslinked polymer by chemical modification; this route is particularly attractive with polystyrene-based supports because their aromatic rings can be modified easily by simple reactions to give a variety of functionalities. Among these, halomethylation [4] and metalation [5-81 are particularly important reactions in the preparation of reactive polymers [9,10], because of the ease with which displacement or addition reactions can be performed on halomethylated polystyrene or on metalated polystyrene. Although the chemical modification approach has been successfully applied to the preparation of number of functional polymers, care must be taken to avoid undesired side reactions on the polymer. In chemical modification reactions on a polymer, any side reaction which occurs can result in the permanent attachment of undesired functionalities to the polymer. Incomplete reactions during chemical modification sequences also afford a polymer containing at least two distinguishable functionalities. These undesired functionalities can reduce the effectiveness of the final polymeric catalyst. Another approach to the preparation of polymer-supported metal Lewis acids is based on polymerization of functional monomers. If synthesis of the functional monomer is not difficult, polymerization should afford structurally pure functional polymers. because the polymer formed requires no further complicated chemical modification. A variety of substituted styrene monomers are now commercially available; styrene monomers with an appropriate ligand structure can be prepared from these. Several other interesting functional monomers such as glycidyl methacrylate, 2-hydroxyethyl methacrylate, and other acrylics have also been used extensively to prepare functional polymers. In this chapter recent developments in the use of polymer-supported metal Lewis acids in organic synthesis will be discussed. Although most consist of crosslinkcd polystyrene-based supports, other organic polymers and inorganic supports are included as support materials.

21.2 Polymer-Supported Aluminum Chloride Aluminum chloride and its derivatives are the most familiar Lewis acids and are routinely employed in many Lewis acid-promoted synthetic transformations. The first polymer-supported metal Lewis acids to be studied were polymers attached by weak chemical or physical interactions to a Lewis acid. In the 1970s Neckers and coworkers reported the use of styrene-divinylbenzene copolymer-supported AlC13 or BF3 as catalyst in condensations, esterifications, and acetalization of alcohols [11,12]. This type of polymer-supported AlC13 (1) is readily prepared by impregnation of a polystyrene resin with AlC13 in a suitable solvent. Subsequent removal of the solvent leaves a tightly bound complex of the resin and AlC13. The hydrophobic nature of polystyrene protects the moisture-sensitive Lewis acid from hydrolysis, and in this form the Lewis acid is considerably less sensitive to deactivation by hydrolysis. This polymer complex could be used as a mild Lewis acid catalyst for condensation of relatively acid-sensitive dicyclopropylcarbinol to an ether (Eq. 1) [13].

Polymer-Supported Metal Lewis Acids

2

Y

1

HC-OH

*

60 "C, 90 min MeOH

Y Y

HC-0-CH

A h

947

(1)

90.4% 1

In solution, combination of Bronsted acids with Lewis acids gives superacids, which are particularly useful in a variety of organic transformations in organic synthesis [14]. Reaction of A1Cl3 with sulfonic acid ion-exchange resins gives polymeric superacids 2, which are capable of protonating hydrocarbons [15]. One drawback of the such polystyrene-based catalysts is their instability because of their enhanced acidity. More stable polymeric superacids have been prepared from Nafion-H and AlC13. These catalysts have been used as highly active catalysts in many organic reactions, for example the cracking and isomerization of hydrocarbons, nitration, rearrangement, FriedelCrafts reactions, and esterification [2f]. Another approach to the use of polymer-supported aluminum Lewis acids is the use of hydroxylated propylene. Ziegler-Natta polymerization of boron-containing monomer and propylene followed by oxidation with NaOH/HzOz gave the hydroxylated polypropylene 3. Lewis acids such as EtAIClz are covalently attached to the side-chain of the polypropylene (Eq. 2), and served as catalyst for the cationic polymerization of isobutylene [16]. In this example aluminum chloride was attached to the polymer by an alkoxide linkage. High surface area and good mobility of the polymeric catalyst can result in quite high catalytic activity. It should also be noted that a high molecular weight (Mw = 120 000, Mn = 49 100) was achieved at 4 5 "C by using 4 as catalyst. This polymeric catalyst could be recycled many times without significant loss of its activity. Polymer-supported aluminum-based Lewis acids have also been prepared and used for several other reactions including Diels-Alder and aldol reactions: these will be discussed in Sections 21.10 and 21.11.

AIC13

2

3

I OH

I

4

OAIC12

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Itsuno

Both organic and inorganic polymeric support materials have been used. For example, alumina exposed to aluminum chlorides 5 (Eq. 3) are solid superacids with Lewistype acid behavior [17]. In the presence of those catalysts hexane isomerized to give methylpentanes and dimethylbutanes. Other A1C12-functionalized catalysts have been prepared on S O z , high silica zeolite, and Bz03 [18]. The catalysts were always much more active than the untreated support. Alkylation of aromatics by alkenes and chloroalkanes have been catalyzed by heterogeneous A1Cl3 prepared from Si02, montmorillonite, or alumina. The activity is comparable with that of unsupported AlC13 and the selectivity toward the formation of monoalkylates is considerably better than under homogeneous conditions [19].

-OH -OH -OH

A12C1,j

-

Reflux

(3)

P

cc14

5

alumina, silica

Aluminum chloride supported oninorganic solids

21.3 Polymer-Supported Ti(1V) The catalytic activity of Ti(1V) chloride and its derivatives in several reactions has been well studied. Simple polymer-supported Ti(1V) chloride was prepared as a polymeric Lewis acid catalyst by chemical modification of crosslinked polystyrene as shown in Sch. 1 [20]. Direct lithiation of the polystyrene then addition of Tic& gave the polymeric TiC127, whereas use of polymeric phenyl Grignard reagent 8 prepared by a lithium-magnesium exchange reaction afforded the TiC13-bearing polymeric species 9. Polymeric Grignard reagents can be prepared by the anthracene-Mg method [21]. Figure 1shows a schematic representation of the structure of polymer-supported Ti(1V) chlorides. This catalyst was used for several organic reactions, for example esterification, acetalization, and ketal formation.

Polymer-Supported Metal Lewis Acids

949

TiCI4

6

-4h

tcz TiCI4 ___)

MgBr 8 Scheme 3

Figure 1

Ti alkoxides are also important titanium-based Lewis acids in a variety of organic reactions. Although titanates have usually been employed as homogeneous catalysts, their removal by hydrolysis and filtration is often tedious. The tri(2-chloroisopropyl0xy)titanium moiety was attached to a macroporous polymeric support by chemical modification of a poly(4-hydroxystyrene-co-styrene-co-divinylbenzene) resin with the corresponding chlorotrialkyltitanate. The reactivity and stability of polymer-supported titanates 10 as catalysts for transesterifications have been demonstrated [22]. High catalytic activity was achieved in the transesterification of methyl methacrylate with a high boiling point alcohol, 2-ethylhexanol (Ey. 4).

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Itsuno

Other important titanium alkoxide-based Lewis acids are Ti-TADDOLate (w,a,a’,a’-tetraaryl-l,3-dioxolane-4,5-dimethanol)ates, among the most effective chiral catalysts for several important asymmetric reactions. These will be discussed in the sections on polymer-supported Diels-Alder reactions (Section 21.10) and alkylations (Section 21.9).

21.4 Polymer-Supported Fe(II1) Complex Metal complexes of pyridyl tridentate ligands such as tri(2-pyridy1)methane and tri(2pyridy1)methanol have been extensively studied. To enable more efficient use of the ligands in catalytic reactions, polymer-supported ligands such as 11 and 12 were prepared. The Fe(II1) complexes of the polymer-supported tridentate ligands were used as Lewis acid catalysts in the ring opening of styrene oxide (Eq. 5 ) [23]. The polymeric complex was an efficient catalyst for the reaction, although with slightly lower reactivity than the monomeric analog (13).

-sJh 11

13

Polymer-Supported Metal Lewis Acids

951

reaction time required to obtain complete conversion 12: 45 min 13:<30 min

Salicylic acid resin has also been used as a polymeric support material for FeC13 Lewis acid [24]. This catalyst had high catalytic efficiency in ester synthesis and acetalization. Cationic exchange resins have been used as supports for FeC13. In esterification the catalytic activity of polymeric complexes prepared from porous type resins was much higher than that of complexes prepared from gel type resins [25].

21.5 Polymer-Supported Boron Derivatives Boron trifluoride-diethyl ether complex is a very versatile and useful Lewis acid in several organic reactions. The polymeric ether-BF3 complex poly(p-methoxystyrene)-BF3 (14) has been prepared and is more stable and has higher activity in several organic reactions such as isomerization and epoxide rearrangement [26]. The polymeric version of pyndine-BF3 complex 15 has also been prepared from poly(viny1pyridine) and BF3 [27]. By analogy with the polystyrene-A1C13 complex, simple crosslinked polystyrene also forms a stable complex in chloroform with boron trifluoride 16 [27].

14

15

16

These examples of polymeric catalysts support the Lewis acid BF3 as a pendant group as a result of relatively weak interaction between the polymer support and BF3. Boron can be incorporated into the polymer by covalent bonding to give boron polymers. Some boron-containing polymers can be prepared by methods including the hydroboration, haloboration, and allylboration polymerization developed by Chujo [28-301. These polymers are considered to be poly(Lewis acids). For example, diacetylenic compound 17 reacts repeatedly with boron tribromide to give the corresponding boron-containing polymer 18 (Eq. 6). The BBr-containing polymer has bccn used for ether-cleavage reactions. Polymers with side-chain boron functionality, 20 have been prepared by ZieglerNatta polymerization of boron-containing a-olefins 19 as shown in Eq. (7) [31]. These polymers are not merely polymeric Lewis acids-they can also can be transformed to a variety of functionalized polymers [32].

952

Itsuno

YI

18

21.6 Polymer-Supported SnC14 Stannic chloride has been attached to monomers 21 containing ester (21a), carbazole (21b), pyrrolidone (21c), nitrile (21d) and pyridine (21d) moieties. The polymeric ligands were prepared by copolymerization of styrene, divinylbenzene and functional monomers such as methyl methacrylate, N-vinylcarbazole, N-vinylpyrrolidone, acrylonitrile and 4-vinylpyridine [33]. These polymers were treated with stannic chloride in chloroform to afford the corresponding polymer-supported stannic chloride complexes (Eq. 8). These polymeric complexes have been used as catalysts for such organic reactions including esterification, acetalization, and ketal formation. These complexes had good catalytic activity in the reactions and could be reused many times without loss of activity. Their stability was much better than that of plain polystyrene-stannic chloride complex catalyst. 21a: R1=Me, R2=-COOMe

21

21e: R1=H, R2=

21

+

SnCI4

-

*

Polymer supported SnCI4

(8)

Polymer-Supported Metal Lewis Acids

953

21.7 Polymer-Supported Cu(I1) Several types of copper-loaded polymer have been prepared. Hydrocarbon spacers were introduced between polystyrene and copper (23). Six synthetically useful copper-promoted reactions including a Diels-Alder reaction, an epoxide ring-opening, and an aryl iodide hydrolysis were examined by using the polymeric catalyst [34]. Use of the copper-loaded polymers often either improved the yield or reduced the reaction time compared with those for conventional copper salts.

Me',

N '

J'

R

22

21.8 Polymer-Supported Oxazaborolidines Oxazaborolidines have been found to be a unique catalyst for asymmetric borane reduction of ketones and imines [35,36]. Coordination of BH3 to the nitrogen atom of 24 serves to activate BH3 as a hydride donor and to increase the Lewis acidity of the boron atom (Eq. 9). The Lewis acidity of the boron atom in the oxazaborolidine plays an important role in the reduction. Several types of polymer-supported oxazaborolidine have been reported and are considered to be polymer-supported boron-based Lewis acids.

RrJR" -

R~-N,

/o

?R'

BH3

-

R~-N J

H3B

/o

'0 Rl

(9)

25

24

Oxazaborolidine

The first report of a polymer-supported oxazaborolidine appeared in 1985 [37]. The polymer-supported chiral ligand amino alcohol (27) was prepared by reaction of chloromethylated polystyrene resin and enantiopure amino alcohol 26 with a phenolic hydroxyl group (Eq. 10). Borane reduction of ketones by use of polymer-supported oxazaborolidines proceeded very smoothly to give the corresponding chiral alcohol in quantitative yield. For example, the reduction of butyl phenyl ketone afforded l-phenylpentan-1-01 in 97 % ee (27, Eq. 11). This is somewhat higher than that obtained by

954

Itsuno

use of a low-molecular-weight catalyst in solution (28, 93 % ee). The same polymeric oxazaborolidine was also used successfully for the asymmetric reduction of oxime ethers (Eq. 12) [38]. The polymeric catalyst afforded near-perfect enantioselectivity (99 % ee). In this reaction the polymeric chiral ligand was prepared by suspension polymerization of chiral monomer, styrene, and divinylbenzene as shown in Eq. (13). A linear copolymer of 28 with styrene was also prepared by solution polymerization. Somewhat lower ee was obtained with the linear polymeric catalyst.

27

29

27: 97% ee 28: 93% ee (using low molecularweight catalyst)

27

N,OMe

+

PhABu

BHs-THF

NHZ

-

PhABu 99% ee

(I2’

Polymer-Supported Metal Lewis Acids

955

29

On hydrolytic work-up the polymer-supported oxazaborolidines are decomposed to the polymer-supported amino alcohol, which could be easily separated and reused. Before work-up, however, the polymer and the product in solution can be separated when the polymer is crosslinked. The polymeric catalyst can then be used many times without regeneration [39,40]. One of the most attractive methods of asymmetric synthesis with polymer-supported catalysts might be to use a flow system in which the chiral product can be produced continuously. Because free borane reduction of ketone in solution can occur smoothly to give racemic product, care must be taken to avoid the uncatalyzed reduction during reaction in the flow system. Such a continuous flow system has been successfully achieved by careful introduction of borane and ketone into a column filled with polymer-supported catalyst [39]. By this method the optically active product can be obtained continuously without regeneration of the polymeric catalyst. Another advantageous feature of this system is elimination of damage to the polymeric catalyst, because no stirring is required. Breakdown of the polymer support to a fine powder as a result of vigorous stirring results in a serious problem during separation by filtration. Mechanical strength is important factor, especially when the polymeric catalysts are recycled many times in batch system. The above mentioned polymer-supported oxazaborolidines are prepared from polymeric amino alcohols and borane. Another preparation of polymer-supported oxazaborolidines is based on the reaction of polymeric boronic acid with chiral amino alcohol. This type of polymer can be prepared only by chemical modification. Lithiation of the polymeric bromide then successive treatment with trimethyl borate and hydrochloric acid furnished polymer beads containing arylboronic acid residues 31. Treatment of this polymer with (lR,2S)-(-)-norephedrine and removal of the water produced gave the polymer-supported oxazaborolidine 32 (Eq. 14) [41-43]. If a,a-diphenyl-2-pyrrolidinemethano1 was used instead of norephedrine the oxazaborolidine polymer 33 was obtained. The 2-vinylthiophene-styrene-divinylbenzenecopolymer, 34, has been used as an alternative to the polystyrene support, because the thiophene moiety is easily lithiated with n-butyllithium and can be further functionalized. The oxazaborolidinone polymer 37 was then obtained as shown in Sch. 2. Enantioselectivities obtained by use of these polymeric oxazaborolidines were similar to those obtained by use of the low-molecular-weight counterpart in solution. For instance, acetophenone was reduced enantioselectively to l-phenylethanol with 98 % ee in the presence of 0.6 equiv. polymer 33. Partial elimination of

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Itsuno

the chiral ligand from this type of polymeric oxazaborolidine, can, however, occur during hydrolytic work-up. This might lead to reduced selectivity, which would be a serious problem, especially for recycling uses.

norephedrine

32

Ph Ph

33

The polymeric oxazaborolidine prepared from the linear copolymer of 29 and styrene was used in membrane reactor and resulted in high total turnover number with high enantioselectivity [44]. Another polystyrene-based soluble polymeric oxazaborolidine 38 was used in the same system. Polysiloxanes are also useful polymeric supports of catalyst 39 for the same purpose [45].

Polymer-Supported Metal Lewis Acids

-c-13-

35 34

/

norephedrine

H20/Hf

36

3-$I-

3%-$I-

norephedrine f i H Ph

957

Me

37

Scheme 2

*

Ph

Ph

Ph

H

39

38

21.9 Polymer-Supported Dialkylzinc The slow nucleophilic addition of dialkylzinc reagents to aldehydes can be accelerated by chiral amino alcohols, producing secondary alcohols of high enantiomeric purity. The catalysis and stereochemistry can be interpreted satisfactorily in terms of a sixmembered cyclic transition state assembly [46,47]. In the absence of amino alcohol, dialkylzincs and benzaldehyde have weak donor-acceptor-type interactions. When amino alcohol and dialkylzinc are mixed, the zinc atom acts as a Lewis acid and activates the carbonyl of the aldehyde. Zinc in this amino alcohol-zinc complex is regarded as a kind of chirally modified Lewis acid. Various kinds of polymer-supported chiral amino alcohol have recently been prepared and used as ligands in dialkylzinc alkylation of aldehydes.

958

Itsuno

The first report of a polymer-supported approach to this reaction appeared in 1987 [48]. Enantiopure amino alcohols such as ephedrine, prolinol, and 3-exo-aminoisoborneol were attached to Merrifield polymer. The use of polymer-supported 3-exoaminoisoborneol40 resulted in quite high enantioselectivity (-95 % ee) in the ethylation of aldehydes with diethylzinc (Eq. 15), a result comparable with those obtained from the corresponding low-molecular-weight catalyst system (Eq. 16). A similar system was also reported in 1989, this time using ephedrine derivatives (41,42) and prolino1 derivative (43) [49]. A methylene spacer was introduced between the polymer and the amino alcohol to improve activity [50]. Despite this the selectivity was always somewhat lower than that obtained from the low-molecular-weight catalyst (44). These chiral polymers were all prepared by the chemical modification method using Merrifield polymer.

Toluene, 0" Ar

T

Et

(15)

Ar = 2-OEtPh; 92%, 95% ee Ar = Ph; 91%, 92% ee

40

OH PhCHO

+

ZnEt2

-

Ph&Et

R = Me; 83%, 89% ee in eq. 16

(16'

91Yo,82% ee in eq. 16

959

Polymer-Supported Metal Lewis Acids

Bn ,

o

" T P h N Me

44 43

88%, 99% ee in eq. 16

HOfPh Ph

91Yo,61% ee in eq. 16

Polymer-supported chiral a,a-diphenylamino alcohol (27) has also been used for the enantioselective alkylation of aldehydes using dialkylzinc. Its catalytic activity was improved by the crosslinking structure. The degree of crosslinking and the structure of the crosslinking agent influenced the activity and selectivity of the polymeric catalyst. It is sometimes pointed out that one of the practical drawbacks of styrene-divinylbenzene copolymers is their low mechanical strength. If the spherical beads are not sufficiently stable to withstand stirring over a long period of time, their breakdown during stirring will result in the formation of a fine powder, which drastically hinders their handling during filtration and reduces the possibility of their being reused repeatedly. New divinyl monomers have been developed as crosslinking agents to replace divinylbenzene in the synthesis of polymeric supports [51-531. Chiral amino alcohol-bearing polymer (45) crosslinked with an oligo(oxyethy1ene) chain had excellent activity in the ethylation of 4-chlorobenzaldehyde (95 %, 99 YOee) [54]. As mentioned in Section 21.8, flow reaction systems employing supported chiral catalyst have many advantages in organic synthesis. Polymers 41 (R = Me) [55] and 45 [54]have been used successfully in continuous-flow systems (Eq. 17).

45

n

OH 45, ZnEt2 Toluene, 0"

CI 95%, 99% ee

~

Chiral amino alcohols can be prepared by reaction of chiral epoxides with amines. Enantiopure (2S,3R)-2,3-epoxy-3-phenylpropanol anchored to Merrifield resin has been used for ring-opening with secondary amines in the presence of lithium perchlorate to afford polymer-supported chiral amino alcohols 47 (Eq. 18) [56]. By analogy, (2R,3S)-3-(cis-2,6-dimethylpiperidino)-3-phenyl-l,2-propanediol has been anchored to a 2-chlorotrityl chloride resin (48). Although this polymer had high catalytic activity in the enantioselective addition of diethylzinc to aldehydes, the selectivity of the corresponding monomeric catalyst was higher (97 % ee) in the same reaction.

OH

46

47

48

99%, 94% ee in eq. 16

Enantiopure disulfonamide ligand 49 and Ti(1V) isopropoxide were reported to catalyze the reaction of aldehydes with diethylzinc [57]. Quite high catalytic activity was obtained with 49. The corresponding polystyrene-based solid phase C2-symmetricchiral catalyst 50 was designed for use in the same reaction [58].The enantioselectivity obtained using the polymeric catalyst is as high as that obtained from the low-molecular-weight catalyst in solution. Longer reaction time is required for the heterogeneous system. TiTADDOLate had excellent catalytic activity in this reaction. The use of 51 resulted in almost perfect enantioselection and quantitative yield. The polymer supported TADDOLs (52) were prepared by chemical modification of Merrifield resin [59]. The polymeric Ti-TADDOLate behaved similarly in the ethylation of aldehyde. Not only polystyrene supports, also other polymer supports were used in the preparation of polymeric amino alcohol ligands for dialkylzinc alkylation. For example, a vinylferrocene derivative with N,N'-disubstituted norephedrine was copolymerized with vinylferrocene [60]. This polymeric chiral ligand (53) was used in the ethylation of aldehydes with moderate activity. Brown has reported that chiral oxazaborolidines have catalytic activity in the addition of diethyl zinc to aldehydes [61]. Polymers bearing chiral oxazaborolidines 37 were also active in the reaction and result on moderate enantioselectivity ( 4 8 % ee) (621. Enantiopure a,a'-diphenyl-L-prolinol coupled to a copolymer prepared from 2-hydroxyethylmethacrylate and octadecyl methacrylate

Polymer-Supported Metal Lewis Acids

F3C02SHN

961

NHSO2CFs

0 49

98%, 98% ee (-2OoC, 5h) in eq. 16

H N b N H 50 82%, 98% ee (-7O"C, 24h) in eq. 16

2-NaPh 2-Naph

51

99%, 99% ee in eq. 16

Pti

52 97%, 98% ee in eq. 16

has been used in the same reaction in a membrane reactor system [63,64]. In the presence of this soluble polymer catalyst (54)the addition of diethylzinc to benzaldehyde yielded (S)-1-phenylpropanol with up to 80 % ee. Because a steadily increasing number of solvent-stable membranes is now available for ultrafiltration and nanofiltration, the recovery of homogeneous polymeric catalysts is becoming easier.

Fe

Fe

53

54

PI;

-80% ee in eq. 16

85%, 72% ee in eq. 16

Bi-2-naphthols are among the most successful chiral ligands for several asymmetric catalysts. The synthesis of binaphthyl-based chiral polymers as rigid and sterically regular chiral polymers has recently been studied extensively [65-711. Some recent devel-

962

Itsuno

opments in the use of main-chain chiral polymer catalysts including binaphthyl polymers have been reviewed [72]. Some were used as polymeric chiral ligand for the reaction of aldehydes with diethylzinc [73,74]. Phenylene spacers with long alkyl ether chains are suitable catalysts for the reaction. Excellent catalytic activity was reported when the polymeric 55 was employed. The triphenylene spacer in 56 further enhanced enantioselectivity for both aromatic and aliphatic aldehydes (Sch. 3 ) .

R

R

)$ 55: 89%, 92.2% ee 56: 94%, 98% ee 56: 81Yo,98% ee (cyclohexanecarboxaldehyde)

Scheme 3

Hyperbranched and dendritic macromolecules have recently been the subject of considerable interest. Bolm developed chiral hyperbranched macromolecules 57 that catalyzed the enantioselective addition of diethylzinc to benzaldehyde [75].The enantiocontrol of the hyperbranched chiral catalysts was slightly lower than for the lowmolecular-weight catalyst. TADDOLs linked with dendritic molecules have been synthesized [59]. For example, use of the first generation dendrimer 58 with six terminal TADDOL units resulted in high enantioselectivity.

Polymer-Supported Metal Lewis Acids

-d A0b0

Pro

963

\

p pro~op Pro

0

0

J

-

pro$o

57

84%, 86% ee in eq. 16

OPr

58 26%, 94% ee in eq. 16

964

Itsuno

In addition to organic polymers, inorganic materials such as silica or alumina are also useful as supports. Chiral amino alcohol ligands bound to silica 59 have been prepared from the inorganic support functionalized with silane coupling agents [76]. Reaction rates and enantioselectivities are, however, both lower for the heterogeneous system. This result was attributed to restricted accessibility to the catalytic sites in heterogeneous catalysis.

59

silica

98%, 41% ee in eq. 16

The amino alcohol-dialkylzinc system can be applied to chiral amine synthesis. Polymer-supported ephedrine was found to be an effective chiral ligand in the reaction of N-diphenylphosphinoylimineswith diethylzinc (Eq. 19) [77-791. The polymeric catalysts were, however, less efficient than monomeric model reactions. Several dendrimeric chiral ligands containing the ephedrine moiety (60, 61) have also been synthesized and used in the asymmetric alkylation of N-diphenylphosphinyliminesby diethylzinc [SO]. Both yield and enantioselectivity of the reaction were, however, lower when the dendrimeric ligands were used.

Ph Ph

R4N.I

+ Et2Zn

Polymer-supported ephedrine 41 (R = Et)

Ph

*

(19)

P’ 0

Et

0

88% ee

PhHMe

HO Me

?-”-

0

N=\

HO Me& PF

M

e

60

Et

Polymer-Supported Metal Lewis Acids

965

61

21.10 Polymer-Supported Diels-Alder Catalysts The Diels-Alder reaction of a diene and a dienophile has become one of the most powerful carbon-carbon bond-forming processes [81]. In normal Diels-Alder reactions of an electron-poor dienophile with an electron-rich diene, the main interaction is between the HOMO of the diene and the LUMO of the dienophile. Coordination of a Lewis acid to the dienophile reduces its frontier orbital energies, and this increases the rate of the reaction. Regio- and stereoselectivity are also markedly affected by the Lewis acid. Recent extensive studies on the design of chiral Lewis acids have led to fruitful results in the control of the stereochemistry of a variety of pericyclic reactions. Several chirally modified Lewis acids have been developed for the asymmetric Diels-Alder reaction [82,83] and spectacular advances have recently been achieved in this area. Various kinds of polymer-supported chiral Lewis acid have also been developed. Polymer-supported A1 Lewis acids such as 62 have been used in the Diels-Alder reaction of cyclopentadiene and methacrolein (Eq. 20) [84] as has polymer-supported Ti alkoxide 63 [84]. These Ti catalysts are readily prepared and have high activity in the Diels-Alder reaction.

966

Itsuno

62 99%, exolendo = 8.2

0

63

The first successful examples of enantioselective Diels-Alder reactions catalyzed by chirally modified Lewis acids were reported by Koga [85]. The catalysts were prepared from menthol and AlEt2Cl [86]. Alumina-supported chiral menthoxy aluminum derivatives (64, 65, 66, 67) have been prepared by simple mixing of (-)-menthol, AIEt2CI, and alumina in toluene under reflux. The reaction of methacrolein with cyclopentadiene (Eq. 20) was conducted with 67 as catalyst at -50 "C and afforded 81 YOconversion with 31 YOee [87]; Koga reported 57 YOee at -78 "C by use of an homogeneous catalyst [85]. Solid catalyst 69, prepared from silica gel-supported prolino1 68 and AlEt2Cl (Eq. 21) is also an active catalyst in the same reaction, but with low enantioselectivity [87]. When the same catalyst was attached to crosslinked polystyrene (70) the ee in the reaction was lower [88].

R' = (1R, 2S,SR)-rnenthyl

exolendo = 90 : 10

8l%, 31% ee in eq. 20

68

69

Polymer-Supported Metal Lewis Acids

967

exo/endo = 11.2 98%, 14% ee in eq. 20

Kobayashi et al. developed chiral Lewis acids derived from N-benzyldiphenylprolino1 and boron tribromide and used these successfully as catalysts in enantioselective Diels-Alder reactions [89]. The corresponding polymeric catalyst 71 was prepared and used for the Diels-Alder reaction of cyclopentadiene with methacrolein [90]. Different polymeric catalysts 72, 73, 74 were prepared from supported chiral amino alcohols and diols functionalized with boron, aluminum and titanium [88,90]. In these polymers copolymerization of styrene with a chiral auxiliary containing two polymerizable groups is a new approach to the preparation of crosslinked chiral polymeric ligands. This chiral monomer unit acts as chiral ligand and as a crosslink.

!qh

b#

P

N ,

\

Br2B0

Ph

72

71 71: endo:exo=5:95, 96%, 54% ee

Br

B Br

73

8 : endo:exo=4:96,98%, 25% ee

968

Itsuno

The same reaction has also been catalyzed by chiral oxazaborolidinones derived from amino acids and boranes. They proved to be efficient catalysts for enantioselective Diels-Alder reaction [91,92]. The polymer-supported chiral oxazaborolidinones 75 were reported to be efficient catalysts [93]. These polymer-supported chiral oxazaborolidinone ligands were prepared both by chemical modification and by the copolymerization shown in Sch. 5 [94]. The polymer-supported chiral ligands were then reacted with borane to give the oxazaborolidines which were used as catalysts in Diels-Alder reaction of cyclopentadiene with methacrolein.

HB-0

I

75 endolexo = 4 : 96

88%, 95% ee in eq. 20

Crosslinked ClSO3H polystyrene

Crosslinking agent

IChemical modification route

Pyridine t

SOC12

+

amino acid, TMSCl

*

TEA, NMP

Divinylbenzene Polymerization route

OH 75a

OH

Scheme 5

These polymeric chiral Lewis acids are efficient catalysts of the Diels-Alder reaction, giving the corresponding adduct in high isolated yield. The enantioselectivity of low-molecular-weight chiral oxazaborolidinone catalysts in solution was reported to be temperature-dependent. Aggregation of the structure of the catalyst in non-polar solvents such as CH2Clz or toluene resulted in a dramatic reduction of enantioselectivity. Immobilization of the catalytic sites to a crosslinked polymer-support might prevent this aggregation to some extent, and the polymeric catalyst 75 in CH2C12 was indeed more enantioselective than that used in solution. In this reaction polymer-sup-

Polymer-Supported Metal Lewis Acids

969

ported catalysts prepared by the polymerization method were much more selective, and resulted in much greater reactivity, than those prepared by chemical modification of crosslinked polystyrene. A further refinement of the polymer support made it possible to realize higher enantioselectivity in the Diels-Alder reaction [95]. As has been shown in the asymmetric alkylation of aldehydes with polymer-supported zinc catalysts, the crosslinking structure strongly influences the character of the polymer support itself and the activity of the supported catalyst -flexible crosslinking resulting in higher enantioselectivity. The oligo(oxyethy1ene) crosslinked polystyrene 7% seems especially suitable as an asymmetric Diels-Alder catalyst. The polymeric catalyst with oxyethylene-chain crosslinking resulted in enantioselectivity as high as 95 YOee, a result superior to those obtained by use of the unsupported catalyst in solution. This is an unusual example of a positive polymer effect. The swelling and diffusive properties of oligo(oxyethy1ene) crosslinked polystyrenes have recently been studied [96]. A continuous flow system has also been realized by use of this polymeric catalyst. In addition to high enantioselectivity, the work-up of the product is simplified because the catalyst is retained in the column. As conversion is almost quantitative, evaporation of the solvent afforded the chiral product in high purity. Chiral oxazaborolidinones supported on silica gel 77 have been prepared as shown in Sch. 6 [87]. Although high conversion was attained with these catalysts, enantioselectivity was low (8 YOee).

silica 0

77

Scheme 6

Since the first report on Ti-TADDOLate-mediated Diels-Alder reactions [97,98] several studies of the same reaction have been reported; these have shown that TiTADDOLate is an efficient chiral Lewis acid in enantioselective Diels-Alder reactions. Polymer- and dendrimer-supported Ti-TADDOLates have been reported and their catalytic activity in several enantioselective reactions has been evaluated [59]. Various kinds of polymeric TADDOLs were prepared both by chemical modification (Eq. 22) and by copolymerization (Eq. 23).

970

Itsuno

NaH

Merrifield resin

ClpTi(OiPr)p_

DMF

HO 78

79

+

80

Styrene

+

Divinylbenzene

suspension polymerization *

ClzTi(OiPr)z *

www

Polymer-supported TADDOL-Ti catalyst 79 prepared by chemical modification was poorly active in the Diels-Alder reaction of 3-crotonoyloxazolidinone with cyclopentadiene (Eq. 24) whereas polymeric TADDOL-Ti 81 prepared by copolymerization of TADDOL monomer 80 with styrene and divinylbenzene had high activity sirnilar to that of the soluble catalyst. In the presence of 0.2 equiv. 81 (R = H, Aryl = 2naphthyl) the Diels-Alder adduct was obtained in 92 YOyield with an endolexo ratio of 87:13. The enantioselectivity of the endo product was 56 YOee. The stability and recyclability of the catalyst were tested in a batch system. The degree of conversion, the endolexo selectivity, and the enantioselectivity hardly changed even after nine runs. Similar polymer-supported Ti-TADDOLate 82 was prepared by the chemical modification method [99]. Although this polymer efficiently catalyzed the same reaction to give the (2R,3S)adduct as a main product, asymmetric induction was less than that obtained by use of a with similar homogeneous species.

Polymer-Supported Metal Lewis Acids

971

82

A related reaction, [3 + 2lcycloaddition of 3-crotonoyloxazoline to nitrones in the presence of polymer- or dendrimer-supported TiTADDOLate, has been investigated (Eq. 25).

Hetero Diels-Alder reactions between prochiral aldehydes and activated dienes such as 84 are also known to be catalyzed by Lewis acids (Eq. 26) and catalysis by chiral Lewis acids supported by dimethylpolysiloxane (83a) has been investigated [loo]. Enantioselectivity up to 43 YOee was achieved by use of polymeric Lewis acids.

972

Itsuno

OMe

85

84

21.11 Polymer-Supported Asymmetric Aldol Catalysts Catalyzed enantioselective Mukaiyama-aldol reactions have been developed extensively [loll and chiral polymer-supported Lewis acids are the catalysts of choice. Polymer-supported chiral N-sulfonyloxazaborolidinones 86 and 87, prepared by copolymerization of styrene, divinylbenzene, and chiral monomers derived from L-valine and L-glutamic acid, respectively, have been used for aldol reactions [102]. The rates of reaction using the polymeric catalysts were slow and enantioselectivity was lower than was obtained by use of the low-molecular-weight counterpart (88). The best ee obtained by use of the polymeric catalyst was 90 YOee with 28 YOisolated yield in the asymmetric aldol reaction of benzaldehyde with 89 (Eq. 27).

OH 87

86

H

OH 88

89 90 86-BH3: -78"C, 28%, 90% ee 87-BH3:-1 0 "C, 40%, 67% ee 88-BH3: -78"C, 60%, 95% ee

Polymer-Supported Metal Lewis Acids

973

One of the most powerful catalysts of the Mukaiyama aldol reaction is a chiral Ti(1V)-Schiff base complex 91 prepared from Ti(OiPr), and enantiomerically pure salicylaldimine reported by Carreira [103-1051. This catalyst furnished aldol adducts in good yields and with excellent enantioselectivity. The Ti(1V)-Schiff base catalyst system is unique among the aldol catalysts yet reported in terms of operational simplicity, catalyst efficiency, chirality transfer, and substrate generality. Because the Ti(1V)-Schiff base complexes are remarkably efficient catalysts for the addition of ketene acetals to a wide variety of aldehydes, the polymeric version of catalyst 92 was prepared [106]. The activity and enantioselectivity of the polymer-supported chiral Ti(1V)-Schiff base complex were, however, much lower than were obtained from the low-molecular-weight catalyst (Eq. 28).

93

94 92: R=Bn; 32%, 26% ee 91: R = Me; 95% ee

Optically active 1,l’-binaphthols are among the most important chiral ligands of a variety of metal species. Binaphthol-aluminum complexes have been used as chiral Lewis acid catalysts. The 1,l’-binaphthyl-based chiral ligands owe their success in a variety of asymmetric reactions to the chiral cavity they create around the metal center [107,108]. In contrast with the wide use of these binaphthyls, the polymer-supported variety has been less popular. The optically active and sterically regular poly(1,l’bi-naphthyls) 96 have been prepared by nickel-catalyzed dehalogenating polycondensation of dibromide monomer 95 (Sch. 7) [lo91 and used to prepare the polybinaphthyl aluminum(II1) catalyst 9 7 this had much greater catalytic activity than the corresponding monomeric catalyst when used in the Mukaiyama aldol reaction (Eq. 29). Unfortunately no enantioselectivity was observed in the aldol reaction.

974

Itsuno

NiCIz/Zn

'

KOH

"

~

PPh3, bipyridine, DMF

\

\

THF/HpO

-

Br

95

OH

OH

OH

OH

EtZAICI

\

t

CH2Clz

OH

OH

OH

OH 96

O.Al 1 0

CI

0'

CI

97

Scheme 7

OSiMe3 g7

PhCHO

+

APh - Phu 98

o

MeaSiO p 99

100%

h

?I Al '0

Polymer-Supported Metal Lewis Acids

975

21.12 Polymer-Supported Rare Earth Metal Catalysts Rare earth metal triflates are recognized as a very efficient Lewis acid catalysts of several reactions including the aldol reaction, the Michael reaction, allylation, the DielsAlder reaction, the Friedel-Crafts reaction, and glycosylation [110]. A polymer-supported scandium catalyst has been developed and used for quinoline library synthesis (Sch. 8) [111],because lanthanide triflates were known to be effective in the synthesis of quinolines from N-arylimines [112,113]. This catalyst (103) was readily prepared from poly(acrylonitri1e) 100 by chemical modification. A variety of combinations of aldehydes, amines, and olefins are possible in this reaction. Use of the polymer-supported catalyst has several advantages in quinoline library construction.

Sc(OTf)2

101

100

102

R’CHO

103

103

+

R’ R2

H 104

The same catalyst is also effective in three-component reactions between aldehydes, amines, and silylated nucleophiles, leading to amino ketone, amino ester, and amino nitrile derivatives, respectively (Eq. 30) [114]. It is reported that 103 can be recovered and that continuous use is possible without any loss of activity. More interestingly, in competitive reaction of aldehyde, aldimine and silyl enolate, the less reactive aldimine reacted exclusively with silyl enolate in the presence of 103. This unique selectivity was explained by the polymer effect [115].

Nafion is another choice of polymer support for Sc-based Lewis acids. Nafion-Sc catalyst is readily prepared by treatment of Nafion with ScC1,. 6H20 in acetonitrile under reflux [116]. Nafion-Sc catalyst has been found to be effective in several synthetic reactions including allylation of carbonyl compounds with tetraallyltin, DielsAlder reaction, Friedel-Crafts acylation, and imino Diels-Alder reactions. The use of Nafion-Sc in flow systems has also been tested. A novel type of polymer-supported Lewis acid, a microencapsulated Lewis acid catalyst was investigated by Kobayashi [117]. Sc(OTf), was immobilized on to polystyrene by microencapsulation- Sc(OTf), is physically enveloped by polystyrene and stabilized by the interaction between the x-electrons of benzene rings and vacant orbitals of the Lewis acid. This microencapsulated catalyst was used successfully in several Lewis acid-catalyzed carbon-carbon bond-forming reactions (imino aldol, aza Diels-

976

Itsuno

Alder, cyanation, allylation, Michael reaction, and Friedel-Crafts acylation). The same catalyst was also effective in three-component reactions such as Mannich-type reactions, Strecker, and quinoline-forming reactions. The polymer catalyst was recovered and reused many times without loss of activity (Eq. 31).

1st use; 92%, 2nd use; 97%, 3rd use; 95%

Lanthanide(II1) ions in aqueous solution exchange with cation-exchange resins to form stable ionic complexes which can be used as polymer-supported lanthanide(II1) catalysts (Sch. 9) [118]. Polymer-supported Yb(II1) prepared from Amberlyst XN1010 and Amberlyst 15 had high activity in the reaction of indole with hexanal (Eq. 32). This polymeric catalyst is also effective in other important organic reactions including the Mukaiyama-aldol reaction, acetalization, reaction of imines with silyl enol ethers, allylation of aldehyde with tetraallyltin, the aza Diels-Alder reaction, ring opening of epoxides, and glycosylation with glycosyl fluoride.

OiH+ +

Ln3+C1i

Cation exchange resin

H20

Polymer-supported Ln(lll) Lewis acid

Scheme 9 H

+ -CHO .

Y b(III)-resin .

(32)

*

.. H

H 92%

Polymer-Supported Metal Lewis Acids

977

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Lewis Acids in Organic Synthesis Edited bv Hisashi Yamarnoto Copyright 0WILEY-VCH Verlaa GmbH.2000

Index (NO)-acetal 663,752 (N,P)-acetal 752 (0,P)-acetal 752 (OJ-acetal 680 (0,Se)-acetal 680 (SJ-acetal 752 acetal 549,600ff, 605 f, 659, 884,905 - acetonides 549 - allylation 606 - cleavage 600ff - conversion to alcohols 600 f - conversion to aldehydes 602 - conversion to esters 600 - conversion to ketones 600 f - conversion to 0-alkylated cyanohydrins 603 f - conversion to thioacetals 603 - cyanation 603f - formation 602f acetalization 747,895 acetone cyanohydrin 200 acetone-TiCI4 654 acetophenone 937 acetylacetone 923 3-acetyl - 1,3-oxazotidin -2-one 892 3-acetyl-1,3-oxazolin-2-one 893 ACF (AlCl,F,) 192 Achiral silver(1) compounds 575 ff, 591 ff Acid chlorides 597 ff Ac-Phe-OH 26 acrylate 911 acrylonitrile 911 actinide 911 acyclic transition state 45 acylal formation 895 acylation 551,895 - reaction of ketones and nitriles 107 acyl cyanide 664 Acylhydrazones 887 y-acyl-6-lactam derivatives 886 acylnitrium ions 580 acyloxazolidinone 674 acyl-l,3-oxazolidin-2-one 894 acyloxazolidinone-TiCI4 654 (acy1oxy)borane (CAB) 139 addition 330, 916 - 1,2- 16,582,584, 616,616 ff, 625 f -, - of organoboron compounds 616 -, - of organolithium compounds 616,625 f -, - of organomagnesium compounds 616,625 -, - to aromatic amines 625 -, - to imines 625 f - 1,4- 16,691,920 -, - of allylstannane 701

[3+4]- 720 [4+2]- 10 - tonitriles 414 eryfhro-AHPA 935 AIBN 235 N-akenyl-nitrosonium ion 576 A1Br3 191 AlC13 191,887 f alcohols - conversion to acetals 603 - conversion to esters 630 - conversion to ethers 600 - in aldehyde allylation 617 f - in aldehyde reduction 616f - in aldol reaction 623 - in ehter cleavage 598 f - in epoxide ring opening 610ff - in hetero-ene reaction 645 ff - in ketone reduction 616 alcoholysis 550,552 - glycosylation 550 - isocyanates 552 aldehyde 622 f, 626 f, 883 f, 886 f, 890,898 f, 901,904 - conversion to acetals 603 - conversion to alcohols 616 ff - conversion to epoxides 623 f - conversion to gem-diacetates 603 - conversion to 0-silylated cyanohydrins 618f - conversion to thioacetals 603 - reduction 616 - see also aldol reaction aldehyde allylation 617 f aldehyde cyanation 616,618f aldirnine 663 aldolization 46 aldol reaction 9,45f, 111,114,121,284ff, 361,369, 387 f, 397,400,412,428,445,558,583,605 f, 622 f, 626 ff, 656,658,673,817,865ff, 883f, 896 f, 901, 905,972 f - addition 583,593 - adduct 585 - aqueous media 911,914 - asymmetric 931,935 - chelation 917 - condensation 207 - of a-Naphthol 869 - selectivityin 914 AIEtzC1 966 aliphatic aldehydes 887,900 aliphatic nitrones 891 alkali metal-(halide) salt 10,52 alkene 891,921,929 alkenylation 701 -

-

982

Index

alkenylsilane 703 alkenylstannane 703 a-alkoxyaldehyde 45,46 2-alkoxyallyl halides 575 p-alkoxyester 664 (0-alkoxyketone)-TiCl4 654 alkoxyselenation 552 alkylation 109 alkyl halide 689 N-alkylidene- or N-arylidene-2-hydroxyaniline 894 a-alkyl-a-isocyanocarboxylates 589 4-alkyl-2-oxazoline-4-carboxylates589 5-alkyl-2-oxazoline-4-carboxylates586 t~uns-5-alkyl-2-oxazoline-4-phosphonates 590 truns-5-alkyl-4-tosyI-2-oxazolines591 alkynylation 427,701 1-alkynylsilane 704 alkynyl sulfides 892 allenic haloindium reagents 518 ff - additions to aldehydes 519f - racemization of 519 synthesis of 518 f allenic halotin reagents 514ff - additions to aldehydes 516f - regioselectivity of additions to aldehydes 509ff, 516 - stereoselectivity of additions to aldehydes 515 - synthesis of 509 ff allenic tributyltin reagents 511 ff - addition to aldehydes 511 f - regioselectivity of additions to aldehydes 511 - synthesis of 509ff, 515ff allenic triphenyltin reagents 507 f - chirality 508 - regioselectivity in formation of 508 - synthesis of 507 f allenylsilane 702 allenylstannane 702 AILi?tris(binaphthoxide) 35 allylation 39,41,47,67,69ff, SOf, 115,331 f, 363, 365,389,399,407,409,427,447,606,617 f, 681, 871,898 - of aldehydes 581 - of imines 860 4-allylazetidinone 578 allylic alcohol 39 - rearrangement 12 - substitution 39 allylic and allenic trichlorosilanes 384 H allylic halotin reagents 474ff - addition to aldehydes 475 ff - selectivity of additions 475 - synthesis of 478 f - via metathesis 476 allylic indium halide additions 499ff - addition to aldehydes 499ff 13-allylic strain (1,3-A-strain) 34 -

allylic 1,3-transposition 918 allylic tributyltin reagents 453 ff - additions to aldehydes 458 ff - synthesis of 455 f - thermal additions to aldehydes 453,456f allylic triethyltin reagents, addition to aldehydes 456 allylic triphenyltin reagents 455 - addition to aldehydes 457 - synthesis of 455 allyl organometallics 898 allylsilane 39, 676, 861, 871 - optically active 365 ff, 383 ff, 690 allylstannane 47,558, 676,871, 916 ally1 transfer reaction 73 f allyltributyltin 275, 582, 898 allyltrimethylsilane 231 allyl vinyl ether 50,215 allysilicates and allylic siliconates 382 ff AI(OBu'),-t-BuOOH 201 AI(OPri)3 194 alumina 964 aluminium Lewis acids 597 aluminum alkoxides 191 aluminum chloride 946 ff aluminum halides 191 aluminum porphyrin 271 aluminum tris(2,6-diphenylphenoxide) (ATPH) 243 aluminum tris(2-a-naphthyl-6-phenylphenoxide) (ATNP) 2.51 aluminum tris[2,6-bis(3,4,5trifluorophenyl)phenoxide] (3,4,5,-F3ATPH)

249

amidation 126 amide - conversion to esters 606 - formation of 630 - methanolysis of 606 amide methanolysis 606 amidine 920 amine 52,625,886,898 f, 904,913,920,923 - conversion to amides 630 - conversion to imides 630ff - formation of 615 - in aziridine ring opening 615 - in conjugate addition 619 - in electrophilic cyclizaion 624 ff - in epoxide ring opening 611 - in hetero-ene reaction 646 f reaction with epoxides 611 - reaction with nitriles 630 0-Amino acid and p-lactam libraries 904 amino acids 285 a-amino acids 900 amino acids 968 0-amino alcohol 201,891,929,933 amino alcohol library 904 -

Index amino alcohols 284,310 a-aminoaldehyde 36 N-(P-aminoalky1)benzotriazoles 886 B-amino carbonyl compound 663,921 P-amino ester 885 ff, 899,920 3-exo-aminoisoborneol 958 B-amino ketone 885,899f aminolysis 52,216, 920 - of oxiranes 53 a-amino nitrile 900 amino thioester 886 0-amino thioesters 904 amphiphilic alkylation 239 amphiphilic conjugate alkylations 242 amphiphilic reduction 241 aniline 900 animation 84 p-anisaldehyde 926 [3+n] annulation 396 a-anomer 43f 0-anoiner 43 f anomerization 44,602.754 anthracene-9-carbinol 17 anti aldol adduct 585 anti-Cram 240 anti-Felkin path 658 anti-ferroelectric 808 anti migration 252 antimony alkoxide 524 antimony pentahalide 525 antimony trihalide 523 aqueous media 896,898 f, 901 - aza-Diels-Alder reaction in 913 - catalytic activity in 914 - formalin 911 - hydrate of aldehydes 911 - lanthanide triflates 920 - Michael reaction 91 I - Mukaiyama-aldol reactions in 91 1, 914 arylalkylhydroximoyl chloride 708 arylboronic acid 126 aryl C-glycoside, gilvocarcin V 855,856 - vineomycinone BZ 855 arylidene imines 577 1,Z-aryl migration 51 arylsilane 703 arylstannane 703 asymmetric - activation 811 - aldol reaction 866 - alkali-metal catalyst 34 - amplification 810 - benzylation 23 - borane reduction 953 - cyclization 34 - [4+2] cycloaddition 34 - desymmetrization 809 - Diels-Alder reaction 207,714,892

983

epoxidation 773 fumarates 256 - MPV reduction 196 - protonation 20 - reactions 581 ff 1,2-asymmetric induction 658 I ,3-asymmetric induction 658 atom-tansfer 69 ATPH 5 auto-induction 314,317 axial attack 20 aza-Cope rearrangement 719 aza Diels-Alder reaction 67,586, 890,894, 913,921, 927 azadiene 921 azetine intermediates 892 azides 610ff aziridination 421,762 aziridine 555,615,624,872,916,920f - ringopening 615 azomethine ylide 576 -

-

Ba(C10& 11 basic catalyst 932 Baylis-Hillman reaction 920 Beckmann rearrangement-alkylation 202 benzaldehyde 36,45 f, 883,896, 914,923, 926,933 a-(N-benzhydry1)amino nitriles 900 benzoic anhydride 888 benzoylation 888 benzoyl chloride 888 benzoylhydrazine 887 benzoylhydrazone 887 3-benzoyl-1,3-oxazolin-2-one 893 benzylamine 900.920 benzyibenzylideneamine N-oxide 895 benzyl bromide 19 N-benzyldiphenylprolinol 967 N-benzylhydroxylamine 891 benzyiic chloroformates 579 N-benzylideneaniline 890,927 N-benzylidenebenzylamine N-oxide 929 N-benzylidene-2-hydroxyaniline 927 a-(or Z)-benzyloxyaldehyde 36 a-benzyloxypropanal 914,917 benzyi propionate 886 BF3.OEtz 213,887,890,904,916 bicyclic lactone 925 bicyclo[3.2.l]octenedione 37 bicyclo[3.2.l]oct-6-en-3-one 575 bidentate 914 - achiral ligand 23 - amine 23 - Lewis-acid 195 lithium 33 bimetallic 33 ~

984

Index

- catalysts 289,339ff BINAP-AgOTf 473,474 binaphthol-aluminum complexes 973 hi-naphthol [BINOL] 77,892ff. 920,923,925,927, 929,932,961 binaphthyl-based chiral polymers 961 BINAP-silver(1) complexes 581 ff BINOL-TiQ 472 BINOL-Ti(Oi-Pr)d 473 binuclear phydroxo palladium(I1) complexes 593 bis(3,5-bis(trifluoromethyl)-phenylthio)methyllithium 16 bis(oxazo1ine) 62,64 f, 72 ff, 81 f, 85 bisphosphine-AgOTf complex 586 bis(su1fonamide) 78 f, 84 f bis(tributy1tin) oxide 900 bis(trimethylsily1)peroxide 381 P-blocker 933

n-bonding 272 cr-bonding 272 BOPagent 26 borane reduction 955 boric acid 90 bornyloxyaluminum dichloride 202 boron Lewis acid 89 boron tribromide 967 boron trihalide 91.96 boryl enolate 672 Brdnsted acid-assisted chiral Lewis acid (BLA) 149, 162, I83 Brassard’s diene 5’9 (6-Br)-BINOL-Ti 800,802,811,829 a-bromoacetone 0-methyloxime 576 a-bromo imidate 581 bromo-oxime ether 581 n-BuLi 15, 19,20,2.5 Bulky aluminum reagent 4 BuZMg 231 Bu,SnAIEt, 23.5 Bu2SnCI,/TMSC1 467 Bu3SnCN 900f Bu3SnH 214 Bu3SnMgMe 237 Bu3SnzZn 237 3-(2-butenoyl)-1,3-oxazolidin-2-one 895,929 terr-butyldimethylsilyl triflate (TBSOTf) 135 butyl glyoxylate 927 tert-butyl5-hydroxyhexanoate 18 2,6-di-tert-butyl-4-methylpyridine (DTBMP) 894 2,6-di-t-butylpyridine see DTBP

CAB 470f see also chiral carbene 616 ff carboalumination 230, 877 carbohydrate synthesis 849 carbometalation 429,861,877 -

3-carbomethoxy-2-pyrone 925 carbonates 609 f carbonyl additions 286 ff carbonylation 556 carbonyl compound 12 carbonyl compound-TiC1, 654 carbonyl-ene cyclization 5’94 carbonyl-ene reaction 75,720,805,920 - see also hetero-ene reaction carboranyl alcohol 677 carbosilylation 232 carbozincation 877 carnitine 821 cationic complex 861 cationic exchange resin 976 cationic exchange resins 951 cationic hetero [4+2] cyclization 719 cationic Hf reagent 856 cationic metal complexes 581 cetyltrimethylammoniurn bromide (CTAB) 896 C-glycosidation of pyridyl thioglycosies 579 C-glycoside 579,856 chelation 45,917 chelation-control 36,47,61,67,80,212,656,65’8 chemical modification 946 chemoselectivity 916 chiral - (acy1oxy)borane (CAB) 160,163,176 - amino alcohol 957 - auxiliary 69,71,75, 552 -, - acylation 552 - bisoxazolines 558 ff - boron Lewis acid 135 - boronreceptor 187 - ferrocenylphosphine-silver(1)complex 590 f - Lewis-acid catalyzed additions 470 ff -, - of allylic stannanes 472 ff -, - of crotyl stannanes 470ff - Lewis acids 892 - lithium amide 19,22 - oxazaborolidinones 968 - poisoning 811 scandium catalyst 895 - Sc catalyst 892f - sulfinylgroup 34 - Ti(1V)-Schiff base complex 973 - Yb catalyst 892f, 895 chiral-at-metal 77 chloral 807 chloroacetaldehyde 896 a-chloroacylsilane 677 a-chloro aldehydes 258 a-chloro-a’-alkylated ketones 38 a-chloro-a’-methoxy-ketone 38 chloromethylated polystyrene 953 2-chlorotrityl chloride resin 960 cinnamyl chloride 12 citronella1 75 f -

Index Ciufolini, M.A. 920 Claisen condensation 674 Claisen rearrangement 179,215,292ff, 375 ff cIeavage of ethers, acetals, and esters 91 co-catalyst 62,64,81 coenzyme Q1 49 combinatorial approach 67 s-truns conformation 268 conjugate 619f - addition 16,47f, 73,85,243,561,616,619ff allylation 49,246 - reaction 619ff - reduction 246 contact ion pair (CIP) 16 continuous flow system 969 copper hexafluorophosphate 571 copper-loaded polymer 953 copper nitrate 565 - Diels-Alder reaction 565 copper oxide CuO 546 ff copper pcrchlorate 561,565,571 - Diels-Alder 565 - imines 561 copper sulfate 544 ff, 549,555 - acetal deprotection 546 - acetonide 549 - dehydration 544f - epoxidc ring opening 555 coronafacic acid, synthesis of 348 coupling reactions 886 CpzHfCIz 861 ff Cp2Ti(Ol'f)2 709 Cp2TiPh 779 CpTiX3 653 Cp2TiX2 6.53 CpzZrClz 230 Cp2Zr(H)C1 192 Cram's rule 240 Cr(C0)6 204 cross-aldol reaction 867 crosslinked polymer 945 crosslinked polystyrene 945 crosslinking agent 959 crotonaldehyde 11 crotonate 920 3-crotonoyloxazoline 971 (E)-crotyltributyltin 582 (Z)-crotyltributyltin 583 Cu(BF4)z 563 - Diels-Alder reaction 563 CuBr2 549ff - transesterification 5SOf CuCl 545,552 - isocyanates 552 CuC12 543,545 ff, 558 acylation 550 - aldol rcaction 558 alkoxyselenation 552 -

-

-

985

dehydration 545 hydrolysis 546ff CuCN 237 C U F ~543,549 Cu(OCOCH3)z 543,556 - decarboxylation 556 CuOTf 548 f, 551,553 f, 556 f, 562 f, 567 - acetal formation 549 - carbonylation 556 - cycloaddition 562 f - elimination 553 - free-radical reaction 554,557 - fi-Iactams 551 - thioacetal hydrolysis 548 Cu(OTf)Z 543 ff, 551,553ff, 559 ff, 564 ff, 570 f - acylation 551 - aldol reactions 559 f - allylation 558 - conjugate addition 561 - dehydration 545 - Dicls-Aldcr 564 ff - ene reactions 570f - epoxide ring opening 555 - Friedel-Crafts 553 f - glycosylation 550 - nucleophilic addition 558 Cu(SbF6)z 543 f, 559,561,564 f, 567 - aldol reactions 559 - conjugate addition 561 - Diels-Alder 564 f, 567 cyanation 408,603f, 616,618f cyanide 916,928 cyanoenamine formation 631 cyanohydrin 82 f, 603 f, 606,616,618f, 836 cyanosilylation 916,918 cyclic carbonate 609 - formation 600ff cyclic transition-state structures 585 cyclization 75 f, 99,330,436 - [4+2]- 35f cycloaddition 562 ff - 1,4- 575 - [2+1]- 300ff,833,838 [2+2]- 209,297 ff, 562,578,719,833,838,875,892 - [2+3]- 833,838 - [3+2]- 576,971 - [4+2]- 28,207,302 ff, 334ff - [4+3]- 38 - [5+2]- 37 - [m+n]- 421 - Diels-Alder 562 ff - nitrone 569 - see also 1,3-dipolar cycloaddition cyclodehydration 756 cyclohexadiene 260 cyclohexanecarhoxaldehyde 937 1,4-cyclohexanedione 259 2-cyclohexene-1-one 16 -

-

986

Index

cyclopentadiene (CP) 9,17,29,33 f, 207,890,901, 921,925,927,965 cyclopentanone 938 cyclopropanation 78 f, 226

DABCO 24,920 Danishefsky, S. 918,923 Danishefsky's diene 36,59,67,586,640f,890,918, 921,926,927 DATMP 236 DBU 24,894,927 DCCI 26 DCCI-HOBt 26 deacetalization 758 deactivation, selective of one enantiomer of catalyst 338 debenzylation 415 cis-decalin 591 decarbonylation 896 decarboxylation 556 20-deethyltubifolidine, synthesis of 349 dehydration 121,544ff, 896 - copper sulfate 544 f - Cu(0Tf)Z 545 - nitroaldols 546 demethoxybenzylation 399 dendritic macromolecules 962 (t)-dendrobine 580 depolymerization 750 deprotection 776 deprotonation 12,21,25 designer Lewis acid 1 desilation reaction 106 destannylation reaction 107 desymmetrization 22,24,328 dialdose 47 2,h-dialkylphenol 861 ff dialkylzinc 957 diamnes 299 ff, 320 ff, 331 f diarylborane 125 diarylborinic acid 121 1,4-diazabicyclo[2.2.2]octane see DABCO diazoester 921 DIBAH 203 N,N-dibenzyl-protected aminoaldehyde 46 6.6'-dibromobinaphthol 35 dibutyltin bis(triflate) (DBTT) 274 1,s-dicarbonyl compound 885,905 dicarbonyl compound 923 Diels-Alder reaction 9,11,29,35 f, 104, 115, 135, 283,302 ff, 368,369,562 ff, 631 ff, 632,639 f, 709, 873,888,901,918,923,925,965 1,3-diene 890 diene 913,923,925,965 dienophile 717,890,965 diethylaluminum amides 216 diethylaluminum phenylacetylide 215

diethylaluminum 2,2,6,6-tetramethylpiperidide 236 diethylaluminum trimethylsilylacetylide 225 diethyl phthalate-TiC1, 654 dihydro pyrans 640 ff dihydropyridine 913 dihydropyridone 921 . .. fhreo-dihydrosphingosine 935 lu,25-dihydroxyvitamin D3 264 diisobutylaluminum hydride-BuLi ate complex 246 diisopropoxyti tanium dihalides, XzTi(OPr')2:X=Br orC1 805 diketene 285 P-diketo ester synthesis 397 1Jdiketone 923 1,6-diketone 580 1,2-diketone-TiCI4 654 (-)-dimenthy1 fumarate 10,208 0-or m-dimethoxybenzene 888 2,6-dimethylbenzoquinone 28 2,s-dimethyl-p-benzoquinone 260 2,7-dimethyl-l,8-biphenylenediol 195 (2,7-dimethyl-l,8-biphenylenedioxy)bis(diisopropoxya1uminum) 195

(2,7-dimethyl-1,8-biphenylenedioxy)bis(dimethyla1uminum) 195 2,3-dimethyl-2-butene 37 dimethyl fumarate 36 N,N-dimethyl-a-isocyanoacetamide 589 1,4-dimethyl-2,5-piperazinedione259 dimethylpolysiloxane 971 diol 284 f, 291,306 ff, 344 f 1,3-diol library 901 1,3-diol monoethers 905 DIOP 288 dipeptide 287 N-diphenylphosphonoylimines 964 u,a'-diphenyl-L-prolinol 960 f 1,3-dipolar cycloaddition 81,185,569,577,593, 631 ff, 719,891,895,921,929 dipolarophile 895 direct catalytic asymmetric aldol reaction 935 d-lactone 59 double electrophilic activation 195 double ligand exchange 850 DTBP 927 dysprosium triflate 913

(*)-eldanolide 579 electrophilic aromatic substitution 597 f electrophilic cyclization 624 f elimination 553 - sulfides 553 emino alcohols 904 enamine 758 enaminone 203 enantioenriched allenic indium halides 518 ff - addition to achiral aldehydes 519

Index addition to chiral aldehydes 519f synthesis of 518 enantioenriched allenic tin reagents 509 ff, 514 ff addition of allenylhalostannanes to achiral aldehydes 509ff, 515 ff - addition of allenylhalostannanes to chiral aldehydes 516 f - addition of allenyltributylstannanes to aldehydes, achiral aldehydes 51 1 -, - chiral aldehydes 512 f - doublc diastereoselection in additions to aldehydes 513,517 - transition states for additions to aldehydes 513, 515,518 enantioenriched allylic indium halides 500 ff enantioenriched allylic tin reagents 484 ff - additions to aldehydes 484ff, 490 ff equilibration of u- and y-oxygenated 488 - in carbohyrate synthesis 493 - MgBr2-promotedadditions 492 ff synthesis of 484 f, 489 f enantiomer-selective deactivation 811 enantioselective reactions aldol reaction 559 f - benzylation 19,21 conjugate additions 561 - Diels-Alder reactions 563 ff - ene reactions 570f - nucleophilic addition 560 endo selectivity 261 I-(m,n) ene cyclization 814 ene reaction 205,325ff, 417,570 f, 585,645,709,920 - aldehydes 570 - glyoxalate 571 - imines 571 enolate 17 enol ethcr 745 enolization 13, 18 en01 silanes 558,559 enol silyl ether 656,860, 911, 914,916€, 921 N-enoyloxazolidinones 895 ephedrine 958 epibatidine 576 epoxidation 762 epoxide 555,609 ff, 623 f - formation 608 f, 762 - kinetic resolution 613 f - opening 327ff, 610ff. 916,918 - rearrangement 609 epoxy alcohols 201 epoxysilanes 254 epoxy silyl ethers 252 equatorial attack 20 equilibration of - a- and y-crotylstannanes 476 - a- and $1-oxygenated allylic indium halides 501 f - u- and y-oxygenated allylic stannanes 488,507 - oxygenated allylic stannanes 495,497 f -

-

-

-

-

-

987

propargylic and allenic halostannanes 510,515 propargylic and allenic indium halides 518 eserine 288 ester 884f ester formation 606 esterification 427,443,606,747,859 Et,AI 226 EtA1C12 207 Et2AICI 207 EtzAlF 217 EtzAIN3 237 Et2AISiPhMe, 235 EtZAISPh 215 Et,B 269 ether - cleavage of 598 ff - formation of acetal aldol reaction 605 f - formation of acetal cyanation 603 f - formation of epoxide opening 610,613 etherification 427 ethyl acetate-TiC1, 654 ethyl acrylate 911 N-ethylmaleimide 17 ethyl p-methoxybenzoate-TiCI4 654 EtZNLi 18 Et3SiH 204,706 Eu(Fod)3 918 EU(hfC)? 923 europium catalyst 914,918,933 exo/endo selectivity 719 ex0 selectivity 262 external quench (EQ) 22 -

z-facial selectivity 34 p-F-ATPH 247 Felkin-Anh 821 Felkin-Anh induction 682 Felkin-Anhmodel 716 Ferrier reaction 663 Ferrier-type reaction 40 ferrocenylphosphine-gold(1) complex 586 ff Fischer indole synthesis 236 flow system 955 fluoral 807 fluorinated benzaldehyde 591 fluoro carbonyl compounds 212 fluoro epoxides 218 fluorophilicity 850 Fmoc-Ala-OPfp (Pfp = pentafluoro-phenyl) 27 Fmoc-Ala-PH 27 formaldehyde 258,808,896 f formylation 534,730 - caboxylation catalyzed by 534 - oxyfunctionalization catalyzed by 535 four-center transition state 15 four-component 886 free radical reactions 329ff, 557

988

Index

Friedel-Crafts acylation 98,725,870,887 f Friedel-Crafts alkylation 97,680,726,870,896 Friedel-Crafts reaction 333 f, 525,531,553,597 f, 725,838,858,870,887f, 896 - cyclization catalyzed by 533 - formation of aromatic sulfoxides catalyzed by 534 - isomerization catalyzed by 528,532 - rearrangement catalyzed by 528,532 Fries rearrangement 859,870,888 functional-group tolerance 47 functional monomers 946

GABOB 820 gadolinium triflate 911 Gassman-type Diels-Alder reaction 31 Gd(OTf), see gadolinium triflate gem-diacetate cleavage 602 gem-diacetate formation 602 f gem-diacetates 602f geometry, square planar 544,564,567 - square pyramidal 544,559 - tetrahedral 544 - trigonal bipyramidal 544,570 L-glutamic acid 972 glycoconjugate 849 glycosidation 43, 95,398,415,602,754 glycosilation 895 glycosyl carbonate 854 glycosyl fluoride 849,850 glyoxal 900 glyoxylate 80.5,807,809,831,927 glyoxylate benzoylhydrazones 887 gracilins B and C 324 Grignard reagents 288 guanidium formation 895

hafnium derivative 849 hafnocene 850 H-(Ah),-Phe-(resin) 27 halohydrin 610 - kinetic resolution 608 f a-halo imines 581 a-halosulfide 689 HC1.H-Ala-OMe 26 Heck reactions 591 Henry reaction see nitroaldol reaction hetero addition, [2+2]- 719 a-beteroatom-substituted aldehyde 36 heterobimetallic catalyst 35,932,936 heterocyclic compound 756 hetero Diels-Alder reaction 11,36,45,160,202, 339,370,567 ff, 640 ff, 716,815,823,826,873, 918,923,926,971 - acyl phosphonates 567

azadienes 569 imines 568 hetero-ene reaction 645 ff heteropolymetallic complex 937 hexanal 938 n-hexylzirconocene chloride 581 Hf-centered Lewis acid 849 HfC1, 231,861 f Hf(0Tf)d 858 ff, 862,904 high endo selectivity 889 HIV protease inhibitor 819 HMPA 16,18,22,24,48 HOMO 69 homoallylic amines 898 homoallylic hydrazines 887 homo-dimer 21 homologation, of ketone 862 Homer-Wadsworth-Emmons (HWE) reaction 24 HTi( O-i-Pr)3 708 hydeocyanation 180 1,2-hydride shift 51 cis-hydrindane 591 hydroalumination 877 hydroboration 125 hydrocinnamaldehyde 46,933,937 hydrogen cyanide 287 ff [1,5]-hydrogen shift 814 hydrolysis 128,546ff - acetals 547 - aminonitriles 548 - benzyl ester 546 - copper chloride 547 f - copper sulfate 546,548 - dithianes 546ff - hydrazones 546 - thioacetals 547 - vinylogous thioacetals 548 hydrolysis constant 914 hydrometalation 861,876 hydrosilation 117 hydrosilylation 861 hydrostannation 861,877 hydrostannylation 118 (I-hydroxy aldehydes 902 rhreo-p-hydroxy a-amino acids 586 h-hydroxy butenolides 360 a-hydroxy carbonyl compound 933 13-hydroxycarboxylic acids 902 hydroxyepoxidation 765 fl-hydroxyester 664 a-hydroxyethylene-2-indanone 51 2-hydroxyethylmethacrylate 960 p-hydroxy ketones 891 8-hydroxyquinoline derivatives 894 hydroxysulfoxide 64 hydrozirconation 192 hyperbaric additions 458 hyperbranched macromolecules 962 -

-

Index hyper-coordinate aluminum 286,291 ff, 298,314ff, 320, 326,328 ff, 332 f, 335 ff, 341,344,346 ff hypervalent silicates 355,382 ff

i-Bu,Al 223 imine 663,758,886 f, 890,892.898,900,904,916, 921,928 iminium salts 886 imino compound 12 imino Diels-Alder reactions 890 imino-ene reaction 721 a-imino esters 585 Inanaga, J. 926 InCI3/TMSCI 467 indole 39,41,913 indolenine 41 indolizidine derivative 591 induction period 78 in-plane coordination 654 intermolecular [3+4] cycloaddition 722 internal quench (10) 22 intramolecular additions 503 ff - cyclization to a 14-membered ring 507 - cyclization to a 6-membered ring 504 f - cyclization to an oxane 506 - cyclization to an oxepane 506 iodotrimethylsilane 357,375 i-PrLi-(-)sparteine 14 ipsdienol 807 isocyanoacetate 577,590 a-isocyanocarboxylates 586 ff (isocyanomethy1)phosphonate 590 a-isocyano Weinreb amide 590 erythro-isomer 36 fhreo-isomer 36 isomerization - of a cyclopropane ring 375 - of silyl enol ethers 434 isonitrile-TiCI4 654 isophorol 41 isoprene 10 isopulegol 76 f isotope effect 938 isoxazolidine 593,895,921 - derivatives 891 isoxazoline 929

juvenile hormone 328

(-)-a-kainic acid 586 KBF, 52 KC10, 9,52 KCN 52 ketene silyl acetal 41,45 ff, 213,664,884,885 ff, 897

989

see also enol silyl ether p-keto ester 911 ketone 884f, 911,913,916,918,936 - cyanation 616 - enolate 52 - reduction 616 Kh see hydrolysis constant kinetic resolution 328 f, 350,608,613 f, 809 Knoevenagel condensation 674 KSCN 27 -

p-lactam 551,885,887 lactone 607 - ring cleavage 607 ladder-trimer 18 La(NTf&.HZO 29 lanthanide triflate (Ln(0Tf)3) 883,889,911,975 - activation of C-N double bond 921 - aqueous media 911,913 - a m Diels-Alder reactions 927 - chemoselectivity 916 - enantioselective Mukaiyama-aldol reaction 931 - tolerance of amine 920 lanthanum(II1) chloride 932 lanthanum(II1) isopropoxide 932 (-)-lardohm 225 LDA 13,18,25 Lewis acid 3,883,888,890,896,904 - promoted additions of, allylic and crotylstannanes 459 ff -, - a- and y-oxygenated allylic stannanes 481 ff Lewis acid-base interaction 12 Lewis acid - Brmnstedt acid 3 Lewis acidity 10,23,41 Lewis base 385ff, 911,920 - catalytic diastereo- and enantioselective aldol reaction 386 - enantioselective allylation 385 ff Lewis basicity 47 LiAI[OC(Ph)(CF3)2], 42,48 LiBH4 902,905 LiBr 19ff, 25 ff, 51 - MeLi- 20 Li[Bu&~AlMe~l 235 LiCl 17 f, 20,22,26,28 - -DMPU 27 - -i-Pr,NEt 24 - -NMP 27 [LiC~(B~CzHii)zl48 LiF 20 ligand-accelerated 198 LiI 18,20f, 25 LiOBu' 20 Li'(OEt2)2C10,~ 12 liquid crystal 808 lithium acetylide 52 lithium amide 10,12,17,23

990

Index

lithium bis(trifluoromethanesu1fonamide) (LiNTf,) 9, 28,43 f - acetone 28f EtzO 28f - MeCN 36 lithium cation 11,34,35,44,51 lithium coblt-bis(dicarbo1lide) [LiCo(B9C~H1d2141 lithium enolate 19f lithium enolate-LiX (LiBr) aggregate 20 f lithium halide 24 lithium hexafluorophosphate (LiPF6) 9 lithium perchlorate (LiC104) 9, 11,26f, 43f, 46f, 51 f, 888 acetone 51 - benzene-MeC" 31 - CHzC12 29 f, 34,36,45 - D M E 48 - DMF-CHZCIZ 27 - EtOAc 37,40 - Et,O (LPDE) 9f - ( 3 mol%)-CH2CI2 47, 48 - toluene 51 lithium salt (LiX) 17, 18,20,24,34 - effect 17,21 lithium tetrafluoroborate (LiBF4) 9,25 ff, 51 f - benzene-McCN 31 lithium 2,2,6,6-tetramethylpiperidide (LTMP) 18 lithium trifluoromethanesulfonate (lithium triflate: LiOTf) 9,18,20,52 f LiTMP 236 LLB 932 f, 935,937 f LnLi3tris((R)-6,6'-dibromobinaphthoxide) 34 Ln(OTf), 883,888,911 LPDE 28 f, 31,34,36 f, 39 f, 45,47 f, 50 - AcOH 39 - camphorsulfonic acid (CSA) 29 ff LTMP 18 2,h-lutidine 926 ~

~

MA 10,28f,34 MABR 469 macrocyclization 551,784 macrolide antibiotic 849 MAD 238 MAD and MABR as cocatalysts 358 ff malate 36 maleic anhydride 34 manganese Lewis acids 632 Mannich-type reaction 115,180,585,593,869. 885 f, 899,904,921,940,976 - ofimine 860 Mannich-type three-component reactions 904 Marl6, I.E. 928 masked acyl cation 576 MAT 238 MeiAl 195

MezAIC= CPh 212 MeZAIC1 205 Me2AISeMe 234 MeBmt 586

cis-[(2,4,5-Me3C6HzCHO)2TiC14] 654 [((Me2CO)TiCl,),(p-CCl)2] 654 Meerwein-Ponndorf-Verley (MPV) reduction 194, 290 Meerwein-Ponndorf-Verley-type reduction 876 (MeLi)z 15 membrane reactor 961 menthol 75,966 Merrifield resin 958, 960 mesembrine 265 MelSiBr 21 Me3SiCI 21 f, 231 Me3SiI 21 Me3SiOTf 37,213 (Me3Si),SiH 269 metallocene 861 metallo-l,3-dipole 877 metallyltributylstannane 582 metal salts 11 methacrolein 968 o-methoxybenzaldehyde 914 4-methoxybenzophenone 888 N-methoxy-N-methyl-a-isocyanoacetamide590 1-methoxy-2-methyl-3-( trimethylsiloxy)-l,3butadiene 923 2-methoxyphenylamino group 900 2-methoxypropene 920 2-truns-methoxy-3-trimethylsiloxy-l,3butadiene 890 l-methoxy-3-(trimethylsiloxy)-l,3-butadiene see Danishefsky's diene methyl acrylate (MA) 9 methylaluminoxane 861 methylaluminum bis(2,6-di-tert-buty1-4alkylphenoxide) 238 methylaluminum bis(2,6-di-terf-buty1-4bromophenoxide) (MABR) 251 methylaluminum bis(2,6-diphenylphenoxide) (MAPH) 257 methylation 25

N-methyl-bis[(R)-1-(1-naphthyl)ethyl]amine 929 methyl glyoxylate 899 methyl isobutyrate 884 methyl vinyl ketone (MVK) 17,29,33,889 MgBrz 24 MgClz 24 Mg(C104)~ 11 ~ g ~ f , )29, micellar systems 896 ff Michael reaction 9,47, 115,245,339ff, 397,412, 428,445,619ff, 626,629,825,885,905,911,914 microencapsulation 975 mircowave irradiation 194

Index mixed aggregate 19f - anhydride 26 - cyclic-trimer 18 - dimer 18 f, 22,25 MMA 271 MNEA see N-methyl-bis[(R)-1(1-naphthyl)ethyl]aminc molecular sieves 82 molecular-weight-distribution (MWD) 271 MOM vinyl ether 39 monomer 12ff mono(oxazo1ine) 66 montmorillonite 948 MPValkynylations 198 Mukaiyama aldol reaction 162,622 ff, 867 - see also aldol reaction Mukaiyama-Michael 561 Mukaiyama-type Michael reaction see Michael reaction -

iminoEster 560 nucleoside synthesis 857

-

0-C glycoside rearrangement 855 0-acryloyllactate-TiCl~ 654 0-acylated cyanohydrin 606 octahedral Sc(II1)-dienophile complex 894 0-glycoside 856 oligo(oxyethy1ene) 959 - crosslinked polystyrene 969 oligopeptide 25 oligosaccharide 850,854 one-pot glycosylation 854 open dimer 12ff Oppenauer oxidation 122,197 Oppenauer-type oxidation 876 organo - cerium 44 - lithium 10,12,15 f, 44 - magnesium 44 tin(IV) 443 organosilicon Lewis acids 356,370 orthoester 31 orthogonal glycosylation 850 out-of-plane coordination 654 oxazoborolidines 953 ff oxazoborolidinone polymer 955 oxazole 286 oxazolidinone 207, 616 ff, 631 f, 642 ff, 923 oxazoline 286 his-Oxazoline-ZnX2 474 oxidation 875 oxime ethers 954 oxime sulfonates 203 oxirane 51,872 oxyethylene-chain crosslinking 969 oxygenophilicity 202 -

NaBr 20,25 NaCIO, 9,11,27,52 NADH equivalents 291 Nafion-H 947 Nafion-Sc catalyst 975 NaNi 52 NaNTf, 9 naphthoquinone 901 Nazarov cyclization 372 p-N’-benzoylhydrazino esters 887 Nd(OTf)3 see neodymium triflate neodymium triflate 911 neoisopulegol 76 nitration 862,896 nitrile 619 f, 630f nitrile reaction 631 nitroaldol reaction 932 f nitroalkane 935 nitroalkene 265 p-nitrobenaldehyde 914 a-nitro ester 911 nitro-Mannich-type reaction 940 nitromethane 619,933 nitrone 82, 719, 891, 895, 921, 929, 971 nitro olefins 545 NMR shift reagent 923 N,N,N’,N’-tetramethylethylenediamine (TMEDA) 23 non-catalyzed aldol reactions 387 non-chelation 241 non-chelation control 36,46 non-linear effect 810 - on induction 308,314 (1R,2S)-(-)-norephedrine 955 nucleophilic addition 80 - conjugate addition 561

p-methoxyneophyl p-toluenesulfonate 12 pair-selectivc aldol reaction 668 palladium diaquo complexes 593 palladium enolate 593 D-pantolactone 263 pantolactone 714 Pd(PPh3)4 235 Pd(PPh7)zCIZ 469 pentacoordinate 211 y-pentadienylated optically active alcohols 583 2,4-pentadienylstannanes 583 pentafluorophenylborane 4 3-pentanone 18 perchlorate ion 17 pericyclic reaction 60 periselectivity 815 PhCECLi 220

991

992

Index

PhC = CMgBr 21 9 PhCE CTiCI(OPr’)2 219 Phe-Ala 26 phenols 289,296 3-phenylacetylacetone 892 I-pher)ylallyl chloride 12 phenylene spacers 962 phenylglyoxal monohydrate 899 N-phenylmaleimide 891 3-phenyl-2,4-pentadione 925 3-phenylpropionaldehyde 884,896 3-phenylpropionaldehyde dimethyl acetal 884 0-phenylsulfonyl-y-oxo arenebutanenitrile 44 1-phenyl-1-trimethylsiloxyethcne 899 phenyl vinyl sulfide 925 photooxygenation 765 Ph3SiH 706 Pictet-Spengler reaction 185 pinacol-type rearrangement 772 trans-piperylene 28 platoquinones 49 poly(1,l’-bi-naphthyls) 973 poly(acrylonitri1e) 975 poly(N,N-dimethylacrylamide) on ‘Kieselgur’ (PDMAA-KG) 27 poly(ethy1ene oxide) on polystyrene (PEO-PS) 27 polyfluoromethylation 229 poly(Lewis acids) 951 polymeric - boronic acid 955 - catalysts 945 - ether-BF, complex 9.51 - Grignard reagents 948 - oxazaborolidine 956 reagents 945 - superacids 947 polymer-immobilized titanium salt 710 polymerization 611 ff, 750 polymer-supported - allylsilane 681 - aluminium chloride 946 ff - amino alcohol 955 - 3-exo-aminoisoborneo1 958 - asymmetric aldol catalyst 972 ff - boron 951 - catalysts 945ff - chiral amino alcohol 957 - chiral Lewis acid 965 ff - CU(I1) 953 - dialkylzinc 957f - Diels-Alder catalysts 965 ff - ephedrine 964 - Fe(Il1) complex 950 f - lanthanide (111) catalysts 976 - Lewisacid 946 - oxazaborolidine 953 - rare earth metal catalysts 975 f - reagents 945ff -

- scandium catalyst 975 - silyl enol ethers (PSSEEs) 901 - SnC14 952 - TADDOLS 960 - Ti alkoxide 965 - Ti(1V) chloride 948 - TiTADDOLate 970f poly@-methoxystyrene)-BF3 951 polypeptide 25 polysiloxanes 956 praseodyum triflate 911 proline derivative 577 prolinol 958 propargylation 701 propargyl silane 39,703 propiophenone 896 prostaglandin 217,322,349 protective group of amine 128 (PriO)zTi2CI2 257 protodesilylation 356 protonation reaction 430 prototropic ene 818 proxiphomin 32 pseudorotation 387 PSSEEs 904f Pudovik reaction 289 pumiliotoxin C 203 PYBOX 288,929 pyrazolones 887 pyridine-BF, complex 951 y-pyronc 59f pyrrolidine derivatives 576 A’- or A2-pyrrolines 577,580 pyrrolo[l,2-a]indole 576 pyrrolophenanthridine alkaloids 32

quassinoid families 32 quaternary sulfur center 34 quinone 738

radical addition 71 ff radical cyclization 235 radical reaction 67,71 f, 779 radical reduction 67 rare earth metal triflates 975 - see also lanthanide triflate (Ln(OTf),) rate enhancement - of catalytic asymmetric reactions 591 rearrangement 50 - [1,3]- 50f - [3,3]- SOf, 101,117,557,862 - of acylaziridines 400 - of allylic acetals 415 - of epoxides 376f - of oxaspiropentanes 51

Index reduction 616,705,875 reface 268 remote asymmetric induction 809 ribofuranose 51 Rieche-Gross formylation 730 ring-opening aldol-type reaction 868 ring-opening functionalization of oxirane 9, 52 ring opening of epoxide 766 Robinson Annelation reaction 869 RySlH 705 RISnH 705

Sakurai-Hosomi allylation reaction 45,176 salen 351 salicylaldimine 973 salicylic acid resin 951 salting-out effect 45 scandium (Sc) 883 scandium trifluoromethanesulfonate (Sc(OTf)3) 468,883 ff, 892,894 ff, 904 f Schiff base 287,822 Schlenk equilibrium 79 Schmidt reaction 783 Schwartz reagent 581 Scytophycin C 40 SDS 898ff anri-SF2’ mechanism 690 anti-SE2’ mode 676 SETregiospecificity 676 secondary alcohols 581 1,4-selectivity 16,48 separated ion pair (SIP) 16 Sharpless epoxidation 252,376 ff, 773,838 siface 268 sigmatropic rearrangement 9,215 silacyclobutanes 388 f silane coupling agents 964 silatropic ene 820 silica 964 silica gel-supported prolinol 966 p-siloxy aldehydes 252 siloxycyclopropanes 580 siloxydiene 923 siloxyfuran 664 p-silver ketone 580 a-silylaldehydes 254 silylalumination 237 silyl enolate 20,884 ff, 896,899 silyl enol ether 203,579, 883,890,896f, 900,901 silyl ether cleavage 598 ff silylium ion 355,370 silylketene acetals 559,561 Simmons-Smith reaction 76 f, 227,300,302 single electron-transfer (SET) 67 SiOz 948 - see also silica SnCI4 887,904

993

Sn(OTf)*) 550 sodium amide 19 sodium dodecylsulfate (SDS) 896 solenopsin A and B 203 solid-phase 901,905 - peptide synthesis 27 solid-supported synthesis 365 ff solvent effects 308 SOMO 69 o-erythro-sphingosine 586 o-tho-sphingosine 586 spirocyclic compounds 592 3,3-spirooxindol 592 square-planar 16-electron Pd’ intermediate 591 SR-MAS NMR technique 905 stannic chloride 952 stereochemistry - of epoxidation 762 stereoelectronic effect 20 stereoregulation 861 anti-stereoselective aldol reaction 672 stereoselective alkylation 20 stereoselectivity 856 Strecker Reaction 350 f, 838,900f y-substituted allylmetals 582 substituted furans 579 substitution 9,578 - reactions of indol 913 N-sulfinyl p-toluenesulfonamide 890 sulfonamide 931 (sulfony1amino)oxazoline 64 N-sulfonyl imine 890 super acids 530 - generation of stable carbocations catalyzed by 530 suppression of alkalene isomerization 592 symmetrical anhydride 26

TADDOL 291,331,800 tandem Michael aldol reactions 341 f, 350 tautomycin 658 TBTU agent 26 template effect 269 tetraallyltin 887, 898 tetradentate chiral ligand 23 - derivative 890 tetrahydroquinoline 921, 927 - derivative 890 2,2,6,6-tetramethylpiperidide 236 thermal additions - allylic and crotyl stannanes 453,456 f - oxygenated allylic stannanes 480 f, 484 thiirane 610 thioacetal 444,602 f - allylation 606ff - formation 603 thioanisole 888

994

Index

thioester 884 f, 91 1 thioethers 611,613,621 f thioglycoside 602,850,895 thiol 918 thiol ester-TiC1, 654 [((thiol ester)TiCI~)~(p.-Cl),1654 thionolactone 607 f - ring cleavage 607 f thiopyran 643 three-component coupling reaction 891,899 three-component reaction 860,887,898,913,921 thulium triflate 911 tin dihalide 396 tin(I1) triflate 400 tin(IV) chloride 408,916 - acetal 440 - B r~ ns te d acid 430 - tributylamine 429 - zinc dichloride 427 Tischenko-type dimerization of aldehyde 879 Ti-TADDOLate 950 titanium alkoxides 949 titanium chelate 655 titanium(II1) chloride 771 titanium(1V) chloride 213,658,886f, 904f, 914, 916,948 titanium Lewis acids 606 titanium perchlorate 594 titanium silicate molecular sieves (TS-1) 653,764 TiC1(OTf)3 747 Ti(O-i-Pr)2C12 664 TiX4 653 TMEDA-LDA 13 TMSCN see trimethylsilyl cyanide TMSM3 see trimethylsilyl azide Torgov cyclizaion 838 tosyl aziridine 222 tosylmethyl isocyanide 591 toxicity, alkyltin compounds 454 f (TPP)AIMe 271 transacetalization 601 f transesterification 550,747,949 - 2-pyridylthioesters 551 transglycosidation 379 transition states - for hyperbaric additions 458 - intramolecular additions 504 f - Lewis-acid promoted additions of -, - achiral allylic halostannanes 454,475 -, - achiral allylic stannanes 453,460 f, 463 f, 466

-, - chiral allenic halostannanes 515,518 513 -, - chiral allylic halostannanes 495,497,499 -, - chiral allylic indium halides 467,501 -, chiral allylic stannanes 484,486 f, 493 - thermal additions 453,457 transmetalation 192 - BuSnCI3 475f -, - chiral allenic stannanes

-

of allenic tributyltin compounds 514ff BuSnCI3 517 InBr3 519f InCI3 518f SnC1, 514ff - of allylic tributyltin compounds 474 ff -, - Bu2SnCIZ 475 -, - InCI3 478 -, - SnClz 476f -, - SnCI4 477ff -, - TiCI4 477 transposition of acyl group 749 trialkylaluminum halides 191 triarylboron 114 a-(N-tributy1tin)amino nitrile 900 tributyltin chloride 901 tributyltin enolates 584 tributyltin hydride 861 trichlorotitanium enolate 673 triethanolamine 920 triethylamine 923 trifluoroacetic acid (TFA) 194 trifluoromethanesulfonate (MeOTf) 135 3,3,3-trifluoropropeneoxide (TFPO) 220 trimethylallylstannane 47 trimethyl borate 955 cis-l,2,6-trimethylpiperidine 892,895,923,929 1.3,s-trimethylpiperidine 927 2-(trimethylsiloxy)allyl cation 575 1-trimethylsiloxycyclohexene 883 trimethylsilyl azide 39, 201 trimethylsilyl bis(trifluorormethanesulfonyl)imide, allylation of acetals 363 - Diels-Alder reaction 369 - preparation of 357 trimethylsilyl cyanide 39,47,287 ff, 900 - see also cyanide 2-(trimethylsilyl)ethoxomethylation 440 trimethylsilyl perchlorate - glycosidation 378 ff - preparation of 357 trimeth ylsilyl -

-, - ,_ -, -, -

tetrakis(triflurormethanesulfony1)borate aldol reaction 358 - allylation 362ff - preparation of 357 ff trimethylsilyl triflate 355 ff, 916 - aldol reaction 359,361 - allylation 36.5 - Bayer-Villiger oxidation 381 - Diels-Alder reaction 368 ff - glycosidation 378 ff - hetero Diels-Alder reaction 370ff - intramolecular aldol-type reaction and allylation 366 ff - isomerization of -, - a cyclic acetal 374 ff -, - epoxides 374 -

Index Nazarov cyclizaion 372 preparation of 357 - rearrangement of epoxides 377 - reduction of acctals 381 - ring contraction 372 ff - ringexpansion 373 - silyl modified Sakurai (SMS) reaction 363 ff - [2,3] Wittig rearrangement 376 triphenylene spacer 962 triquinane isocomene 38 tris(2,6-di-teut-butyl-4-methylphenoxide) (ATD) 245 tris(1-hexyny1)aluminum 226 Triton X-100 896 tubifolidine 349 two-directional 819 -

vinyl thioether 921 vitamin - E 49 - K 49 VO(acac)z 201 Wagner-Meerwein type process 41 water exchange rate constant 914 Weinreb amides 210 WERC see water exchange rate constant Wittig reaction 24

-

Yh(fod).i 920 Yb(II1) phosphate 926 Yb(OTf)3 468,883,886,889,892,894 ff - see also ytterbium triflate ytterbium catalyst 923,925,927,929 ytterbium cyanide 916 ytterbium triflate - activation of C-N double bond 921 - aqueous media 911 aqueous Michael reaction 911 aziridine opening 920 - catalytic asymmetric aza Diels-Alder reaction 927 - catalytic asymmetric Diels-Alder reaction 923 - catalytic asymmetric 1,3-dipolar cycloaddition reaction 929 - chemoselectivity 916 yttrium triflate (Y(OTf)3) 883, 889

a,@-unsaturated 900 aldehyde 887,911 - carbonyl compound 47,885 - hydrazone 36 - ketone 16,31,242,905,911 - thioester 886 - thioimidate 892 b,e-unsaturated ketone 580 -

~

~

~

r-valine 972 VANOL 316 VAPOL 316-320 vinblastine 581 vinylallylation 701 vinyl bromide 581 vinyl ether 890,899,921, 927 vinylogous ene reaction 720 vinylsilylation 232 vinylstannane 861 vinyl sulfide 762, 890

995

Ziegler-Natta polymerization Zinc reagent 6 zirconium 86.5 enolate 86.5 Zn(NTf& 29 Z-protection 26 ZrC14 861f Zr(OTf)4 860, 862 ~

861, 947