Organic Synthesis: State of the Art 2007 - 2009

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Organic Synthesis State of the Art 2007–2009

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Organic Synthesis State of the Art 2007–2009

Douglass F. Taber

1

1 Oxford University Press, Inc., publishes works that further Oxford University’s objective of excellence in research, scholarship, and education. Oxford

New York

Auckland Cape Town Dar es Salaam Hong Kong Karachi Kuala Lumpur Madrid Melbourne Mexico City Nairobi New Delhi Shanghai Taipei Toronto With ofﬁces in Argentina Austria Brazil Chile Czech Republic France Greece Guatemala Hungary Italy Japan Poland Portugal Singapore South Korea Switzerland Thailand Turkey Ukraine Vietnam

Copyright © 2011 by Oxford University Press Published by Oxford University Press, Inc. 198 Madison Avenue, New York, New York 10016 www.oup.com Oxford is a registered trademark of Oxford University Press All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior permission of Oxford University Press. Library of Congress Cataloging-in-Publication Data Taber, D. F. (Douglass F.), 1948Organic synthesis : state of the art 2007–2009 / Douglass F. Taber. p. cm. ISBN 978-0-19-976454-9 (hardcover : alk. paper) 1. Organic compounds–Synthesis–Research. I. Title. QD262.T284 2011 547'.2–dc22 2010020627

1 3 5 7 9 8 6 4 2 Printed in the United States of America on acid-free paper

Contents

Preface

xi

Organic Functional Group Interconversion and Protection 1. Best Synthetic Methods: Oxidation and Reduction

2

2. Functional Group Transformations

4

3. Best Synthetic Methods: Oxidation

6

4. Best Synthetic Methods: Reduction

8

5. Best Synthetic Methods: Functional Group Transformation

10

6. New Methods for Functional Group Conversion

12

7. Organic Functional Group Interconversion: (-)-β-Conhydrine (Barua) and (+)-6'-Hydroxyarenarol (Anderson)

14

8. New Methods for Functional Group Conversion

16

9. Protection of Organic Functional Groups

18

10. Best Synthetic Methods: Functional Group Protection

20

11. Functional Group Protection

22

C-H Functionalization 12. Intermolecular and Intramolecular C-H Functionalization

24

13. C-H Functionalization to Form C-O, C-N, and C-C Bonds

26

14. Functionalization of C-H Bonds: The Baran Synthesis of Dihydroxyeudesmane

28

Carbon-Carbon Bond Construction 15. New Methods for Carbon-Carbon Bond Construction

30

16. Best Synthetic Methods: Carbon-Carbon Bond Construction

32

17. C-C Single Bond Construction

34

18. Construction of Alkenes, Alkynes and Allenes

36

Reactions of Alkenes 19. Reduction, Oxidation and Homologation of Alkenes

38

20. Reactions of Alkenes

40

21. Selective Reactions of Alkenes

42

Alkene and Alkyne Metathesis 22. Developments in Alkene Metathesis

44

23. Developments in Alkene and Alkyne Metathesis

46

v

CONTENTS 24. Advances in Alkene and Alkyne Metathesis

48

25. Developments in Alkene Metathesis

50

26. Alkene Metathesis: Synthesis of Kainic Acid, Pladienolide B and Amphidinolide Y

52

27. Alkene and Alkyne Metathesis: Phaseolinic Acid (Selvakumar), Methyl 7-Dihydro-trioxacarcinoside B (Koert), Arglabin (Reiser) and Amphidinolide V (Fürstner)

54

28. Alkene Metathesis: Synthesis of Panaxytriol (Lee), Isofagomine (Imahori and Takahata), Elatol (Stoltz), 5-F2t-Isoprostane (Snapper), and Ottelione B (Clive)

56

29. Total Synthesis by Alkene Metathesis: Amphidinolide X (Urpí/Vilarrasa), Dactylolide (Jennings), Cytotrienin A (Hayashi), Lepadin B (Charette), Blumiolide C (Altmann)

58

Enantioselective Construction of Acyclic Stereogenic Centers 30. Enantioselective Assembly of Oxygenated Stereogenic Centers

60

31. Enantioselective Assembly of Aminated Stereogenic Centers

62

32. Enantioselective Preparation of Secondary Alcohols and Amines

64

33. Enantioselective Preparation of Alcohols and Amines

66

34. Enantioselective Synthesis of Alcohols and Amines

68

35. Enantioselective Assembly of Alkylated Stereogenic Centers

70

36. Enantioselective Construction of Alkylated Stereogenic Centers

72

37. Enantioselective Construction of Alkylated Centers

74

38. Enantioselective Construction of Alkylated Stereogenic Centers

76

39. Stereocontrolled Construction of Arrays of Stereogenic Centers

78

40. Enantioselective Construction of Arrays of Stereogenic Centers

80

41. Stereocontrolled Construction of Arrays of Stereogenic Centers

82

42. Practical Enantioselective Construction of Arrays of Stereogenic Centers: The Jørgensen Synthesis of the Autoregulator IM-2

84

Construction of C-O Rings 43. Enantioselective Synthesis of Lactones and Cyclic Ethers

86

44. Stereocontrolled C-O Ring Construction: The Fuwa/Sasaki Synthesis of Attenol A

88

45. Stereoselective C-O Ring Construction: The Oguri-Oikawa Synthesis of Lasalocid A

90

46. Stereocontrolled C-O Ring Construction: The Morimoto Synthesis of (+)-Omaezakianol

92

47. Synthesis of Dysiherbaine (Hatakeyama), Jerangolid D (Markó) and (+)-Spirolaxine Me Ether (Trost)

94

48. C-O Ring Containing Natural Products: Paeonilactone B (Taylor), Deoxymonate B (de la Pradilla), Sanguiin H-5 (Spring), Solandelactone A (White), Spirastrellolide A (Paterson)

96

vi

CONTENTS 49. C-O Ring Natural Products: (-)-Serotobenine (Fukuyama-Kan), (-)-Aureonitol (Cox), Salmochelin SX (Gagné), Botcinin F (Shiina), (-)-Saliniketal B (Paterson), Haterumalide NA (Borhan) 50. Complex Cyclic Ethers: (+)-Conocarpan (Hashimoto), (-)-Brevisamide (Satake/Tachibana), (+)-Bruguierol A (Fañanás/Rodríguez), (-)-Berkelic Acid (Snider), and (-)-Aigialomycin D (Harvey)

98

100

Construction of C-N Rings 51. New Methods for Stereoselective Construction of N-Containing Rings

102

52. Stereoselective C-N Ring Construction

104

53. New Methods for C-N Ring Construction

106

54. Stereocontrolled Construction of C-N Rings: The Vanderwal Synthesis of Norﬂuorocurarine

108

55. Alkaloid Synthesis: Paliurine F, Lepadiformine, and 7-Deoxypancratistatin

110

56. Adventures in Alkaloid Synthesis: (+)-α-Kainic Acid (Jung), 223AB (Ma), Pumiliotoxin 251F (Jamison), Spirotryprostatin B (Trost), (-)-Drupacine (Stoltz)

112

57. Stereocontrolled Alkaloid Construction: Rhazinicine (Gaunt), 9-epi-Pentazocine (Zhai and Li), Fawcettidine (Dake), Strychnine (Padwa), and Yohimbine (Jacobsen)

114

58. Alkaloid Synthesis: (-)-Aurantioclavine (Stoltz), (-)-Esermethole (Nakao/Hiyama/Ogoshi), (-)-Kainic Acid (Tomooka), Dasycarpidone (Bennasar), (-)-Cephalotaxine (Ishibashi) and Lysergic Acid (Fujii/Ohno)

116

59. Alkaloid Synthesis: Crispine A (Zhou), Cermizine C (Zhang), Tangutorine (Poupon), FR901483 (Kerr), Serratezomine A (Johnston)

118

Substituted Benzene Derivatives 60. Synthesis of Substituted Benzenes: The Carter Synthesis of Siamenol

120

61. Preparation of Benzene Derivatives

122

62. Preparation of Benzene Derivatives: The Barrett Syntheses of Dehydroaltenuene B and 15G256β

124

63. Substituted Benzenes: The Alvarez-Manzaneda Synthesis of (-)-Taiwaniquinone G

126

Heteroaromatic Derivatives 64. Synthesis of Heteroaromatics

128

65. Preparation of Heteroaromatic Derivatives

130

66. Preparation of Heteroaromatics

132

67. Heterocycle Construction: The Chang Synthesis of Louisianin C

134

vii

CONTENTS Organocatalyzed C-C Ring Construction 68. Enantioselective Organocatalytic Construction of Carbocycles: The Nicolaou Synthesis of Biyouyanagin A

136

69. Organocatalytic Ring Construction: The Corey Synthesis of Coraxeniolide A

138

70. Enantioselective Organocatalyzed Construction of Carbocyclic Rings

140

71. Organocatalytic C-C Ring Construction: (+)-Ricciocarpin A (List) and (-)-Aromadendranediol (MacMillan)

142

Transition Metal Catalyzed C-C Ring Construction 72. Transition Metal-Mediated Construction of Carbocycles: Dimethyl Gloiosiphone A (Takahashi), Pasteurestin A (Mulzer), and Pentalenene (Fox)

144

73. Transition Metal-Mediated Ring Construction: The Yu Synthesis of 1-Desoxyhypnophilin

146

74. Transition Metal Catalyzed Construction of Carbocyclic Rings: (-)-Hamigeran B

148

75. Transition Metal-Mediated C-C Ring Construction: The Stoltz Synthesis of (-)-Cyanthiwigin F

150

Intermolecular and Intramolecular Diels-Alder Reactions 76. Intermolecular and Intramolecular Diels-Alder Reactions: (-)-Oseltamivir (Fukuyama), Platensimycin (Yamamoto) and 11,12-Diacetoxydrimane (Jacobsen)

152

77. Intermolecular and Intramolecular Diels-Alder Reactions: Platencin (Banwell), Platensimycin (Matsuo), (-)-Halenaquinone (Trauner), (+)-Cassaine (Deslongchamps)

154

Stereocontrolled C-C Ring Construction 78. Stereocontrolled Carbocyclic Construction: The Trauner Synthesis of the Shimalactones

156

79. Stereocontrolled Carbocyclic Construction: (-)-Mintlactone (Bates), (-)-Gleenol (Kobayashi), (-)-Vibralactone C (Snider)

158

80. Stereocontrolled Carbocyclic Construction: The Mulzer Synthesis of (-)-Penifulvin A

160

Classics in Total Synthesis 81. The Sammakia Synthesis of the Macrolide RK-397

162

82. The Maier Synthesis of Cruentaren A

164

83. The Betzer and Ardisson Synthesis of (+)-Discodermolide

166

84. The Smith Synthesis of (+)-Lyconadin A

168

85. The Rychnovsky Synthesis of Leucascandrolide A

170

86. The Burke Synthesis of (+)-Didemniserinolipid B

172

viii

CONTENTS 87. The Kozmin Synthesis of Spirofungin A

174

88. The Ley Synthesis of Rapamycin

176

89. The Toste Synthesis of (+)-Fawcettimine

178

90. The Bergman-Ellman Synthesis of (-)-Incarvillateine

180

91. The Roush Synthesis of (+)-Superstolide A

182

92. The Takayama Synthesis of (-)-Cernuine

184

93. The Wood Synthesis of Welwitindolinone A Isonitrile

186

94. The Paquette Synthesis of Fomannosin

188

95. The Zakarian Synthesis of (+)-Pinnatoxin A

190

96. The Hoveyda Synthesis of (-)-Clavirolide C

192

97. The Carter Synthesis of (-)-Lycopodine

194

98. The Johnson Synthesis of Zaragozic Acid C

196

99. The Keck Synthesis of Epothilone B

198

100. The Overman Syntheses of Nankakurines A and B

200

101. The Trost Synthesis of (-)-Ushikulide A

202

102. The Castle Synthesis of (-)-Acutumine

204

103. The Kobayashi Synthesis of (-)-Norzoanthamine

206

104. The Davies/Williams Synthesis of (-)-5-epi-Vibansin E

208

Cumulative Author Index

211

Cumulative Reaction Index

225

ix

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Preface

With this third volume in the series, the chapters have been grouped by topic. With this change, this volume becomes a practical ﬁeld guide to recent developments in organic synthesis, from functional group transformations to complex total synthesis. The cumulative subject/transformation index that is also included as part of this volume covers all three volumes in this series. For many recent developments, such as organocatalysis, these volumes together provide a comprehensive overview of the ﬁeld. With the able assistance of Reto Mueller, webmaster of www.organic-chemistry.org, the Organic Highlights columns that are collected in this volume appeared weekly. These are still available, with active links to the journal articles cited. The weekly Organic Highlights columns provide in-depth coverage of new developments across the ﬁeld. Some topics, such as asymmetric organocatalysis and C-H functionalization, are often mentioned in the scientiﬁc press. Other topics, such as new methods for C-C bond construction, receive little popular notice, but are at least as important. I often consult these volumes myself in my day-to-day work of teaching and research. These three volumes together (and the later biennial volumes that will follow) are a valuable resource that should be on the bookshelf of every practicing organic synthesis chemist. DOUGLASS F. TABER Newark, DE April 25, 2010

xi

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Organic Synthesis State of the Art 2007–2009

1. Best Synthetic Methods: Oxidation and Reduction March 17, 2008

Although methods both for reduction and for oxidation are well developed, there is always room for improvement. While ketones are usually reduced using metal hydrides, hydrogen gas is much less expensive on scale. Charles P. Casey of the University of Wisconsin has devised (J. Am. Chem. Soc. 2007, 129, 5816) an Fe-based catalyst that effects the transformation of 1 to 2. Note that the usually very reactive monosubstituted alkene is not reduced and does not migrate. Takeshi Oriyama of Ibaraki University has developed a catalyst, also Fe-based (Chemistry Lett. 2007, 38) for reducing aldehydes to ethers. Using this approach, an alcohol such as 3 can be converted into a variety of substituted benzyl ethers, including 5. Simple aliphatic aldehydes and alcohols also work well. Fe cat 3 atm H2 RT

O 1 H

OH 2

O Fe cat

+

Et3SiH RT

OH

O

4

3

5

Oxidation of alcohols to aldehydes or ketones is one of the most common of organic transformations. Several new processes catalytic in metal have been put forward. Tharmalingam Punniyamurthy of the Indian Institute of Technology, Guwahati has found (Adv. Synth. Cat. 2007, 349, 846) that catalytic V(IV) oxide on silica gel, stirred with t-butyl hydroperoxide in t-butyl alcohol at room temperature smoothly oxidized 6 to 7. After the reaction, the catalyst was separated by ﬁltration. Another carbonyl can also serve as the hydride acceptor, but then the transfer can be reversible. Jonathan M. J. Williams of the University of Bath has shown (Tetrahedron Lett. 2007, 48, 3639) that with a Ru catalyst, methyl levulinate 9 could serve as the hydride acceptor, with the byproduct alcohol being drained off as the lactone 11. Hansjörg Grützmacher of the ETH Zürich developed an Ir catalyst (Angew. Chem. Int. Ed. 2007, 46, 3567) with benzoquinone as the net oxidant. that showed marked preference for the oxidation of primary over secondary alcohols. Yasuhiro Uozumi of the Institute for Molecular Science, Aichi, has devised (Angew. Chem. Int. Ed. 2007, 46, 704) a nanoencapsulated Pt catalyst that worked well with O2 or even with air. The catalyst was easily separated from the product, and maintained its activity over several cycles. O

OH V cat t-BuOOH 7

6

2

BEST SYNTHETIC METHODS: OXIDATION AND REDUCTION OH

O

O

Ru cat

O

+ H3CO2C

8

10

9

11

O

HO

HO

Ir cat OH

O H

BQ

12 OH

13 O

Pt cat O2

14

15

Oxidation can also be carried out without metal catalysis, but this requires stoichiometric reagent, so excess reagent and byproducts must be separated. Yoon-Sik Lee of Seoul National University has described (Tetrahedron Lett. 2007, 48, 3731) the preparation of an easilyswellable polymeric hypervalent iodine reagent that oxidized alcohols to aldehydes and ketones, including 16 to 17. The spent reagent was removed by ﬁltration. An alternative is to use volatile/ water soluble reagents. Xinquan Hu of the Zhejiang University of Technology has devised (J. Org. Chem. 2007, 72, 4288) a combination of HBr, oxygen and t-butyl nitrite that, with catalytic TEMPO, oxidized 18 to 19. This inexpensive protocol was easily scaled. H

poly-IBX OH

O

16

17 O ONO

N S

N

OH O2

NH2

N

H N

S

NH2

TEMPO/HBr 18

19

Three procedures for the oxidation of aldehydes to acids have recently appeared. Gwangil An of the Korea Institute of Radiological and Medical Sciences and Hakjune Rhee of Hanyang University have described (Tetrahedron Lett. 2007, 48, 3835) conditions leading to the carboxylic acid, Chao-Jun Li of McGill University has developed (Tetrahedron Lett. 2007, 48, 1033) an aldehyde to ester conversion that accommodated methanol as well as a range of primary and secondary alcohols, and B. P. Bandgar of Swami Ramanand Teerth Marathwada University has found (Tetrahedron Lett. 2007, 48, 1287) conditions for the oxidation of an aldehyde directly to the thioester. O

O H 20

OH

NaBH4 KOH/air

Cu cat/In cat H

21

20

N-BuOH t-butylOOH O

O

Dess-Martin H

23

O

O

Pd/C

SPh NaN3 PhSH

24

3

O 22

2. Functional Group Transformations May 19, 2008

Jeffrey C. Pelletier of Wyeth Research, Collegeville, PA has developed (Tetrahedron Lett. 2007, 48, 7745) a easy work-up Mitsunobu procedure for the conversion of a primary alcohol such as 1 to the corresponding primary amine 2. Shlomo Rozen of Tel-Aviv University has taken advantage (J. Org. Chem. 2007, 72, 6500) of his own method for oxidation of a primary amine to the nitro compound to effect net conversion of an amino ester 3 to the alkylated amino ester 5. Note that the free amine of 3 or 5 would react immediately with methyl iodide. Keith A. Woerpel of the University of California, Irvine has uncovered (J. Am. Chem. Soc. 2007, 129, 12602) a Cu catalyst that, with 7, effected direct conversion of silyl ethers such as 6 to the allyl silane 8. An Ag catalyst gave 9, which also shows arllyl silane reactivity. Biswanath Das of the Indian Institute of Chemical Technology, Hyderabad has established (Tetrahedron Lett. 2007, 48, 6681) a compact procedure for the direct conversion of an aromatic aldehyde such as 10 to the benzylic halide 11. This will be especially useful for directly generating benzylic halides that are particularly reactive.

(Boc)2NH OH

NH2

tBuO2N=NCO2tBu Poly-TPP

2

1 CO2Et HOF.CH3CN 3

NH2

CO2Et 4

Si

5

NH2

tBu BnO Si tBu tBu Si tBu

tBu BnO Si tBu

tBu Cu cat

CO2Et

2. H2 / Pd-C

NO2

OBn +

1. CH3I /PTC

tBu 6

7

8

CH3O CH3O H 10

CH3O CH3O

Me2S.Br2

CH3O

9

PMHS

Br

CH3O

O

11

α-Sulﬁnylation of ketones often requires intial generation of the enolate. J. S. Yadav, also of the Indian Institute of Chemical Technology, Hyderabad, has devised (Tetrahedron Lett. 2007, 48, 5243) an oxidative protocol for installing sulfur adjacent to a ketone. In a related development, Richard S. Grainger of the University of Birmingham has established (Angew. Chem. Int. Ed. 2007, 46, 5377) a simple procedure for the conversion of thio esters 4

FUNCTIONAL GROUP TRANSFORMATIONS such as 14 to the corresponding ketone 16. Yoshiya Fukumoto of Osaka University has shown (J. Am. Chem. Soc. 2007, 129, 13792) that a terminal alkyne 17 can be directly converted into the enamine 18 by Rh-catalyzed addition of a secondary amine. Lukas Hintermann and Carsten Bolm of RWTH Aachen have found (J. Org. Chem. 2007, 72, 5704) that inclusion of water gave the aldehyde, which could be oxidized with the residual Ru catalyst to the acid. O

O NH4SCN

SCN

I2 12

13 O

O Et2N

h

S N

S

O

O

MCPBA

N

TEMPO

O

N

14

N

15 H N

16

O N O

Rh cat

H 17 H

N

18 H

1. Ru cat H2O

Ts

N

Ts CO2H

2. NaIO4 H

19

20

Yasuharu Yoshimi and Minoru Hatanaka of the University of Fukui have described (Chem. Comm. 2007, 5244) a convenient procedure for the reductive decarboxylation of acids such as 21 to the corresponding alkane 22. Teruaki Mukaiyama of the Kitasato Institute, Tokyo has developed (Chemistry Lett. 2007, 36, 1456) a simple protocol for the activation of carboxylic acids for amide formation. DMAP-mediated coupling of the acid with 25 gave the mixed anhydride, which combined efﬁciently with the amine 24 to give the amide 26. O

HO

HO CH3

OH h /Phen/DCB RSH 21

HO

OH O

22

HO

N

+

H

O OO O S S O Ph 25

N

Ph

O

DMAP 23

24

26

5

3. Best Synthetic Methods: Oxidation May 26, 2008

Although the enantioselective oxidation of alkyl aryl sulﬁdes is well developed, much less is known about dialkyl sulﬁdes. Tsutomu Katsuki of Kyushu University has designed (J. Am. Chem. Soc. 2007, 129, 8940) an Fe(salan) complex that combines with aqueous H2O2 to oxidize alkyl methyl sulﬁdes in high ee. Fe* cat 30% H2O2

S 1

S O

94% ee

2

The oxidation of alcohols to aldehydes and ketones is one of the most widely practiced of synthetic transformations. Ge Wang of the University of Science and Technology in Beijing has developed (Chem. Lett. 2007, 36, 1236) a Mo catalyst that used aqueous H2O2 to effect this transformation. Secondary alcohols are oxidized more rapidly than primary alcohols. Vinod K. Singh of the Indian Institute of Technology, Kanpur, has found (Synth. Comm. 2007, 37, 4099) that the solid, inexpensive 6 can take the place of oxalyl chloride in the Swern oxidation. Viktor V. Zhdankin of the University of Minnesota, Duluth has devised (J. Org. Chem. 2007, 72, 8149) a polymer-bound hypervalent iodine reagent that is easily separated after use, and reoxidized for reuse. Mo cat 30% H2O2 OH

3

O

4 Cl Cl P N N Cl P P Cl N OH Cl 6 Cl OH DMSO

O H H

5

7

O

poly-IB H 8

OH

9

O

Enones such as 11 are versatile intermediates for organic synthesis. Makoto Tokunaga, now at Kyushu University, and Yasushi Tsuji, now at Kyoto University, have found (Tetrahedron Lett. 2007, 48, 6860) a Pd catalyst that, in the presence of O2, will oxidize a cyclic ketone such as 10 to the enone. 6

BEST SYNTHETIC METHODS: OXIDATION O

O Pd cat O2 11

10

The direct oxidation of an alcohol to the acid is not always an efﬁcient process, so the conversion of 12 to 13 would often be carried out over at least three steps. David Milstein of the Weizmann Institute of Science has devised (Science 2007, 317, 790) a Ru catalyst that effected the transformation in a single step, generating H2 as a byproduct as the oxidation proceeded. O PhCH2NH2

OH

N H

Ru cat 12

Ph + H2

13

The oxidation of an aldehyde to the corresponding amide is also a useful transformation. Noritaka Mizuno of the University of Tokyo has designed (Angew. Chem. Int. Ed. 2007, 46, 5202) a Rh catalyst that can combine, in water, the aldehyde 14 and NH2OH to give the primary amide 15. Johann Chan of Amgen Inc., Thousand Oaks, CA has found (J. Am. Chem. Soc. 2007, 129, 14106) a different Rh catalyst that mediated the oxidation of a sulfonamide to the nitrene, which under the reaction conditions inserted into the aldehyde H to give the amide 17. NH2OH . H2SO4 H

NH2

Rh cat

14 O

O

15 H

O

SO2R N H

RSO2NH2 PhI(RCO2)2 Rh cat

O

16

17

Krishnacharya G. Akamanchi of the Institute of Chemical Technology, Matunga, Mumbai has shown (Tetrahedron Lett. 2007, 48, 5661) that t-butyl hypochlorite and NaN3 will convert an aldehyde 18 to the acyl azide 19. The acyl azide 19 can be carried on to the nitrile 20, or, on warming, to the inverted isocyanate 21.

H O

CN

tBuOCl

N3

NaN3

20

O

18

19

N=C=O 21

7

4. Best Synthetic Methods: Reduction June 9, 2008

Jaiwook Park of Pohang University of Science and Technology has developed (Org. Lett. 2007, 9, 3417) a procedure for the preparation of Pd-impregnated magnetic Fe nanoparticles. This effective hydrogenation catalyst was attracted to an external magnet and so was easily separated from the reaction matrix. Duk Keun An of Kangwon National University has found (Chem. Lett. 2007, 36, 886) that by including NaOtBu, Dibal reduction of an ester such as 3 can be made to reliably stop at the aldehyde 4. By using the easily-prepared pentaﬂurophenyl ester 5, Panagiota Moutevelis-Minakakis of the University of Athens was able to reduce an acid to the alcohol 6. Lionel A. Saudan of Firmenich SA, Geneva has devised (Angew. Chem. Int. Ed. 2007, 46, 7473) a Ru catalyst that will hydrogenate an ester such as 7 to the alcohol 8 without reducing an internal alkene. OH

O

H2 Pd cat

1

2 O

O Dibal O

H

NaOtBu 4

3 F F NaBH4

O O

F

F F

5

OCH3 7

OH

THF 6 Ru cat

OH

H2

O

8

Norio Sakai of the Tokyo University of Science has established (J. Org. Chem. 2007, 72, 5920) what promises to be a general route to ethers 10, by direct reduction of the corresponding ester 9. Hideo Nagashima of Kyushu University has developed (Chem. Commun. 2007, 4916) a Ru catalyst that effected selective hydrogenation of an amide 11 to the amine 12 without reducing ketones or esters. Alternatively, Jason S. Tedrow of Amgen Inc., Thousand Oaks, CA has found (J. Org. Chem. 2007, 72, 8870) that a protocol developed by Robert E. Maleczka, Jr. of Michigan State University was effective for reducing an aryl ketone 13 to the corresponding hydrocarbon 14 without reducing the amide.

8

BEST SYNTHETIC METHODS: REDUCTION O Br

O

cat InBr3 Et3SiH

O

Br

9

10 Ru cat

N

O 11

O

N

O

Ph PhMe2SiH

Ph

12

OCH3

OCH3 Pd(OAc)2

O

PhCl N

13

O

PMHS / KF

N

14

O

O

O

The stereocontrolled reductive amination of cyclic ketones such as 15 has been a continuing challenge. Shawn Cabral of Pﬁzer, Inc. in Groton, CT has reported (Tetrahedron Lett. 2007, 48, 7134) complementary reagent combinations, leading selectively to either 16 or 17. PhCH2NH2

+

O 15

16

N H

N 17 H

Ph

LiBH4

78 : 22

NaBH(OAc)3

15 : 85

Ph

To control catalytic hydrogenation, it is often desirable to control the H2 supply. John S. McMurray of the University of Texas M. D. Anderson Cancer Center in Houston has shown (J. Org. Chem. 2007, 72, 6599) that Et3SiH is a convenient H2 source. CO2tBu

Pd/C

HO

HO

18 NO2 20

NO2

CO2tBu

Et3SiH 19

SmI2

NH2

NH2 / H2O

21

NO2

H2

H + 22

Pd(OH)2 O

OH 23

24

OH

94% ee 25

Nitro alkanes add to aldehydes to give nitro alkenes such as 20. Göran Hilmersson of Göteborg University has developed (Tetrahedron Lett. 2007, 48, 5707) conditions for the reduction of such a nitro alkene directly to the corresponding saturated amine 21. Erick M. Carreira of ETH Hönggerberg has coupled (Angew. Chem. Int. Ed. 2007, 46, 2078) the enantioselective addition of benzylic nitro compounds such as 22 to aldehydes with catalytic hydrogenolysis, to deliver the secondary alcohol 25 in high ee. 9

5. Best Synthetic Methods: Functional Group Transformation October 27, 2008

François Morvan of the Université de Montpellier, using the inexpensive dimethyl phosphite, optimized (Tetrahedron Lett. 2008, 49, 3288) the free radical reduction of 1 to 2. Pawan K. Sharma of Kurukshetra University found (Tetrahedron Lett. 2008, 48, 8704) that NaBH4 in the presence of a catalytic amount of RuCl3.xH2O reduced monosubstituted and disubstituted alkenes, such as 3, to the corresponding alkanes. Note that benzyl ethers were stable to these conditions. OBz N

O BzO (CH3O)2PH

O N

O S

O O

1

O O

2 O

O O

RuCl3.x H2O

O BnO

O

benzoyl peroxide

O O

O O

NaBH4

O O

BnO

4

3

Ken Suzuki of Asahi Kasei Chemicals and Shun-Ichi Murahashi of Okayama University of Science established conditions (Angew. Chem. Int. Ed. 2008, 47, 2079) for the oxidation of primary amines such as 5 to oximes. Both ketoximes such as 6 and aldoximes were prepared using this protocol. Primary and secondary alcohols were stable to these conditions. NH2 HO 5

WO3 / Al2O3 HO O2

O2N

N OH

cat DPPH

Ph DPPH =

N N

NO2

Ph 6

O2N

Three noteworthy procedures for the oxidation of an aldehyde to the acid oxidation state were recently reported. Jonathan M. J. Williams of the University of Bath demonstrated (Chem. Commun. 2008, 624) that crotonitrile could serve as the hydrogen acceptor in the oxidation of an aldehyde 7 to the methyl ester 8. Note that isolated alkenes were stable to these conditions. Vikas N. Telvekar the University Institute of Chemical Technology, Mumbai improved (Tetrahedron Lett. 2008, 49, 2213) the oxidative amination of an aldehyde 9 to the nitrile 10. G. Sekar of the Indian Institute of Technology Madras effected

10

BEST SYNTHETIC METHODS: FUNCTIONAL GROUP TRANSFORMATION (Tetrahedron Lett. 2008, 49, 1083) oxidation of an aldehyde 11 to the acid 12, under conditions that would be expected to not oxidize a primary or secondary alcohol. O

O H

Ru cat

OCH3

NaICl2

O

CH3OH CN

O

7

H

8

O

O

NH4OH / H2O

CN

O

9

O

10 O

cat CuCl H

OH

t-BuOOH

11

12

J. S. Yadav of the Indian Institute of Chemical Technology, Hyderabad observed (Tetrahedron Lett. 2008, 49, 3015) that the activation of a thiophenol 14 with N-chlorosuccimide generated a species that added regioselectively to a ketone 13 to give the thioether 15. Oxidation of the sulﬁde 15 followed by heating of the resulting sulfoxide would give the enone 16. This appears to be an easily scalable procedure.

Cl

O

SH 14 NCS

13

O

O

MCPBA;

15 ArS

16

It is well known that an acid 17 and an amine 18 will condense at elevated temperature to give the amide 20. Dennis G. Hall of the University of Alberta has now shown (Angew. Chem. Int. Ed. 2008, 47, 2876) that a simple boronic acid 19 will catalyze this reaction at room temperature. NH2 OH

O cat 19

+

N

OH

H

B OH

O

Br

17

20

18

19

Liming Zhang of the University of Nevada, Reno devised (J. Am. Chem. Soc. 2008, 130, 3740) a new route to oxygenated dienes such as 22, based on Au-catalyzed rearrangement of a propargylic ester such as 21. Note that the oxygen has shifted to the adjacent carbon in the course of this transformation. The product dienes participated smoothly in Diels-Alder cycloaddition.

O

O

CO2CH3

O

CO2CH3

Au cat

O

O

MeAlCl2 O

O O

O

O 21

CO2CH3

22

11

O

23

O

6. New Methods for Functional Group Conversion March 23, 2009

Yujiro Hayashi of Tokyo University of Science and Teruaki Mukaiyama of the Kitasato Institute developed (Chem. Lett. 2008, 37, 592) a reduction-oxidation method for converting primary, secondary (such as 1, with clean inversion) and tertiary alcohols to sulﬁdes. Peter A. Crooks of the University of Kentucky found (Chem. Lett. 2008, 37, 528) that tetrabenzylpyrophosphate 5 was an effective agent for condensing an acid 4 with an amine 6 to give the amide 7. This protocol, that runs in near quantitative yield in an hour at room temperature, with all impurities readily removable by washing with aqueous base and aqueous acid, appears to be well-suited both for scale-up, and for solid-phase synthesis. S SH N 2

Ph OH

H3CO

1

O

SBtz > 99% ee

3

O

[(BnO)2PO]2O 5

PhO

Ph

O / PhOPPh2

OH

O

Ph

NH2 6 4-DMAP

4

Ph

PhO N 7 H

H3CO

Balchandra M. Bhanage of the University of Mumbai reported (Tetrahedron Lett. 2008, 49, 965) the reductive amination of aldehydes, including 8, and ketones to the corresponding amines, using H2 and an inexpensive Fe catalyst. André Charette of the Université de Montréal showed (J. Am. Chem. Soc. 2008, 130, 18) that the Hantzsch ester 12, in the presence of Tf2O, reduced amides selectively to amines. Esters, epoxides, ketones, nitriles and alkynes were stable to these conditions. E H

O H

NH2

+

EDTA-Na2 H2 / H2O

9

CO2Et CO2Et

Ph

10

OH

Br2

O

13 HO SmI2 O

16

N Ph

11

O

15

Ph

Tf2O

O

OH NaBH4

N

Ph

N 12 H

Fe cat Ph

8

14

Ph

N

E

O

HO

THF/H2O

O 17

O

Matthew Tudge of Merck Rahway demonstrated (Tetrahedron Lett. 2008, 49, 1041) that Br2 in DME activated NaBH4, allowing facile reduction of esters, including the congested diester 14, at ambient temperature. David J. Procter of the University of Manchester made (J. Am. Chem. Soc. 2008, 130, 1136) the remarkable observation that six-membered

12

NEW METHODS FOR FUNCTIONAL GROUP CONVERSION ring lactones such as 16 were reduced to the corresponding diol with SmI2. Five-membered ring and seven-membered ring lactones were not reduced under these conditions.

CuH

CuH t-BuOH

19

O

18

O

20

HO

Bruce H. Lipshutz of the University of California, Santa Barbara devised (Organic Lett. 2008, 10, 289) a convenient and economical procedure for CuH, using Cu and an inexpensive ligand in catalytic amounts, with PMHS as the bulk reductant. The reduction of 18 presumably proceeds by electron transfer, as with dissolving metal reduction, delivering 19 with the more stable trans ring fusion. In the presence of t-BuOH as a proton source, the reduction goes on to the alcohol 20. This may be the current method of choice for selectively reducing a cyclohexanone to the equatorial alcohol. It is well known that tertiary allylic alcohols such as 21 can be oxidized to the corresponding enone 23 with chromium reagents. Yoshiharu Iwabuchi of Tohoku University observed (J. Org. Chem. 2008, 73, 4750) that the oxammonium salt 22 derived from TEMPO effected the same transformation. David E. Richardson of the University of Florida found (Tetrahedron Lett. 2008, 49, 1071) that H2O2 could be used to oxidize N-methylmorpholine in situ to the N-oxide, that in turn reoxidized catalytic OsO4. In the presence of the Sharpless ligand, the dihydroxylation proceeded with high ee. This approach could offer cost and waste stream advantages over currently used oxidants. O HO SbF6

N O 22

N

21

23

24

26

cat OsO4

cat CuCl

O

N

27

28

La[N(TMS)2]3 H

H +

OH

25

H2O2/L*

O

t-BuOOH OH

HO OH

O

29

90% ee

O

(cat)

N 30

G. Sekar of the Indian Institute of Technology Madras, in Chennai, established (Tetrahedron Lett. 2008, 49, 2457) a convenient procedure for oxidizing primary alcohols such as 26 to the acid 27. Secondary alcohols were oxidized to ketones. Allylic and benzylic alcohols could be oxidized in preference to saturated alcohols. Tobin J. Marks of Northwestern University devised (Organic Lett. 2008, 10, 317) a La catalyst for the oxidative amination of aldehydes. In its present incarnation, excess aldehyde served as the reductant. If a less expensive reductant could be found, this would be a very useful procedure, avoiding the carboxylic acid activation usually required for amide formation.

13

7. Organic Functional Group Interconversion: (-)-β-Conhydrine (Barua) and (+)-6'-Hydroxyarenarol (Anderson) September 21, 2009

V. T. Perchyonok and Kellie L. Tuck of Monash University found (Tetrahedron Lett. 2008, 49, 4777) that a concentrated solution of Bu4NCl and H3PO2 in water effected free radical reductions and cyclizations. Stéphane G. Ouellet of Merck Frosst demonstrated (Tetrahedron Lett. 2008, 49, 6707) that an oxazoline such as 3 could be converted to the alcohol 4 by acylation followed by reduction. Elizabeth R. Burkhardt of BASF developed (Tetrahedron Lett. 2008, 49, 5152) a protocol for scalable reductive amination using an easily metered liquid pyridine-borane complex. Mohammad Movassaghi of MIT devised (Angew. Chem. Int. Ed. 2008, 47, 8909) a strategy for conversion of an allylic carbonate 8 by way of the allylic diazene to the terminal alkene 9. 1. ClCO2CH3

Bu4N H2PO2 Br

H

AIBN or Et3B

1

O

H N

Ph-NH2

O

N BH3 7

6

/ AcOH

OH

2. LiBH4 4

O S

.

5

O

N 3

2

N K NO2

1.

N

OCO2Me 8 / Pd cat

Ph

2. AcOH

Ph 9

Philippe Compain of the Université d’Orleans uncovered (J. Org. Chem. 2008, 73, 8647) a practical procedure for oxidizing an inexpensive aldose such as 10 to the amide 12, a valuable chiral pool starting material. Karl A. Scheidt of Northwestern University extended (Organic Lett. 2008, 10, 4331) activated MnO2 oxidation to saturated aldehydes such as 13, leading to the ester 15. Tohru Fukuyama of the University of Tokyo showed (Organic Lett. 2008, 10, 2259) that halides such as 16 could be oxidized to the oxime 18 with the reagent 17. The product oximes are readily dehydrated to the corresponding nitriles. Chutima Kuhakarn of Mahidol HO OBn O BnO BnO

OH

OBn

HO

11

K2CO3 / I2

BnO BnO

10

Br N

13

N N

N cat 14

O 15

CN

NH2 IBX / I2

OH

DMSO

Cs2CO3 16

O

/ DBU MnO2*

O

BnO O 12

H TsNHOTBS 17

OH

H

OBn OH N H

NH2

18

19

14

20

ORGANIC FUNCTIONAL GROUP INTERCONVERSION University devised (Synthesis 2008, 2045) a simple protocol for the oxidation of a primary amine such as 19 to the nitrile 20. Nasser Iranpoor and Habib Firouzabadi of Shiraz University developed (J. Org. Chem. 2008, 73, 4882) the reagent 22 for Mitsunobu coupling. The stereochemical course of this reaction with simple acyclic secondary alcohols such as 21 was not reported. Salvatore D. Lepore of Florida Atlantic University optimized (Angew. Chem. Int. Ed. 2008, 47, 7511) the quisylate 24 for the displacement with retention to give the azide 25. Hideki Yorimitsu and Koichiro Oshima of Kyoto University optimized (J. Am. Chem. Soc. 2008, 130, 11276) a Co catalyst for the conversion of a secondary halide such as 26 to the terminal alkene 27. Base-mediated elimination gave primarily the internal alkene. Christian E. Schafmeister of the University of Pennsylvania established (J. Am. Chem. Soc. 2008, 130, 14382) that acyl ﬂuorides such as 28 couple efﬁciently even with unreactive amino acids such as 29. N CO2H

N

OH N

+

O

O

O

22

23

NO2

24

Br R3SiCH2MgBr Fmoc

Co cat 26

N3

TiF4 / TMSN3

N

Ph3P

21

O O S

Ar

N

27

H N

25

H

O

OH

N 29 O

F

HFIP

Fmoc

H N

O OH

N

28

30

O

In the course of a synthesis of (-)-β-conhydrine 33 (Tetrahedron Lett. 2008, 49, 6508), Nabin C. Barua of North East Institute of Science and Technology needed to reduce the nitro group of 31 to the amine without reducing the very reactive monosubstituted alkene. Zn/NH4Cl served well. James C. Anderson of the University of Nottingham solved (J. Org. Chem. 2008, 73, 8033) a similar problem in a synthesis of (+)-6’-hydroxyarenarol 36. In that case, Raney Ni reduced the carbon-sulfur bond without affecting the monosubstituted alkene. HO

NO2

31

OH NH4Cl

N

NH2

Zn

HO

H Ra Ni

OH 32

OH

OH

33

O

(-)-β-Conhydrine

15

34 SCH3

O

35

36 (+)-6'-Hydroxyarenarol

8. New Methods for Functional Group Conversion October 26, 2009

Ilya M. Lyapkalo of the Academy of Sciences of the Czech Republic, Prague, showed (Synlett 2009, 558) that a ketone 1 reacted with the inexpensive nonaﬂuorobutanesulfonyl ﬂuoride in the presence of a phosphazene base to give ﬁrst the enol sulfonate, and then the alkyne 2. The method worked well for aldehydes also.

RFSO2F

cat FeCl3

phosphazene

H2 O

1

2

4

3

NH2

CO2Et

H 6 5

O

H

H

O

N

Rh cat

Ar

O

Au cat

7

8

9

CO2Et

Christophe Darcel of the Université de Rennes I developed (Adv. Synth. Cat. 2009, 351, 367) an inexpensive Fe catalyst for the hydration of a terminal alkyne 3 to the ketone 4. Carlos Alonso-Moreno and Antonio Otero of the Universidad de Castilla-La Mancha devised (Adv. Synth. Cat. 2009, 351, 881) a Rh catalyst for the complementary hydration of a terminal alkyne 5 to the aldehyde, by way of the imine 7. Internal alkynes often give mixtures of ketones on hydration, but Bo Xu and Gerald B. Hammond of the University of Louisville found (J. Org. Chem. 2009, 74, 1640) a gold catalyst that converted an alkynyl ester 8 into the γ-keto ester 9. Jonathan M. J. Williams of the University of Bath developed (J. Am. Chem. Soc. 2009, 131, 1766; Tetrahedron Lett. 2009, 50, 3374) a Ru-catalyzed protocol for the alkylation of an amine 11 with an alcohol 10. The reaction proceeded by oxidation of the alcohol to the aldehyde, imine formation, and reduction using the hydride generated by the initial oxidation. José Luis García Ruano of the Universidad Autónoma de Madrid uncovered (Chem. Commun. 2009, 404) a similar conversion mediated by Raney Ni.

OH 10

O

N H 11

Ru cat

N 12

O

There has been a great deal of work recently on the preparation and reaction of amides. Susumu Saito of Nagoya University prepared (J. Am. Chem. Soc. 2009, 131, 8748) a diaryl boronic acid that catalyzed the methanolysis of an imide 13 to the methyl ester 14 and the oxazolidinone 15. Jaume Vilarrasa of the Universitat de Barcelona reported (J. Org. Chem. 2009, 74, 2203) the catalyzed condensation of an acid 16 with an azide 17 to give

16

NEW METHODS FOR FUNCTIONAL GROUP CONVERSION the amide 18. Both aryl and aliphatic azides participated in the reaction, and the enantiomeric integrity of the amide was maintained. Christian G. Bochet of the University of Fribourg developed (J. Org. Chem. 2009, 74, 4519) the photolabile amide 19. Long wave UV radiation, that did not disturb other photoactivatable protecting groups, then effected acylation of 20 to give 21, with maintenance of the enantiomeric integrity of 19. O

O O

O

O

N

OCH3

cat Ph

13

Boc N H

O O2N

Ph

20 Ph NO2 h

N

O O

CH3OH

15

NH2

O

O

N3

Ph

TBSO

N H cat PhSeSePh TBSO 18 Me3P

16

Ph

O

Ph

1. PhNH2 23

N H Ph

17

OH

+

14

19

Ph

NH

H

N

S

H Boc

21

N Cbz

2. O

O 22

Ph

NH

O H

N SO2Ar N 24 Cbz

O N O

25

Cs2CO3

David Crich, now at CNRS de Gif-sur-Yvette, found (J. Org. Chem. 2009, 74, 3886) that the enantiomerically-pure thioanhydride 22 could be coupled sequentially ﬁrst with an amine 23 and then with an arenesulfonamide 24 to give the unsymmetrical diamide 25. This approach was used to prepare diastereomerically-pure glycodipeptides. Cl

Ph O

NH2 CO2H 26

27 O

OH

N

K3PO4 28

H CO2H

O 29

N 30 H

N O

cat K60 31

Li Zhang of Boehringer Ingelheim took (Tetrahedron Lett. 2009, 50, 2964) a simpler approach to amide construction, demonstrating that K3PO4 mediated the coupling of 26 and 27 to give 28 with minimal racemization. James H. Clark of the University of York established (Chem. Commun. 2009, 2562) an even milder protocol, heating (toluene, reﬂux) the acid 29 with the amine 30 in the presence of 10 weight percent of calcined Kieselgel 60 to give the amide 31.

17

9. Protection of Organic Functional Groups March 31, 2008

Several noteworthy new developments in the protection and deprotection of alcohols have been reported. Andrea Bifﬁs of the Università di Padova has developed (Adv. Synth. Catal. 2007, 349, 2485) a Rh catalyst that effected silylation of alcohols such as 1 to the TES ether 2 at just 0.01% loading. Joshua Rokach of the Florida Institute of Technology has observed (Tetrahedron Lett. 2007, 48, 5289) that the reverse reaction, Rh-catalyzed desilylation of 3, was highly selective for the less congested site, even removing the usually less reactive TBS ether of 3 and leaving the more hindered TES ether. Hirokazu Tsukamoto of Tohoku University has devised (Tetrahedron Lett. 2007, 48, 8438) an improved procedure for the deprotection of allyl ethers such as 5. Filtration of the reaction mixture through polymerbound diethanolamine removed > 95% of the Pd from the product. Patrick Pale of the Université Louis Pasteur has established (Tetrahedron Lett. 2007, 48, 8895) improved conditions for preparing diphenylmethyl ethers such as 10. The protecting group was removed with the Pd catalyst and ethanol. OH

Et3SiH

OSiEt3

Rh cat 2

1 O

O

O

O

catechol borane Rh cat

TESO

TESO

OTBS

3

OH

4

BO Pd cat/

O

6;

OH

polymerethanolamine OTBS

OTBS 5 OH Ph 9 Ph

OH

7

Ph O

Ph

PdCl2 cat OBn

8

OBn

10

Amines can be activated for alkylation by N-formylation. Subsequent deformylation of the alkylated formamide 11 has been a challenge. Longqin Hu of Rutgers University has developed (Tetrahedron Lett. 2007, 48, 4585) microwave conditions that work well. Carbamates are stable, but esters are not. Protection of amides can also be important. Michael J. Zacuto of Merck Process in Rahway, NJ has optimized (J. Org. Chem. 2007, 72, 6298) the Rh-catalyzed deallylation of 13 to give 14. 18

PROTECTION OF ORGANIC FUNCTIONAL GROUPS H

O N

H N

KF / Al2O3

O

microwave O2N

N H

11

O

O2N

N H

12

O

O

O N

Rh cat

Ph

PrOH / O2N

O

N H

O 2N

13

Ph

14

Carbonyl protection and deprotection is also important. Yoshihisa Kobayashi of the University of California, San Diego has devised (J. Org. Chem. 2007, 72, 3913) the isonitrile 15. Usually, the product 16 after Ugi condensation would be very difﬁcult to hydrolyze. In the case of 16, mild acid effected cyclization to the acyl indole 17, which was easy to hydrolyze. In a different approach, Francesco Naso of the Università di Bari has shown (Chem. Commun. 2007, 3756) that acid chlorides such as 18 condensed with 19 to give the furan 20. Such furans are easily oxidized, liberating the starting acid. OCH3

CH3O

H N

Ugi

CN CH3O

O

OCH3 N

15

Cl

N

16

O

17

AlCl3

Me3Si +

O

Me3Si

18

H N

O

H

O O

H+

19

20

Acetals and ketals are usually removed with acid. Robert G. Bergman and Kenneth N. Raymond of the University of California, Berkeley have devised (Angew. Chem. Int. Ed. 2007, 46, 8587) a self-assembling supramolecular catalyst that hydrolysed dimethyl acetals and ketals such as 21 in water at pH = 10. Pengfei Wang of the University of Alabama, Birmingham has designed (Organic Lett. 2007, 9, 2831) a protecting group 23 for aldehydes and ketones that was efﬁciently removed by photolysis. OCH3

O

OCH3 21

cat 22

pH = 10

OCH3

O

h O

O 23

24

OCH3

19

10. Best Synthetic Methods: Functional Group Protection November 10, 2008

Benzyl esters are easily deprotected by hydrogenolysis. It is often observed, however, as exempliﬁed by the conversion of 1 to 2 reported (Adv. Synth. Catal. 2008, 350, 406) by Hironao Sajiki of Gifu Pharmacutical University, that alkene hydrogenation can be carried out selectively. Fernando Albericio of the University of Barcelona has developed (Tetrahedron Lett. 2008, 49, 3304) a family of thiophene-based esters 3 that can be removed with acid in the presence of t-butyl esters, and that are stable to the removal of FMOC groups. Vassiliki Theodorou of the University of Ioannina has found (Tetrahedron Lett. 2008, 49, 8230) that esters were rapidly saponiﬁed by methanolic NaOH in solvent CH2Cl2. O

O H2

OBn

OBn

Pd cat

1

2 O

O O

H

N 3 O O

FMoc O

S

Ar

TFA

O H

O

N

H

FMoc

4 HO O H

NaOH CH3OH / CH2Cl2

5

+

O 6

7

Speciﬁc oligosaccharide synthesis depends heavily on the use of orthogonal methods for alcohol protection and deprotection. This is illustrated by the work (J. Org. Chem. 2008, 73, 1008) of Carolyn R. Bertozzi of the University of California, Berkeley, who deployed p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMB), p-chlorobenzyl (PCB) and p-iodobenzyl (PIB) ethers to enable construction of a disaccharide, by way of 9. Piers R. J. Gaffney of Imperial College London has reported (Tetrahedron Lett. 2008, 49, 1836) a practical preparation of the ether 11, that should make this symmetrical protecting group more readily available. George W. J. Fleet of the University of Oxford and Sigthur Petursson of the University of Akureyri have found (Tetrahedron Lett. 2008, 49, 2196) that diphenyl diazomethane 14, easily prepared from benzophenone, reacted under neutral conditions with primary, secondary and tertiary alcohols to form the benzyhydryl ethers. Harsh conditions have often been employed to remove aryl methyl ethers such as 16. Wei Wang of the University of New Mexico and Wenhu Duan of the Shanghai Institute of Materia Medica have developed (Tetrahedron Lett. 2008, 49, 4054) a simple protocol to effect this transformation, by heating the ether to reﬂux in DMF in the presence of iodocyclohexane 17.

20

BEST SYNTHETIC METHODS: FUNCTIONAL GROUP PROTECTION O O

Ph

O O

PCBO O

8 HO HO

OH

HO

OH

O O PCBO

O PIBO ODMB

9

OCH3

AnO

AnO CH3O O

O

+ OH

AnO

O

10 O

O

HO O

Ph

Ph

O

14

Br

O

17

O

Br

O

OH

DMF

16

O

O 15

OCH3

An = p-MeOC6H4C(=O)

12

Ph

Ph + N2

13

OAn AnO

11

18

Dithianes such as 19 have often been deprotected with stoichiometric heavy metals. Andreas Kirschning of Leibniz Universität Hannover has devised (J. Org. Chem. 2008, 73, 2018) a set of three anionic resins, charged, respectively, with I(O2CCF3)2-, HCO3-, and S2O3-. Exposure of 19 to the three resins in sequence delivered the very sensitive ketone 20. PivO

PivO O O

S

O

Resin x 3

O

O

S

O

19

O 20

Clotilde Ferroud of the Conservatoire National des Arts et Métiers, Paris has established (Tetrahedron Lett. 2008, 49, 3004) microwave conditions for the direct acetylation of an amine such as 21 with vinyl acetate 22. Samad Khaksar of the Islamic Azad University, Iran has found (Tetrahedron Lett. 2008, 49, 3527) that thiourea 25 catalyzed the protection of an amine 24 with Boc2O under similarly mild conditions. Darren J. Dixon of the University of Manchester employed (Chem. Commun. 2008, 2474) the protocol developed by Romo to convert the sulfonamide 27 to the triﬂuoracetate 28. Uno Mäeorg of the University of Tartu showed (Tetrahedron Lett. 2008, 49, 1373) that sulfonamides can also be deprotected with the inexpensive mischmetal in the presence of TiCl4. H N

NH2

OAc 22

O H N

MW

23

21 H N

Boc N

Boc2O

O

H2N

25

NH2

26

27

21

H O

CO2CH3

S 24

N

1. TFAA

N SO2Mes 2. SmI2 H

CO2CH3

28

N H

O CF3

11. Functional Group Protection May 18, 2009

Alcohols are usually protected as alkyl or silyl ethers. Michael P. Jennings of the University of Alabama found (Tetrahedron Lett. 2008, 49, 5175) that pyridinium tribromide can selectively remove the TBS (or TES) protection from the primary alcohol of a protected primary-secondary alcohol such as 1. Propargyl ethers are useful because they are stable, but can be selectively removed in the presence of other protecting groups. Shino Manabe and Yukishige Ito at RIKEN showed (Tetrahedron Lett. 2008, 49, 5159) that SmI2 could reductively remove a propargyl group in the presence of acetonides (illustrated, 3), MOM, benzyl and TBS ethers. Hisanaka Ito of the Tokyo University of Pharmacy and Life Sciences took advantage (Organic Lett. 2008, 10, 3873) of the reducing power of Cp2Zr to selectively remove the allyl ethers from 5, to give 6. These conditions might also remove propargyl ethers. O TBSO

O

O N

TBSO

1

O

Py.Br3

TBSO

N

CH3OH HO

Bn

2

O

O

O

O O

O 3

Bn

iPrNH2 H2O

O HO

4

H

OTBS

OTBS

Ar

Cp2ZrCl2

O Au cat

2 x BuLi O

SmI2

O

O HO

7

OH

5

HO 8

6

Esters can also be useful protecting groups. Naoki Asao of Tohoku University developed (Tetrahedron Lett. 2008, 49, 7046) the o-alkynyl ester 7. Au catalyst in EtOH removed the ester, leaving benzoates, acetates, OTBS and OTHP intact. Alternatively, an o-iodobenzoate can be removed by Sonogashira coupling followed by the Au hydrolysis. N-Formylation is usually accomplished using mixed anhydrides. Weige Zhang and Maosheng Chang of Shenyang Pharmaceutical University put forward (Chem. Commun. 2008, 5429) an intriguing alternative, heating a secondary amine 9 with KCN in the presence of dimethyl malonate to give 10. HO

H N

HO

H

KCN, ester

H

O

N

N

MeOH 9

10

11

22

H 1. Boc2O OCH3 2. CAN

N 12

Boc

FUNCTIONAL GROUP PROTECTION Many of the current methods for amination that have been developed deliver the aryl amine. John F. Hartwig of the University of Illinois established (J. Am. Chem. Soc. 2008, 130, 12220) that exposure of the amine 11 to Boc2O followed by CAN led to the protected, dearylated amine 12. Adam McCluskey of The University of Newcastle observed (Tetrahedron Lett. 2008, 49, 6962) that microwave heating removed Boc protecting groups when there was a free carboxylic acid elsewhere in the molecule. Michael Lefenfeld of SiGNa Chemistry and James E. Jackson of Michigan State University used (Organic Lett. 2008, 10, 5441) easilyhandled Na/silica gel to remove primary and secondary sulfonamides (e.g. 15 → 16). Methanesulfonamides were also removed under these conditions. Ph

Ph H H

N

N Boc

H

O

H2O OH

H

microwave

O Na-SG

N

N H

OH

THF

N 14

13

Ts

N

15

16

H

Carboxylates are good SN2 nucleophiles. Santos Fustero of the Universidad de Valencia took advantage of this (J. Org. Chem. 2008, 73, 5617) in developing a transesteriﬁcation of TMSE esters. Exposure of 17 to TBAF in the presence of 18 gave 19. Akihiko Ouchi of the University of Tsukuba showed (J. Org. Chem. 2008, 73, 8861) that an aryl selenide such as 20 could be unmasked by photo-oxygenation to give the corresponding aldehyde 21. Secondary selenides gave ketones. Liam R. Cox of the University of Birmingham converted (Tetrahedron Lett. 2008, 49, 4596) halosilanes such as 22 to the corresponding alkyne 23 by exposure to TBAF. OCH3

O

TBAF

Se

N

18

N F3C 17 O

OCH3

Br O

F3C

O2

19 O

SiMe3

H hν

20

21

HO Ph2t BuSi

)2

)2

HO HO

Ph

22 F

Ph

O HO

23

HO NO2 CelB

O

TBAF

O

24

HO

O

microwave HO

OH HO 25

There has been much discussion about the exact role microwaves play in promoting organic reactions. It is clear that microwaves can activate peptide bond rotation. This may be a factor in the observation (J. Am. Chem. Soc. 2008, 130, 10048) by Alexander Deiters of North Carolina State University that the rate of the hydrolysis of 24 to 25 by the β-glucosidase CelB from the hyperthermophilic archaeon Pyrococcus furiosus increased by at least four orders of magnitude under microwave irradiation.

23

12. Intermolecular and Intramolecular C-H Functionalization September 22, 2008

Peter Legzdins of the University of British Columbia has described (J. Am. Chem. Soc. 2007, 129, 5372) a stoichiometric tungsten complex that speciﬁcally functionalized the primary H of an alkane 1 to give the organometallic 2. Neither the scope of the reactivity of 2 nor the functional group compatibility of this process have as yet been explored.

W

W complex

1

I

I2

NO

2

3

Ruggero Curci of the Università di Bari has reported (Tetrahedron Lett. 2007, 48, 3575) the stereospeciﬁc hydroxylation of 1,3-dimethyl cyclohexane 4 to the diol 6. Yasuyuki Kita of Osaka University has developed (Organic Lett. 2007, 9, 3129) conditions for speciﬁc benzylic oxidation, converting 7 into 8 with high diastereocontrol. Larry E. Overman of the University of California, Irvine has established (Organic Lett. 2007, 9, 5267) that by using a slow H-atom donor, it was possible to effect intramolecular H abstraction, leading, by oxidation of the intermediate captodatively-stabilized radical, from 9 to the acetate 10. H3C CF3 O O 5

OH ArI(OAc)2

OH

4

7

HO 6 O Si O

N O

N

O

Br (TMS)3SiH N

Cu(OAc)2 O

AIBN 9 OAc

KBr

O 8

O dr = 20:1

O Si OAc O N

10 OAc

The target C-H of 9 is activated by being adjacent to the ring nitrogen. There are many other ways that nitrogen, easily oxidized, has been used to activate a C-H for bond formation. Takehiko Yoshimitsu and Tetsuaki Tanaka of Osaka University have established (Organic Lett. 2007, 9, 5115) a free-radical route for the homologation of a tertiary amine such as 11 with phenyl isocyanate 12. Chuan He of the University of Chicago has devised (Angew. Chem. Int. Ed. 2007, 46, 5184) an Ag catalyst for the oxidative cyclization of sulfamates such as 15. M. Christina White of the University of Illinois has developed (J. Am. Chem. Soc. 2007, 129, 7274) a ligand system that allows the diastereoselective Pd-mediated allylic oxidation of 16 to 17.

24

INTERMOLECULAR AND INTRAMOLECULAR C-H FUNCTIONALIZATION O Ph-N=C=O 12

N

N

Et3B / air 11

H2 N

H N

Ph

14

Pd cat

15

N Ts

O

PhI(OAc)2

quinone

H 17

16 Si N

NH

O

Ts

H

O

PhI(OAc)2

13 N

O

Ag cat

O

O

O

O

19

Ts SPh

H

21

PhSH

H

N MeO2C

20

N

I2

Ts

18

Si N

Co cat

N

N

AIBN

CO2Me

MeO2C CO2Me 23

22

The cyclization of 18 to 19 developed (J. Org. Chem. 2007, 72, 8994) by Renhua Fan of Fudan University is thought to be proceeding via H atom abstraction by an intermediate nitrogen radical. The oxidation of the amine 20 to the endocyclic enamine 21 reported (J. Am. Chem. Soc. 2007, 129, 14544) by Maurice Brookhart of the University of North Carolina depended on the ease of oxidative addition of an intermediate alkenyl Co complex into the C-H bond adjacent to the nitrogen. The multistep cyclization of 22 to 23 devised (Organic Lett. 2007, 9, 4375) by Philippe Renaud of the Universität Bern depended on the ease of H atom abstraction adjacent to nitrogen. Carbon-carbon bonds can also be established by C-H functionalization. Justin Du Bois of Stanford University has shown (Organic Lett. 2007, 9, 4363) that sulfonates such as 24 can be cyclized to the sultone with high diastereocontrol. Kálmán J. Szabó of Stockholm University has found (Angew. Chem. Int. Ed. 2007, 46, 6891) that depending on conditions, either the alkenyl (illustrated) or the allylic C-H of a cycloalkene such as 27 can be activated for bond formation. Maurizio Fagnoni of the University of Pavia has delineated conditions (Angew. Chem. Int. Ed. 2007, 46, 6495) for direct biphenyl formation from easily oxidized aromatics such as 31 bearing leaving groups. Gerhard Hilt of the Philipps-Universität Marburg has established (Angew. Chem. Int. Ed. 2007, 46, 8500) a Co catalyst for the efﬁcient Alder ene homologation of a terminal alkene 34 to the unsaturated ester 36. O O

S

O

27

O

O S

CO2Et 1. NaCN

PhI=O

Ph

24 +

O CO2Et Rh cat

Ph

25

CO2Et

CN

2. (COCl)2; Zn(Cu)

NH2 26

Ph

Ir cat; O

B

O 2

28

Cl 29

hν I Pd cat

+ 34

CO2Et

Cl +

Cl H2N 30

31

Co cat

TFE 32

CO2Et

35

36

25

33 E : Z = 9:1

13. C-H Functionalization to Form C-O, C-N, and C-C Bonds December 29, 2008

A classic example of C-H functionalization is the familiar NBS bromination of a benzylic site. Recent updates of this approach allow for direct alkoxylation (J. Am. Chem. Soc. 2008, 130, 7824) and net amination (Organic Lett. 2008, 10, 1863). For the amination of simple aliphatic H’s, Holger F. Bettinger of Ruhr-Universität Bochum developed (Angew. Chem. Int. Ed. 2008, 47, 4744) the boryl azide 2. The insertion with 1 proceeded to give a statistical mixture of the nitrene insertion products 3 and 4. The tethered C-H functionalization devised (J. Am. Chem. Soc. 2008, 130, 7247) by Phil S. Baran of Scripps-La Jolla is selective, as in the conversion to 5 to 6, but appears to be limited to tertiary and benzylic C-H sites.

O

B O N + H 3 6:1

hν

1 O O

O

O B 2 N3

O

B O N H 4

O N

CF3 1.hν / CBr 4

Br

O

t-BuOH

2. AgOAc

5

7

6 I O

9

O

Rh cat

O

Pd cat

O

10

8

H+/H2O

OH H + 11

O 12

Michael P. Doyle of the University of Maryland established (J. Org. Chem. 2008, 73, 4317) an elegant protocol for the oxidation of an alkyne such as 7 to the ynone 8. Note that the oxidation did not move the alkyne. Marta Catellani of the Università di Parma reported (Adv. Synth. Cat. 2008, 350, 565) the intriguing Pd-catalyzed conversion of 9 to 10. Under mild conditions, it might likely be possible to hydrolyze the vinyl ether to reveal the phenol 11. Another way of looking at this overall transformation would be to consider the ether 10 to be a protected form of the aldehyde 12. C-H activation can also lead to C-C bond formation. Irena S. Akhrem of the Nesmeyanov Institute, Moscow, described (Tetrahedron Lett. 2008, 49, 1399) a hydride-abstraction protocol for three-component coupling of a hydrocarbon 13, an amine 14, and CO, leading to the homologated amide 15. Hua Fu of Tsinghua University, Beijing, showed (J. Org. Chem. 2008, 73, 3961) that oxidation of an amine 16 led to an intermediate that could be coupled with an alkyne 17 to give the propargylic amine 18. Products 15 and 18 are the result of sp2 and sp coupling, respectively. C-H functionalization leading to sp3-sp3 coupling is less common. Jin-Quan Yu of Scripps/La Jolla found (J. Am. Chem. Soc. 2008, 130, 7190) that activation of the N-methoxy amide 19 in the presence of the alkyl boronic acid 20 gave smooth coupling, to 21.

26

C-H FUNCTIONALIZATION TO FORM C-O, C-N, AND C-C BONDS

CBr4/AlBr3 H

H O

CO;

H

13

15

NH2

N H

14 H N

+

N CuBr/NBS

17

16

OH B OH

OCH3 N H + 19

18

O

OCH3 N H

Pd cat air

20

21

O

Carbocyclic rings can be constructed using intramolecular C-H functionalization. Antonio J. Herrera and Ernesto Suárez of the CSIC, La Laguna, observed (J. Org. Chem. 2008, 73, 3384) that 1,2-diketones such as 23, easily prepared by oxidation of the corresponding alkyne, on irradation cyclized with high diastereocontrol to the cyclobutanone, in this case 24. Jayanta K. Ray of the Indian Institute of Technology, Kharagpur found (Tetrahedron Lett. 2008, 49, 851) that exposure of 25 to a Pd catalyst initated a cascade cyclization, delivering the tetracycle 26. It would be interesting to try the same cyclization with the bromide 27. Cyclization might be faster than epimerization and subsequent β-hydride elimination.

H

OCH3 OBn Ru cat OBn OBn NaIO4 O 22

Br

O

O O

H

OCH3 OBn OBn OBn O 23

O hν

OH OCH3 OBn OBn OBn O 24

Br

O

Pd cat Cs2CO3

CH3O

CH3O

CH3O

25

26

27

27

O

14. Functionalization of C-H Bonds: The Baran Synthesis of Dihydroxyeudesmane September 28, 2009

Arumugam Sudalai of the National Chemical Laboratory, Pune reported (Tetrahedron Lett. 2008, 49, 6401) a procedure for hydrocarbon iodination. With straight chain hydrocarbons, only secondary iodination was observed. Chao-Jun Li of McGill University uncovered (Adv. Synth. Cat. 2009, 351, 353) a procedure for direct hydrocarbon amination, converting cyclohexane 1 into the amine 3. Justin Du Bois of Stanford University established (Angew. Chem. Int. Ed. 2009, 48, 4513) a procedure for alkane hydroxylation, converting 4 selectively into the alcohol 6. The oxirane 8 usually also preferentially ozidizes methines, hydroxylating steroids at the C-14 position. Ruggero Curci of the University of Bari found (Tetrahedron Lett. 2008, 49, 5614) that the substrate 7 showed some C-14 hydroxylation, but also a useful yield of the ketone 9. The authors suggested that the C-7 acetoxy group may be deactivating the C-14 C-H. I NaIO4/KI

PhNO2

NaN3/AcOH

tBuOOH

1

1

2

5 4

O HO N O S O O (cat) 6

50% H2O2

OBz

O

OAc

16

F3C 14 OBz

7

AcO

Ph

3

F3C

C6F5

H N

H3C 8

OAc

O O 9

AcO

OAc

OAc

C-H bonds can also be converted directly to carbon-carbon bonds. Mark E. Wood of the University of Exeter found (Tetrahedron Lett. 2009, 50, 3400) that free-radical removal of iodine from 10 followed by intramolecular H-atom abstraction in the presence of the trapping agent 11 delivered 12 with good diastereocontrol. Professor Li observed (Angew. Chem. Int. Ed. 2008, 47, 6278) that under Ru catalysis, hydrocarbons such as 13 could be directly arylated. He also established (Tetrahedron Lett. 2008, 49, 5601) conditions for the direct aminoalkylation of hydrocarbons such as 13, to give 17. Huw M. L. Davies of Emory University converted (Synlett 2009, 151) the ester 4 to the homologated diester 19 in

I

O N

O

11

SnBu3

N

O N

hν O 10

12

N

14

O O 4:1 dr

28

Ru cat/peroxide 13

15

FUNCTIONALIZATION OF C-H BONDS preparatively useful yield using the diazo ester 18, the precursor to a selective, push-pull stabilized carbene. N

Ph H

N

16

Ph

Peroxide

CO2CH3

Ph

N2 Ph

Ph

13

O 17

Ph

Ph

18

Rh cat

O 4

O

Ph O

CO2CH3

19

Intramolecular bond formation to an unactivated C-H can be even more selective. Guoshen Liu of the Shanghai Institute of Organic Chemistry developed (Organic Lett. 2009, 11, 2707) an oxidative Pd system that cyclized 20 to the seven-membered ring lactam 21. Professor Du Bois devised (J. Am. Chem. Soc. 2008, 130, 9220) a Rh catalyst that effected allylic amination of 22, to give 23 with substantial enantiocontrol. Dalibor Sames of Columbia University designed (J. Am. Chem. Soc. 2009, 131, 402) a remarkable cascade approach to C-H functionalization. Exposure of 24 to Lewis acid led to intramolecular hydride abstraction. Cyclization of the resulting stabilized carbocation delivered the tetrahydropyan 25 with remarkable diastereocontrol. O O S H2N O

Pd cat O

H N Ts 20

O

DMA/O2

Rh* cat

O O S N O

PhI=O

N Ts

H

84% ee

22

21

23

O O

O

O

BF3. OEt2 O O

Ph

Ph

24

25

The oxidation (Nature 2009, 459, 824) of the eudesmol carbamate 26 by Phil S. Baran of Scripps/La Jolla presents an interesting case study. Direct intermolecular oxidation with the same reagent used by Professor Curci, TFDO 8, proceeded selectively, with retention of absolute conﬁguration, to give the equatorial alcohol 27. In contrast, distal bromination directed by the carbamate followed by hydrolysis, using the protocol developed by the Baran group, gave the complementary diol, Dihydroxyeudesmane 28. F3C

O H 3C 8 O HO

H

27 F C 3

O

O N

H

1. CH3CO2Br 2. hν H

O

26 F C 3

29

O N

H

3. Ag2CO3 4. LiOH

H

OH

OH

28 Dihydroxyeudesmane

15. New Methods for Carbon-Carbon Bond Construction June 16, 2008

Mohammad Navid Soltani Rad of Shiraz University of Technology has shown (Tetrahedron Lett. 2007, 48, 6779) that with tosylimidazole (TsIm) activation in the presence of NaCN, primary, secondary and tertiary alcohols are converted into the corresponding nitriles. Gregory C. Fu of MIT has devised (J. Am. Chem. Soc. 2007, 129, 9602) a Ni catalyst that mediated the coupling of sp3-hybridized halides such as 3 with sp3-hybridized organoboranes such as 4, to give 5. CN

OH NaCN TsIm Bu4NI

1

Br

BR2

2

CO2CH3

Ni cat

+ CO2CH3 4

3

5 R'

BuLi; LiDBB;

OH SPh

R

OH

R'

R

O

OSEM O

6

O

OSEM 7

N

8 O

O

OH CO2CH3

IBX/Sc(OTf)3

CO2CH3

CO2CH3

SiMe3 9

11

10 O

O + 13

N N N

MgBr2.OEt2

12 O

O

i-Pr2NEt 14

15

Usually, carbanions with good leaving groups in the beta position do not couple efﬁciently, but just eliminate. Scott D. Rychnovsky of the University of California, Irvine has found (Organic Lett. 2007, 9, 4757) that initial protection of 6 as the alkoxide allowed smooth reduction of the sulﬁde and addition of the derived alkyl lithium to the amide 7 to give 8. Doubly-activated Michael acceptors such as 11 are often too unstable to isolate. J. S. Yadav of the Indian Institute of Chemical Technology, Hyderabad has shown (Tetrahedron Lett. 2007, 48, 7546) that Baylis-Hillman adducts such as 9 can be oxidized in situ, with concomitant Sakurai addition to give 12. Rather than use the usual Li or Na or

30

NEW METHODS FOR CARBON-CARBON BOND CONSTRUCTION K enolate, Don M. Coltart of Duke University has found (Organic Lett. 2007, 9, 4139) that ketones such as 13 will condense with amides such as 14 to give the diketone 15 on exposure to MgBr2. OEt2 and i-Pr2NEt. Simultaneously, Gérard Cahiez of the Université de Cergy (Organic Lett. 2007, 9, 3253) and Janine Cossy of ESPCI Paris (Angew. Chem. Int. Ed. 2007, 46, 6521) reported that Fe salts will catalyze the coupling of sp2-hybridized Grignard reagents such as 17 with alkyl halides. John Montgomery of the University of Michigan has described (J. Am. Chem. Soc. 2007, 129, 9568) the Ni-mediated regio- and enantioselective addition of an alkynes 20 to an aldehyde 19 to give the allylic alcohol 21. In a third example of sp2- sp3 coupling, Troels Skrydstrup of the University of Aarhus has established (J. Org. Chem. 2007, 72, 6464) that Negishi coupling with alkenyl phosponates such as 23 proceeded efﬁciently. José M. Concellón of the Universidad de Oviedo has developed (J. Org. Chem. 2007, 72, 7974) a linchpin approach to enone construction, reductive condensation of a dihalo amide 27 with an aldehyde 26 to give the amide 28, then addition of an alkyl lithium 29 to 28 to give 30.

MgBr

Br 17 CO2Et 16

cat Fe(acac)3

18 Ph

O

OSiEt3

Et3SiH

H +

Ph 81% ee

Ni* cat

19

20

O

O

CO2Et

21

OP(O)(OPh)2

O O

O 22

24

23

H

Cl +

N Cl

26

25

O Mn*

Li N

O

O

Cl

Cl

29

O

27

CN

O

CN

O

O

O

ZnBr Pd cat

+

28

30

Two useful new methods for alkyne construction have been put forward. Professor Yadav has developed (Tetrahedron Lett. 2007, 48, 5335) an elegant homologation of lactones such as 31 to alkynes, and Marc A. J. Johnson of the University of Michigan has reduced to practice (J. Am. Chem. Soc. 2007, 129, 3800) the long-sought metathetical coupling of two nitriles such as 34 to form the alkyne 35. O

Cl Ph3P

O BnO

CCl4

Cl Li

O

31

HO

32

CH3O

CN

Et

Et W cat

H

HO

BnO

33

CH3O

34

OCH3 35

31

16. Best Synthetic Methods: Carbon-Carbon Bond Construction March 16, 2009

In the context of peptidyl ketone synthesis, Troels Skrydstrup of the University of Aarhus developed (J. Org. Chem. 2008, 73, 1088) the elegant SmI2-mediated conjugate addition of acyl oxazolidinones such as 1 to acceptors such as 2. Sadagopan Raghavan of the Indian Institute of Chemical Technology, Hyderabad reported (Tetrahedron Lett. 2008, 49, 1601) that the addition of a Pummerer intermediate, generated by exposure of 4 to TFAA, to the terminal alkene 5 and SnCl4 led to efﬁcient C-C bond formation, to give the sulﬁde 6 as a single (unassigned) diastereomer. O

O

CN TrHN

N

FmocHN O

O

O

H

N

TrHN

2 O

N

FmocHN

SmI2

Bn

4

CN

3 SAr S

Ar

O

O

Bn

O

1 O

O

H

Br

TFAA;

O

SnCl4

O Br

5

6

Pd-catalyzed carbonylation of aryl halides and triﬂates is a well-established process. Stephen L. Buchwald of MIT has now (J. Am. Chem. Soc. 2008, 130, 2754) extended this transformation to much less expensive tosylates and mesylates such as 7. β-Amino acids have often been prepared from α-amino acids by Arndt-Eistert homologation. Geoffrey W. Coates of Cornell University has devised (Angew. Chem. Int. Ed. 2008, 47, 3979) a more practical alternative, the direct Co-catalyzed carbonylation of an oxazoline 9 to the 2-oxazine-6-one 10. OMs

CO2Et

CO/EtOH

O Co cat

N N 8

O

Ar

N

CO 99% ee

Pd cat N 7

Ar

O

99% ee

9

10 CO2CH3

MgBr

OTf

CO2CH3

12 13

14

32

OTBS

Pd cat

I

Co cat 11

SnBu3

+ 15

OTBS

16

BEST SYNTHETIC METHODS: CARBON-CARBON BOND CONSTRUCTION Eiji Shirakawa and Tamio Hayashi of Kyoto University also used (Chem. Lett. 2008, 37, 654) a Co catalyst to promote the coupling of aryl and alkenyl Grignard reagents with enol triﬂates such as 11. Alois Fürstner of the Max-Planck-Institut, Mülheim optimized (Chem. Commun. 2008, 2873) promoters for the Pd-catalyzed Stille-Migata coupling of iodo alkenes such as 14 with alkenyl stannanes such as 15 to give 16. It is particularly noteworthy that their system is ﬂuoride free. The stereocontrolled construction of trisubstituted alkenes continues to be challenging. We described (J. Org. Chem. 2008, 73, 1605) the facile preparation of the diioide 18 from the inexpensive 2-butyn-1,4-diol 17. Sequential coupling of 18 with an aryl Grignard followed by CH3Li delivered 19. Brian S. J. Blagg of the University of Kansas established (Tetrahedron Lett. 2008, 49, 141) that Still-Genari homologation of 20 with 21 gave (E)-22 with high geometric control. Biao Jiang of the Shangahi Institute of Organic Chemistry reported (Organic Lett. 2008, 10, 593) a convenient alternative protocol to give (Z)-αbromo unsaturated esters. OH

I

TMSCl NaI

O

1. ArMgBr

18

I

CuBr

CH3O2C

H

2. CH3Li

OH

17

(F3CH2CO)2P

OH

HO

19

O 21 Br

Br

t-BuOK 18-C-6

20

CO2CH3

22

OCH3

Carston Bolm of RWTH Aachen University found (Angew. Chem. Int. Ed. 2008, 47, 4862) that an inexpensive Fe catalyst could replace Pd in the Sonogashira coupling of 24 to 23. Hiriyakkanavar Ila of the Indian Institute of Technology, Kanpur devised (Organic Lett. 2008, 10, 965) a complementary route to aryl acetylenes, with concomitant ortho nitrile transfer. Matthias Brewer of the University of Vermont (J. Am. Chem. Soc. 2008, 130, 3766, 29 → 31) and Gregory B. Dudley of Florida State University (J. Am. Chem. Soc. 2008, 130, 5050 – not illustrated) devised fragmentation schemes for alkyne construction. Kazunori Koide of the University of Pittsburgh found (J. Org. Chem. 2008, 73, 1093) that exposure of an epoxide 32 to a silver acetylide 33 followed by stoichiometric Cp2ZrCl2 and catalytic AgOTf led to alcohol 34. This is as though the epoxide 32 had rearranged to the aldehyde 35, a long-sought goal of organic synthesis. S

SiEt3 24

I N 23

SiEt3

H Ph

Fe cat CsCO3

N

OTBS 1.

N2

30

1.

27

SCH3

2. CH3I

Br 26

O +

CH3O CH3O

3. BuLi OTHP

CO2Et O

CN

28 OTHP

HO

H

Cp2ZrCl2

H

2. SnCl4 29

CN

CH3O

25 Ph CO2Et

O

H

CH3O

O

Ag 31

32

33

33

34

35

17. C-C Single Bond Construction May 25, 2009

Several remarkable one-carbon homologations have recently appeared. André B. Charette of the Université de Montréal reported (J. Org. Chem. 2008, 73, 8097) the alkylation of diiodomethane with alkyl iodides such as 1, to give the diiodoalkane 2. Carlo Punta and the late Ombretta Porta of the Politecnico di Milano effected (Organic Lett. 2008, 10, 5063) reductive condensation of an amine 3 with an aldehyde 4 in the presence of methanol, to give the amino alcohol 5. Timothy S. Snowden of the University of Alabama showed (Organic Lett. 2008, 10, 3853) that NaBH4 reduced the carbinol 7, easily prepared from the aldehyde 6, to the acid 8. Ram N. Ram of the Indian Institute of Technology, Delhi found (J. Org. Chem. 2008, 73, 5633) that CuCl reduced 7 to the chloro ketone 9. NH2

I I CH I 22

I

O +

H

NaHMDS 1

2

TiCl3 t -BuOOH CH3OH

4

3 OCH3

H

CCl3

DMF

O

OH

CO2H 8

NaOH/t-BuOH 2CuCl/2bpy

Cl 9 O

7

6

OH

5

NaBH4 Cl3CCO2Na

H N

H3CO

Kálmán J. Szabó of Stockholm University extended (Chem. Commun. 2008, 3420) his elegant work on in situ borinate formation, coupling, in one pot, the allylic alcohol 10 with the acetal 11 (hydrolysed in situ) to deliver the alcohol 12 as a single diastereomer. Samir Z. Zard of the Ecole Polytechnique developed (J. Am. Chem. Soc. 2008, 130, 8898) the 6-ﬂuoropyridyloxy ether of 13 as an effective radical leaving group, enabling efﬁcient coupling with 14, activated by dilauroyl peroxide, to give 15. F OH

CO2CH3 10

B2pin2 H+/H2O

H

OH

N NHTs

11

S 14

O

S O O

Pd cat EtO NHTs EtO

O

DLP CO2CH3

12

13

15

Shu Kobayashi of the University of Tokyo established (Chem. Commun. 2008, 6354) that the anion of the sulfonyl imidate 17 participated in direct Pd-mediated allylic coupling with the carbonate 16. The product sulfonyl imidate 18 is itself of medicinal interest. It is also easily converted to other functional groups, including the aldehyde 19.

34

C-C SINGLE BOND CONSTRUCTION ArSO2 + 16

O O

H

DBU 17

O

N

Pd cat

O

O

O

ArSO2

N

18

19

Jianliang Xiao of the University of Liverpool found (J. Am. Chem. Soc. 2008, 130, 10510) that Pd-mediated coupling of an aldehyde 21 in the presence of pyrrolidine led to the ketone 22. The reaction is probably proceeding via Heck coupling of the aryl halide with the in situ generated enamine. Alois Fürstner of the Max Planck Institut, Mülheim observed (J. Am. Chem. Soc. 2008, 130, 8773) that in the presence of the simple catalyst Fe(acac)3 a Grignard reagent 24 coupled smoothly with an aryl halide 23 to give 25. Akio Baba of Osaka University established (Angew. Chem. Int. Ed. 2008, 47, 6620) that the GeCl2-driven Reformatsky-like addition of a halo ketone 27 to an imine 26 worked best in the presence of a catalytic Lewis acid. O Br

O

20

MgBr

Fe cat

Cl 22

25

23

Br

N 26

O 27 GeCl2 cat Yb(OTf)3

OCH3

24

OCH3

pyrrolidine CH3O

CH3O

O

O

H 21 Pd cat

O

Si

NH O

O

O CAN

O H 15:1 dr

28

29

30

The oxidative cross-coupling of ketone enolates, leading to the 1,4-diketone, has great potential as a method for rapidly assembling molecular complexity. Attempted hetero cross-coupling, however, can also lead to the homo coupled products as contaminants. Regan J. Thomson of Northwestern University has now shown (Organic Lett. 2008, 10, 5621) that it is possible to ﬁrst prepare the hetero-coupled mixed silyl enol ethers, such as 29. Oxidation of 29 delivered 30 as predominantly a single diastereomer.

35

18. Construction of Alkenes, Alkynes and Allenes June 8, 2009

Products such as 3 and 6 are usually prepared by phosphonate condensation. J. S. Yadav of the Indian Institute of Technology, Hyderabad found (Tetrahedron Lett. 2008, 49, 4498) that the cation-exchange resin Amberlyst-15 in CH2Cl2 mediated the condensation of a terminal alkyne such as 1 with an aldehyde to give the enone 3. Similarly, Teruaki Mukaiyama of Kitasato University showed (Chemistry Lett. 2008, 37, 704) that tetrabutylammonium acetate mediated the condensation of 5 with an aldehyde such as 4 to give the ester 6. David M. Hodgson of the University of Oxford described (J. Am. Chem. Soc. 2008, 130, 16500) the optimization of the Schlosser protocol for the condensation of a phosphorane with an aldehyde 7 followed by deprotonation and halogenation, to deliver the alkenyl halide 9 with good geometric control. Jun Terao of Kyoyo University and Nobuaki Kambe of Osaka University accomplished (Chem. Commun. 2008, 5836) the homologation of a halide such as 10 to the corresponding allylic Grignard reagent 12. Primary, secondary and tertiary halides worked well. Jennifer Love of the University of British Columbia developed (Organic Lett. 2008, 10, 3941) a Rh catalyst for the addition of thiols to terminal alkynes such as 13, and found that the product thioether 14 coupled smoothly with Grignard reagents to deliver the 1,1-disubstituted alkene 15. Glenn C. Micalizio, now at Scripps Florida, established (J. Am. Chem. Soc. 2008, 130, 16870) what appears to be a general method for the construction of Z-trisubstituted alkenes such as 18. O

H 1

8 H

n-PrSH

S

6

MgCl

PPh3 ;

I Br 9

H

90:10 E /Z

10

BnMgCl

OLi

Ni cat

Rh cat 13

cat Bu4NOAc

4

3

PhLi . LiBr; I2

7

CO2Et

OEt H TMS 5

Amberlyst-15

O

OTMS

O

O 2 H

14

15

16

3x

11

cat Cp2TiCl2

MgCl 12

SiMe3 17; ClTi(O-i -Pr)3 c-C5H9MgCl

SiMe3

18

The Ohira protocol has become the method of choice for converting an aldehyde 19 to the alkyne 21. We have found (Tetrahedron Lett. 2008, 49, 6904) that the reagent 20 offers advantages in price, preparation and handling. Bo Xu and Gerald B. Hammond of the University of Louisville observed (Organic Lett. 2008, 10, 3713) that an allene ester such as 22 is readily homologated to the alkyne 23. Ashton C. Partridge of Massey University 36

CONSTRUCTION OF ALKENES, ALKYNES AND ALLENES extended (Tetrahedron Lett. 2008, 49, 5632) condensation with the aryl phosphonate 25 to porphyrin aldehydes, leading to alkynes such as 26. Toyohiko Aoyama of Nagoya City University established (Tetrahedron Lett. 2008, 49, 4965) that the halomagnesium salt of TMS diazomethane was the most efﬁcient for converting 27 to 28 [CAUTION: Two deaths were recently reported from use of TMS diazomethane without proper ventilation!]. O

O

H

BnO

P(OMe)2

Ph

O

N2

H

20

H

BnO

K2CO3/MeOH

19

CO2Et 21

CO2Et

LDA; Br

22

23 CO2Et

O

Porph-CH=O 24

P(OPh)2 25 Porph t -BuOK 26

O CO2Et Me3SiC(N2)MgBr

Cl

CH3O

27

28 CH3O

Masahiru Miura, also of Osaka University, reported (Chem. Commun. 2008, 3405) that the Rh catalyzed homologation of a terminal alkyne 13 to the enyne 30 proceeded with high geometric control. Wei Sun and Chungu Xia of the Lanzhou Institute of Chemical Physics devised (Organic Lett. 2008, 10, 3933) a magnetically-retrievable Pd catalyst, the utility of which they illustrated with the carbonylative Sonogashira coupling of 1 with 31 to give 32. Gregory C. Fu of MIT optimized (Angew. Chem. Int. Ed. 2008, 47, 9334) the Ni catalyzed coupling of organozinc reagents such as 34 with a propargylic halide 33 to give 36.

H

29

Ι 31

Si(i-Pr)3 Si(i-Pr)3

Rh cat

H 1

30

13

Pd cat / Fe3O4 CO/Et3N

O

32

Si(i -Pr)3 Si(i -Pr)3 34

Br

H ZnI

N

Ni cat 33

35

36

Ga cat H2O

O 37

In an elegant extension of their “nanozyme” work, Robert G. Bergman and Kenneth N. Raymond of the University of California, Berkeley devised (J. Am. Chem. Soc. 2008, 130, 10977) an encapsulating Ga complex that catalyzed the rearrangement of 36 to the allene 37. Depending on how well the quaternary ammonium salt ﬁt in the encapsulating complex, they observed rate accelerations of more than two orders of magnitude for the rearrangement.

37

19. Reduction, Oxidation and Homologation of Alkenes March 24, 2008

Alkenes are usually reduced by catalytic hydrogenation. Diimide reduction is a mild and neutral alternative. Keith R. Buszek, now at the University of Missouri, Kansas City, has shown (J. Org. Chem. 2007, 72, 3125) that the reduction can conveniently be carried out on resin-bound alkenes, using 2-NBSH (o-nitrobenzenesulfonylhydrazide) with Et3N for convenient room temperature diimide generation.

O

O

1. 2-NBSH Et3N

O

2.

HO

H+

1

2

Ozone can be difﬁcult to dispense accurately on small scale. Masahito Ochiai of the University of Tokushima has uncovered (J. Am. Chem. Soc. 2007, 129, 2772) an alternative, using acid-promoted Ph-I=O. Isolated alkenes also work well. O Ph-I=O

H

HBF4 3

4 O

MCPBA is the reagent most commonly used for alkene epoxidation. Payne oxidation (H2O2 / CH3CN) is a convenient and inexpensive alternative. In the course of a study of the enantioselective enzymatic hydrolysis of 6, Takeshi Sugai of Keio University has described (Tetrahedron Lett. 2007, 48, 979) a practical procedure for multigram Payne epoxidation of 5. CH3CN O

Ph

O

H2O2

5

O

Ph

6

Several procedures have been put forward for functionalizing terminal alkenes, exempliﬁed by 7. Stefan Grimme and Armido Studer of the Universität Münster have developed (J. Am. Chem. Soc. 2007, 129, 4498) a free radical alkene amination, represented by the conversion of 7 to 9. Tehshik P. Yoon of the University of Wisconsin has found (J. Am. Chem. Soc. 2007, 129, 1866) that Cu catalyzes the addition of oxaziridines such as 10 to alkenes, to make 11. Shinji Nakamura of the University of Tokyo and Masanobu Uchiyama of the University of Tokyo and RIKEN have established (J. Am. Chem. Soc. 2007, 129, 28) that the anion from Cu promoted addition of the silyl zinc reagent to alkenes is long-lived enough to be trapped by electrophiles, including H+ to give 12. Hideki Yorimitsu and Koichiro Oshima of Kyoto University have developed (J. Am. Chem. Soc. 2007, 129, 6094) 38

REDUCTION, OXIDATION AND HOMOLOGATION OF ALKENES a complementary transformation, Ni-catalyzed addition of 13 to give 14. The conversion of 7 to 15 reported (Organic Lett. 2007, 9, 53) by Li-Biao Han of the National Institute of Advanced Industrial Science and Technology, Tsukuba, is likely also a free-radical process. Moc N

N R

O CO2CH3

8

H

Si

R

(R3Si)2ZnOR

Si

13

Ph O P H Ph 15

Cu cat

11

Si

7

Ph 12

O

10

Cu cat R

Ph

Bs N

Ph

RSH

9

R

N Bs

H

Moc

R

Ni cat

Ph

14

O Ph P Ph 16

R

Several procedures have also been developed for homologating terminal alkenes, again exempliﬁed by 7. The homologation can be either branching, as with 18 [John F. Hartwig, University of Illinois (J. Am. Chem. Soc. 2007, 129, 6690)], 20 [Timothy F. Jamison, MIT (Organic Lett. 2007, 9, 875)], and 21 [Timothy F. Jamison, (Angew. Chem. Int. Ed. 2007, 46, 782)], or linear, as with 22 [Maurice Brookhart, University of North Carolina (J. Am. Chem. Soc. 2007, 129, 2082)],24 [David R. Liu, Harvard (J. Am. Chem. Soc. 2007, 129, 2230)] and 26 [Samir Z. Zard, Ecole Polytechnique (Organic Lett. 2007, 9, 1773)]. The Liu procedure can also be used to prepare 1,5-dicarbonyl compounds. The Zard protocol is particularly noteworthy, as the product chloroketone 26 can be carried on to the xanthate, which can be added to another alkene, so 25 serves as a linchpin reagent. H N 17

H t-Bu R

ArCH=O

Ta cat

R 18

N

O

N H

Ar R

Rh cat

O

t-Bu O

Et3SiO

N C O 19 Ni cat

20 Ar

22

ArCH=O

R

7

H

23 Pd cat

Cl

S O 25

O N

N Ph R S

O

SEt

S

SEt Cl

Ni cat R

24

S

R

21

39

26

O

Ph

20. Reactions of Alkenes September 29, 2008

One of the most powerful of alkene transformations is enantioselective epoxidation. Tsutomu Katsuki of Kyushu University has developed (Angew. Chem. Int. Ed. 2007, 46, 4559) a Ti catalyst that with H2O2, selectively epoxidized terminal alkenes with high ee. The same catalyst converted a Z 2-alkene such as 3 into the epoxide. This is signiﬁcant, because such epoxides are opened with nucleophiles selectively at the less congested center. Nu Ti* cat

Ti* cat

O

30% H2O2

ee = 82%

1

O

30% H2O2

ee = 74% 4

3

2

Novel procedures for alkene functionalization have been put forward. Philippe Renaud of the University of Berne has developed (Adv. Synth. Cat. 2008, 350, 1163) a simple protocol for terminal halogenation, based on catalyzed addition of catecholborane, followed by free radical substitution. Sulﬁdes and selenides were also prepared. H. Zoghlami of the Faculty of Sciences of Tunis has devised (Tetrahedron Lett. 2007, 48, 5645) an oxidative sulﬁnylation, converting a terminal alkene 7 to the sulﬁde 8. M. Christina White of the University of Illinois (J. Am. Chem. Soc. 2008, 130, 3316) and Guosheng Liu of the Shanghai Institute of Organic Chemistry (Angew. Chem. Int. Ed. 2008, 47, 4733) independently developed Pd catalysts for the oxidation of a terminal alkene 9 to the terminal allylic amine 10. Shannon S. Stahl of the University of Wisconsin-Madison has established (Organic Lett. 2007, 9, 4331) conditions for the complementary transformation of a terminal alkene 11 to the enamide 12. Douglas B. Grotjahn of San Diego State University has optimized (J. Am. Chem. Soc. 2007, 129, 9592) Ru-catalyzed alkene (“zipper”) migration, effecting the conversion of 13 to 14 and of 15 to 16. CatBH; PhSO2Br

5

TsNHCO2t Bu BnO

Pd cat O2

9

PhSH

Br

BnO

BnO

6

SPh

NBS DBU

7

8 O

Phthalimide

BnO 10

Ts

N CO2t Bu

OH Ru cat

BnO

Pd cat O2

11

N

BnO 12

O

Ru cat

O

OSiR3

OSiR3 13

15

14

16

There have been several new observations on alkene cleavage. Marcus A. Tius of the University of Hawaii and Bakthan Singaram of the University of California, Santa Cruz have found (Tetrahedron Lett. 2008, 49, 2764) that epoxides such as 17 are cleaved directly by NaIO4, providing a simple alternative to ozonolysis. Rolando A. Spanevello of the Universidad Nacional de Rosario has extended (Tetrahedron 2007, 63, 11410) 40

REACTIONS OF ALKENES unsymmetrical ozonolysis to highly substituted norbornene derivatives such as 19, observing 20 as the only product. Patrick H. Dussault of the University of Nebraska–Lincoln has established (J. Org. Chem. 2008, 73, 4688) that alkene ozonolysis in wet acetone delivered the ketone or aldehyde directly, without reductive workup. O O

NaIO4

H

THF/H2O 17

O

O

OCH3

O

Ph

O

19

OCH3 CO2CH3

O

Ph

AcO H 20

H

O3 AcO

O3, CH3OH; Ac2O /Et3N

AcO

18

O

O

O

O AcO

H2O/Acetone 21

22

In a very simple procedure, Takashi Kamitanaka and Tadao Harada of Ryukoku University and the Industrial Research Center of Shiga Prefecture have found (Tetrahedron Lett. 2008, 48, 8460) that acetone, acetonitrile or an alcohol added without catalyst to a terminal alkene at 340 °C. Yoshiji Takemoto of Kyoto University has reported (J. Org. Chem. 2007, 72, 5898) Pd-catalyzed acylation of 9-BBN adducts, and Michael G. Organ of York University has described (Chem. Commun. 2008, 735) a convenient Pd catalyst for coupling of 9-BBN adducts with primary alkyl bromides at ambient temperature. Dieter Vogt of the Eindhoven University of Technology (Adv. Synth. Cat. 2008, 350, 332) and Maurizio Taddei of the Università degli Studi di Siena (Tetrahedron Lett. 2008, 48, 8501) have reported hydroformylation in the presence of a secondary amine to give net aminomethylation, and Bernhard Breit of the Albert-Ludwigs-Universität Freiburg has found (Adv. Synth. Cat. 2008, 350, 989) that hydroformylation can be followed by Knoevenagel condensation, to give three-carbon homologation, to 28. Melanie S. Sanford of the University of Michigan has devised (J. Am. Chem. Soc. 2008, 130, 2150) strategies for interrupting Heck arylation, to give selectively either 29 or 30, and Andrew J. Phillips of the University of Colorado has taken advantage of Kulinkovich cyclopropanation to give selectively either 31 or 32 (Organic Lett. 2007, 9, 2717; 2008, 10, 1083). O EtOAc / Ti; 32

R

R

O

24 O

O 1. 9-BBN

Fe(NO3)3 NCS/DBU

EtOAc / Ti; R

1. 9-BBN

Fe(NO3)3 Bu3SnH

Cl

NR'2

2. R'2NC(O)Cl Pdcat

O

31

25

R

Ph

2. Br-(CH2)3-Ph Pdcat

R 23

R

26

Ph R

PhCl/Pdcat;

30 or Ph

R

PhICl2 or CuCl2

Rh cat CO2H

Cl 29

CO/H2/R'2NH

CO/H2Rhcat; CH2(CO2H)2

R

28

41

R

27

NR'2

21. Selective Reactions of Alkenes March 30, 2009

Fabio Doctorovich of the Universidad de Buenos Aires reported (J. Org. Chem. 2008, 73, 5379) that hydroxylamine in the presence of an Fe catalyst reduced alkenes such as 1, but not ketones or esters. Erick Carreira of ETH Zürich developed (Angew. Chem. Int. Ed. 2008, 47, 5758) mild conditions for the hydrochlorination of mono-, di- and trisubstituted alkenes. Ramgopal Bhattacharyya of Jadavpur University established (Tetrahedron Lett. 2008, 49, 6205) a simple Mo-catalyzed protocol for alkene epoxidation. H3O2C

H2N-OH

H3O2C

1

CO2CH3

Cl

TsCl/PhSiH3

Fe cat

BnO

CO2CH3

2

3

Co cat

BnO

4 NO2

H2O2 OH

NaNO2

O

Mo cat

HOAc

PhO

OH

5

7

6

PhO 8

Nitro alkenes are of increasing importance as acceptors for enantioselective organocatalyzed carbon-carbon bond formation. Matthias Beller of the Universität Rostock found (Adv. Synth. Cat. 2008, 350, 2493) that an alkene such as 7 was readily converted to the corresponding nitroalkene 8 by exposure to of NO gas. The reaction could also be effected with NaNO2/HOAC. Two complementary protocols for Rh-catalyzed alkene hydroformylation have been reported. Xumu Zhang of Rutgers University devised (Organic Lett. 2008, 10, 3469) a ligand system that cleanly migrated the alkene of 9, then terminally hydroformylated the resulting monosubstituted alkene, to give 10. Kian L. Tan of Boston College designed (J. Am. Chem. Soc. 2008, 130, 9210) a ligand such that the hydroformylation of the internal alkene of 11 was directed to the end of the alkene proximal to the directing OH, delivering 12. O

CO/H2 H

Rh cat 9

OH

CO/H2 OH

10

11

O

Rh cat 12

Several other methods for the functionalizing homologation of alkenes have been put forward. Chul-Ho Jun of Yonsei University assembled (J. Org. Chem. 2008, 73, 5598) a Rh catalyst that effected the oxidative acylation of a terminal alkene 13 with a primary benzylic alcohol, to give the ketone 14. For now, this approach is limited to less expensive alkenes, as the alkene, used in excess, is the reductant in the reaction. The other procedures outlined here require only stoichiometric alkene. Yasuhiro Shiraishi of Osaka University devised (Organic Lett. 2008, 10, 3117) a simple photoprocess for adding acetone to a 42

SELECTIVE REACTIONS OF ALKENES terminal alkene 13 to give the methyl ketone 14, in what is presumably a free radical reaction. Chaozhong Li of the Shanghai Institute of Organic Chemistry found (Tetrahedron Lett. 2008, 49, 7380) that reduction of a benzenediazonium salt with aqueous TiCl3 generated an effective catalyst for the free radical atom transfer addition of α-iodoesters and α-iodonitriles to alkenes such as 17, to give the adduct 18. OH O

O

13

14

O

H2O hν

Rh cat 13

15

O I

I

O

O

N

CO2Et

O

H N CO2Et

19

17

BF3 . OEt2

O

+

cat ArN2 cat TiCl3

16

TBSO

18

13

H3CO2C

CO2CH3

CO2CH3 22

21

20

O N

PhCH2NHOH Ph

CO2CH3 23

Dipolar cycloaddition can also be used to homologate alkenes. Osamu Tamura of Showa Pharmaceutical University found (J. Org. Chem. 2008, 73, 7164) that exposure of 19 to BF3.OEt2 generated a species that added to the alkene 13 with high diastereocontrol, to give 20. Gilles Dujardin of the Université du Maine combined (Organic Lett. 2008, 10, 4493) the acetylenic ester 22 with N-benzylhydroxylamine to give a dipole, that added to the alkene 21 to give 23, establishing a quaternary center with high diastereocontrol. The Heck reaction has mostly been used with alkenes bearing electron-withdrawing groups, but in fact the intermediate aryl organopalladium species can insert into a wide variety of alkenes. Michèle David of the Université de Rennes1 took advantage(Tetrahedron Lett. 2008, 49, 6607) of this, adding the iodide 25 to the alkene 24, to give 26. DDQ oxidation of 26 gave the lactone Yangonin 27, derived from the kava-kava root. I

OCH3 + O

O 24

25

OCH3 Pd cat

OCH3

OCH3 DDQ

O

O

O 26

OCH3

43

O 27 Yangonin

OCH3

22. Developments in Alkene Metathesis January 21, 2008

Alkene metathesis has been extended to increasingly complex starting materials and products. Nitriles are good donors to coordinatively-unsaturated transition metal centers, so tend to inhibit the reaction. Ren He of Dalian University of Technology has found (Tetrahedron Lett. 2007, 48, 4203) that inclusion of the loosely-coordinating 2-methyl pyridine in the reaction enables facile cross-coupling with acrylonitrile 2. Although crosscoupling with (Z, Z)-sorbate is not efﬁcient, Dennis P. Curran of the University of Pittsburgh has shown (Organic Lett. 2007, 9, 5) that cross-coupling with (E, Z)-sorbate 5 works well. For large scale work, he has developed a Hoveyda-type catalyst with a perﬂuoro tail, that is recoverable in 70% recrystallized yield from the reaction mixture. Shigefumi Kuwahara of Tohoku University has reported (Tetrahedron Lett. 2007, 48, 3163) a practical alternative for direct metathesis to deliver (E, E)-dienyl esters. CN

CN

+

cat G2

3:1Z/E

N 1

3

2 CO2CH3 +

cat G2 H3CO2C

4

5

6

O R

cat 9; H

+

CO2Et

CO2R

7

8a R = CH3 8b R = H O +

N2 10a R = Et 10b R = t Bu

N

N Mes Cl

Ru Cl PCy3 9

11

O

cat G2

O

Mes

O

O B Cl

12

13

15

O 14

Continuing the investigation of tandem Ru-catalyzed reactions, Marc L. Snapper of Boston College effected (Organic Lett. 2007, 9, 1749) metathesis with methacrolein 8a, then added Ph3P and diazoacetate, to give the diene 11. A range of common Ru catalysts worked well for this transformation. In an alternative approach to trisubstituted alkene

44

DEVELOPMENTS IN ALKENE METATHESIS construction, Stellios Arseniyadis and Janine Cossy of ESPCI Paris have demonstrated (Organic Lett. 2007, 9, 1695) that inclusion of Cl-catecholborane 14 allows clean cross metathesis with the lactone 13. The construction of tetrasubstituted alkenes has been more challenging. Yann Schrodi of Materia, Inc. (Organic Lett. 2007, 9, 1589) has described a catalyst 17 that is particularly effective. Complex 17 was superior to a catalyst reported (Organic Lett. 2007, 9, 1339) shortly earlier by Robert H. Grubbs of Caltech.

N CO2Et

CO2Et

cat 17

CO2Et

CO2Et

16

N

Cl Ru Cl O

18

17

Debendra K. Mohapatra of the National Chemical Laboratory, Pune, and Professor Grubbs, in a new approach to macrocyclic stereocontrol, have made (Tetrahedron Lett. 2007, 48, 2621) the remarkable observation that the cyclization of the bis ether 19a gave 20 in a 9:1 E / Z ratio, while cyclization of the diol 9b gave only Z-21. Oligomer formation can often compete in such medium ring-forming reactions. Deryn E. Fogg of the University of Ottawa has raised (J. Am. Chem. Soc. 2007, 129, 1024) the cautionary (but happy!) observation that while the cyclization, for instance, of 22 proceeded efﬁciently to give 23, at an intermediate point in the transformation the product was more than half oligomer. O

OR

O cat G2

O

O vs

O

OH

O

OPMB 19a R = PMB 19b R = H

OR

O

OPMB 20

cat G2

21 OH

O + oligomers O

O 22

23

Removal of Ru residue at the end of the reaction is always an issue. Professor Grubbs has decribed (Organic Lett. 2007, 9, 1955) a PEG-based catalyst that is easy to separate from the metathesis products. Alternatively, Steven T. Diver of the University at Buffalo has shown (Organic Lett. 2007, 9, 1203) that workup of the reaction mixture from G1 or G2 with a polar isocyanide led to products having less than 5 ppm Ru.

45

23. Developments in Alkene and Alkyne Metathesis June 23, 2008

Jon D. Rainier of the University of Utah has put forward (J. Am. Chem. Soc. 2007, 129, 12604) an elegant alternative to Ru-catalyzed alkene metathesis, demonstrating that an ω-alkenyl ester such as 1 will cyclize to the enol ether 2 under Tebbe conditions.

TiCl4 / Zn

O

PbCl2 CH3CHBr2 TMEDA

O

O 1

O

O

O O

2

The particular reactivity of free alcohols in Ru-catalyzed alkene metathesis is underscored by the observation (Tetrahedron Lett. 2007, 48, 6905) by Javed Iqbal of Dr. Reddy’s Laboratories, Ltd., Miyapur that attempted metathesis of the ether 4a failed, but metathesis of the diol 4b proceeded efﬁciently. Kazunori Koide of the University of Pittsburgh has demonstrated (Organic Lett. 2007, 9, 5235) that the yields of cross-metathesis with an alkenyl alcohol could be enhanced by binding it to a trityl resin. He observed that the Grela catalyst 8 was particularly effective in this application. R3SiO R3SiO

+

OH

N H

O ( )3

O Ar

4a, X = PMB 4b, X = H

HO

R3SiO

5 OPMB

OBz

Ar

O

BzO

OSiR3

cat G2

XO

OPMB

3

R3SiO

OSiR3

7

OBz

HO

cat 8

6

9

OH

Mes

N

N Mes

Cl Ru Cl O

NO2 8

Residual Ru species do not interfere with some subsequent transformations. Rodrigo B. Andrade of Temple University has demonstrated (Tetrahedron Lett. 2007, 48, 5367) that metathesis with an α,β-unsaturated aldehyde such as 11 can be followed directly by phosphonate condensation to give the doubly-homologated product 12. Philip J. Parsons of the University of Sussex has found (Organic Lett. 2007, 9, 2613) that the nitro functional group is compatible with the Ru catalyst. The product nitro alkene 15 could be cyclized (intramolecular Michael addition) to the cyclopentane 16, or (intramolecular dipolar cycloaddition) to the cyclopentane 17.

46

DEVELOPMENTS IN ALKENE AND ALKYNE METATHESIS

H

+ OTBS 10

cat G2;

CO2Et

(EtO)2P(O)CH2CO2Et

O

OTBS

NaH

11

12 CO2t-Bu CO2t -Bu

O2N

CO2t -Bu

+ 13

cat G2

TBAF

O2N

NO2 Ph-N=C=O

15

14

16

N O CO2t-Bu

17

There has been much interest in carrying out the several alkene metathesis transformations (cross metathesis, ring closing metathesis, ring-opening metathesis polymerization) in water. Robert H. Grubbs of the California Institute of Technology has designed (Angew. Chem. Int. Ed. 2007, 46, 5152) the ammonium salt 18 for this purpose, and Karol Grela of the Polish Academy of Sciences in Warsaw and Marc Mauduit of ENSC Rennes have jointly(Chem. Commun. 2007, 3771) put forward the pyridinium salt 19. Remarkably, Ronald T. Raines of the University of Wisconsin has shown (Organic Lett. 2007, 9, 4885) that the Hoveyda catalyst 20 is sufﬁciently stable in aqueous acetone and aqueous DME to function efﬁciently.

Mes

N

N Mes Mes

Cl Ru Cl O

N

N

N Mes

Cl Ru Cl O

18

N

Mes N

N Mes

Cl Ru Cl O

19

20

Although alkyne metathesis is now well developed as a synthetic method, it has been limited to internal alkynes. For this reason, methyl alkynes are often specially prepared to set the stage for C-C triple bond formation by metathesis. André Mortreux of ENSC-Lille has now designed (Adv. Synth. Cat. 2007, 349, 2259) a binuclear catalyst 22 that works well with terminal alkynes such as 21. What remains to be determined is the functional group compatibility of 22.

H 21

cat 22

CH3O 23

O O O O W W O OO O

OCH3

CH3O 22

47

OCH3

24. Advances in Alkene and Alkyne Metathesis January 12, 2009

As alkene metathesis is extended to more and more challenging substrates, improved catalysts and solvents are required. Robert H. Grubbs of Caltech developed (Organic Lett. 2008, 10, 441) the diisopropyl complex 1, that efﬁciently formed the trisubstituted alkene 6 by cross metathesis of 4 with 5. Hervé Clavier and Stephen P. Nolan of ICIQ, Tarragona, and Marc Mauduit of ENSC Rennes found (J. Org. Chem. 2008, 73, 4225) that after cyclization of 7 with the complex 2b, simple ﬁltration of the reaction mixture through silica gel delivered the product 8 containing only 5.5 ppm Ru. i Pr

i Pr N

N N Cl Cl Ru

N

Cl i Pr Cl Ru

i Pr

N

O

O X

1

2a, X=H 2b, X = N H

CF3

N

Cl Cl Ru Cy3P Ph 3

2c, X = NO2 O cat 2b

cat 1

+ OBz

Ts N

OBz

OBz

4

5

OAc

OAc

CH2Cl2

EtO2C CO2Et

OBz

Ts N

8 Ts

EtO2C CO2Et

0.25% 3

2% 3

Ts N

N

H2O / PTS

HOAc 9

CH2Cl2 7

6

11

10

12

The merit of CH2Cl2 as a solvent for alkene metathesis is that the catalysts (e.g. 1-3) are very stable. Claire S. Adjiman of Imperial College and Paul C. Taylor of the University of Warwick established (Chem. Commun. 2008, 2806) that although the second generation Grubbs catalyst 3 is not as stable in acetic acid, for the cyclization of 9 to 10 it is a much more active catalyst in acetic acid than in CH2Cl2. Bruce H. Lipshutz of the University of California, Santa Barbara observed (Adv. Synth. Cat. 2008, 350, 953) that even water could serve as the reaction solvent for the challenging cyclization of 11 to 12, so long as the solubility-enhancing amphiphile PTS was included. Ernesto G. Mata of the Universidad Nacional de Rosario explored (J. Org. Chem. 2008, 73, 2024) resin isolation to optimize cross-metathesis, ﬁnding that the acrylate 13 worked particularly well. Karol Grela of the Polish Academy of Sciences, Warsaw optimized (Chem. Commun. 2008, 2468) cross-metathesis with a halogenated alkene 16.

48

ADVANCES IN ALKENE AND ALKYNE METATHESIS O

Cl

1. cat 2a

+

O 13

14

cat 2c

+

2. TFA; CH2N2 H3CO2C

Cl

Cl 15

16

OTBS

17

18 OTBS

Jean-Marc Campagne of ENSC Montpellier extended (J. Am. Chem. Soc. 2008, 130, 1562) ring-closing metathesis to enynes such as 19. The product diene 20 was a reactive Diels-Alder dienophile. István E. Markó of the Université Catholique de Louvain applied (Tetrahedron Lett. 2008, 49, 1523) the known (OHL 20070122) ring-closing metathesis of enol ethers to the cyclization of the Tebbe product from 23. The ether 24 was oxidized directly to the lactone 25. Jacques Eustache of the Université de Haute-Alsace observed (Tetrahedron Lett. 2008, 49, 1192) that ring-opening/ring-closing metathesis proceeded efﬁciently with 26, but not with the ether epimeric at the indicated position. O O + N N

cat 2c Ph

Ph

N N

N Ph

Ph

N Ph O

O 19

O CH3O

20

O

OEt

1. TiCl4/ CH2Br2

OTBS

2. cat 3

21 O

OEt PCC

O

O

OTBS

CH3O

23

22

OTBS

CH3O 25

24 O

O

O

O

cat 3 O

O 26

27

Jeffrey S. Moore of the University of Illinois prepared (J. Org. Chem. 2008, 73, 4256) a Mo alkyne metathesis catalyst on fumed silica gel that converted 28 to 29 at room temperature. The cyclization was driven by the vacuum removal of 3-hexyne 30. In the same paper, Professor Moore used the insolubility of a product diaryl alkyne 31 to drive other cyclizations. O

O O O

Mo cat

O

O O O

+

Ar

rt 28

29

49

30

Ar 31

25. Developments in Alkene Metathesis June 15, 2009

Hervé Clavier and Steven P. Nolan, now at St. Andrew’s University, found (Adv. Synth. Cat. 2008, 350, 2959) that the indenylidene Ru complex 1 was an excellent pre-catalyst for alkene metathesis. A combination of 1 and the ligand 2 effected cross metathesis of 3 and 4 in just 15 minutes under microwave heating. Robert H. Grubbs of Caltech designed (Organic Lett. 2008, 10, 2693) the Ru catalyst 6 for the preparation of tri- and tetrasubstituted alkenes, as illustrated by the conversion of 7 to 8. The catalyst 6 also worked well for cross metathesis and ring opening metathesis polymerization (ROMP). O

OTBS

OTBS Ph

L Cl Ru Cl PCy3

4 N

L=2

1

N

N

2

3

N

cat 6 5 mol %

EtO2C

Cl Ru Cl O

EtO2C

60 °C 20 min 98%

7

6

O

cat 2 mol % microwave 15 min 77%

5

EtO2C EtO2C 8

For some biological applications, it would be desirable to run alkene cross metathesis under aqueous conditions. Benjamin G. Davis of the University of Oxford observed (J. Am. Chem. Soc. 2008, 130, 9642) that allyl sulﬁdes such as 9 were unusually reactive in cross metathesis. Indeed, aqueous cross methathesis with such an allyl sulﬁde incorporated in a protein worked well, although added MgCl2 was required. The protein, a serine protease, maintained its activity after cross metathesis. OH

OH S H

N

CO2CH3

Boc

9

10

S

cat H2 1 : 1 t-BuOH/H2O

H

N Boc

CO2CH3 11

α,β-Unsaturated thioesters such as 14 are excellent substrates for, inter alia, enantioselective Cu-catalyzed conjugate addition of Grignard reagents. Adriaan J. Minnaard and Ben L. Feringa of the University of Groningen found (J. Org. Chem. 2008, 73, 5651) that the thioacrylate 13 was an excellent substrate for cross methathesis, allowing ready preparation of 14.

50

DEVELOPMENTS IN ALKENE METATHESIS O S

S

13 O

cat H2 1 mol %

12

14

Although alkene metathesis is often run in CH2Cl2, benzene or toluene, these are not necessarily the optimal solvents. Siegfried Blechert of the TU Berlin established (Tetrahedron Lett. 2008, 49, 5968) that for the difﬁcult cyclization of 16 to 17, hexaﬂuorobenzene worked particularly well.

N 15

N

EtO2C

cat 15

EtO2C

EtO2C

C6F6

EtO2C

Cl Ru Cl Ph PCy3

17

16

The extended conformation (illustrated for 18) of an ester is more stable than the lactone conformation by about 5 kcal/mol. It is therefore not surprising that SonBinh T. Nguyen of Northwestern University observed (Organic Lett. 2008, 10, 5613) that attempted ringclosing metathesis of 18 gave only the dimer 20. On addition of the bulky Lewis acid 21, which can complex 18 in the lactone conformation, the reaction delivered the desired monomer 19. This should be a generally useful strategy for the cyclization of difﬁcult ester substrates. Ph O O

O cat G2

O

O

O vs. O

18

19

O

20

Ph O Al Ph O O Ph Ph Ph 21

Su Seong Lee and Jackie Y. Ying of the Institute of Bioengineering and Nanotechnology, Singapore, constructed (Chem. Commun. 2008, 4312) the metathesis catalyst 22, covalently bound to siliceous mesocellular foam. At 5% catalyst loading, the tenth cycle for the cyclization of 23 to 24 gave the same yield as the ﬁrst cycle, 97%. Ru residues in solution were only 5-8 ppm.

N Cl

N O

Ru ( )n

Cl 22

O

Si

MCF

51

5 mol% 22 97%

Ph 23

O Ph 24

26. Alkene Metathesis: Synthesis of Kainic Acid, Pladienolide B and Amphidinolide Y January 28, 2008

As alkene metathesis has developed into one of the tools of organic synthesis, many practical questions have arisen. In the course of a synthesis (Organic Lett. 2007, 9, 1635) of the important neuropharmacological tool (-)-kainic acid 7, Tohru Fukuyama of the University of Tokyo prepared the key intermediate 1 by chiral auxiliary mediated coupling of crotonyl chloride with acetadehyde. Dibal reduction gave the hemiaminal, which underwent reductive amination with glycine methyl ester, leading to the alkene 2. Alkene metathesis of the derived ester 3 to form the unsaturated lactone 4 was then examined in detail. It was found that 0.5 mol % of the second generation Hoveyda catalyst was sufﬁcient to cyclize 3 to 4 in 92% yield. With 0.8 mol %, the yield was 99%. The key to the efﬁcacy of this cyclization was the use of 1,2-dichloroethane at reﬂux as the reaction solvent. O O

H3CO2C

Bn N

H3CO2C

H N

O

Boc N

O H2 cat

O O

CO2CH3 N Boc 4

O TBSO

TBSO 2

1 O

3

O

O

CO2H

CO2CH3

LiHMDS N

CO2CH3

Boc 5

CO2CH3 N Boc 6

N H

CO2H

7 (-)-Kainic acid

The macrolide pladienolide D 14 induces in vivo tumor regression in several human cancer xenograft models. This activity was important enough that a team at Esai Co., Ltd in Tsukuba headed by Yoshihiko Kotake undertook the total synthesis (Angew. Chem. Int. Ed. 2007, 46, 4350). Their approach used two alkene metathesis steps. To prepare the substrate for the macrolide construction, the alcohol 8 and the acid 9, each prepared by chiral auxiliary control, were coupled to give the ester 10. An extensive investigation led to alkene metathesis conditions that were satisfactory, the use of the second generation Hoveyda catalyst in reﬂuxing toluene. A signiﬁcant competing side reaction was the migration of the monosubstituted alkene of 10 to make the alkenyl ether. The second alkene metathesis step was the coupling of 12 with 13. The most effective catalyst in this case was the second generation Grubbs. Note that the free alcohol 13 participated successfully in the cross-coupling. According to the authors, this is one of just a few examples of successful cross coupling of an alkene adjacent to a quaternary center.

52

ALKENE METATHESIS Ph

Ph

Ph

O

O

O O

O

O H2 cat

PMBO

O

O

OH

PMBO

O

HO 8

O PMBO

9

O

10

OAc

11 OAc

OH G2 cat

+

O

OH

OH

OH

O

O

O

O

O

OH

OH 13

12

14 Pladienolide D

The stereocontrolled construction of trisubstituted alkenes by metathesis is a particular challenge. In his synthesis (Organic Lett. 2007, 9, 2585) of amphidinolide Y 21, a modestly cytotoxic macrolide antibiotic, Wei-Min Dai of Zhejian University and the Hong Kong University of Science and Technology took up this challenge. The substrate for cyclization was prepared by coupling the acid 15 with the alcohol 16, followed by selective deprotection and oxidation. Medium-ring conformational effects played an important role in this metathesis. The cyclization was also attempted with the TES ethers of the two diastereomeric secondary alcohols corresponding to the ketone of 17. One of those diastereomers cyclized modestly well. The other diastereomer did not cyclize at all. OTBS TESO

OTBS O

OTES

+

OH 15

O

TESO

O

HO

O

16

O

17 O

TBSO

HO O

TESO G2 cat

O

O

HO O

O O

O

O 19 Amphidinolide Y

18

53

27. Alkene and Alkyne Metathesis: Phaseolinic Acid (Selvakumar), Methyl 7-Dihydro-trioxacarcinoside B (Koert), Arglabin (Reiser) and Amphidinolide V (Fürstner) June 30, 2008

As N. Selvakumar of Dr. Reddy’s Laboratories, Ltd., Hyderabad approached (Tetrahedron Lett. 2007, 48, 2021) the synthesis of phaseolinic acid 6, there was some concern about the projected cyclization of 2 to 3, as this would involve the coupling of two electron-deﬁcient alkenes. In fact, the Ru-mediated ring-closing metathesis proceeded efﬁciently. The product unsaturated lactone 3 could be reduced selectively to either the trans product 4 or the cis product 5. CO2Et H

1.

O

O

O

C(O)Cl

2.

CO2Et

cat G2

CO2Et

Ti(Oi-Pr)4

1

O

O

2

3

CO2Et

CO2Et

O

O

O 4

2. NaHMDS; CH3I

O 5

CuH:

100

:

0

Pd-C/NH4 formate: 1

:

4

CO2H

1. HCl/H2O

+

O

O 6 Phaseolinic Acid

There has been relatively little work on the synthesis of the higher branched sugars, such as the octalose 13, a component of several natural products. The synthesis of 13 (Organic Lett. 2007, 9, 4777) by Ulrich Koert of the Philipps-University Marburg also began with a Baylis-Hillman product, the easily-resolved secondary alcohol 8. As had been observed in other contexts, cyclization of the protected allylic alcohol 9a failed, but cyclization of the O OH

O H

O

O

1. 8

> 99% ee

BnO 2. Vcat O t -BuOOH 3. BnBr 11

O

O

cat G2

9a R = SiR3 9b R = H

OH 1. Dibal

OR

O

HO

2. Amano AK 7

O

O

OCH3 BnO HClO4; CH3OH

HO 12

54

O

OCH3 1. PdCl2 2. H2 / Pd-C

10 O

OCH3

HO HO

OH 13 Methyl 7-Dihydro-trioxacarcinoside B

ALKENE AND ALKYNE METATHESIS free alcohol 9b proceeded smoothly. V-directed epoxidation then set the relative conﬁguration of the stereogenic centers on the ring. Ring-closing metathesis to construct tetrasubstituted alkenes has been a challenge, and specially-designed Ru complexes have been put forward speciﬁcally for this transformation. Oliver Reiser of the Universität Regensburg was pleased to observe (Angew. Chem. Int. Ed. 2007, 46, 6361) that the second-generation Grubbs catalyst itself worked well for the cyclization of 17 to 18. Again in this synthesis, catalytic V was used to direct the relative conﬁguration of the epoxide.

CO2Et

O H O

CO2Et 14

15

OPMB

2. Ba(OH)2

1. O

O

2. Ac2O

H 16

AcO

OPMB

V cat O

O

t-BuOOH

18

O

O

H OPMB

17

AcO

1. cat G2 2. DDQ

AcO

H

1. BF3.OEt2

+

SiMe3

O

SiMe3

O

O

O

19

OH

O

O

O O 20

OH

(+)-Arglabin

Intramolecular alkyne metathesis is now well-established as a robust and useful method for organic synthesis. It was also known that Ru-mediated metathesis of an alkyne with ethylene could lead to the diene. The question facing (Angew. Chem. Int. Ed. 2007, 46, 5545) Alois Fürstner of the Max-Planck-Institut, Mülheim was whether these transformations could be carried out on the very delicate epoxy alkene 21. In fact, the transformations of 21 to 22 and of 22 to 23 proceeded well, setting the stage for the total synthesis of Amphidinolide V 25. H

O H H OTBS O

OTBS Mo cat

cat G2

O 22 H

O H O

O O

O H OH O O

H 24

25 Amphidinolide V

55

OTBS O O 23

H

OTBS

O H

CH2=CH2

O

21

2. DM

H OTBS

OTBS

O

1. MeOH

O H

OTBS

28. Alkene Metathesis: Synthesis of Panaxytriol (Lee), Isofagomine (Imahori and Takahata), Elatol (Stoltz), 5-F2t-Isoprostane (Snapper), and Ottelione B (Clive) January 19, 2009

Alkene metathesis has been used to prepare more and more challenging natural products. The ﬁrst and second generation Grubbs catalysts 1 and 2 and the Hoveyda catalyst 3 are the most widely used.

N

PCy3 Cl Cl Ru Cy3P Ph

N

N

Cl Cl Ru Cy3P Ph

1

N

Cl Cl Ru O 2

3

Daesung Lee of the University of Illinois at Chicago designed (Organic Lett. 2008, 10, 257) a clever chain-walking cross metathesis, combining 4 and 5 to make 6. The diyne 3 was carried on (3R, 9R, 10R)-Panaxytriol 7. OAc O

OAc +

O O

H

4

OH

cat 2 OH

O

OAc 5

O

OH

6

7

(3R, 9R, 10R ) -Panaxytriol

Tatsushi Imahori and Hiroki Takahata of Tohoku Pharmaceutical University found (Tetrahedron Lett. 2008, 49, 265) that of the several derivatives investigated, the unprotected alcohol 8 cyclized most efﬁciently. Selective cleavage of the monosubstituted alkene followed by hydroboration delivered the alkaloid Isofagomine 10. H

HO HO

HO

cat 1 N

8

HO

Boc

9

OH

N

N

Boc

H 10 Isofagomine

56

ALKENE METATHESIS Brian M. Stoltz of Caltech established (J. Am. Chem. Soc. 2008, 130, 810) the absolute conﬁguration of the halogenated chamigrene Elatol 14 using the enantioselective enolate allylation that he had previously devised. A key feature of this synthesis was the stereocontrolled preparation of the cis bromohydrin. Cl O O

O

cat Pd*

O

O

Cl

cat 3 Cl

Cl iBuO

11

i BuO

HO

iBuO

12

13

14 Br Elatol

Marc L. Snapper of Boston College opened (J. Org. Chem. 2008, 73, 3754) the strained cyclobutene 15 with ethylene to give the diene 16. Remarkably, cross metathesis with 17 delivered 18 with high regioselectivity, setting the stage for the preparation of the 5-F2tIsoprostane 19. HO

HO

O

cat 1

cat 3

+

CH2=CH2 TBSO

TBSO

15

CO2CH3

CO2CH3

HO

18

TBSO

OH

HO

O

HO

CO2CH3

17

16

19

5-F2t-Isoprostane

Derrick L. J. Clive of the University of Alberta assembled (J. Org. Chem. 2008, 73, 3078) Ottelione B 26 from the enantiomerically-pure aldehyde 20. Conjugate addition of the Grignard reagent 21 derived from chloroprene gave the kinetic product 22, that was equilibrated to the more stable 23. Addition of vinyl Grignard followed by selective ringclosing metathesis then led to 26. MgCl H

21

OH

23 OCH3

OH OTBS

MgBr

H

22

OCH3

Ar

O DBU

H

+ 20

Ar

O

Ar

O

OCH3

O

OH

OTBS

cat 1 24

25

26

57

Ottelione B

29. Total Synthesis by Alkene Metathesis: Amphidinolide X (Urpí / Vilarrasa), Dactylolide (Jennings), Cytotrienin A (Hayashi), Lepadin B (Charette), Blumiolide C (Altmann) June 22, 2009

To assemble the framework of the cytotoxic macrolide Amphidinolide X 3, Fèlix Urpí and Jaume Vilarrasa of the Universitat de Barcelona devised (Organic Lett. 2008, 10, 5191) the ring-closing metathesis of the alkenyl silane 1. No Ru catalyst was effective, but the Schrock Mo catalyst worked well. O

O Si O

PMBO Mo cat

O

Si O

PMBO

O

O

O

O

O

O 1

O

O 2

O

3 Amphidinolide X

In the course of a synthesis of (-)-Dactylolide 6, Michael P. Jennings of the University of Alabama offered (J. Org. Chem. 2008, 73, 5965) a timely reminder of the particular reactivity of allylic alcohols in ring-closing metathesis. The cyclization of 4 to 5 proceeded smoothly, but attempted ring closing of the corresponding bis silyl ether failed. O

O HO

OH HO cat G2

O

OH

4

N H

O

O

O

O

O

O

O O

5

6 (-)-Dactylolide

Polyenes such as (+)-Cytotrienin A 8 are notoriously unstable. It is remarkable that Yujiro Hayashi of the Tokyo University of Science could (Angew. Chem. Int. Ed. 2008, 47, 6657) assemble the triene of 8 by the ring-closing metathesis of the highly functionalized precursor 7.

58

TOTAL SYNTHESIS BY ALKENE METATHESIS HO

TESO

N TESO

TESO H N

H

N

1. cat G1 2. H+/H2O

O

O

H N

OCH3 O

7

O

HO

HO

H

O

O

OCH3 O

O

8 (+)-CytotrieninA

Bicyclo [2.2.2] structures such as 9 are readily available by the addition of, in this case, methyl acrylate to an enantiomerically-pure 2-methylated dihydropyridine. André B. Charette of the Université de Montréal found (J. Am. Chem. Soc. 2008, 130, 13873) that 9 responded well to ring-opening/ring-closing metathesis, to give the octahydroquinoline 10. Functional group manipulation converted 10 into the Clavelina alkaloid (+)-Lepadin B 11. O Ph

O N

Ph

H N

N

cat G2

OH OBn

BnO

9

11

10

(+)-LepadinB

The construction of trisubstituted alkenes by ring-closing metathesis can be difﬁcult, and medium rings with their transannular strain are notoriously challenging to form. Nevertheless, Karl-Heinz Altmann of the ETH Zürich was able (Angew. Chem. Int. Ed. 2008, 47, 10081), using the H2 catalyst, to cyclize 12 to cyclononene 13, the precursor to the Xenia lactone (+)-Blumiolide C 14. OH O

O

cat H2 O PMBO 12

OTBS

O

O PMBO 13

OTBS

O O

14 (+)-Blumiolide C

It is noteworthy that these ﬁve syntheses used four different metathesis catalysts in the key alkene forming step. For the cyclization of 7, the use of the Grubbs ﬁrst generation catalyst G1, that couples terminal alkenes but tends not to interact with internal alkenes, was probably critical to success. The Hoveyda catalyst H2 is more expensive than the Grubbs second generation catalyst G2, but can often be effective in applications in which G2 is sluggish. The Schrock Mo catalyst is less user friendly than the (relatively) air and moisture stable Ru catalysts, but is very reactive.

59

30. Enantioselective Assembly of Oxygenated Stereogenic Centers February 11, 2008

Reaction with an enantiomerically-pure epoxide is an efﬁcient way to construct a molecule incorporating an enantiomerically-pure oxygenated stereogenic center. The Jacobsen hydrolytic resolution has made such enantiomerically-pure epoxides readily available from the corresponding racemates. Christopher Jones and Marcus Weck of the Georgia Institute of Technology have now (J. Am. Chem. Soc. 2007, 129, 1105) developed an oligomeric salen complex that effects the enantioselective hydrolysis at remarkably low catalyst loading. Any such approach depends on monitoring the progress of the hydrolysis, usually by chiral GC or HPLC. In a complementary approach, we (J. Org. Chem. 2007, 72, 431) have found that on exposure to NBS and the inexpensive mandelic acid 2, a terminal alkene such as 1 was converted into the two bromomandelates 3 and 4. These were readily separated by column chromatography. Individually, 3 and 4 can each be carried on the same enantiomer of the epoxide 5. As 3 and 4 are directly enantiomerically pure, epoxide 5 of high ee can be prepared reliably without intermediate monitoring by chiral GC or HPLC. OTr OH OTr

Ph

2

CO2H

OTr

R*CO2 +

NBS

3 Br OTr

1

O 5

R*CO2

4 Br

Another way to incorporate an enantiomerically-pure oxygenated stereogenic center into a molecule is the enantioface-selective addition of hydride to a ketone such as 6. Alain Burgos and his team at PPG-SIPSY in France have described (Tetrahedron Lett. 2007, 48, 2123) a NaBH4-based protocol for taking the Itsuno-Corey reduction to industrial scale.

O

6

O

cat 7

N

Ph O

Ph Ph

O

HO

O

O

N

BH3 . Et2NPh 8

Ph O

98.2% de

N B 7

O

CH3

In the past, aldehydes have been efﬁciently α-oxygenated using two-electron chemistry. Mukund P. Sibi of North Dakota State University has recently (J. Am. Chem. Soc. 2007, 129, 4124) described a novel one-electron alternative. The organocatalyst 10 formed an

60

ENANTIOSELECTIVE ASSEMBLY OF OXYGENATED STEREOGENIC CENTERS imine with the aldehyde. One-electron oxidation led to an α-radical, which was trapped by the stable free radical TEMPO to give, after hydrolysis, the α-oxygenated aldehyde 11.

O

cat 10 FeCl3 / NaNO2

H O

N

H

O O

TEMPO 9

N

Ph

N

90% ee

H

11

10

High ee oxygenated secondary centers can also be prepared by homologation of aldehydes. Optimization of the enantioselective addition of the inexpensive acetylene surrogate 13 was recently reported (Chem. Commun. 2007, 948) by Masakatsu Shibasaki of the University of Tokyo. Note that the free alcohol of 13 does not need to be protected. O

H

OH

OH 13

H

2. K2CO3 OH

In* cat 12

14

R3N

R3SiO

1. R3SiCl

H 15

99% ee

A protocol for enantioselective allenylation was recently developed (J. Am. Chem. Soc. 2007, 129, 496) by Hisashi Yamamoto of the University of Chicago. The conversion of 17 to 18 should be straightforward, leading to net enantioselective propargylation. O H

Br 16

Me3Si

TESO

Cr* cat Mn / TESCl

12

TESO

17

H

18

90% ee

The enantioselective homologation of ketones, in particular methyl ketones, can also be accomplished. In this procedure described (J. Am. Chem. Soc. 2007, 129, 7439) by Professor Shibasaki and Motomu Kanai, also of the University of Tokyo, the alkyl group from the Zn was incorporated into the product. Alternative dialkyl zincs worked as well. O

O O

OEt +

19

20

Et2Zn Cu* cat DMSO

61

O 96% ee 21

31. Enantioselective Assembly of Aminated Stereogenic Centers February 18, 2008

Although natural amino acids are readily available, there is a continuing need for unnatural amino acids. Jon C. Antilla of the University of South Florida has described (J. Am. Chem. Soc. 2007, 129, 5830) a promising approach, based on the enantioselective organocatalytic reduction of imines such as 1 derived from α-keto esters. The aryl group is easily removed to give the primary amine. H

Ph Ph

N CO2Et

CO2Et

EtO2C

N

CO2Et

2

HN

O O P O HO 3

cat 3 OCH3

1

4

OCH3 96% ee

Mukund P. Sibi of North Dakota State University has developed (J. Am. Chem. Soc. 2007, 129, 4522) an enantioselective Mg catalyst that mediated the addition of benzyl hydrazine 6 to imides such as 5. The initial adduct cyclized to the pyrazolidinone 7. Karl Anker Jørgensen of Aarhus University has reported (Angew. Chem. Int. Ed. 2007, 46, 1983) a complementary protocol for the enantioselective conjugate addition of a nitrogen nucleophile. O O

O H N

BnO

Ph

+

N

Mg* cat

NH2

N H N

H

Ph

5

BnO 7

6

Ph 99% ee

Enantioselective homologation can also be a powerful approach. Benjamin List of the Max-Planck-Institute, Mülheim has found (Angew. Chem. Int. Ed. 2007, 46, 612; Organic Lett. 2007, 9, 1149) that three-component coupling of acetyl cyanide, an aldehyde and benzylamine under the inﬂuence of the Jacobsen thiourea catalyst 10 delivered the onecarbon homologated nitrile 12 in high ee.

O H 8

NH2

+ Ph

Ph

CN 10

N

cat 11 9

S

O

O

CN

N

N H

O 92% ee

N H

N

HO 11

12

OPiv

Other homologation methods are also effective. Li Deng of Brandeis University has shown (Organic Lett. 2007, 9, 603) that under the inﬂuence of cinchona-derived quaternary 62

ENANTIOSELECTIVE ASSEMBLY OF AMINATED STEREOGENIC CENTERS salts, malonates will add to racemic amido sulfones such as 13 to give the β-amino malonate 14 in high ee. Fujie Tanaka and Carlos F. Barbas III of Scripps/La Jolla have found (Angew. Chem. Int. Ed. 2007, 46, 1878) that the simple organocatalyst proline will mediate the azaBaylis Hillman addition of an unsaturated aldehyde such as 15 to 16 in high ee. The alkene 17 is the kinetic product. On prolonged exposure to the reaction conditions, 17 was equilibrated to the more stable 18. Ming-Hua Xu and Guo-Qiang Lin of the Shanghai Institute of Organic Chemistry have established (J. Am. Chem. Soc. 2007, 129, 5336) a robust protocol for the enantioselective assembly of -arylated benzylamines such as 21. H N

CO2Bn

CO2Bn

CO2Bn

CBz

Ts

CO2Bn

cat Q*

H

PMP +

H 15

O HN

proline

N

H

imidazole

CO2Et

H

93% ee

PMP

O HN H

CO2Et

98% ee 17

Ts

18 H

OH B OH

+

Ts

N

Rh* cat 99% ee

Cl

CH3O

PMP

imidazole CO2Et

16 N

CBz

14

13 O

N

Cl

CH3O

19

20

21

Other routes to enantiomerically-pure amines have been put forward. Knowing that CAL-B would selectively acylate just the R enantiomer of the racemic α-methyl primary amine 22, Stéphane Gastaldi, Gérard Gil and Michèle P. Bertrand of the Université Paul Cézanne devised (Organic Lett. 2007, 9, 837) a thiyl-based method for equilibrating 22, leading to a net deracemizing acylation. O NH2

H

N

CAL-B R'-CO2Et

99% ee

R-SH

22

R'

23

Jonathan Clayden of the University of Manchester has uncovered (J. Am. Chem. Soc. 2007, 129, 7488) a powerful enantioselective route to bis-α-aryl amines such as 25. It is remarkable that the deprotonation and subsequent rearrangement of 24 proceeded with such high enantiocontrol. H N N

CH3O

O N

s-BuLi

O

N 94% ee 24

CH3O

63

25

32. Enantioselective Preparation of Secondary Alcohols and Amines July 28, 2008

Secondary alcohols can be prepared in high enantiomeric excess by catalytic hydrogenation of ketones. Zhaoguo Zhang of Shanghai Jiaotong University has established (Organic Lett. 2007, 9, 5613) that β-keto sulfones such as 1 are suitable substrates for this hydrogenation. Reinhard Brückner of the Universität Freiburg has demonstrated (Angew. Chem. Int. Ed. 2007, 46, 6537) that the rate of hydrogenation of β-keto esters such as 3 and 5 depends on the alcohol from which the ester is derived, so 3 can be reduced to 4 in the presence of 5. OH

O

SO2Ph

Ru* cat

SO2Ph

H2 / I2

99% ee 2

1 O

O

OH Ru* cat

O 3 O

O

O

97% ee

4

H2

CF3 O

O

O

O

CF3

CF3 O

5

CF3

6

Enantiomerically-pure secondary alcohols and amines can also be prepared by adding an oxygen or a nitrogen to an existing carbon skeleton. Both Srivari Chandrasekhar of the Indian Institute of Chemical Technology, Hyderabad (Tetrahedron Lett. 2007, 48, 7339) and Arumugam Sudalai of the National Chemical Laboratory, Pune (Tetrahedron Lett. 2007, 48, 8544) have taken advantage of the previously-described enantioselective α-aminoxylation of aldehydes to establish what appears to be a robust preparative route to the enantiomerically-pure epoxides such as 9 of terminal alkenes. Karl Anker Jørgensen of Aarhus University has developed (Chem. Commun. 2007, 3646) a catalyst for the enantioselective addition of 11 to nitroalkenes such as 10. Armando Córdova of Stockholm University has shown (Tetrahedron Lett. 2007, 48, 5976) that epoxy aldehydes such as 14, easily prepared by the protocol he developed, are converted by the Bode catalyst to β-hydroxy esters such as 15. 1. Ph-N=O D-proline

O

OH

H TBSO 7

2. NaBH4 3. CuSO4

10

9 NO2

cat*

11

O 12

64

O

TBSO

> 95% de

8

CO2Et NO2 + N HO

OH

TBSO

TsCl

N

91% ee CO2Et

ENANTIOSELECTIVE PREPARATION OF SECONDARY ALCOHOLS AND AMINES O

H2O2 H

O

OH O

cat carbene H

cat*

13

O

EtOH

14

O 93% ee

15

Hyunsoo Han of the University of Texas, San Antonio has described (Tetrahedron Lett. 2007, 48, 7094) an improved protocol for the enantioselective conversion of primary allylic carbonates 16 to secondary amines 17. René Peters of ETH Zurich has used (Angew. Chem. Int. Ed. 2007, 46, 7704) a related procedure for the construction of aminated quaternary centers. Mukund P. Sibi of North Dakota State University has devised (J. Am. Chem. Soc. 2007, 129, 8064) a catalyst for the conjugate addition of the benzyloxyamine 20 to acyl pyrazoles, and Claudio Palomo of the Universidad de País Vasco has found (Angew. Chem. Int. Ed. 2007, 46, 8054) that a simple diphenyl prolinol catalyst will effect enantioselective α-amination of aldehydes.

+

H

Boc

OCO2Et H

N O

17

16

1. Ir* cat

N

97% ee

2. K2CO3 18 BnO

O

OBn

PMPO

N N

19

+

H

N

cat*

O N N

H 21

1. Ph-N=O cat* H

H

N

PMPO

20 O

Boc

98% ee

OH

2. NaBH4

HO

22

N

96% ee

Ph

23

Carbon-carbon bond formation can also be used to assemble enantiomerically-pure secondary alcohols. Herfried Griengl of Graz University of Technology has found (Adv. Synth. Cat. 2007, 349, 1445) that a commercial nitrile lyase effects addition of nitromethane to an aldehyde such as 24 to give the nitro alcohol 25 in high ee. Markus Kalesse of Leibniz Universität Hannover has constructed a catalyst (Organic Lett. 2007, 9, 5637) for the enantioselective addition of the ketene silyl acetal 27 to aldehydes. Hajime Ito and Masaya Sawamura of Hokkaido University (J. Am. Chem. Soc. 2007, 129, 14856) (depicted), and Dennis G. Hall of the University of Alberta (Angew. Chem. Int. Ed. 2007, 46, 5913) have reported complementary enantioselective preparations of allyl boronates such as 31. O 24

H

O B B O O 30

O

96% ee

OH cat*

CO2CH3

27 OCO2CH3

+

25

OCH3

+

26

29

NO2

Hydroxynitrile Lyase

TBSO

O

OH

CH3NO2 H

94% ee

28 Ph

(pin)B Ph-CH=O

Cu cat* 31

65

BF3 . OEt2

32

OH 94% ee

33. Enantioselective Preparation of Alcohols and Amines February 16, 2009

Enzymatic reduction of a ketone can proceed in high enantiomeric excess, but this would require a stoichiometric amount of a reducing agent. Wolfgang Kroutil of the KarlFranzens-Universität Graz devised (Angew. Chem. Int. Ed. 2008, 47, 741) a protocol for preparing the alcohol 2 in high ee starting from the racemic alcohol. The alcohol dehydrogenase chosen was selective for the R-alcohol, and the microorganism reduced the ketone so produced selectively to the S alcohol. OH

OH O

A. faecalis

N

Alcohol dehydrogenase 1

> 99% ee

2

O

O

PhB(OH)2

(RO)2BH; ox

H

OH

6

N

H OH 93% ee

4

3

OBn OH

BnOH

OAc

Q* cat 5

O

cat Rh*

Ir* cat

OH 98% ee

7

84% ee

8

James M. Takacs of the University of Nebraska established (J. Am. Chem. Soc. 2008, 130, 3734) that chiral Rh catalyzed addition of pinacolborane to a β,γ-unsaturated N-phenyl amide 3 proceeded with high enantiocontrol. The product organoborane was oxidized to the alcohol 4. J. R. Falck of the UT Southwestern Medical Center used (J. Am. Chem. Soc. 2008, 130, 46) an organocatalyst to effect addition of phenylboronic acid to the γ-hydroxy enone 5, to give, after hydrolysis, the diol 6. John F. Hartwig of the University of Illinois effectively telescoped (Angew. Chem. Int. Ed. 2008, 47, 1928) alcohol formation and protection into a single step, by developing a procedure for the direct conversion of a primary allylic acetate 7 to the enantiomerically-enriched secondary benzyl ether 8. Tsutomu Katsuki of Kyushu University designed (Chemistry Lett. 2008, 37, 502) a catalyst for the enantioselective hydrocyanation of an aldehyde 9, by HCN transfer from the inexpensive 10. Mei-Xiang Wang of the Chinese Academy of Sciences, Beijing and Jieping Zhu of CNRS, Gif-sur-Yvette devised (Angew. Chem. Int. Ed. 2008, 47, 388) a catalyst for a complementary one-carbon homologation, the enantioselective Passerini three-component coupling of an aldehyde 12, an isonitrile 13, and an acid 14. HO CN

O H

10

NC

OH

O

CN

H +

11

98% ee

12

13

66

14

OH Cl O

O O

Al* cat

V* cat 9

Cl

15 O

H N

Ar 93% ee

ENANTIOSELECTIVE PREPARATION OF ALCOHOLS AND AMINES O

H

OH OBz AD-mix;

Ph

Ph

16

17

H

OH

NaBH4

Ph

Ph

18 94% ee

MgCl (i -PrO)4Ti 20 2 mol % ArBinol*

19

OH

Ph

21

92% ee

Joseph M. Ready, also of UT Southwestern, developed (J. Am. Chem. Soc. 2008, 130, 7828) the preparation of enol benzoates such as 17 from the corresponding alkynes. Sharpless asymmetric dihydroxylation of 17 proceeded with high ee to give, after reduction, the diol 18. Toshiro Harada of the Kyoto Institute of Technology described (Angew. Chem. Int. Ed. 2008, 47, 1088) a potentially very practical enantioselective homologation, the catalyzed addition of an alkyl titanium, prepared in situ from the corresponding Grignard reagent, to the aldehyde 19, to give 21 in high ee. Thomas C. Nugent of Jacobs University Bremen reported (J. Org. Chem. 2008, 73, 1297) that added Yb(OAc)3 improved the de in the reductive amination of ketones such as 22 with Raney Ni and 23. Yong-Gui Zhou of the Dalian Institute of Chemical Physics found (Organic Lett. 2008, 10, 2071) that cyclic sulfamidates such as 25 were easily prepared from the corresponding hydroxy ketone. Enantioselective hydrogenation of 25 gave 26 with high ee. Note that the cyclic sulfamidates 26 so produced will be versatile intermediates for further transformations, as the O is easily displaced by nucleophiles. Armido Studer of Westfälische-Wilhelms-Universität has been investigating (OHL March 24, 2008) the radical amination of alkenes. He has developed (Angew. Chem. Int. Ed. 2008, 47, 779) an easily-prepared N donor, 28, and found that addition to the alkenyl oxazolidinone 27 proceeded with high de. H

O H2N 22 O O

N N

+ 27

EtO2C

28

O N S O O

Ph

Ph 89% de

Yb(OAc)3 Raney Ni H

N

23

N

H2

25

Boc

O PhSH O

O N S O O 96% ee

cat Pd*

24

Et3B CO2Et

H

26

p -Tol H2N

N

29 H N Boc

13:1 dr 30

N

Ts 31 O

PhI(O2CR)2 Rh* cat

H Ar N N

Ts

O 90% de 32

The alkene 30 has ten chemically distinct C-H bonds. Paul Müller of the University of Geneva and Robert H. Dodd and Philippe Dauban of CNRS, Gif-sur-Yvette established (J. Am. Chem. Soc. 2008, 130, 343) that insertion by a Rh nitrene proceeded with high selectivity primarily into just one of those C-H bonds, delivering 32 in high de.

67

34. Enantioselective Synthesis of Alcohols and Amines July 20, 2009

Enantiomerically-enriched alkoxy stannanes such as 3 are versatile intermediates for synthesis. John R. Falck of UT Southwestern found (Angew. Chem. Int. Ed. 2008, 47, 6586) that the simple combination of Bu3SnH and Et2Zn generated a reagent that added to aldehydes such as 1 under catalysis by the MIB amino alcohol introduced by Nugent (Chem. Commun. 1999, 1369) to give the adduct 3 in high ee. Gonzalo Blay and José R. Pedro of the Universitat de València showed (Chem. Commun. 2008, 4840) that it was possible to modulate the reactivity of the acidic 4, allowing catalyzed formation of the high ee adduct 5 to dominate. Xiaoming Feng of Sichuan University developed (J. Am. Chem. Soc. 2008, 130, 15770) a Ni catalyst for the intermolecular ene reaction of 6 with 7 to give 8 in high ee. S O

N

Bu3SnH / Et2Zn

H

OH

O

3

7

O H OTBDPS 9

98% ee 8

OSiEt3 13

90% ee

Br Br 10 Cr* / Mn

OH Br OTBDPS 93% ee 11

O

Cl

Cl

16 O)2C=O

BnO

O 93% ee

Ir* cat 12

Br 5

HO AcO

NO2

1

CO2Et

OH BnO

NO2

Cu* cat

98% ee

OH CO2Et

Ni* cat

6

H

4

2

O H

Br SnBu3

N

1

OH

O

O

14

15

O

O

Pd* cat

O 92% ee

17

Enantioselective allylation is a key transformation in current organic synthesis. Yoshito Kishi of Harvard University optimized (Organic Lett. 2008, 10, 3073) enantioselective Cr-mediated allylation, with a ligand that can be easily recovered and recycled. Michael J. Krische of UT Austin devised (J. Am. Chem. Soc. 2008, 130, 14891) a ligand-catalyst combination for effecting the enantioselective allylation of alcohols such as 12. Brian M. Stoltz of Caltech developed (Angew. Chem. Int. Ed. 2008, 47, 6873) a protocol for the enantioselective allylation of the enol ether 15, leading to the construction of oxygenated quaternary centers. Adducts such as 11 and 17 are of interest, inter alia, as direct precursors, by elimination, of the corresponding alkynes. Simon Blakey of Emory University designed (Angew. Chem. Int. Ed. 2008, 47, 6825) a Ru catalyst that mediated enantioselective intramolecular C-H amination, converting the 68

ENANTIOSELECTIVE SYNTHESIS OF ALCOHOLS AND AMINES simple alcohol derivative 18 into the versatile secondary amine 19 in high ee. We established (J. Org. Chem. 2008, 73, 9334) a procedure, based on diazo transfer followed by Rh-mediated intermolecular N-H insertion, for aminating menthyl esters and separating the product diastereomers. The menthyl group, easily removed (TFA) from 21, served as a useful reporter of ee, by 1H NMR of the upﬁeld methyl doublets. Wolfgang Kroutil of the University of Graz found (Adv. Synth. Cat. 2008, 350, 2761) that ω-transaminases could effect the reductive amination of methyl ketones such as 22 in high ee. In many cases, either enantiomer of the amine could be prepared, depending on the transaminase used. O

O S

H2N

Ru* cat

O

O

H

N

O S

O

O

Ph

O

89% ee 18

19

20

NH2

O

O

Bn

PMP H

O 28

N

H

O

O O

Ph

Naphth

Boc

Ph

93% ee

N

OH

Ph O

30

N

H

Q* cat 87% ee 27

Fmoc

26 H

Naphth PMP

N

N

O

24

O N

Bn

Boc N H 25

Q* cat

Ph

98% ee 23

H

21

ω-transaminase 22

Ph

O

steps

O

PhI(O2CR)2

98% ee

29

1

31

Li Deng of Brandeis University developed (Angew. Chem. Int. Ed. 2008, 47, 7710) a cinchona alkaloid derived catalyst for the enantioselective conjugate addition of 25 to enones. Manabu Node of Kyoto Pharmaceutical University reported (Organic Lett. 2008, 10, 2653) a related procedure for the addition of a recyclable enantiomerically-pure amine to α,β-unsaturated esters. Géraldine Masson and Jieping Zhu of CNRS Gif-sur-Yvette devised (J. Am. Chem. Soc. 2008, 130, 12596) a catalyst, also based on cinchona alkaloids, for the enantioselecitve aza Morita-Baylis-Hillman reaction, converting the imine 27 into 29 in substantial ee. Teck-Peng Loh of Nanyang Technological University designed (Organic Lett. 2008, 10, 2805) the enantiomerically- and diastereomerically-pure hydroxylamine 30. The initial adduct of 30 with the aldehyde 1 rearranged to deliver 31 in high ee and as a single geometric isomer.

69

35. Enantioselective Assembly of Alkylated Stereogenic Centers February 25, 2008

Oxygenated secondary stereogenic centers are readily available. There is a limited range of carbon nucleophiles that will displace a secondary leaving group in high yield with clean inversion. Teruaki Mukaiyama of the Kitasato Institute has described (Chem. Lett. 2007, 36, 2) an elegant addition to this list. Phosphinites such as 1 are easily prepared from the corresponding alcohols. Quinone oxidation in the presence of a nucleophile led via efﬁcient displacement to the coupled product 2. The sulfone could be reduced with SmI2 to give 3. CN SmI2

SO2Ph Ph

OPPh2

CN

Ph

ox

1

2

CN

Ph 3

SO2Ph

99% ee

Enantioselective reduction of trisubstituted alkenes is also a powerful method for establishing alkylated stereogenic centers. Juan C. Carretero of the Universidad Autonoma de Madrid has found (Angew. Chem. Int. Ed. 2007, 46, 3329) that the enantioselective reduction of unsaturated pyridyl sulfones such as 4 was directed by the sulfone, so the other geometric isomer of 4 gave the opposite enantiomer of 5. The protected hydroxy sulfone 5 is a versatile chiral building block. O O S N

THPO

Cu* cat

O O S N

THPO

Ph-SiH3

91% ee

4

5

Samuel H. Gellman of the University of Wisconsin has reported (J. Am. Chem. Soc. 2007, 129, 6050) an improved procedure for the aminomethylation of aldehydes. L-Proline-catalyzed condensation with the matched α-methyl benzylamine derivavative 7 gave the aldehyde, which was immediately reduced to the alcohol 8 to avoid racemization. The amino alcohol 8 was easily separated in diastereomerically-pure form. O

CH3O

H

+ 6

L-Proline; N Bn

Ph

HO

N Bn

NaBH4

7

8

Ph 62% isolated yield of major diastereomer

In the past, aldehydes have been efﬁciently α-alkylated using two-electron chemistry. David W. C. Macmillan of Princeton University has developed (Science 2007, 316, 582; J. Am. Chem. Soc. 2007, 129, 7004) a one-electron alternative. The organocatalyst 9 formed an imine with the aldehyde. One-electron oxidation led to an α-radical, which was trapped by the allyl silane (or, not pictured, a silyl enol ether) leading to the α-alkylated 70

ENANTIOSELECTIVE ASSEMBLY OF ALKYLATED STEREOGENIC CENTERS aldehyde 10. This is mechnistically related to the work reported independently by Mukund P. Sibi (J. Am. Chem. Soc. 2007, 129, 4124; OHL Feb. 11, 2008) on one-electron α-oxygenation of aldehydes. O

O SiMe3

H

O

H

N

Ph

CAN cat 9

N

91% ee

H

H

6

10

9

Secondary alkylated centers can also be prepared by SN2’ alkylation of prochiral substrates such as 11. Ben L. Feringa of the University of Groningen has shown (J. Org. Chem. 2007, 72, 2558) that the displacement proceeded with high ee even with conventional Grignard reagents. The products so formed are versatile intermediates for further transformation. CH3MgBr

BnO

Br

BnO

Cu* cat

92% ee

11

12

The enantioselective construction of acyclic alkylated quaternary stereogenic centers is a continuing challenge in organic synthesis. Several promising approaches have recently appeared. Li Deng of Brandeis University has established conditions (J. Am. Chem. Soc. 2007, 129, 768) for the catalyzed conjugate addition of aryl cyanoacetates such as 13 to acrylonitrile to give the adduct 14 in high ee. Eric N. Jacobsen of Harvard University has developed (Angew. Chem. Int. Ed. 2007, 46, 3701) a chiral Cr catalyst that mediated the alkylation of tributyltin enolates such as 15 to give 16 in high ee. Amir H. Hoveyda of Boston College has designed (J. Am. Chem. Soc. 2007, 129, 3824) a chiral Ru metathesis catalyst that crossed 18 with the readily-prepared prochiral 17 to give 19, also in high ee. CN

CN CO2Et Cl

NC CO2Et CN

Q* cat

93% ee Cl

13 I

Bu3SnO

14

O

87% ee

Cr* cat 15

16

TBSO

O TBSO

+ 17

O

Ru* cat

86% ee O

18

19

71

O

36. Enantioselective Construction of Alkylated Stereogenic Centers September 8, 2008

The enantioselectivity of alkene reduction usually depends on the geometric purity of the alkene. Bruce H. Lipshutz of the University of California, Santa Barbara used (Organic Lett. 2007, 9, 4713) carboalumination of the alkyne 1 to prepare 2, which was selectively reduced to 3 in high ee. André B. Charette of the Université de Montréal reported (Angew. Chem. Int. Ed. 2007, 46, 5955) a related reduction of unsaturated sulfones such as 4. Juan C. Carretero of the Universidad Autónoma de Madrid has developed (J. Org. Chem. 2007, 72, 9924) a complementary route to enantiomerically-enriched sulfones, by conjugate addition to the unsaturated pyridyl sulfone 6. Speciﬁcally for styrene derivatives, Hans-Günther Schmalz of the University of Cologne has shown (Organic Lett. 2007, 9, 3555) that the product 11 from enantioselective Rh-catalyzed hydroboration can be homologated to 13. H

Me3Al Zr cat;

CO2Bu

Cu* cat

BuO2CCl 1

2 SO2Ph

SO2Ph TrO

Cu* cat

90% ee

4

5 Ph 7

S O O

N

8 B H O

Rh* cat; pinacol 9

Ph

Rh* cat

O

CH3O

B(OH)2

6

10

99% ee

3

PhSiH3

TrO

CH3O

CO2Bu

PMHS

CH3O

N 92% ee OTBS

O B O

CH3O

S O O

LiCH2Cl x 2; s-BuLi; TBSO

Br / Pd cat 12

11

CH3O 93% ee CH3O 13

Conjugate addition of stabilized carbanions can also be carried out with high enantiocontrol. David A. Evans of Harvard University has described (J. Am. Chem. Soc. 2007, 129, 11583) the Ni-catalyzed addition of malonate 15 to nitroalkenes such as 14. Claudio Palomo of the Universidad de País Vasco (Angew. Chem. Int. Ed. 2007, 46, 8431) and concurrently Yujiro Hayashi of the Tokyo University of Science (Organic Lett. 2007, 9, 5307) have developed organocatalytic protocols for the addition of nitromethane 18 to unsaturated aldehydes such as 17. J. Michael Chong of the University of Waterloo has found (J. Am. Chem. Soc. 2007, 129, 4908) that the Binol-mediated enantioselective conjugate addition of alkenylboronic acids such as 22 required the additional activation of the aryl ketone. Shun-Jun Li of

72

ENANTIOSELECTIVE CONSTRUCTION OF ALKYLATED STEREOGENIC CENTERS Suzhou University and Teck-Peng Loh of Nanyang Technical University have extended (J. Am. Chem. Soc. 2007, 129, 276) enantioselective conjugate to unsaturated esters such as 24 to more highly substituted Grignard reagents. Alexandre Alexakis of the University of Geneva has demonstrated (Tetrahedron Lett. 2007, 48, 7408) that Ac2O is compatible with Et2Zn conjugate addition conditions, leading directly to the trapped enolate 27. Selective cleavage of 27 can then be used to prepare acyclic derivatives. EtO2C

CO2Et NO2

CO2Et

CO2Et NO2

15

Ni* cat

14

89% ee

16 O

O

H3C-NO2 H

H

18

cat 19

17

N

NO2

H

91% ee

20

OTMS 19

O O Ph

Ph

B(OCH3)2

22 Binol cat

21

98% ee

23

CO2CH3

MgBr

CO2CH3

Cu* cat

24 O

94% ee

OAc

Et2Zn

96% ee

Cu* cat Ac2O

26

25

27

Benjamin List of the Max-Planck-Institut, Mülheim has taken advantage (J. Am. Chem. Soc. 2007, 129, 11336) of the large-small differential of the substituents on the aldehyde 28. Enantioselective Pd-mediated rearrangement of the protonated enamine derived from condensation of 28 with 29 delivered the aldehyde 30 in high ee. Ph

Ph H + H

N

Pd* cat

H

O 28

O 30

29

73

92% ee

37. Enantioselective Construction of Alkylated Centers February 23, 2009

Unsaturated half acid esters such as 1 are readily prepared by Stobbe condensation between dialkyl succinate and an aldehyde. Johannes G. de Vries of DSM and Floris P. J. T. Rutjes of Radboud University Nijmegen observed (Adv. Synth. Catal. 2008, 350, 85) that these acids were excellent substrates for enantioselective hydrogenation. Kazuaki Kudo of the University of Tokyo designed (Organic Lett. 2008, 10, 2035) a resin bound peptide catalyst for the transfer reduction of unsaturated aldehydes such as 3, using 4 as the net H2 donor. Note that 5 was produced with high enantiocontrol from 3 that was a ~ 2:1 mixture of geometric isomers. EtO2C O H2 HO2C 1

H

Rh* cat CO2CH3

HO2C

99% ee CO2CH3

2

CO2Et O

N H 4

H 96% ee

resin cat* 5

3

Motomu Kanai and Masakatsu Shibasaki of the University of Tokyo devised (J. Am. Chem. Soc. 2008, 130, 6072) a chiral Gd catalyst that mediated the conjugate cyanation of enones such as 6 with high ee. Eric N. Jacobsen of Harvard University prepared (Angew. Chem. Int. Ed. 2008, 47, 1762) a dimeric Al salen catalyst that showed improved activity over the monomeric catalysts. Even congested imides such as 8 could be cyanated efﬁciently, delivering alkylated quaternary stereogenic centers. CN O

O

O H

TBSCN Gd* cat

6

7

98% ee

O

O TMSCN H

N Ph 8

Al* cat

CN

N

O

Ph 9

92% ee

Takahiro Nishimura and Tamio Hayashi of Kyoto University optimized (J. Am. Chem. Soc. 2008, 130, 1576) the Rh∗-catalyzed enantioselective conjugate addition of silyl acetylenes to enones such as 10, to give 12. Adriaan J. Minnaard and Ben L. Feringa of the University of Groningen devised (Angew. Chem. Int. Ed. 2008, 47, 398) conditions for the enantioselective 1,6-conjugate addition of alkyl Grignard reagents to diene esters such as the inexpensive ethyl sorbate 14. The product 16 incorporated, in addition to the newly formed stereogenic center, a geometrically deﬁned E alkene. CO2Et O

10

H

11

SiR3

Rh* cat

O 95% ee 12

SiR3

14

74

MgBr 15 Cu* cat

EtO2C 92% ee 16

ENANTIOSELECTIVE CONSTRUCTION OF ALKYLATED CENTERS William S. Bechara and André B. Charette of the Université de Montréal found (Organic Lett. 2008, 10, 2315) that alkyl Grignard reagents could be induced to add with high enantioselectivity to pyridyl sulfones such as 17. In a different approach, Gregory C. Fu of MIT developed (J. Am. Chem. Soc. 2008, 130, 3302; J. Am. Chem. Soc. 2008, 130, 2756) conditions for the enantioselective alkenylation of racemic bromo esters such as 19, The latter reference is to the analogous enantioselective coupling of organozinc bromides with racemic allylic chlorides.

O O S

MgBr Ph Zn(OMe)2

N

O O S

Si(OMe)3

t-Bu

20

O

Br

N

Cu*cat

17

90% ee Ph

18

19

t-Bu O

Ni* cat

O t -Bu

21

O 93% ee t-Bu

Organocatalyst-mediated coupling has also been used to prepare alkylated stereogenic centers. Benedek Vakulya and Tibor Soós of the Hungarian Academy of Sciences, Budapest devised (J. Org. Chem. 2008, 73, 3475) a Cinchona alkaloid-based catalyst for the addition of nitromethane 23 to activated amides such as 22. Benjamin List of the Max-PlanckInstitut, Mülheim showed (Angew. Chem. Int. Ed. 2008, 47, 4719) that with the versatile catalyst 27, acetaldehyde itself could be added with high ee to nitroalkenes such as 25. In a continuation of his work with single-electron chemistry, David W. C. MacMillan of Princeton University effected (J. Am. Chem. Soc. 2008, 130, 398) enantioselective alkenylation of aldehydes, using catalytic 31 and the stoichiometric oxidant ceric ammonium nitrate. CH3-NO2 23 Q* cat

O N

O2N

N

Ph 22

Ph 24 BF3K

O H

30

Ph

O H

N

Ph Ph N OTMS NO2 H 27 28 94% ee

NO2

O

Ph

34

H 94% ee

O

cat 27 25

93% ee

O 29

CH3CH=O H NO2 26

O

cat peptide Ph

32

33

O

NO2

O O

H Ph

98% ee 35

Ph

36

N Ph cat 31 H CAN

Using a designed catalytic peptide, Helma Wennemers of the University of Basel alkylated (J. Am. Chem. Soc. 2008, 130, 5610) aldehydes such as 33 with nitroethylene. Samuel H. Gellman of the University of Wisconsin effected (J. Am. Chem. Soc. 2008, 130, 5608) the same transformation using the catalyst 27. Professor Wennemers showed that reduction of 35 followed by Mioskowski oxidation of the nitro group to the acid delivered the γ-lactone 36. Enantiomerically-pure γ-lactones such as 36 are powerful intermediates for the enantioselective construction of natural products.

75

38. Enantioselective Construction of Alkylated Stereogenic Centers July 27, 2009

Carsten Bolm of RWTH Aachen developed (Angew. Chem. Int. Ed. 2008, 47, 8920) an Ir catalyst that effected hydrogenation of trisubstituted enones such as 1 with high ee. Benjamin List of the Max-Planck-Institut Mülheim devised (J. Am. Chem. Soc. 2008, 130, 13862) an organocatalyst for the enantioselective reduction of nitro acrylates such as 3 with the Hantzsch ester 4. t BuO2C O

O

Ir* cat Ph

Ph 87% ee

H2

1

NO2

EtO2C

CO2tBu N 4 H organocat*

5

3

2

NO2 95% ee

EtO2C

Gregory C. Fu of MIT optimized (J. Am. Chem. Soc. 2008, 130, 12645) a Ni catalyst for the enantioselective arylation of propargylic halides such as 6. Both enantiomers of 6 were converted to the single enantiomer of 8. Michael C. Willis of the University of Oxford established (J. Am. Chem. Soc. 2008, 130, 17232) that hydroacylation with a Rh catalyst was selective for one enantiomer of the allene 9, delivering 11 in high ee. Similarly, José Luis García Ruano of the Universidad Autónoma de Madrid found (Angew. Chem. Int. Ed. 2008, 47, 6836) that one enantiomer of racemic 13 reacted selectively with the enantiomerically-pure anion 12, to give 14 in high diastereomeric excess. Ei-chi Negishi of Purdue University described (Organic Lett. 2008, 10, 4311) the Zr-catalyzed asymmetric carboalumination (ZACA reaction) of the alkene 15 to give the useful chiron 16. MeS

CH3O Br racemic

OCH3

racemic

91% ee

OMs 13

O 91% ee 11

1. (-)-ZACA; O2

95 : 5 de Ph 14

SMe

OH

Ar O S

Ph

Rh* cat

9

8

Ar O S

Ph

10

Ni* cat

6

12

H

ZnEt

7

O

Ph

15

H

98% ee

2. Amano PS lipase OSiR3 vinyl acetate 16 OSiR3

David W. C. MacMillan of Princeton University developed (Science 2008, 322, 77) an intriguing visible light-powered oxidation-reduction approach to enantioselective aldehyde alkylation. The catalytic chiral secondary amine adds to the aldehyde to form an enamine, that then couples with the radical produced by reduction of the haloester.

76

ENANTIOSELECTIVE CONSTRUCTION OF ALKYLATED STEREOGENIC CENTERS Bn

O

O Ru cat/hν

H

CO2R

H

CO2R / N* cat Br 18

17

O Ph

O

19

LDA/LiCl;

N

N*

21 20

O Ph

N Bn O

CH2=NBn2

N O S O

92% ee

Ph

TMSOTf/Et3N;

22

Ph

N

Br

OH

OH 23

24 19:1 dr

Two other alkylations were based on readily-available chiral auxiliaries. Philippe Karoyan of the Université Pierre et Marie Curie observed (Tetrahedron Lett. 2008, 49, 4704) that the acylated Oppolzer camphor sultam 20 condensed with the Mannich reagent 21 to give 22 as a single diastereomer. Andrew G. Myers of Harvard University developed the pseudoephedrine chiral auxiliary of 23 to direct the construction of ternary alkylated centers. He has now established (J. Am. Chem. Soc. 2008, 130, 13231) that further alkylation gave 24, having a quaternary alkylated center, in high diastereomeric excess. O O (EtO) P 2 24 H

N

23

25 Ar

O

O

CO2Et

NO2

O Ar OTMS

Ph

95% ee

27

26

NH2 Ph

O

28 H

Ph NO2

H

88% ee

CO2Li cat 29

30

O2N SO2Py

CH3NO2 N

N 31

O

Ni* cat

N

N 32 O

96% ee

SO2Py 94% ee

MgBr Cu* cat

33

34

Karl Anker Jørgensen of Aarhus University developed (J. Org. Chem. 2008, 73, 8337) an enantioselective route to 4-alkyl α-methylene lactones such as 26, based on conjugate addition of an aldehyde to the activated acceptor 24. Masanori Yoshida of Hokkaido University found (Chem. Commun. 2008, 6242) that the Li salt 29 of phenylalanine was an effective catalyst for the conjugate addition of aldehydes to nitroalkenes such as 27. Masayuki Hasegawa and Shuji Kanemasa of Kyushu University designed (Tetrahedron Lett. 2008, 49, 5105, 5220) a Ni catalyst for the enantioselective addition of nitromethane to acyl pyrazoles such as 31. Ben L. Feringa of the University of Groningen established (Organic Lett. 2008, 10, 4219) what may be one of the most ﬂexible of approaches to alkylated chirons, the enantioselective conjugate addition of Grignard reagents to unsaturated sulfones such as 33.

77

39. Stereocontrolled Construction of Arrays of Stereogenic Centers March 10, 2008

Complex natural products and even some complex pharmaceuticals contain arrays of stereogenic centers. Sometimes, the desired array is readily available from a natural product, but usually, such arrays of multiple stereogenic centers must be assembled. Armando Córdova of Stockholm University has reported (Angew. Chem. Int. Ed. 2007, 46, 778) a simple procedure for the organocatalyst-mediated addition of the nitrene equivalent 2 to an α,β-unsaturated aldehyde to give the protected aziridine 4 in high ee. Organocatalysis was also used (Organic Lett. 2007, 9, 1001) by Arumugam Sudalai of the National Chemical Laboratory, Pune, to effect coupling of the aldehyde 5 with dibenzylazodicarboxylate 6 to give, following the List procedure, the intermediate aldehyde 7. Osmylation of the derived unsaturated ester 8 proceeded with high diastereocontrol, to give 9. O H

H

Cbz N OAc 2 cat 3

1 Cbz Cbz N N H 6 5

cat proline

O

Cbz O

N

H

4

Cbz N Cbz N H 7

H 96% ee

N H 3 OTMS

Cbz N Cbz H N

O

8

OsO4

CO2Et 99% ee

H

Cbz Cbz N N OH CO2Et 9 OH

Products 4 and 9 have adjacent stereogenic centers. Hisashi Yamamoto of the University of Chicago has introduced (J. Am. Chem. Soc. 2007, 129, 2762) the linchpin reagent acetaldehyde “super”silyl enol ether 11. Diastereoselective addition of 11 to the enantiomerically-pure aldehyde 10, with concomitant silyl transfer, followed by the addition of allyl magnesium bromide delivered the protected triol 12 in high de and ee. MgBr O

OTBS

H 10

OSi(TMS)3 11

HO

cat Tf2NH

OSi OTBS

12

Arrays that combine alkylated and oxygenated or aminated centers are also important. Akio Kamimura of Yamaguchi University took (J. Org. Chem. 2007, 72, 3569) a BaylisHillman like approach, adding thiophenoxide to t-butyl acrylate in the presence of an enantiomerically-pure aldehyde N-sulﬁnimine such as 13 to give the adduct 14 with high diastereocontrol. Keiji Maruoka of Kyoto University has designed (Angew. Chem. Int. Ed. 2007, 46, 1738) the chiral amine 17, that catalyzed the condensation of an aldehyde with ethyl glyoxylate 16 with high enantiocontrol. In a very thoughtful approach, Liu-Zhu Gong of the University of Science and Technology of China in Hefei extended (Chem. Commun. 2007, 736) the now-classic aldol condensation of cyclohexanone to 4-substituted 78

STEREOCONTROLLED CONSTRUCTION OF ARRAYS OF STEREOGENIC CENTERS cyclohexanones such as 19. The product 21 could be carried in many directions, including to the Bayer-Villiger product 22. O S

N

O CO2t Bu

Ar

NH CO2t Bu

H

13

S

Ar

PhSMgBr

14

H N SO CF 2 3

95 : 5 dr

SPh

O H

O H

OEt O 16

15

cat 17

O

HO

O

EtO2C 18

O Ar-CH=O

N H H 95% ee

OH

H

17 TBSO

O MCPBA

Ar

N H

Ar

cat 20 19

99% ee

21

H N

OH

O

O

OH Ph Ph

20

22

Arrays of alkylated and polyalkylated centers have been among the most challenging to prepare. Professor Córdova has established conditions (Chem. Commun. 2007, 734) under which 3 will catalyze the addition of aliphatic aldehydes such as 23 to imides such as 24 with high enantio- and diastereocontrol. The two carbonyls of the imide would be easily distinguishable by reduction of the aldehyde followed by selective formation of the γ-lactone. Using the same catalyst, Wei Wang of the University of New Mexico effected (Organic Lett. 2007, 9, 1833) the addition of the mercapto ester 27 to unsaturated aldehydes such as 26. The product 28 has three new stereogenic centers. In what may be a very general approach to this problem, Hiroki Hamada of the Okayama University of Science has observed (Tetrahedron Lett. 2007, 48, 1345) that crude puriﬁed p51 and p83 reductases from Glycine max showed complementary selectivity, leading to 30 and 31 respectively. O

O

O

O

cat 3 H

N Ph

+

23

N Ph

H O

24

O

O CO2Et H

25

10:1 dr 99%ee

O cat 3

EtO2C

H

+ BnO

26

HS

27

28

S OBn

p51 or p83 O

O 29

NADPH

O

O 30

79

99% ee

O

O 31

96% ee

7:1 dr 94% ee

40. Enantioselective Construction of Arrays of Stereogenic Centers September 15, 2008

An impressive array of new catalysts for enantioselective homologation have been reported. Carlos F. Barbas III of Scripps/La Jolla has found (Angew. Chem. Int. Ed. 2007, 46, 5572) that the commercial amino acid 3 mediated the addition of dihydroxyacetone 2 to an aldehyde such as 1 to give the triol 4 with high enantio- and diastereocontrol. Takashi Ooi of Nagoya University has devised (J. Am. Chem. Soc. 2007, 129, 12392) the catalyst 6 for the anti addition (Henry reaction) of nitro alkanes such as 5 to aldehydes. Takayoshi Arai of Chiba University has developed (Organic Lett. 2007, 9, 3595) a complementary catalyst (not shown) that mediated syn addition. Jonathan A. Ellman of the University of California, Berkeley has uncovered (J. Am. Chem. Soc. 2007, 129, 15110) the catalyst 10 for the aza-Henry reaction. Yian Shi of Colorado State University has found (J. Am. Chem. Soc. 2007, 129, 11688) ligands for Pd that direct the absolute sense of the addition of 13 to dienes such as 12. OH

O

H

Ot -Bu

OH cat 3

O +

HO

1

OH O

OH

4

2

dr = 9:1 ee = 99% F3C

H2N

NO2 H O +

NO2

1

5

cat 6

OH 7

NO2 +

N

9

12

H

N N

O

CF3

CF3

OH O

cat 10 H

+

H H N N P N N H H 6

NO2

Boc N

8

dr = 4:1 F C 3 ee = 93%

CO2H 3

Boc 11

dr = 88:12 ee = 96%

N H 10

N S O H

N

Pd* cat N

13

O ee = 93%

14

Bernhard Breit of Albert-Ludwigs-Universität, Freiburg has devised conditions (Adv. Synth. Cat. 2007, 349, 1891) for the Rh-catalyzed hydroformylation of α-oleﬁns such as 15, and same-pot proline-catalyzed condensation of the linear aldehyde so produced with a branched aldehyde such as 17 to give, after reductive workup, the branched diol 18. Scott G. Nelson of the University of Pittsburgh has established (J. Am. Chem. Soc. 2007, 129, 11690) conditions, using Cinchona alkaloid derived catalysts, for the condensation of the imine surrogate 19 with the ketene precursor 20, to give the Mannich product 21. Scott E. Schaus of Boston University 80

ENANTIOSELECTIVE CONSTRUCTION OF ARRAYS OF STEREOGENIC CENTERS has developed (J. Am. Chem. Soc. 2007, 129, 15398) a complementary approach, based on catalyzed addition of isolated allyl borinates such as 23 to the activated imine 22. Kálmán J. Szabó of Stockholm University has found (J. Am. Chem. Soc. 2007, 129, 13723) that substituted allyl borinates can be prepared and reacted in situ. HO

Rh cat/CO/H2

15

16 SO2Ar

HN

SEt

dr = 19:1 ee = 97%

O / proline; H NaBH4

O +

HO

17 O

Q* cat

SEt

S

dr = 95:5 ee = >98%

N

Cl

S 19

18

20

O N

O HN

Ph H

Ph

cat 3,3'-Ph2Binol B Oi-Pr

+

dr = >99:1 ee = >98%

Oi -Pr

21

22

23

Martin Hiersemann of the Universität Dortmund has reported (Organic Lett. 2007, 9, 4979) the remarkable Cu∗-catalyzed Claisen rearrangement of the prochiral 24, leading to 25 and thus to the versatile intermediate 27. At least as remarkable is the Claisen rearrangement, mediated by the matched enantiomerically-pure base 28, of 27 to 30, developed (Angew. Chem. Int. Ed. 2007, 46, 7466) by Armen Zakarian, now at the University of California, Santa Barbara. Brian L. Pagenkopf of the University of Western Ontario has devised (Tetrahedron 2007, 63, 8774) a general route to both cyclic and acyclic alkylated stereogenic centers, by opening trisubstituted epoxides such as 30 with alkynes. O

O O

CH3O

Cu* cat

OBn

O OCH3

O

BnO 24

25

K-Selectride OCH3

de: > 90% ee: 99%

OH

BnO 26

R3SiO OPMB

OSiR3 O

OSiR3

28

N

HO2C dr = 10:1

O

AlMe3Li

OSiR3

CF3

29

OSiR3

O

BF3.OEt2

OBn

OBn

+ 30

Li

OPMB

27

N

R3SiO

OH 31

32

81

28

41. Stereocontrolled Construction of Arrays of Stereogenic Centers March 9, 2009

The Sharpless osmium-catalyzed asymmetric dihydroxylation is widely used. Lawrence Que, Jr. of the University of Minnesota designed (Angew. Chem. Int. Ed. 2008, 47, 1887) a catalyst with the inexpensive Fe that appears to be at least as effective, converting 1 to 2 in high ee. In an alternative approach, Bernd Plietker of the Universität Stuttgart used (J. Org. Chem. 2008, 73, 3218) chiral auxiliary control to direct dihydroxylation. The diastereomers of 4 were readily differentiated. OH O

Fe* cat H2O2

OH

1

97% ee

2

S O O

Bu4NIO4 3

O N

O

Ar

H

N

Ar

NO2

HO 6 OH H

5 H2N

7

Ot Bu cat CO2H

2 : 1 dr 86% ee

HO HO 8

N CH3O2C

10

OH

N S O O

HO

9:1

4

Ar NO2 CO2CH3

H

chiral Brønsted acid catalyst

9

O

cat Ru

N

H 11

N

7 : 1 dr Ar 92% ee

Deﬁned arrays of stereogenic centers can also be constructed by homologation. Armando Córdova of Stockholm University condensed (Tetrahedron Lett. 2008, 49, 803) dihydroxy acetone 6 with an in situ generated imine 5 to give the amino diol 8. In parallel work, Carlos F. Barbas III of Scripps/La Jolla described (Organic Lett. 2008, 10, 1621) a related addition to aldehydes. Magnus Rueping of University Frankfurt found (Organic Lett. 2008, 10, 1731) conditions for the addition of a nitro alkane such as 9 to the imine 10 to give 11. Keiji Maruoka of Kyoto University devised (J. Am. Chem. Soc. 2008, 130, 3728) a chiral amine that mediated the enantioselective iodination of aldehydes such as 12. Direct cyanohydrin formation delivered 13 in high de and ee. The epoxide 14 is readily prepared in high ee from crotyl alcohol. Barry M. Trost of Stanford University found (Organic Lett. 2008, 10, 1893) that 14 could be opened with 15, to give 16 with high regio- and diastereocontrol. I H O 12

SiMe3

OTMS TMSCN

CN

HO

15

NIS/cat*;

O 12 : 1dr 90% ee

HO

13

Me3Si

OH

Et2AlCl 14

16

Jérôme Blanchet of the Université de Caen Basse-Normandie optimized (Organic Lett. 2008, 10, 1029) the amine 19 as a catalyst for the condensation of ketones such as 17 with the imine 18, to give 20. Michael J. Krische of the University of Texas has explored 82

STEREOCONTROLLED CONSTRUCTION OF ARRAYS OF STEREOGENIC CENTERS (J. Am. Chem. Soc. 2008, 130, 2746) the in situ generation of chiral Rh enolates from enones such as 21, and the subsequent aldol condensation with aldehydes such as 22. O O

N

Ar

H

N

+

19

NHTf cat

O

N

Ar

O +

CO2Et

CO2Et 18

17

H

9 :1 dr > 99% ee

20

H

O

N

O

OH

O cat Rh* / H2

NPth 25 : 1 dr 92% ee

23

22

21

Ph CO2CH3 Ph

H3CO2C

+

cat Ca*

Ph

N CO2t-Bu >99 : 1 dr 99% ee 26

25

N 27

N H N

+ CO2t -Bu

24

N

O

O

O

N

Ph

O O

2. LiHMDS;

Ph OCH3

1. TiCl4*

28

3. BzCl

N N

I 29

Ph

Shu Kobayashi of the University of Tokyo found (Organic Lett. 2008, 10, 807) that the conjugate addition of 25 to 24 mediated by a chiral Ca catalyst proceeded with high enantiocontrol at both of the newly formed stereogenic centers, to give 26. In a chiral auxiliary based approach, Dennis C. Liotta found (J. Org. Chem. 2008, 73, 1264) that condensation of 27 with 28 gave predominantly just two of the possible four diastereomeric azetines. Alkylation of the cis diastereomer, followed by benzoylation and hydrolysis, then delivered the α-quaternary β-amino acid derivative 29 as a single enantiomerically-pure diastereomer. Professor Córdova showed (Adv. Synth. Cat. 2008, 350, 657) that aldehydes could be added to alkylidene malonates such as 30 to give, after reduction, the lactone 32. Dawei Ma of the Shanghai Institute of Organic Chemistry found (Angew. Chem. Int. Ed. 2008, 47, 545) that aldehydes could also be added to nitroalkenes such as 34 with high enantio- and diasterocontrol. Kathlyn A. Parker of SUNY Stony Brook took advantage (Organic Lett. 2008, 10, 1349) of the enantioselective addition of an alkenyl zinc halide 37 to an aldehyde 36 to set the relative and absolute conﬁguration of an extended array of stereogenic centers. O CO2CH3 CO2CH3

H 31 1. / cat* O 2. NaBH3CN

30

O

O

CO2CH3

H

>10 : 1 dr 95% ee

32

O2N

CO2CH3 34

NO2

H

cat* 33

35 HO

H

O

ZnBr +

1. cat*

O

2. 36

37

38

Br

39

CO2CH3

O

CH3O

1. n -BuLi HO

1. CH3I

2. CH3MgCl CuI 40

2. 9-BBN; ox

83

41

98 : 2 dr > 99% ee

42. Practical Enantioselective Construction of Arrays of Stereogenic Centers: The Jørgensen Synthesis of the Autoregulator IM-2 September 14, 2009

Armando Córdova of Stockholm University found (Angew. Chem. Int. Ed. 2008, 47, 8468) that the enantiomerically-enriched diastereomers from aminosulfenylation of 1 were readily separable by silica gel chromatography. Benjamin List of the Max-Planck-Institut, Mülheim developed (Angew. Chem. Int. Ed. 2008, 47, 8112) what appears to be a general protocol for the enantioselective epoxidation of enones such as 4. Paolo Melchiorre of the Università di Bologna devised (Angew. Chem. Int. Ed. 2008, 47, 8703) a related protocol for the enantioselective aziridination of enones. Xue-Long Hue of the Shanghai Institute of Organic Chemistry and Yun-Dong Wu of the Hong Kong University of Science and Technology optimized (J. Am. Chem. Soc. 2008, 130, 14362) a Cu catalyst for enantioselective Mannich homologation of imines such as 6. Guofu Zhong of Nanyang Technological University, Singapore established (Angew. Chem. Int. Ed. 2008, 47, 10187; Organic Lett. 2008, 10, 4585) that enantioselective α-aminoxylation of an ω-alkenyl aldehyde such as 9 could lead to deﬁned arrays of stereogenic centers.

O

SBn N O 2

O H

O

cat*

NTs Ph

CO2CH3 Ts

2. NaOH

O CO2CH3

N 8

O

Ph >95:5 dr 99% ee Ph

O

Ph 97% ee 5

4

H

N7

1. H2O2 Q* cat

Ph

N

Cu* cat 6

O

H SBn 77:23 dr 97% ee 3

1

Ph

O O

N

O Ph-N=O H 10

H O N

cat L-proline NO2 9

Ph 11

O2N

>99:1 dr 99% ee

George A. O’Doherty of West Virginia University devised (Organic Lett. 2008, 10, 3149) a protocol for the enantioselective hydration of 12 to 13. René Peters, now at the University of Stuttgart, designed (Angew. Chem. Int. Ed. 2008, 47, 5461) an Al catalyst for the enantioselective combination of an acyl bromide 15 with an aldehyde 14 to deliver the β–lactone O CO2Et 1. catOs*

OH

CO2Et

3. Pd cat HCO2H/Et3N

15 H

2. (Cl3CO)2CO 12

O

13

14

84

Br

Al* cat i Pr2NEt

O O

16

>98:2 dr 95% ee

PRACTICAL ENANTIOSELECTIVE CONSTRUCTION OF ARRAYS OF STEREOGENIC CENTERS 16. Hajime Ito and Masaya Sawamura of Hokkaido University established (J. Am. Chem. Soc. 2008, 130, 15774) that the allenyl borane from 17 added to aldehydes such as 18 with high ee. Keiji Maruoka of Kyoto University developed (Tetrahedron Lett. 2008, 49, 5369) an organocatalyst for the Mannich homologation of an aldehyde such as 20 to 21. PMP

O B B O O O

OCO2Me

O

Cu cat; O / BF3 . OEt2 H 18

17 97% ee

OH

H 20

19

N

21

CO2Et O

H

N

organocat* H

PMP CO2Et 22 >20:1dr >99% ee

>87:13 dr 96% ee

R. Karl Dieter of Clemson University showed (Organic Lett. 2008, 10, 2087) that 23, readily prepared in high ee, could be displaced sequentially with two different Grignard reagents, to give 24. Jeffrey W. Bode, now at the University of Pennsylvania, found (Organic Lett. 2008, 10, 3817) that bisulﬁte adducts such as 25 served well for the addition of unstable chloroaldehydes to 26 to give 27. Sunggak Kim of KAIST, Daejeon observed (Organic Lett. 2008, 10, 3149) that the radical addition of 29 to 28 with allylation of the intermediate radical delivered 30 with high diastereocontrol. Peter A. Jacobi of Dartmouth College prepared (Organic Lett. 2008, 10, 2837) the ester 31 by enantioselective reduction of the enone. Claisen rearrangement followed by TBAF elimination gave 32. O CO2Et

AcO

OH

CO2Et

1. n-BuMgBr/Cu

Ph 2. EtMgBr

SO3Na

95:5 dr

23 Cl

Cl

24 I

O MeO P MeO

O

O 29 Ph

28

O MeO P MeO

O

O

O CO2Et

Ph 94% ee

O 31

Ph

O

99% ee CO2Et

cat*

25

27 CN

O

Zn cat* SnBu3 30

26

MeO2C

1. LiHMDS Br 93% ee 2. TBAF CO2CH3

CO2H 10:1 dr 32 NC

Karl Anker Jørgensen of Aarhus University, Denmark used (Chem. Commun. 2008, 5827) a Chincona based catalyst to effect enantioselective addition of 33 to 34. Enantioselective reduction of the ketone 35 to the alcohol followed by conversion of the nitro group to the alcohol led to IM-2 36, an autoregulator derived from Streptomyces. O

N 33

O2N 1.

O

O

O

34 OTBS

O

O

organocat

O

2. HCl O2N

35

OH 1. Ru*cat Et3NH/HCO2H 2. NaNO2 3. BH3

O O

HO 36 IM-2

It is a measure of the progress that has been made in this area that ﬁfteen years ago, developing a route to a family of drug products that contained two adjacent ternary alkylated stereogenic centers was a signiﬁcant challenge for the process group of a major pharmaceutical company.

85

43. Enantioselective Synthesis of Lactones and Cyclic Ethers April 14, 2008

Developments in organocatalysis have turned toward the enantioselective construction of lactones. Shi-Wei Luo and Liu-Zhu Gong of the University of Science and Technology of China have found (J. Org. Chem. 2007, 71, 9905) that catalyzed addition of acetone to an α-hydroxy acid 1 proceeded with high ee. Esteriﬁcation of the addition product followed by reduction and acid work-up delivered the lactone 4 with high dr and ee. In a complementary approach, Jean-Marc Vincent and Yannick Landais of the University Bourdeaux-1 showed (Chem. Commun. 2007, 4782) that catalyzed condensation of an aldehyde with an α-hydroxy acid 5 delivered the tetronic acid 8 in high ee. It may be that 8 could also be reduced with useful selectivity. Cong-Gui Zhao of the University of Texas, San Antonio has devised conditions (Organic Lett. 2007, 9, 2745) for the condensation of the keto phosphonates such as 10 with aldehydes to give, after oxidation, the δ-lactone 12. O O CO2H 1

H N

O

1.

2

OH

O

cat 3 2. CH2N2

N H

97 : 3 dr 96% ee

4

N

O 3

3. NaBH(OAc)3 O O

H CO2H

O

6

O

cat 7

5

H N

OH

8

N H

87% ee

N 7

O O

1. H

9

10

P(O)(OEt)2

O

O

P(O)(OEt)2 89% ee

cat 11 2. PCC

12

S N H

S 11

Carbohydrates such as glucose 13 are inexpensive, molecularly-complex starting materials. Subhash Chandra Taneja of the Indian Institute of Integrative Medicine, Jammu Tawi, has found conditions (J. Org. Chem. 2007, 72, 8965) for the single-step I2-catalyzed transformation of 13 to 14, in which each of the alcohols have been differentiated. In a complementary approach described (Tetrahedron Lett. 2007, 48, 6389) by Tushar Kanti Chakraborty of the Indian Institute of Chemical Technology, Hyderabad, Ti-mediated reduction of 15 was shown to be highly diastereoselective, setting the two new stereogenic centers (marked by ∗) in 16. Building on work by Mead, Daniel Romo of Texas A&M has shown (J. Org. Chem. 2007, 72, 9053) that reductive cyclization of 18 also proceeded with high diastereocontrol, to give 19.

86

ENANTIOSELECTIVE SYNTHESIS OF LACTONES AND CYCLIC ETHERS OAc

AcO OAc

OH

H

O

HO HO

O OH

AcO

cat I2

OH

O

O O

O *

Cp2TiCl2

CO2CH3

Zn

CO2CH3 OH

*

HO

15

HO

O

14

13 D-glucose

16

O

O

O

O

H

OSiR3 CO2H

Et3SiH

H

OSiR3

BnO 17

18

O BnO

BF3.OEt2

OBn

19

As illustrated by the conversion of 20 to 21 reported (Tetrahedron Lett. 2007, 48, 7351) by Zsuzsa Juhász and László Somsák of the University of Debrecen, six-membered ring cyclic ethers can also be formed from carbohydrate precursors. Richard E. Taylor of the University of Notre Dame has taken advantage (Angew. Chem. Int. Ed. 2007, 46, 6874) of the “chemical chameleon” nature of a sulfone, using it both the stablilize the anion for intramolecular alkylation, to form 23, and as a leaving group, leading to 24. Andrew J. Phillips of the University of Colorado has oxidized (Organic Lett. 2007, 9, 5299), the enantiomerically-pure furan 25 to give, after reduction, the ring-expanded cyclic ether 26. CO2CH3

OAc O

AcO AcO

AcO 20

OCH3

Ph

O

PhSO2

22

OCH3

SiMe3 Ph

O

CO2CH3

21

LiHMDS

PhSO2

AcO

Cr-2 / EDTA H 2O

Br

OCH3 I

OAc O

AcO AcO

AlCl3

O

Ph

24

23 O 1. tBuOOH OTBS

HO

2. Et2SiH

O

H

O

OTBS

H

25

26

Spiroketals such as 28 are usual prepared under equilibrating conditions, leading to the most stable diastereromer. Yet, there are spiroketal natural products that are the less stable diastereomer, prepared under kinetic conditions. Scott D. Rychnovsky of the University of California, Irvine has found (Organic Lett. 2007, 9, 711) that the reductive cyclization of a halo nitrile 27 can kinetically establish the less-stable spiroketal 28. TIPSO

TIPSO OTBS

O O 27

CN

Cl

O 28

87

OTBS

O

LiDBB

44. Stereocontrolled C-O Ring Construction: The Fuwa/Sasaki Synthesis of Attenol A January 26, 2009

Since ﬁve-membered ring ethers often do not show good selectivity on equilibration, single diastereomers are best formed under kinetic control. Aaron Aponick of the University of Florida demonstrated (Organic Lett. 2008, 10, 669) that under gold catalysis, the allylic alcohol 1 cyclized to 2 with remarkable diastereocontrol. Six-membered rings also formed with high cis stereocontrol. Ian Cumpstey of Stockholm University showed (Chem. Commun. 2008, 1246) that with protic acid, allylic acetates such as 3 cyclized with clean inversion at the allylic center, and concomitant debenzylation. J. Stephen Clark of the University of Glasgow found (J. Org. Chem. 2008, 73, 1040) that Rh catalyzed cyclization of 5 proceeded with high selectivity for insertion into Ha, leading to the alcohol 6. Saumen Hajra of the Indian Institute of Technology, Kharagpur took advantage (J. Org. Chem. 2008, 73, 3935) of the reactivity of the aldehyde of 7, effecting selective addition of 7 to 8, to deliver, after reduction, the lactone 9. Tomislav Rovis of Colorado State University observed (J. Org. Chem. 2008, 73, 612) that 10 could be cyclized selectively to either 11 or 12. OH HO

O

Ha O

N2

5

PMBO

O

O 6

O OTIPS

O

TMSOTf

H

BnO F3CCO2H CH CN AcO 3

O OBn

BnO 4

OAc

CO2CH3 + H

1. Rh cat OTIPS 2. CH3MgCl

OPMB

BnO 3

HO

Hb

OBn

BnO

2

1 O

OAc

BnO Au cat

7

SnCl4

O

H

1. l-proline

H 2. NaBH4

OH

O O

> 24:1 dr 9 > 99% ee

8

O H

O O

11

10

O

12

Nadège Lubin-Germain, Jacques Uziel and Jacques Augé of the University of CergyPontoise devised (Organic Lett. 2008, 10, 725) conditions for the indium-mediated coupling of glycosyl ﬂuorides such as 13 with iodoalkynes such as 14 to give the axial C-glycoside 15. Katsukiyo Miura and Akira Hosomi of the University of Tsukuba employed (Chemistry Lett. 2008, 37, 270) Pt catalysis to effect in situ equilibration of the alkene 16 to the more stable regioisomer. Subsequent condensation with the aldehyde 17 led via Prins cyclization to the ether 18.

88

STEREOCONTROLLED C-O RING CONSTRUCTION OBn O

BnO BnO 13

Ph In(0)

+ F

BnO

14

16

17

18

1. (Me3Sn)2 Pdcat 2.H O / TMSOTf

O

CH3O

19

O

AgOTf

Ph

O DDQ

cat PtCl2

+ H

15

OAc

CH3O

O

OH

BnO I

O

OBn O

BnO BnO

OTMS 20

O

21

22

Paul E. Floreancig of the University of Pittsburgh showed (Angew. Chem. Int. Ed. 2008, 47, 4184) that Prins cyclization could be also be initiated by oxidation of the benzyl ether 19 to the corresponding carbocation. Chan-Mo Yu of Sungkyunkwan University developed (Organic Lett. 2008, 10, 265) a stereocontrolled route to seven-membered ring ethers, by Pd-mediated stannylation of allenes such as 21, followed by condensation with an aldehyde. George A. O’Doherty of West Virginia University devised (J. Org. Chem. 2008, 73, 1935) an alternative route toward C-glycosides, by enantioselective reduction of the furyl ketone 23 followed by oxidative rearrangement. Haruhiko Fuwa and Makato Sasaki of Tohoku University, en route to a synthesis of Attenol A, established (Organic Lett. 2008, 10, 2549) a highly-convergent route to spiro ethers such as 30, based on Pd-catalyzed coupling of enol phosphates such as 27, followed by ring-closing metathesis and acid-catalyzed cyclization.

O

O

Cbz 2. NBS HO N H

23

PhO PhO P O O O OBn

O O

H N

O

1. Noyori

O O

Cbz

O

H OH N

24

25 TBSO O

OBn Pd cat

OBn cat G2

MOMO 26

27

28

TBSO

MOMO

OBn

O

1. TBAF 2.

29

OSiR3

OMOM O

Cbz

O

BnO

O

H+

HO

OSiR3

89

30

OBn

45. Stereoselective C-O Ring Construction: The Oguri-Oikawa Synthesis of Lasalocid A April 13, 2009

O-Centered radicals have been little used for C-O ring formation. Glenn M. Sammis of the University of British Columbia showed (Organic Lett. 2008, 10, 5083) that O-centered radicals could be generated efﬁciently, and that they cyclized with high diasterecontrol. Liming Zhang of the University of Nevada, Reno, continuing his studies of Au-activation of alkynes, uncovered (J. Am. Chem. Soc. 2008, 130, 12598) the bimolecular condensation of polarized alkynes such as 3 with aldehydes and ketones, including 4, to give the dihydrofuran with high diastereocontrol. OCH3

O N

Bu3SnH O

OTBS

O

OTBS

2

O O

3

CO2Et

4

OH

BF3.OEt2 O

HO PPTS

CO2Me O

O

OH

AcO 7 CO2Me

TBSO

11:1 dr

5

CO2Me HO

OAc

6

O EtO2C

BnO BnO

O

+

AIBN

1

MeO2C

Au cat CH3O

O

O

8

OTBS 9

Margarita Brovetto of the Universidad de la República, Montevideo, Uruguay, prepared (J. Org. Chem. 2008, 73, 5776) the precursor to the enantiomercially triol 6 by fermentation of bromobenzene with Pseudomonas putida 39/D. Cyclization of 6 gave 7 with high diastereocontrol. Petri M. Pihko of the University of Jyväskylä, Finland, found (Organic Lett. 2008, 10, 4179) that cyclization of 8, prepared by Sharpless asymmetric epoxidation followed by Sharpless asymmetric dihydroxylation, also proceeded with high diastereocontrol. Vincent Aucagne of the Université d’Orléans observed (Tetrahedron Lett. 2008, 49, 4750) that brief exposure of the sulfone 10 to t-BuOK at low temperature gave clean conversion to the kinetic diastereomer 11. At room temperature, similar conditions delivered the other, more stable diastereomer. Angeles Martín and Ernesto Suárez of the C. S. I. C., PhthO O

O

O O MeO2S

O cat t -BuOK

OH

MeO

O

O OMe

MeO 11

MeO

SO2Me

90

OH SnBu3 MeO 13

O

O either one

10

O

12

AIBN

O OMe

MeO MeO

14

STEREOSELECTIVE C-O RING CONSTRUCTION La Laguna, took advantage (Tetrahedron Lett. 2008, 49, 5179) of the facile generation of O-centered radicals in converting 12 to 14, having a stereocontrolled quaternary center. The transformation is thought to be proceeding by H-atom abstraction, then diastereocontrolled trapping of the C-radical so formed with the allyl stannane 13. Much of the effort toward alkylated cyclic ether construction has been focused on alkyl group attachment adjacent to the ring oxygen. Torsten Linker of the University of Potsdam developed (J. Am. Chem. Soc. 2008, 130, 16003) a complementary approach, stereocontrolled oxidative radical addition of malonate 16 to glycals such as 15 to give the 3-alkyl substituted 17. BnO

BnO

CO2Me

O BnO

O

16

CO2Me

OMe CO2Me

BnO

CAN/MeOH BnO

BnO

CO2Me

15

17

Richard C. Hartley of the University of Glasgow established (Tetrahedron Lett. 2008, 49, 4771) what promises to be a powerful strategy for the convergent assembly of spiro ketals, based on the condensation of the Ti alkylidene derived from a thioacetal such as 19 with a lactone such as 18. James A. Marshall of the University of Virgina nicely reduced to practice (J. Org. Chem. 2008, 73, 6753) the preparation and reductive cyclization of polyepoxides such as 22. Hiroki Oguri and Hideaki Oikawa of Hokkaido University demonstrated (J. Am. Chem. Soc. 2008, 130, 12230) that overexpressed enzyme Lsd19 converted 24 to lasolacid A 26. With acid, 24 cyclized to 25. TBSO PhS O

O PhS

19

TBSO

O

O O

H+

Cp2Ti[P(OEt)3]2 18

20 O

OTBS O

Zn O

O

Br

21

OTBS

OH

O

TBAI

22

23 HO2C

OH

HO

HO H+

HO2C HO

O

O

Lsd19

O

HO

HO O O

O

HO 25

HO2C

HO

O

24

91

HO

O

O Lasalocid A 26

46. Stereocontrolled C-O Ring Construction: The Morimoto Synthesis of (+)-Omaezakianol November 9, 2009

Tobin J. Marks of Northwestern University observed (J. Am. Chem. Soc. 2009, 131, 263) high geometric control in the cyclization of 1 to 2. Tristan H. Lambert of Columbia University found (Organic Lett. 2009, 11, 1381) that Bi could catalyze both the addition of the ketene silyl acetal 4 to 3, and the subsequent cyclization of the secondary alcohol so formed, to give the product ether 5 with high diastereocontrol. Glenn M. Sammis of the University of British Columbia devised (Organic Lett. 2009, 11, 2019) a radical relay cyclization of 6 to 7, again with high diastereocontrol. Eric Fillion of the University of Waterloo established (Organic Lett. 2009, 11, 1919) that conjugate addition to the Meldrum’s acid derivative 8 proceeded with high stereoselectivity, delivering the useful chiron 10.

OH

O

La(HMDS)3 cat

1

EtO

O

H

2

OTMS 4 EtO

O O

TrO

ONPhth Bu3SnH H

6

O TrO

OH

O

O

7

O

O

O

89:11 dr

AIBN

5.9:1 dr

O 5

cat Bi(OTf)3

3

O

O 8

9

cat Sc(OTf)3

CO2Me

O

SnPh3

> 20:1 dr

HO 10

Gregory C. Fu of MIT found (Angew. Chem. Int. Ed. 2009, 48, 2225) that both ﬁve- and six-membered ring ethers could be formed with high enantiocontrol from alkyne alcohols such as 11. The catalyst was a chiral phosphine. Christian M. Rojas of Barnard College established (Organic Lett. 2009, 11, 1527) a route to 2-amino sugars such as 15, by Rh-mediated intramolecular nitrene addition in the presence of the trapping agent 14. J. S. Yadav of the Indian Institute of Chemical Technology, Hyderabad devised (Tetrahedron Lett. 2009, 50, 81) a route to C-glycosides such as 18, by condensation of a glycal 16 with an isonitrile 17. Michel R. Gagné of the University of North Carolina developed (Organic Lett. 2009, 11, 879) a complementary route to C-glycosides such as 21, with control of side chain relative conﬁguration. Note that the addition to the methacrylate 20 is likely proceeding by initial one-electron reduction, since reductive β-elimination is not observed.

cat P* HO 11

CO2Et

PhCO2H

TsO

O

14

90% ee

O 12

Rh cat PhIO

AcO 13 O

CO2Et

NH2 O

92

OH TsO

O

AcO 15 O

O N H O

STEREOCONTROLLED C-O RING CONSTRUCTION O AcO

O

NC 17 AcO

O

N

H

AcO 18

AcO cat FeCl3 16 OAc

O

BzO

CO2Me 20 BzO

Br

OBz Ni* cat BzO Zn 19 OBz

O

CO2Me

BzO OBz 5:1 dr 21 OBz

It is also possible to construct larger rings. Frank E. McDonald of Emory University devised a ﬂexible route to protected tetraols such as 22, and showed (Organic Lett. 2009, 11, 851) that it could be cyclized selectively to the septanoside 23. Kenshu Fujiwara of Hokkaido University found (Tetrahedron Lett. 2009, 50, 1236) that ring-closing metathesis of 24 delivered the eight-membered ring product 25 in near quantitative yield. HO

O

W(CO)6

HO O

CO2Me

H

DABCO O hν 22

O

O

HO O

HO

H2O

O

H

26

N

O 25

O

HO

O

O

O

24

23

O

N

O

O

O

CO2Me O

cat G2

O

H 27

O

For the synthesis of the ladder ethers, six-membered ring formation, as illustrated by the cyclization of 26 to 27, is required. Timothy F. Jamison of MIT found (J. Am. Chem. Soc. 2009, 131, 6678; Angew. Chem. Int. Ed. 2009, 48, 4430) that six-membered ring formation can best be accomplished if the cyclization is carried out in water, without catalyst. The preference for six-membered ring formation is still dominant even in cases where methyl substitution would usually direct ﬁve-membered ring formation. O CSA

O

O

O HO

H

O

H

OH

HO H

O

O

O

O

O

OH

29 (+)-Omaezakianol

28

Acid-catalyzed cyclization of polyepoxides such as 28 strongly favors ﬁve-membered ring formation. In that cyclization, the central reaction in the synthesis of (+)-omaezakianol 29 reported (Angew. Chem. Int. Ed. 2009, 48, 2538) by Yoshiki Morimoto of Osaka City University, three of the four tetrahydrofuran rings of 29 are formed in a single step, each with high stereocontrol.

93

47. Synthesis of Dysiherbaine (Hatakeyama), Jerangolid D (Markó) and (+)-Spirolaxine Me Ether (Trost) April 21, 2008

Several new developments in enantioselective C-O ring construction have been applied in the syntheses of natural products. To achieve control, the oxygenated quaternary center of dysiherbaine 9 must be established under kinetic conditions. One approach would be SN2 opening, but this would require displacement at a fully-substituted center. Susumi Hatakeyama of Nagasaki University has shown (Chem. Commun. 2007, 4158) that the epoxide 6, prepared by the Sharpless procedure, undergoes just such an opening under mild acid catalysis. O THPO

O NH2

O

K osmate

H

O

O

1. H3CO2C

RO

N

HO 4

O

Pd cat

BocNH

H3CO2C

2. TBAF

Boc H3CO2C

O

N OH PPTS O

Boc OH HCl

N Boc

R = TES

6

O

H3CO2C

O

Boc HO O

H3CO2C

R = TES N

OH

BocNH

2. TBAF

N

O BocNH HO

HO 1. SAE

OR

5

3

Boc

RO

Boc OR

I

O 2

ZnI

HO

N

OH

(cat)

1

BocNH

TESO

N

THPO

O

H OH

O H2N HO2C

O

7

N

HO2C

8

9

O Dysiherbaine

Another approach to highly-substituted tetrahydrofurans and tetrahydropyrans is to join two carbons of a preformed chiral ether, such as 18. This is the strategy that István E. Markó employed in his recent (J. Am. Chem. Soc. 2007, 129, 3516) synthesis of jerangolid D 22. The key step was the three-component coupling of 15, 16, and 17, using a protocol recently developed in his group. Again using a procedure his group had developed, the trisubstituted alkene of 21 was prepared by modiﬁed Julia coupling of the ketone 19 with the anion of sulfone 20, followed be esteriﬁcation and reduction. O CN

Et2AlCN

O

OBn 10

OBn

HO

Br

12 Zn

HO

CO2CH3 2. FeCl 3 13 OBn

11

94

O

1. TMSCl MeOH

CO2CH3

3. Swern

O H

CH3O 14

O

SYNTHESIS OF DYSIHERBAINE, JERANGOLID D AND (+)-SPIROLAXINE ME ETHER TBSO H

17

+

15

O

TBSO

16

1. BzCl

1. TBAF 2. PTSH Ph3P/DIAD

O

2. SmI2 TBSO

+ 20 SO2Ph

19

CH3O

O O

3. MCPBA 4. KHMDS/14

21

O

2. TBAF 3. Dess-Martin

18

OTBS

O

1. G1 (cat)

TMSOTf

TMSO

O

SiMe3

Jerangolid D 22

O

The spiroketal (+)-spiroxaline methyl ether 31 contains three secondary oxygenated stereogenic centers. In a showcase of current chiral technology, Barry M. Trost of Stanford University constructed (Angew. Chem. Int. Ed. 2007, 46, 7664) the ﬁrst two of the three alcohols by the enantioselective addition of an alkyne to an aldehyde. The chiral catalyst 25 that directed the alkyne additions was derived from a commercial ligand. The last alcohol center was derived from R-(+)-epoxypropane. Note that the spiroketal was not prepared in the usual way, by acid-catalyzed cyclization of a dihydroxy ketone, but by Pd-catalyzed cyclization of the alkyne diol 30.

CH3O

O

OTBS 24

H

OTBS

Ph Ph O

Zn O

N

N cat 25

CH3O

Ph Ph O

OH

CH3O

CH3O

90% ee 26

23

25

EtO CH3O

O O

O OEt

CH3O 29

HO

CH3O

O O

CH3O

OH EtO

5 : 1 dr

27 CH3O

O

H cat 25

CH3O

CH3O

OEt 28

O

O

Pd cat OH

CH3O

30

31

95

O

O O

(+)-Spirolaxine Me Ether

48. C-O Ring Containing Natural Products: Paeonilactone B (Taylor), Deoxymonate B (de la Pradilla), Sanguiin H-5 (Spring), Solandelactone A (White), Spirastrellolide A (Paterson) February 9, 2009

Richard J. K. Taylor of the University of York has developed (Angew. Chem. Int. Ed. 2008, 47, 1935) the diasteroselective intramolecular Michael cyclization of phosphonates such as 2. Quenching of the cyclized product with paraformaldehyde delivered (+)-Paeonilactone B 3. O O

O

OH OH

t -BuOK; (H2CO)n

1 OSiR3

EtO EtO P

O O

O

O O

2

3

(+)-Paeonilactone B

Roberto Fernández de la Pradilla of the CSIC, Madrid established (Tetrahedron Lett. 2008, 49, 4167) the diastereoselective intramolecular hetero Michael addition of alcohols to enantiomerically-pure acyclic sulfoxides such as 4 to give the allylic sulfoxide 5. Mislow-Evans rearrangement converted 5 into 6, the enantiomerically-pure core of Ethyl Deoxymonate B 7. O S

O S

Ph LDA

HO

HO Ph

HO DABCO

O OSiR3 4

OH OH

O 5

OSiR3

6

HO OSiR3

7

O

Ethyl Deoxymonate B

CO2Et

The ellagitannins, represented by 10, are single atropisomers around the biphenyl linkage. David R. Spring of the University of Cambridge found (Organic Lett. 2008, 10, 2593) that the chiral constraint of the carbohydrate backbone of 9 directed the absolute sense of the oxidative coupling of the mixed cuprate derived from 9, leading to Sanguiin H-5 10 with high diastereomeric control.

96

C-O RING CONTAINING NATURAL PRODUCTS BnO O

O Ph O O O

OBn

O

O Ph O O O

O

O O

Zn*;

CuBr.Me2S; OBn ox BnO OBn BnO

Br Br BnO OBn BnO

BnO

BnO

OBn O

O

O

O HO O

HO

OBn

HO

9

OH OH

O

HO

OBn

BnO OBn

8

OBn

O O

O

HO

OBn

O

O

HO OH OH 10 Sanguiin H-5

O

OH

A key challenge in the synthesis of the solandelactones, exempliﬁed by 14, is the stereocontrolled construction of the unsaturated eight-membered ring lactone. James D. White of Oregon State University found (J. Org. Chem. 2008, 73, 4139) an elegant solution to this problem, by exposure of the cyclic carbonate 11 to the Petasis reagent, to give 12. Subsequent Claisen rearrangement delivered the eight-membered ring lactone, at the same time installing the ring alkene of Solandelactone E 14. HO

O

O

O HO

O X

O

O

R3SiO Cp2TiMe2

R3SiO

11, X = O 12, X = CH2

13

14 Solandelactone E

AD-mix usually proceeds with only modest enantiocontrol with terminal alkenes. None the less, Ian Paterson, also of the University of Cambridge, observed (Angew. Chem. Int. Ed. 2008, 47, 3016, Angew. Chem. Int. Ed. 2008, 47, 3021) that bis-dihydroxylation of the diene 17 proceeded to give, after acid-mediated cyclization, the bis-spiro ketal core 18 of Spirastrellolide A Methyl Ester 19 with high diastereocontrol. O

O

BnO O

HO

15 O

+

O

Cl

CH3O

OCH3

O O

O

O CH3O

OH

18 OH AD-mix O

O

HO

Cl

HO O O

CH3O OBn 17

O

O

Cl

H

OBn 16

OCH3 O

O

Cl

HO

OH OCH3

19 Spirastrellolide A Me Ester

97

49. C-O Ring Natural Products: (-)-Serotobenine (Fukuyama-Kan), (-)-Aureonitol (Cox), Salmochelin SX (Gagné), Botcinin F (Shiina), (-)-Saliniketal B (Paterson), Haterumalide NA (Borhan) April 20, 2009

Tohru Fukuyama of the University of Tokyo and Toshiyuki Kan of the University of Shizuoka devised (J. Am. Chem. Soc. 2008, 130, 16854) the chiral auxiliary-directed Rh-mediated cyclization of 1, setting the two stereogenic centers of 2 with high stereocontrol. The ester 2 was carried on to the indole alkaloid (-)-Serotobenine 3.

N2

HO

Ph

O

N

O

O

O

OCH3

Ar Rh* cat

H N

O

CO2R*

O O

N Ts

N

1

BnO

OCH3

2

Ts

93% de

N H (-)-Serotobenine 3

In the course of a synthesis of (-)-Aureonitol 6, Liam R. Cox of the University of Birmingham developed (J. Org. Chem. 2008, 73, 7616) the diastereoselective intramolecular addition of an allyl silane 4 to give the tetrahydrofuran 5. In analogy to what is known about the intramolecular ene reaction, the diastereocontrol observed for this cyclization may depend on the allyl silane being Z. SiMe3 MeSO3H

O H TPDPSO

O 4

O OH

O OH

TPDPSO 5

6 (-)-Aureonitol

Michel R. Gagné of the University of North Carolina found (J. Am. Chem. Soc. 2008, 130, 12177) that the Ni-catalyzed coupling of organozinc halides could be extended to glycosyl halides such as 7. This opened ready access to C-alkyl and C-aryl glycosides, including Salmochelin SX 10.

98

C-O RING NATURAL PRODUCTS OH O

AcO

Br

OBn Ni cat

+ OAc

AcO

OH

OBn

7

HO

O

O

IZn .LiCl

OAc

O OH H

HO OBn

OH

8

N O

OH OH

9 Salmochelin SX

Isamu Shiina of the Tokyo University of Science established (Organic Lett. 2008, 10, 3153) that the acid-mediated cyclization of the Sharpless-derived epoxide 10 proceeded with clean inversion, to give 11. The highly-substituted tetrahydropyran core 11 was then elaborated to the antifungal Botcinin F 12. OH

HO

PPTS

O

O

OPMB

PMBO

O

O O

O

O 10

OH

H

HO

11

12 Botcinin F

Ian Paterson of Cambridge University optimized (Organic Lett. 2008, 10, 3295) the Pd-catalyzed spirocyclization of the ene diol 13, leading to 14, the enantiomerically-pure bicyclic core of (-)-Saliniketal B 15. OH OH OBn

HO

cat PdCl2

O O

CuCl2 / O2 13

O O

OBn

O

HO 14

NH2

15 (-)-Saliniketal B

OH

Haterumalide NA 18 presented the particular challenge of assembling the geometricallydeﬁned chloroalkene, in addition to closing the macrolide ring. Babak Borhan of Michigan State University addressed (J. Am. Chem. Soc. 2008, 130, 12228) both of these challenges together, electing to employ a chlorovinylidene chromium carbenoid, as developed by Falck and Mioskowski, to effect the macrocyclization of 16 to 17. OTr

O O

H Cl3C

TBSO

OTr

HO

O

CrCl2 Cl

TBSO

O 16

HO

O

O

OH

Cl O O

17

99

AcO

O

O

O 18 Haterumalide NA

50. Complex Cyclic Ethers: (+)-Conocarpan (Hashimoto), (-)-Brevisamide (Satake/ Tachibana), (+)-Bruguierol A (Fañanás/ Rodríguez), (-)-Berkelic Acid (Snider), and (-)-Aigialomycin D (Harvey) November 16, 2009

(+)-Conocarpan 3, isolated from the wood of Conocarpus erectus, exhibits insecticidal, antifungal and antitrypanosomal activity. Shunichi Hashimoto of Hokkaido University developed (J. Org. Chem. 2009, 74, 4418) a chiral Rh (II) carboxylate that effected the cyclization of 1 to 2, setting the absolute conﬁguration of 3. Br

CO2CH3 Br

N2

CO2CH3 Rh* cat

97:3 dr 84% ee OTIPS

O 2

O 1

3

O OH

(+)-Conocarpan

OTIPS

The dinoﬂagellate Karenia brevis produces the brevetoxins, a family of complex polyethers. Recently, the ﬁrst N-containing cyclic ether, (-)-Brevisamide 6, was isolated from K. brevis. Masayuki Satake and Kazuo Tachibana of the University of Tokyo, in their synthesis of 6 (Organic Lett. 2009, 11, 217) found it convenient to set the relative conﬁguration around the six-membered ring by double hydroboration/oxidation of the diene 4. OH OH

thexylborane;

R3SiO

H 4

O

H2O2 / NaOH R3SiO

H

O

OH

H

5

H

H O

O

H N H

6 (-)-Brevisamide

O

(+)-Bruguierol A 9, isolated from the mangrove Bruguiera gymmorrhiza, has an unusual bridged structure. Francisco J. Fañanás and Félix Rodríguez of the Universidad de Oviedo conceived (J. Org. Chem. 2009, 74, 932) an elegant approach to the construction of 9, based on the Pt-mediated addition of the alcohol of 7 to the alkyne to give a transient enol ether. It is not clear whether the subsequent intramolecular electrophilic addition to the aromatic ring is mediated by the Pt, or by a trace of adventitious acid. The overall transformation was remarkably efﬁcient.

100

COMPLEX CYCLIC ETHERS OH

OSIR3 H

OSIR3

cat PtCl4

OH

TBAF H

O

7

O

H 8

9 (+)-Bruguierol A

The Berkeley Pit in Butte, Montana, is an abandoned open-pit copper mine ﬁlled with 30 billion gallons of pH = 2.5 water heavily contaminated with, inter alia, copper, cadmium, arsenic and zinc. Remarkably, microorganisms can be cultured from that water. (-)-Berkelic Acid 13, isolated from a Penicillium fungus, showed selective activity against OVCAR-3 ovarian cancer. Barry B. Snider of Brandeis University set (Angew. Chem. Int. Ed. 2009, 48, 1283) the absolute conﬁguration of the central ﬁve-membered ring ether of 13 by conjugate addition of the enantiomerically-pure reagent 11 to the prochiral lactone 10. MeO2C

O H

O +

O 10

O

O

N O P N 11 H

12

O

O

H N P O N H

CO2H OH

O 13 (-)-Berkelic Acid

(-)-Aigialomycin D 17, isolated from the mangrove fungus Aigialus parvus, was found to be a selective inhibitor of the kinases CDK1, CDK5 and GSK3. The synthesis of 17 reported (J. Org. Chem. 2009, 74, 2271) by Joanne Harvey of Victoria University of Wellington illustrated the power of the Ramberg-Bäcklund reaction for the closure of medium rings. Three-component coupling allowed the facile assembly of the sulfone 14. Ring-closing metathesis gave 15, that on oxidative SO2 extrusion followed by deprotection gave (-)-Aigialomycin D 17. MOMO

O

MOMO O

MOMO

MOMO O

MOMO

O S O

O

O 15

HO

O

CCl4 KOH

O

cat G2

O S O 14

O

HCl

O

MeOH/H2O

MOMO 16

O O

101

O

O O

HO OH 17 OH (-)-Aigialomycin D

51. New Methods for the Stereoselective Construction of N-Containing Rings April 28, 2008

Several methods have been reported for the stereocontrolled preparation of pyrrolidine and piperidine derivatives. Alison J. Frontier of the University of Rochester has observed (Organic Lett. 2007, 9, 4939) that hydrogenation of acyl pyrroles such as 1 gave good control not just around the ring, but also on the sidechain. Chi-Ming Che of the University of Hong Kong has devised (J. Am. Chem. Soc. 2007, 129, 5828) a catalyst that converted amides such as 3 into the cyclized product 4, also with high diastereocontrol. Jean Ollivier of the Université de Paris-Sud, following the Sato procedure, has applied (Tetrahedron Lett. 2007, 48, 8765) the Kulinkovich reaction to allylated amino acid esters such as 5, to give, after Fe-mediated fragmentation, the enantiomerically-pure piperidone 7. Richard C. Hartley of the University of Glasgow has reported (J. Org. Chem. 2007, 72, 10287) what are, remarkably, the ﬁrst examples of the aza-Petasis-Ferrier reaction, converting an ester such as 9, by carbonyl methylenation followed by Mannich cyclization, into the piperidone 10. CH3O

CH3O CO2Et N

H2

CO2Et

Rh cat

N

O 2

1 O

O N H

Bn

O

Au cat

3

H3CO2CH2

4

HO Ti(OiPr)4

5

N

Bn

H3CO2C H

O

Bn N

FeCl3 O

6

7

OCH3

O 11 NH .HCl 2

O

Ar

CH3O

N Bn

MgBr

Bn

N

H OH

1. Cp2Ti(CH3)2 N

8

9

O

2. Al(iBu)3 Ar 10

N H

Procedures for catalytic enantioselective C-N ring construction have also been developed. Armando Córdova of Stockholm University has shown (Tetrahedron Lett. 2007, 48, 8695) that condensation of 11 with 12 led to 14, which on reduction and hydrolysis delivered the 3-aryl proline 15. In an even simpler case, Santos Fustero of the Universidad de Valencia found (Organic Lett. 2007, 9, 5283) that the aldehyde 16 could cyclize to 17 with 102

NEW METHODS FOR THE STEREOSELECTIVE CONSTRUCTION OF N-CONTAINING RINGS high ee. In a different approach (J. Am. Chem. Soc. 2007, 129, 14811), William E. Greenberg and Chi-Huey Wong of Scripps/La Jolla harnessed the power of an enzyme to mediate the addition of 19 to 18, leading to the pyrrolidine 21. Daniel P. Furkert of the University of Bath has applied (Organic Lett. 2007, 9, 3769) the powerful Itsuno-Corey reduction to the piperidone 22, leading, after SN2’ displacement, to the alkene 23. EtO2C EtO2C

O Ph

H

O

Ph

N 12 H

HO

cat 13b

11

CO2H

N

2. hydrolysis O 97% ee

15

13a Ar = Ph

H cat 13b 17

16

N Boc

O H +

CF3 HO

O

cat Pd(OH)2

OH 19 Br

OH

H2

N3

HO

13b, Ar =

93% ee

HO

FSA

18

Ph OTMS Ph

CF3

O

O

N H

O

O

H

N3

1. Et3SiH

N CO Et 2 14

Boc N H

Ph

CO2Et

N 21 Boc

20 Br 1. Itsuno-Corey

O

2. (EtO)2P(O)Cl

N SO2t Bu

91% ee

N

3. CH3MgBr/Cu

SO2t Bu 23

22

To construct larger rings, Barry M. Trost of Stanford University has employed (Angew. Chem. Int. Ed. 2007, 46, 6123) his powerful Pd catalyst to effect opening of the racemic aziridine 24, leading, after metathesis, to the amine 27. Huw M. L. Davies of the University at Buffalo used the Rh catalyst he has devised (J. Am. Chem. Soc. 2007, 129, 10312) to mediate the addition of 29 to the pyrrole 28, giving the bicyclic 30 in high ee. H Cbz N racemic

H

N

N

25

Pd* cat

H Cbz

N

Cbz 26

24 CH3O2C

27

OTBS

Boc CO2CH3

N2 29

Boc

N

88% ee

Cbz

N N

N

G2

OTBS

Rh* cat 30

28

103

96% ee

Cbz

Cbz

52. Stereoselective C-N Ring Construction November 17, 2008

Ryoichi Kuwano of Kyushu University showed (J. Am. Chem. Soc. 2008, 130, 808) that diastereomerically and enantiomerically pure pyrollidines such as 2 could be prepared by hydrogenation of the corresponding pyrrole. Victor S. Martín of Universidad de la Laguna found (Organic Lett. 2008, 10, 2349) that the stereochemical outcome of the pyrrolidineforming Nicholas cyclization could be directed by the protecting group on the N. Jianbo Wang of Peking University established (J. Org. Chem. 2008, 73, 1971) a convenient route to diazo esters such as 6. N-H insertion led to the pyrrolidine, which Zhen-Jiang Xu of the Shanghai Institute of Organic Chemistry and Chi-Ming Che of the University of Hong Kong showed (Organic Lett. 2008, 10, 1529) could be reduced with high diastereoselectivity to the hydroxy ester 7. Alternatively, Professor Wang found that photochemical Wolff rearrangement of 6 delivered the pyrrolidone 8. Martin J. Slater and Shiping Xie of GlaxoSmithKline optimized (J. Org. Chem. 2008, 73, 3094) the hydroquinine catalyzed enantioselective 3+2 cycloaddition of 9 and 10, leading to the pyrrolidine 11 with high diastereocontrol. H2 CO2CH3

N

CO2CH3 N 96% ee 2 Boc X N Boc BF .OEt 3 2 CO2CH3 HO X = Ts Me Si 3 SiMe3 Co2(CO)8 3 Ru* cat

1 Boc BF3.OEt2 Me3Si 4

N Bz

CO2CH3 X = Bz 10:1 trans

N Ts 5

O

OH Ru cat; CO2CH3 N Boc 7

NaBH4

R'

> 99: 1 cis

CO2Allyl

Boc N H

CO2CH3

CO2R N2 R = CH3 6 R = Allyl

hν N

O

Boc 8 CO2tBu

t -BuO2C

N +

N 9

S

CO2t Bu Q* cat 10

t -BuO2C

N N S H 11

84% ee

Shu Kobayashi of the University of Tokyo developed (Adv. Synth. Cat. 2008, 350, 647) a practical protocol for the aza Diels-Alder construction of enantiomerically-pure piperidines such as 14. Biao Yu of the Shanghai Institute of Organic Chemistry cyclized (Tetrahedron Lett. 2008, 49, 672) the product from the proline-catalyzed enantioselective aldol of 15 and 16, leading to the substituted piperidine 17. Michael Shipman of the University of Warwick described (Tetrahedron Lett. 2008, 49, 250) the cyclization of the aziridine derived from 18, that proceeded to give 19 as a single diastereomer, apparently via kinetic side-chain protonation.

104

STEREOSELECTIVE C-N RING CONSTRUCTION HO Ot -Bu Nb* cat

N

+

N

OH

Me3SiO 12 O H N Cbz

H

H N

13

H

cat proline

H

HO BnO

CO2Bn

OTBS OBn

15

18

N 16

Ph3P

HO

H3CO2C

14

O +

92% ee

O

H3CO2C

N3

17

Cbz H3CO2C

N N

Cbz

H

N

H

19

H

N Cbz

SPh 20

Takeo Kawabata of Kyoto University found (J. Am. Chem. Soc. 2008, 130, 4153) that intramolecular alkylation to form four, ﬁve and six-membered rings from amino esters such as 21 proceeded with remarkable enantioretention.

CO2Et Boc

KOH DMSO

Br

N

EtO2C

21

N Boc

22

Géraldine Masson and Jieping Zhu of CNRS, Gif-sur-Yvette, condensed (Organic Lett. 2008, 10, 1509) cinnamaldehyde 23 with cyanide and an ω-alkenyl amine to give the intramolecular aza-Diels-Alder substrate 24. Hongbin Zhai of the Shanghai Institute of Organic Chemistry acylated (J. Org. Chem. 2008, 73, 3589) 26 with 27, leading to the ring-closing metathesis precursor 28. Tomislav Rovis of Colorado State University developed (Organic Lett. 2008, 10, 1231) the Rh-catalyzed condensation of the isocyanate 30 with alkyl alkynes to give 31, and with aryl alkynes to give 32. CN

CN

23 O

O

N

MW

N

H

25 H

24

N(i-Pr)2 G2 cat

+ O N

CO2CH3 N Boc 27

26

N

O N

R

H

O

95% ee

N Ts

N

28

29

Ar C

Ar

N

Rh* cat

Rh* cat 31

Ts N

R 30

105

H

N O 32

94% ee

53. New Methods for C-N Ring Construction April 27, 2009

Chaozhong Li of the Shanghai Institute of Organic Chemistry demonstrated (Organic Lett. 2008, 10, 4037) facile and selective Cu-catalyzed β-lactam formation, converting 1 to 2. Paul Helquist of the University of Notre Dame devised (Organic Lett. 2008, 10, 3903) an effective catalyst for intramolecular alkyne hydroamination, converting 3 into the imine 4. Six-membered ring construction worked well also. Br

H

Ph N

Ph

N

Cu cat

Ag cat

O

O

H2 N

K2CO3 1

2

Br

N 4

3

Br

Jon T. Njardarson of Cornell University found (Organic Lett. 2008, 10, 5023) a Cu catalyst for the rearrangement of alkenyl aziridines such as 5 to the pyrroline 6. Philippe Karoyan of the UPMC, Paris developed (J. Org. Chem. 2008, 73, 6706) an interesting chiral auxiliary directed cascade process, converting the simple precursor 7 into the complex pyrrolidine 9. Sherry R. Chemler of the State University of New York, Buffalo devised (J. Am. Chem. Soc. 2008, 130, 17638) a chiral Cu catalyst for the cyclization of 10, to give 12 with substantial enantiocontrol. Wei Wang of the University of New Mexico demonstrated (Chem. Commun. 2008, 5636) the organocatalyzed condensation of 13 and 14 to give 16 with high enantio- and diastereocontrol. Boc N

I CO2CH3 Cu cat N Ts 5

6

N Ts

CO2CH3

N Ph

CO2Bn

LDA; ZnBr2;

Ts

Ph Ph Ph OTMS

H +

N Ts 82% ee

N O 11

O

Cu* cat 10 12

N

CH3O Ts 13

H N

CO2Bn

N

7 O

N H

N 8 Boc

CO2Et

O

N H 15 cat

14

9

CO2Et H N

Ts 16 30:1 dr H3CO 99% ee

Two complementary routes to azepines/azepinones have appeared. F. Dean Toste of the University of California, Berkeley showed (J. Am. Chem. Soc. 2008, 130, 9244) that a gold complex catalyzed the condensation of 17 and 18 to give 19. Frederick G. West of the University of Alberta found (Organic Lett. 2008, 10, 3985) that lactams such as 20 could be ring-expanded by the addition of the propiolate anion 21. 106

NEW METHODS FOR C-N RING CONSTRUCTION Ar N

Ar N

OBz Au cat

+ 17

CO2t-Bu OBz

H 18

N Ts

19

O

21

1.

O

N CO2t-Bu Ts 22

2. Py.HOAc

20

Takeo Kawabata of Kyoto University extended (Organic Lett. 2008, 10, 3883) “memory of chirality” studies to the cyclization of 23, demonstrating that 24 was formed in high ee. Paul V. Murphy of University College Dublin took advantage (Organic Lett. 2008, 10, 3777) of the well-known intramolecular addition of azides to alkenes, showing that the intermediate could be intercepted with nucleophiles such as thiophenol, to give the cyclized product 26 with high diastereocontrol. Ryo Shintani and Tamio Hayashi, also of Kyoto University, found (J. Am. Chem. Soc. 2008, 130, 16174) that a chiral Pd catalyst effected condensation of racemic 27 with an aryl isocyanate to give, via decarboxylation, the lactam 28 in high ee. Ying-Chun Chen of Sichuan University optimized (Angew. Chem. Int. Ed. 2008, 47, 9971) the organocatalyst-mediated condensation of 29 with 30 to give 31 with high enantio- and diastereocontrol.

CO2Et CsOH

t-BuO Boc

N

CO2Et

I

Boc

23

N

N

Ar-NCO O

Pd* cat

Ar

Ph

t-BuO2C 28

O O

93% ee

EtO2C

SPh

PhSH

N

BnO

25

O

27

; N3

94% ee BnO 24

O t-BuO2C

O O

t-BuO

26

Ts N +

O H

29

30

cat 15

Ph

31

H

Ts N

OH

CO2Et

99% ee

Guillaume Bélanger of the Université de Sherbrooke devised (Organic Lett. 2008, 10, 4939) an elegant cascade dipole formation and cycloaddition, converting 32 into 33 as a single diastereromer. CO2Et O O

O

H

2. DIPEA N

EtO2C

1. Tf2O/ DTBMP OCH3

N

O O

32

107

33

OCH3

54. Stereocontrolled Construction of C-N Rings: The Vanderwal Synthesis of Norﬂuorocurarine November 23, 2009

Forrest E. Michael of the University of Washington described (Organic Lett. 2009, 11, 1147) the Pd-catalyzed aminative cyclization of 1 to the differentially-protected diamine 3. Peter Somfai of KTH Chemical Science and Engineering observed (Organic Lett. 2009, 11, 919) that [1,2]-rearrangement of 4 proceeded to deliver 5 with near-perfect maintenance of enantiomeric excess. Tushar Kanti Chakraborty of the Central Drug Research Institute, Lucknow applied (Tetrahedron Lett. 2009, 50, 3306) the Ti(III) reduction of epoxides to the Sharpless-derived ether 6, leading to the pyrrolidine 7. Chun-Jiang Wang of Wuhan University devised (Chem. Commun. 2009, 2905) a silver catalyst that directed the absolute sense of the dipolar addition of 9 to 8 to give 10. Br O

F Ph N N PhO2S 2 SO2Ph H Pd cat 3

1 Ts N

Ph N

N N

O SO2Ph N SO2Ph

O

4

BBr3; Et3N

CO2CH3 Cp2TiCl OSiR3

6

N H

N

7

CO2CH3

N O

OSiR3 OH 4:1 dr

O

N Ph 8

9

Ag* cat 10

O

> 95% ee

O H N

CO2CH3

Ts O

N 5

Br

N Ph

CO2CH3 O 92% ee

Homoallyic azides such as 11 are readily prepared in high enantiomeric excess from the corresponding alcohol. Bernhard Breit of Albert-Ludwigs-Universität, Freiburg and André Mann of the Faculté de Pharmacie, Illkirch showed (Organic Lett. 2009, 11, 261) that Rh-mediated hydroformylation could be effected in the presence of the azide. Subsequent reduction delivered the piperidine 12. Jan-E. Bäckvall of Stockholm University applied (J. Org. Chem. 2009, 74, 1988) the protocol for dynamic kinetic asymmetric transformation (DYKAT) that he had developed to the cyanodiol 13. Remarkably, a single enantiomerically-pure diasteromer emerged, which he carried on to 14. Xiaodong Shi of West Virginia University found (Organic Lett. 2009, 11, 2333) that the stereogenic center of 17, even though it ended up outside the ring, directed the absolute conﬁguration of the other centers of 18 as they formed. Jan Vesely of Charles University and Albert Moyano and Ramon Rios of the Universitat de Barcelona established (Tetrahedron Lett. 2009, 50, 1943) that an organocatayst directed the absolute conﬁguration in the addition of 19 to 20 to give 21. TBSO Ph

N3 11

1. Rhcat CO/H2

OH

TBSO

2. Pdcat/H2; Ph CH2=O/MeOH

OH

N 12

13

108

DYKAT CN

N 14 Ts

C11H13

STEREOCONTROLLED CONSTRUCTION OF C-N RINGS

NO2 +

O Ph

17

Ph 15

O2N CO2CH3

CH3OH rt

16

O

HO

NH2

O

EtO

18

O

H

Ar H organocat

+

dr = 6:1

N

H3CO2C

N

Bn

Br

19

HO 21

20

CO2Et 94% ee O

N Bn

Osamu Tamura of Showa Pharmaceutical University effected (Organic Lett. 2009, 11, 1179) cyclization of the malic acid-derived amide 22 to give 23 with high diastereocontrol. Horst Kunz of Johannes Gutenberg-Universität Mainz demonstrated (Angew. Chem. Int. Ed. 2009, 48, 2228) that the galactosylamine-derived auxiliary of 24 directed conjugate addition ﬁrst to prepare 24, then again in the conversion of 24 to 26. Keiji Maruoka of Kyoto University used (Organic Lett. 2009, 11, 2027) an organocatalyst-directed conjugate addition to prepare 27, that he then carried on to 28. Hiroyuki Ishibashi of Kanazawa University established (J. Org. Chem. 2009, 74, 2624) conditions for the cascade cyclization of 29 to 30. AcO O EtO

AcO H N

O

TfOH

O

N

O

Me2S

H

MgBr

O

PivO OPiv O N PivO OPiv

25

O

OTIPS

N O

O

22

23

24

26

Ph H3CO

O

CO2R Hantzsch ester O N O Ph TFA Ph 27

Ph O

N 28

N Bn

90% ee 29 I

CO2R

O

H3CO N Bn H

Pd cat i-Pr2NEt

30 CH3O

CH3O

SiMe3

N N

N

SiMe3

t-BuOK N H

31

O H

N N 32 H

H

O

33 H H O Norfluorocurarine

Diels-Alder cyclization of a triene such as 31 would offer rapid access to polycyclic indole alkaloids. Christopher D. Vanderwal of the University of California, Irvine developed (J. Am. Chem. Soc. 2009, 131, 3472) alkaline conditions for this powerful transformation. He then carried 32 on to the Strychnos alkaloid Norﬂuorocurarine 33.

109

55. Alkaloid Synthesis: Paliurine F, Lepadiformine, and 7-Deoxypancratistatin January 14, 2008

The sedative alkaloid paliurine F 7 is a pentapeptide bridged by an arene. Gwilherm Evano of the Université de Versailles took advantage of this in his synthesis (Angew. Chem. Int. Ed. 2007, 46, 572) of 7, although it was necessary to prepare, from serine, one of the amino acid derivatives, the protected 3-hydroxyprolinol 2. The key step in the synthesis was the Cu-catalyzed intramolecular coupling of 5 to give the macrolactam 6. Deprotection and acylation then gave paliurine F 7. CH3O

OH

OH

O Boc

+ H

OTBS

N

N

Boc

OCH3

O

OTBS

TBSO

Boc 1

N

H

I

2

I

4

3

OCH3 Boc

OCH3

N

H

N

O O

O O N

O O N Boc H 6

5

N

N H

N

I

NH2

O

O

OCH3

O

H

N

N H

H

O O

7 N

Pauliurine F

Lepadiformine 14, isolated from the tunicate Clavelina lepadiformis, shows moderate cytotoxicity, and is also a K+ channel blocker. The synthesis of 14 (Angew. Chem. Int. Ed. 2007, 46, 2631) by Donald Craig of Imperial College started with the aziridine 8, prepared from the corresponding epoxide. Opening of the protected aziridine with the anion of methyl phenyl sulfone set the stage for condensation of the dianion derived from 9 with the aldehyde 10, to give, with high diastereocontrol, the amine 11. Deprotection followed by cyclization then led to the activated ether 12. While the opening of 12 with an alkyl Grignard reagent proceeded with undesired inversion at the reacting center, opening with the alkynyl Grignard delivered mainly the desired 13. Reduction followed by oxidation, epimerization and reduction then gave lepadiformine 14. N

SES

H PhSO2

N

SES

BnO O BnO

O

O O

PhSO2 10

N

O

O 8

H

9

110

O

11

H

ALKALOID SYNTHESIS SO2Ph

HO

SO2Ph

HO

O N

N

12

N

13

14 Lepadiformine

The Amaryllidaceae alkaloid 7-deoxypancratistatin 21 has potent antiviral activity. A challenge in the assembly of 21 is that the ring fusion is trans, less stable than the corresponding cis diastereomer. The synthesis of 21 (J. Org. Chem. 2007, 72, 2570) by Albert Padwa of Emory University started with 17, the preparation of which by the combination 15 and 16 he had previously reported in the course of his synthesis of lycoricidine (OHL December 11, 2006). Ester 17 had the desired trans ring fusion, but with an angular ester substituent that had to be removed. HO O

I

O

Bu3Sn

CO2CH3 16

N

O O

PMB

Pd cat

15

H3CO2C O

N

O 19

O

O

PMB

O

O

PMB

18

O O S O O

O

O N

O

O O

O

O N 17

O

O

O

BnO

Rh cat

BnO H

O

N 20

O

PMB

O

OH OH

HO

O O

O

PMB

O

OH N 21

H

O

7-Deoxypancratistatin

While it would be expected from the mechanism that Rh-mediated decarbonylation of an aldehyde would proceed with retention of absolute conﬁguration, and this had been conﬁrmed experimentally, this reaction had not been applied to such a challenging substrate. In the event, the transformation proceeded smoothly, to give the desired trans 19. Dehydration and dihydroxylation of 19 led to the cyclic sulfate 20, selective SN2 opening of which delivered 7-deoxypancratistatin 21. The decarbonylation of 18 was reported on a 2.1 mmol scale, using 3.2 mmol of Wilkinson’s catalyst, (Ph3P)3RhCl. For larger scale reactions, it will be important to make this transformation truly catalytic. It has been reported (J. Am. Chem. Soc. 1978, 100, 7083; J. Org. Chem. 1984, 49, 3195) that inclusion of a bridging ligand such as 1,3-bis-diphenylphosphinopropane (dppp) in the decarbonylation can lead to turnover numbers in excess of 100,000.

111

56. Adventures in Alkaloid Synthesis: (+)-α-Kainic Acid (Jung), 223AB (Ma), Pumiliotoxin 251F (Jamison), Spirotryprostatin B (Trost), (-)-Drupacine (Stoltz) May 12, 2008

Enantiomerically-pure natural amino acids can serve as starting materials for alkaloid synthesis. In his synthesis (J. Org. Chem. 2007, 72, 10114) of (-)-α-kainic acid 3, Kyung Woon Jung of the University of Southern California prepared the diazo sulfone 1 from (L)-glutamic acid. Rh-mediated intramolecular C-H insertion proceeded with the predicted high diastereoselectivity, to give the lactam 2, containing seven of the ten carbon atoms and two of the three stereogenic centers of (-)-α-kainic acid 3. O PhSO2

O N

N2

O Rh cat

1

R3SiO

N

PhSO2

NH O

O O 3 OH (-)-α-Kainic Acid

2

R3SiO

OH

The absolute conﬁguration of the nitrogen ring system(s) can also be established by chiral catalysis. Dawei Ma of the Shanghai Institute of Organic Chemistry has developed (J. Am. Chem. Soc. 2007, 129, 9300) a chiral Cu catalyst that mediated the addition of alkynyl esters and ketones to the prochiral acylated pyridine 4 in high enantiomeric excess. The dihydropyridines (e.g. 5) so produced will be versatile starting materials both for alkaloid synthesis, as illustrated by the preparation of the Dendrobatid alkaloid 223AB 6, and for the production of pharmaceuticals. cat Cu* N CO2CH3 4

N CO2CH3 CO2n -Pr 91% ee 5

N 6

Alkaloid 223AB

In his synthesis of the Dentrobatid alkaloid pumiliotoxin 251D 9, Timothy F. Jamison took (J. Org. Chem. 2007, 72, 7451) as his starting material another amino acid, proline. Ni-mediated cyclization of the epoxide 8 proceeded with high geometric and regiocontrol, to give 9. The chemistry to convert 7 into 8 with high diastereocontrol and without racemization is a substantial contribution that will have many other applications. Alloc N H3CO2C

7

cat Ni

N O

N Pumiliotoxin 251D

8

112

HO

9

ADVENTURES IN ALKALOID SYNTHESIS In his synthesis (Organic Lett. 2007, 9, 2763) of spirotryprostatin B 12, Barry M. Trost of Stanford University also started with proline, which was readily elaborated to the oxindole 10. The question was, could the Pd-catalyzed decarboxylation of 10 be induced to provide speciﬁcally 11? Counting geometric isomers of the trisubstituted alkene, and allylic regioisomers, as well as diastereomers, there were sixteen possible products from this prenylation. Using chiral Pd control, the rearrangement proceeded with 14:1 regiocontrol, and 16:1 diasterocontrol. Oxidative cyclization of 11 then delivered spirotryprostatin B 12.

O H N

OO

O

O cat Pd* H N

N H

H N

O

N

N

N

H

O

O N

N

O

O

O 10

11

12 Spirotryprostatin B

The Cephalotaxus alkaloid (-)-drupacine 19 has ﬁve stereogenic centers, including four of the ﬁve positions on the cyclopentane ring. Remarkably, Brian M. Stoltz of the California Institute of Technology was able (J. Org. Chem. 2007, 72, 7352) to prepare enantiomerically-pure 19 by initially controlling just the single stereogenic center of 15. Reductive amination of 15 with racemic 14 led to a separable 1:1 mixture of diastereomers. Acidmediated equilibration converted the wrong diastereomer 17 (as well as the correct diastereomer, not shown) to a 2:1 mixture favoring the desired diastereomer 18.

+

O 1. NaBH(OAc) O 3

O

2. LiAlH4 13

O

Br

14 (racemic)

15

1. OsO4

N

O

OH 2. Pdcat 3. Ac2O

2. DMSO TFAA 16

AcO

AcO CH3O

O

OCH3

O N

N O

+

H 17 HO

AcO

O

1. Pdcat O2 H N

TsHN

O

O 18

1. NaBH4 CH3OH

O O

O H HO

+

2. H /H2O

H O OCH3

19

N (-)-Drupacine OCH3

This column is dedicated to the memory of the late John W. Daly, who contributed so much to our knowledge of alkaloid chemistry.

113

57. Stereocontrolled Alkaloid Construction: Rhazinicine (Gaunt), 9-epi-Pentazocine (Zhai and Li), Fawcettidine (Dake), Strychnine (Padwa), and Yohimbine (Jacobsen) November 24, 2008

The power of catalytic C-H functionalization is illustrated by the elegant synthesis of rhazinicine 3 devised (Angew. Chem. Int. Ed. 2008, 47, 3004) by Matthew J. Gaunt of the University of Cambridge. The key step in the synthesis was the oxidative cyclization of 1 to 2. Although 1 has many C-H sites, the Pd catalyst selected for the α position of the pyrrole, leading, after intramolecular Heck addition and β-hydride elimination, to the alkene 2. Reduction and macrolactamization completed the synthesis of 3. O CO2Tes H

O2N N Me3Si

N

t-BuOOBz O

1

NH

O2N

Pd cat

Me3Si

CO2Tes

N O

2

O 3 (±)-Rhazinicine

Hongbin Zhai of the Shanghai Institute of Organic Chemistry and Zhong Li of East China University of Science and Technology prepared (Organic Lett. 2008, 10, 2457) the analgesic (-)-9-epi-pentazocine 8 from the amino ester 4, itself available from D-tyrosine. In the conversion of 5 to 6, the (i-PrO)2Ti formed a ring, leading to 6 as a single diastereomer and geometric isomer. HBr then effected both deprotection of the methyl ether and cyclization, to give 7, which was carried on to 8. Bn N

NH2.HCl CH3O

4

CO2CH3

CH3O

HBr

N

SiMe3

5

Bn

N HO

HO 6

i-PrMgCl

CH3O Me3Si

Bn N

Ti(O-i-Pr)4

7

H3C

CH3

H3C

CH3

8 (-)-9-epi-Pentazocine

The Pt-catalyzed cyclization of 9 to 10 set the stage for the synthesis of (+)-fawcettidine 15 by Gregory R. Dake of the University of British Columbia (Angew. Chem. Int. Ed. 2008, 47, 4221). This synthesis also illustrated the power of the Ramberg-Bäcklund reaction for the assembly of medium rings. The thiolate liberated from 12 readily added to the enone, to give 13.

114

STEREOCONTROLLED ALKALOID CONSTRUCTION Oxidation to the sulfone followed by the Ramberg-Bäcklund reaction (halogenation, intramolecular displacement, chelotropic elimination of SO2) then delivered 14, which was selectively reduced, leading to 15. H

N 9

S

O

N

O

10

NH

S

O

11 O

NH

N 12

S

O

O O

O N

O

NH

O

O

N

S 13

O

O

SeO2

PtCl2 cat

N 15 (+)-Fawcettidine

14

O

Albert Padwa of Emory University has developed (J. Org. Chem. 2008, 73, 3539) a general route to the Strychnos alkaloids, based on the facile cyclization of the furan 16 to the tetracyclic ketone 17. This project culminated in the synthesis of the heptacyclic strychnine 20. I N

N

N

OMOM

O Ac

N

N Ac

N 16

O

O

DMB

17

18

N

N Pd(PPh3)4 N DMB

PhOK

N O

O 20 H (±)-Strychnine

OMOM

19

H

O

Eric N. Jacobsen of Harvard University has devised a family of catalysts for the enantioselective Pictet-Spengler reaction of tryptamine 21. He has now (Organic Lett. 2008, 10, 745) used this approach to prepare the triene 22 in 94% ee. The Diels-Alder cyclization of 22 proceeded with high diastereocontrol to give 23, the immediate precursor of (-)-yohimbine 24.

N 21 H

NH2

N Cbz CH3O2C 22

N

N Cbz

OBz

115

CH3O2C 23

N

N H

N

CH3O2C OBz

OH 24 (-)-Yohimbine

58. Alkaloid Synthesis: (-)-Aurantioclavine (Stoltz), (-)-Esermethole (Nakao/Hiyama/ Ogoshi), (-)-Kainic Acid (Tomooka), Dasycarpidone (Bennasar), (-)-Cephalotaxine (Ishibashi) and Lysergic Acid (Fujii/Ohno) May 11, 2009

Intriguing strategies have been developed for the stereocontrolled assembly of complex alkaloid structures. Brian M. Stoltz of Caltech prepared (J. Am. Chem. Soc. 2008, 130, 13745) the enantiomerically-pure alcohol precursor to the secondary amine 1 by enantioselective oxidation of the racemic alcohol. Intramolecular Mitsunobu coupling of 1 then led to (-)-Aurantioclavine 3. Ns N

Ns N

H

H N

DIAD N 1

Ph3P

OH

Ts

96% ee

2

N Ts

3

N H

(-)-Aurantioclavine

Yoshiaki Nakao and Tamejiro Hiyama of Kyoto University and Sensuke Ogoshi of Osaka University developed (J. Am. Chem. Soc. 2008, 130, 12874) an enantioselective Ni catalyst for the cyclization of 4 to 5. Oxidation and cyclization then delivered (-)-Esermethole 6. CH3O

CN

4

Ni* cat

N CH3

CH3O

CN

CH3O N

N

96% ee CH3

5

N

6

CH3 CH3 (-)-Esermethole

Although the sulfonamide 7 appears to be prochiral, in fact its two most stable conformations are bent, and enantiomers of each other, with a signiﬁcant barrier for interconversion. Katsuhiko Tomooka of Kyushu University separated (Tetrahedron Lett. 2008, 49, 6327) the enantiomers of 7, then carried the enantiomercially-pure 7 on, by Pd-catalyzed Cope rearrangement, to 8 and so to (-)-Kainic Acid 9. CO2H

HO2C Pd cat N Ts 7

> 98% ee

Ts N

H N > 98% ee

8

9 (-)-Kainic Acid

116

ALKALOID SYNTHESIS M.-Lluïsa Bennasar of the University of Barcelona prepared (J. Org. Chem. 2008, 73, 9033) the acyl selenide 11 from the indole 10. While the radical derived from 11 might have been expected to undergo 5-exo cyclization, in the event the 6-endo mode dominated, to give Dasycarpidone 12 and its diastereomer. H

N

N

O O

N 10 Boc

N 11 H

Bu3SnH

SePh

N

N H

Et3B

Dasycarpidone

12

Hiroyuki Ishibashi of Kanazawa University showed (Organic Lett. 2008, 10, 4129) that the radical cascade cyclization of the enamine 13, derived from diethyl tartrate, proceeded with remarkable diastereocontrol, to give 14. The amide 14 was converted to (-)-Cephalotaxine 15. O O O

O Bu3SnH

I

O N

N

O

H TBDPSO

TBDPSO 13 OTBDPS

14

O N

O

H HO OTBDPS

(-)-Cephalotaxine OCH3

15

Nobutaka Fujii and Hiroaki Ohno, also of Kyoto University, used (Organic Lett. 2008, 10, 5239) a Pd catalyst to mediate the cascade cyclization of 16 to 17. Although 16 has two stereogenic centers, including the allene, it is the aminated stereogenic center of 17 that sets the absolute conﬁguration of the product Lysergic Acid 18. One intermediate in the conversion of 16 to the tetracyclic 17 is the tricyclic π-allyl Pd complex. If all the material could be channeled through that pathway, there is a good chance that the chiral Trost catalyst could effectively control the absolute conﬁguration of the aminated stereogenic center as it is formed, leading to the enantiomerically enriched product 18. TIPSO TIPSO N Ns

N

H Br

Ns

HO2C

N

Pd cat

N 16 Ts

N Ts 17

N H 18 Lysergic Acid

117

59. Alkaloid Synthesis: Crispine A (Zhou), Cermizine C (Zhang), Tangutorine (Poupon), FR901483 (Kerr), Serratezomine A (Johnston) November 30, 2009

Enantioselective hydrogenation of enamides is a well-established transformation. The corresponding reduction of enamines has been elusive. Qi-Lin Zhou of Nankai University designed (J. Am. Chem. Soc. 2009, 131, 1366) an Ir catalyst that reduced 2 to the Carpus alkaloid Crispine A 3 in high ee. CH3O

HO

CH3O

N H

1

O

1. POCl3

CH3O

2. NaOH

CH3O

N

Ir* cat / H2 CH3O

N

CH3O 2

90% ee

3 Crispine A

Direct conversion of C-H to C-C bonds is a powerful synthetic transformation. Liming Zhang, now at the University of California, Santa Barbara, observed (J. Am. Chem. Soc. 2009, 131, 8394) that a gold catalyst converted the N-oxide of 4 into 5, that was then deoxygenated to give Cermizine C 6. The gold catalyst and the N-oxide combined to convert the alkyne into an α-keto carbene, in the process reducing the N-oxide back to the amine. The carbene then abstracted a hydride from the carbon adjacent to the amine, generating an intermediate that collapsed to give 5 with high diastereocontrol. H O

1. MCPBA N

N

2. Aucat

4

1. SH SH N

2. Ra Ni

5

6 Cermizine C

Tangutorine 10, isolated from the leaves of Nitraria tangutorum, affects the morphology of human colon cancer cells. In a biomimetic approach, Erwan Poupon of the Université Paris-Sud stirred (Organic Lett. 2009, 11, 1891) glutaraldehyde 7 with bicarbonate to give an unstable carbocyclic dimer. Addition of tryptamine in acetic acid delivered the pentacyclic product 9, that was reduced with borohydride to give the crystalline Tangutorine 10. O H 7

O

H

O NaBH 4 H

NaHCO3; N

AcOH; N H

NH2 8

N H

N N H

9

118

10 Tangutorine

OH

ALKALOID SYNTHESIS FR901483, a potent immunosuppressive isolated from a Cladobotyrum fermentation broth, presents an challenging array of stereogenic centers in its tricyclic skeleton. Michael A. Kerr of the University of Western Ontario prepared (Organic Lett. 2009, 11, 777) the activated cyclopropane 11, then effected intramolecular dipolar opening with an intermediate imine, yielding the tricyclic 12. BnO

H

OCH3

BnO

OBn Yb(OTf)3 (CH2=O)n

NH2

BnO

OCH3

CO2CH3 11 CO2CH3

HO O HO P O

OCH3 N HO

N

H3CO2C CO CH 2 3

12

13 H N FR901483

The Lycopodium alkaloid Serratezomine A 21 presents a similarly challenging array of stereogenic centers in its tetracyclic structure. Jeffrey N. Johnston of Vanderbilt University constructed (J. Am. Chem. Soc. 2009, 131, 3470) the pyrrolidine ring of 15 using the imine free radical acceptor that he had previously developed. Having the alkene-Sn bond in place then enabled coupling with the acid chloride 16. Oxidative deprotection of 17 freed the enamine, that added in a conjugate sense to the unsaturated ester, kinetically setting the axial branch of 18. A second CAN-mediated step, allylation with 19, set the quaternary center of Serratezomine A 21. O

O N PMP

Bu3SnH AIBN

PMP PMP 15

O CAN

SnBu3 Cl +

N

14

H N

CO2Et CH3

CH3CN / H2O

OTBS

OTBS

OTBS

SiMe3 19

EtO2C O N

EtO2C

O

OTBS 20

119

17 O

CO2Et CH3

CAN

18

N

16

H

CH3 N

OH

21 Serratezomine A

60. Synthesis of Substituted Benzenes: The Carter Synthesis of Siamenol July 14, 2008

Tosylates are among the least expensive, but also among the least reactive toward Pd(0) oxidative addition, of aryl sulfonates. Jie Wu of Fudan University has now devised conditions (J. Org. Chem. 2007, 72, 9346) for the Pd-catalyzed coupling of aryl tosylates such as 1 with arene triﬂuoroborates. Kei Manabe of RIKEN has found (Organic Lett. 2007, 9, 5593) that an ortho OH activates an adjacent Cl for Pd-mediated coupling, allowing the conversion of 4 to 6. Philippe Uriac and Pierre van de Weghe of the Université de Rennes I have developed (Organic Lett. 2007, 9, 3623) conditions for the catalytic acylation of aryl halides with alkenyl acetates such as 8. OCH3

OTs

BF3K

+

Pd cat

CH3O 1

CH3O

2 MgBr

OH

OCH3 3 OCH3

OH

Cl

Pd cat +

4

5

6

OCH3

Cl

Cl

OAc

Br

O

Pd cat

+ CH3O

CH3O 7

8

9 CO2t-Bu

CH3O + SiMe3 10

CO2t-Bu

12

I

OTf

CH3O

CsF Pd cat

F3C 11

13

CF3

Multi-component coupling lends itself well to diversity-oriented synthesis. As illustrated by the combination of 10 with 11 and 12 to give 13 reported (Organic Lett. 2007, 9, 5589) by Michael F. Greaney of the University of Edinburgh, benzynes can do double addition with high regiocontrol. For other recent references to unsymmetrical double additions to arynes, see Angew. Chem. Int. Ed. 2007, 46, 5921; Chem. Commun. 2007, 2405; and J. Am. Chem. Soc. 2006, 128, 14042. C-H functionalization of arenes is of increasing importance. John F. Hartwig of the University of Illinois has described (Organic Lett. 2007, 9, 757; 761) improved conditions for Ir-catalyzed meta borylation, and conditions for further coupling of the initial borate 16 120

SYNTHESIS OF SUBSTITUTED BENZENES to give amines such as 17. Lei Liu and Qing-Xiang Guo of the University of Science and Technology, Hefei have found (Tetrahedron Lett. 2007, 48, 5449) that oxygen can be used as the stoichiometric oxidant in the Pd-catalyzed functionalization of H’s ortho to anilides. Two other research groups (J. Am. Chem. Soc. 2007, 129, 6066; Angew. Chem. Int. Ed. 2007, 46, 5554; J. Org. Chem. 2007, 72, 7720) reported advances in this area. In a close competition, Jin-Quan Yu, now at Scripps/La Jolla (J. Am. Chem. Soc. 2007, 129, 3510) and Olafs Daugulis of the University of Houston (J. Am. Chem. Soc. 2007, 129, 9879) both reported that a carboxyl group can activate an ortho H for direct functionalization. Note that metalation of 21 would be expected to proceed ortho to the methoxy group.

F3C

O + O

B B

CH3O 14

O

Ir cat

O

+

CH3O

OCH3

17

Pd cat

CO2Bu

O

21

O

O2

19

CO2H + H3CB(OH)2

CH3O

Cu cat

OCH3

H N

H N

CH3O

H N

F3 C

CH3O 16

15

18

O B O

F3 C

20

CO2Bu

CH3O

Pd cat

CO2H

benzoquinone

22

23 Ph3P / DIAD

+ C10H21 OCH3 HO OH 24 25

CH3

CH3O

microwave

OCH3 OH 26 C10H21

There are other strategies for directly functionalizing ortho positions. Christopher J. Moody of the University of Nottingham has found (J. Org. Chem. 2007, 72, 10298) that phenols such as 24 can be coupled with secondary allylic alcohols to give, after Claisen rearrangement, the alkylated product 26. For highly-substituted benzene derivatives, it is sometimes more efﬁcient to build the aromatic ring. Rich G. Carter of Oregon State University, in the course of a synthesis (J. Org. Chem. 2007, 72, 9857) of siamenol 30, developed the Diels-Alder addition of aryl alkynes such as 27 to enol derivatives such as 28 to give the biphenyl 29. Cl Cl 1.

+

NO2

2. TBAF

NO2

HO

OTMS 27

28

29 OH

121

N H Siamenol

30

61. Preparation of Benzene Derivatives October 13, 2008

Several new methods have been put forward for the functionalization of benzene derivatives. J. S. Yadav of the Indian Institute of Chemical Technology, Hyderabad has devised (Chem. Lett. 2008, 37, 652) a procedure for direct thiocyanation, converting 1 into 2. Sukbok Chang of KAIST has established (Chem. Commun. 2008, 3052) that both NH4Cl and aqueous NH3 could be used to directly aminate an aryl iodide such as 3. John F. Hartwig of the University of Illinois has developed (J. Am. Chem. Soc. 2008, 130, 7534) a protocol for the directed borylation of anilines such as 5 and of phenols, based on a transient silylation. Karsten Menzel of Merck West Point (Tetrahedron Lett. 2008, 49, 415) has observed selective exchange of tribromobenzene derivatives such as 7, with the direction of the selectivity being controlled by the fourth substituent on the benzene. O

NH4SCN

N

NCS

N

NH4Cl

I

TM

Selectfluor

NH2

Cu cat

1

2

4

3 Br

NH

NH

Et2SiH2/Ir cat;

Cl

O

Cl

O B

B2pin2 5

Br Br

MgCl

i -PrMgCl

O 7 Br

6

8 Br

Gary A. Molander of the University of Pennsylvania has extensively developed the stable, readily prepared triﬂuoroborates, exempliﬁed by 10 (J. Org. Chem. 2008, 73, 2052) and 14 (Organic Lett. 2008, 10, 1795) as partners for Suzuki-Miyaura coupling. The conversion of 9 to 10 is complementary to aminocarbonylation, exempliﬁed by the conversion of 12 to 13 reported (Tetrahedron Lett. 2008, 49, 2221) by Bhalchandra M. Bhanage of the Institute of Chemical Technology, University of Mumbai. The coupling of 9 with 14 is complementary to the long-known Heck coupling of an aryl halide such as 16 with an allylic alcohol, as illustrated by the preparation of 18 described (Tetrahedron Lett. 2008, 49, 3279) by Martin E. Maier of the Universität Tübingen. O CH3O

Pd cat

+ Br 9

I

CH3O

N

KF3B

N

Pd cat

O2N

N

O2N

12

11

10

DMF/POCl3 13 O

H

O

CH3O

Pd cat

+ Br 9

KF3B

CH3O

I

O

+

OH Pd cat

Br 14

15

122

16

17

Br 18

PREPARATION OF BENZENE DERIVATIVES Professor Hartwig has also (Organic Lett. 2008, 10, 1545, 1549) optimized conditions for the Pd-catalyzed arylation of ester enolates such as 19. Gang Zhou of Schering-Plough, Kenilworth, NJ has developed (Organic Lett. 2008, 10, 2517) a related transformation, the arylation of deprotonated sulfonamides. Peter Somfai of the Royal Institute of Technology, Stockholm has established (Angew. Chem. Int. Ed. 2008, 47, 1907) a complementary procedure, base-mediated elimination of t-butoxide from 24, followed by 1,2-addition of an aryl or heteroaryl Grignard reagent. Pd cat CH3O

CH3O

Br CO2CH3 9

CO2CH3

19

Cl

20 Cl

Pd cat

+

N

Br

O

S

21

O 22

N S

LiHMDS

O O

23 O LDA;

O Ph

N

Ph

O

N

N

N

MgBr

24

25

CH3O

H 26 OCH3

For some substitution patterns, it is more efﬁcient to construct the benzene ring. Professor Yadav observed (Tetrahedron Lett. 2008, 49, 3810) that 27 was aromatized to 28. Katsuyuki Ogura of Chiba University showed (J. Org. Chem. 2008, 73, 1726) that 29 cyclized to 30. Ken Tanaka of the Tokyo University of Agriculture and Technology established (Organic Lett. 2008, 10, 2537) that enol ethers or enol acetates could take the place of an alkyne partner in a trimerization reaction, as illustrated by the regioselective cycloaromatization of 31 to 33. For a related study, see Tetrahedron Lett. 2008, 49, 445. Sylvain Marque and Damien Prim of the Université de Versailles-Saint-Quentin-en-Yvelines have found (J. Org. Chem. 2008, 73, 2191) that activation of 34 by condensation with a secondary amine set the stage for Diels-Alder cycloaddition and aromatization, leading to 37. For related studies, see Organic Lett. 2008, 10, 233 and Tetrahedron Lett. 2008, 49, 219. CH3O

O

I

Ph

(CH3O)3CH

O

CH3O

27

H3CO2C

CO2CH3 Rh cat

O

O

H3CO

32

OCH3

H O 35

OCH3 O

31

hν

SCH3

H3CO2C 30

29

28

CO2CH3

Ph

I2

I2

Ph N

O

H O

O N Ph

O 33

34

Br

O 36

N H

N

37 O

123

O

62. Preparation of Benzene Derivatives: The Barrett Syntheses of Dehydroaltenuene B and 15G256β June 29, 2009

Several new methods for the direct functionalization of Ar-H have appeared. Hisao Yoshida of Nagoya University observed (Chem. Comm. 2008, 4634) that under irradiation, TiO2 in water effected meta hydroxylation of benzonitrile 1 to give the phenol 2. Anisole showed ortho selectivity, while halo and alkyl aromatics gave mixtures. Melanie S. Sanford of the University of Michigan reported (J. Am. Chem. Soc. 2008, 130, 13285) a complementary study of Pd-catalyzed ortho acetoxylation. Jin-Quan Yu of Scripps/La Jolla developed (Angew. Chem. Int. Ed. 2008, 47, 5215) a Pd-catalyzed protocol for ortho halogenation of aromatic carboxylates such as 3. A related protocol (J. Am. Chem. Soc. 2008, 130, 17676) led to ortho arylation. Trond Vidar Hansen of the University of Oslo devised (Tetrahedron Lett. 2008, 49, 4443) a one-pot procedure for the net ortho cyanation of phenols such as 5 to the salicylnitrile 6. Robin B. Bedford of the University of Bristol, Andrew J. M. Caffyn of the University of the West Indies and Sanjiv Prashar of the Universidad Rey Juan Carlos established (Chem. Comm. 2008, 990) a Rh-catalyzed protocol for ortho arylation of phenols such as 7. CN

CN

CO2Na

hν

Pd cat

H2O/TiO2 1

CO2Na I

IOAc

OH

4

3

2

Br

OH

1. CH2=O

OH

OH CN

OH Rh cat

2. NH3 3. IBX 5

7

6

8

Laurent Désaubry of the Université Louis Pasteur observed (Tetrahedron Lett. 2008, 49, 4588) regioselective coupling of unsymmetrical diﬂuorobenzenes such as 9 to give the ether 10. Fuk Yee Kwong of Hong Kong Polytechnic University extended (Angew. Chem. Int. Ed. 2008, 47, 6402) Pd-mediated amination to the notoriously difﬁcult mesylates, such as 11. John F. Hartwig of the University of Illinois reported (J. Am. Chem. Soc. 2008, 130, 13848) a related method for the amination of aryl tosylates. OMs Br

N H

Br BnOH

F F 9

OBn

NaH

N

Pd cat

F 10

11

124

12

PREPARATION OF BENZENE DERIVATIVES Hong Liu of the Shanghai Institute of Materia Medica found (Organic Lett. 2008, 10, 4513) that the Fe-catalyzed amination of aryl halides such as 13 sometimes gave mixtures of regioisomers. Hideki Yorimitsu and Koichiro Oshima of Kyoto University effected (Angew. Chem. Int. Ed. 2008, 47, 5833) Ag-catalyzed Grignard cross coupling with aryl halides, converting 15 into 16. Note that silyl aromatics such as 16 are readily reduced under dissolving metal conditions to give allyl silanes. O I

O

Me2PhSiCl cat AgNO3

Fe cat tert-BuONa CH3O 14

CH3O 13

Si Ph

MgBr

N

N H

15

16

Frederic G. Buono of the Bristol-Myers Squibb chemical process group optimized (Organic Lett. 2008, 10, 5325) the cyanation of aryl halides, uncovering the valuable cocatalytic role of ZnBr2. Markus R. Heinrich of the Technische Universität München developed (Angew. Chem. Int. Ed. 2008, 47, 9130) an intriguing Ti(III)-catalyzed radical arylation, converting 23 into 24. Ioannis N. Houpis of the Johnson and Johnson chemical process group established (Organic Lett. 2008, 10, 5601) conditions for Pd coupling to selectively convert 19 to either 20 or 21. NH3

N2 Br

Zn(CN)2

CN

+

Pd cat Zn/ZnBr2 17

Cl

18 CO2H

OCH3

19

CO2H

Ar

ArB(OH)2

20

CH3O

21

Cl

CO2H

Br

ArB(OH)2

Br

Pd cat

Pd cat Br 23

NH2 cat TiCl3

Br 22

Ar

24

Anthony G. M. Barrett of Imperial College London took advantage (Organic Lett. 2008, 10, 3833) of regioselective addition the allylic anion 22 to the benzyne 23 to give, after carboxylation, the iodolactone 24, that he carried on to Dehydroaltenuene B. Following up on the work of Thomas M. Harris, Professor Barrett also demonstrated (J. Am. Chem. Soc. 2008, 130, 10293) the facile aromatization of the triketone 25 to the arene 26, that he carried on to the antifungal agent 15G256β. I MgCl +

O

O O

OCH3 25

26

CH3O

OH CO2R

OCH3 CO ; I 2 2

27

OCH3

125

O

CO2R

K2CO3 iso -PrOH HO

O

OSiR3 28

R3SiO 29

63. Substituted Benzenes: The Alvarez-Manzaneda Synthesis of (-)-Taiwaniquinone G October 12, 2009

Continuing efforts toward the direct functionalization of aromatic C-H bonds, Nobutaka Fujii and Hiroaki Ohno of Kyoto University described (Chem. Commun. 2009, 3413) a Pd-mediated protocol for the ortho hydroxylation of aryl tetrahydropyrimidines such as 1. To use a boronic acid as an activating/directing group, Michinori Suginome, also of Kyoto University, devised (J. Am. Chem. Soc. 2009, 131, 7502) the pyrazolylpyridyl derivative 3. The product 4 could be returned to the boronic acid or carried on to the borate ester, in each case with recovery of the directing group. Eiichi Nakamura of the University of Tokyo established (Angew. Chem. Int. Ed. 2009, 49, 2925) that ortho arylation of 5 could be accomplished even in the presence of a reactive aryl halide. In a complementary approach, Matthew J. Gaunt of the University of Cambridge developed (Science 2009, 323, 1593) a procedure for C-H arylation of anilides such as 7 that showed good meta selectivity. O H

1. Cu(OAc)2

N N

CH3O

1

N

Ar

H

N N 2

5

HSiEt3

O

H

N B

N N

4

H N

Ph Ph IOTf 2 O

Ph O

Cu cat

7

6

Br

Et3Si

Ru cat

N N

H N

Cl

Cl Cl

N B 3

Ph PhMgBr/ZnCl2 Fe cat /

Br

O

H2O/O2 2. triphosgene CH3O

Ph

8

Mamoru Tobisu and Naoto Chatani of Osaka University have found (Chem. Lett. 2009, 38, 710) for the conversion of aryl ethers such as 9 to the tertiary amine. Masahito Ochiai of the University of Tokushima observed (J. Am. Chem. Soc. 2009, 131, 8392) the remarkable inversion of an arene sulfonamide such as 11 to the protected aniline 12. Matthias Beller of the Universität Rostock established (Angew. Chem. Int. Ed. 2009, 49, 918) a Pd-mediated procedure for the conversion of even a congested aryl halide 13 to the phenol 14. O OCH3

O

NH

SO2NH2

N

NHSO2F

ArBrF2

Ni cat H3CO2C

9

H3CO2C

CH3O

10

126

11

CH3O

12

SUBSTITUTED BENZENES OCH3 Cl

O

OH

O [ArBO] 3

KOH Pd cat

Ni cat

13

H3CO2C

14

H3CO2C

15

16

The ﬁrst C-C bond formations with phenols used very reactive, but expensive, leaving groups such as triﬂates. With improving ligand design, conditions have been found that work well even with inexpensive mesylates. Now, Zhang-Jie Shi of Peking University (J. Am. Chem. Soc. 2008, 130, 14468) and Neil K. Garg of UCLA (J. Am. Chem. Soc. 2008, 130, 14422), working independently, developed similar procedures for the Ni-mediated arylation of esters such as 15. Both groups found that pivalates worked particularly well. For some highly-substituted benzene derivatives, construction of the aromatic ring can be an economical approach. Atul Goel of the Central Drug Research Institute, Lucknow, found (Tetrahedron Lett. 2009, 50, 2086) that the direct coupling of a pyrone such as 17 with an aldehyde 18 delivered the aryl ester 22. Gerhard Hilt of Philipps-Universität Marburg developed (Organic Lett. 2009, 11, 773) Co catalysts for the Diels-Alder cyclization of 23 with 24, with subsequent oxidation to the arene 25. With the proper choice of catalyst, either regioisomer of the Diels-Alder adduct could be made to dominate. Kazuhiro Yoshida and Akira Yanagisawa of Chiba University found (J. Org. Chem. 2009, 74, 3632) a similar ﬂexibility in a Ru-mediated arene construction. Cyclization of 23 followed by dehydration gave 24, while oxidation followed by cyclization delivered the phenol 25. Enrique Alvarez-Manzaneda of the Universidad de Granada, in the course (Chem. Commun. 2009, 592) of a synthesis of (-)-Taiwaniaquinone G 29, built the aromatic ring by cyclization of 26 to 27, followed by oxidation to 28. O Ph O H3CS

Ph

H

SiMe3

KOH

+

H3CS H3CO2C

O CO2CH3

17

18

21 1. Co cat

SiMe3

2. DDQ

OAc

OAc

19

20

22

OH 1. Ru cat

OH 1. Dess-Martin

2. H+

2. Ru cat

24

23

25

Cl

Cl

Cl CO2CH3

1. LDA; O NC-CO2CH3

OTMS

OCH3

O

OH

O

2. DDQ 26

27

28

29 (-)-Taiwaniaquinone G

127

64. Synthesis of Heteroaromatics July 21, 2008

Yasutaka Ishii of Kansai University has developed (J. Org. Chem. 2007, 72, 8820) a novel route to furans, using a mixed-metal catalyst to effect condensation of an aldehyde or 1,3 diketone such as 1 with an acceptor such as 2 to give the 3-furoate 3. In a complementary approach, Yong-Min Liang of Lanzhou University has found (J. Org. Chem. 2007, 72, 10276) that diazoacetate 5 will condense with an alkynyl ketone to give the 2-furoate 6. David W. Knight of Cardiff University has shown (Tetrahedron Lett. 2007, 48, 7709) that an alkynyl diol such as 7, readily available by dihydroxylation of the corrresponding alkenyl alkyne, cyclized to the furan on exposure to AgNO3 on silica gel. CO2Et O

CO2Et cat Pd/Mo/Ce

+

O

O2

H 1

2

3

O CO2Et

+

cat CuI

N2 4

5

OCH3

O

CH3O

CO2Et

6

HO OTBS

AgNO3

HO

O

SiO2 7

OTBS

8

Professor Knight has also (Tetrahedron Lett. 2007, 48, 7906) established a route to polysubstituted pyrroles 10, by iodination of alkynyl sulfonamides such as 9. Similarly, Richard C. Larock of Iowa State University found (J. Org. Chem. 2007, 72, 9643) that I-Cl cyclized methoximes such as 11 to the corresponding iodo isoxazole 12, and Stephen L. Buchwald of MIT uncovered (Organic Lett. 2007, 9, 5521) the cyclization of an enamide such as 13 CO2Et HO

I CH3O N

NHTs 1. I 2

N Ts

2. MsCl 9

N

10

11 H2N

I2 / DBU EtO2C

13

N H

O EtO2C

I

I-Cl

CO2Et

O

12

CO2CH3 1. TfN

H3CO2C 3

2. BocNH

N 14

15

128

O

16

N N N BocNH

17

SYNTHESIS OF HETEROAROMATICS with I2 to the corresponding oxazole 14. In developing a more efﬁcient route to a new class of materials that he has named “triazolamers”, Paramjit S. Arora of New York University was able (J. Org. Chem. 2007, 72, 7963) to effect diazo transfer to the amine 15 and subsequent condensation with 16 to give 17, without isolation of the intermediate azide. C. V. Asokan and E. R. Anabha of Mahatma Gandhi University have described (Tetrahedron Lett. 2007, 48, 5641) the activation of a ketone 18 followed by condensation with malononitrile 19 to give the pyridine 20. Hans-Ulrich Reissig of the Freie Universität Berlin has established (Organic Lett. 2007, 9, 5541) a complementary three-component coupling of a nitrile 21 with the allenyl anion 22, followed by a carboxylic acid 23 to deliver the pyridine 24. Akio Saito and Yuji Hanzawa of the Showa Pharmaceutical University have reported (Tetrahedron Lett. 2007, 48, 6852) the intramolecular Rh-catalyzed cyclization of a methoxime lactone such as 25 to the pyridine 26. Paul Knochel of the Ludwig-Maximilians-Universität München has demonstrated (J. Am. Chem. Soc. 2007, 129, 12358) that halogen exchange can be directed by an adjacent carbamate, enabling homologation of 27 to 28. CN

O

2.

18

O

Cl

1. POCl3 DMF

N

OCH3

CH3O

N

CN CN 19

CO2H CH3O HO 23

+ NC

20

21

N

22

24

O Rh cat

O

O

N

O

I 25

26

I N 27

N

Zn / LiCl; CuCN . 2LiCl

O

Br

N

O I

N 28

O

Professor Buchwald has also developed (Angew. Chem. Int. Ed. 2007, 46, 7236) a protocol for the Pd-mediated α-arylation of aldehydes. This procedure converted an o-halo aniline 29 to the indole 31. In a C-H activation-based approach, Mark Lautens of the University of Toronto demonstrated (Organic Lett. 2007, 9, 5255) that Pd-catalyzed condensation of 32 with the aniline 33 led to the indole 34. Br Br

NH2 29

Pd cat

+

H O

30

N H 31

+ I

O2N 32

129

H

N

Pd cat

O2N norbornene 33

N 34

65. Preparation of Heteroaromatic Derivatives October 20, 2008

Several new routes to furans and to pyrroles have recently been put forward. Inspired by the Achmatowicz ring expansion, Patrick J. Walsh of the University of Pennsylvania developed (J. Am. Chem. Soc. 2008, 130, 4097) the oxidative rearrangement of 3-hydroxalkyl furans such as 1 to the 3-aldehyde 2. José M. Aurrecoechea of the Universidad del País Vasco established (J. Org. Chem. 2008, 73, 3650) that cumulated alcohols, available by reduction of alkynes such as 3 with SmI2, rearrange under Pd catalysis, and then add to an acceptor alkene such as 4, to give the furan 5. Vladimir Gevorgyan of the University of Illinois at Chicago used (J. Am. Chem. Soc. 2008, 130, 1440) an Au catalyst to rearrange an allene such as 6 to the bromo furan 7. Fabien L. Gagosz of the Ecole Polytechnique, Palaiseau, also found (Organic Lett. 2007, 9, 3181) that an Au catalyst rearranged the eneyne 8 to the pyrrole 9. O OH

CO2Et

H

NBS

1. SmI2 O

OH

O

1

HO

H

CO2Et

5

O CN

H

O

O N 10

N Ts

N 8 Ts

CO2Et

O 11 O 12

4

Au cat 7

H

2. Pdcat CN

Au cat

6

EtO2C

OAc 3

Br

O Br

O

2

N3

CO2Et O 13 EtO2C Cu cat

9

CO2Et

14

N H

Azido esters such as 10 are readily prepared from the corresponding aldehyde by phosphonate condensation. Shunsuke Chiba and Koichi Narasaka of Nanyang Technology University demonstrated (Organic Lett. 2008, 10, 313) that thermal condensation of 10 with acetyl acetone 11 gave the pyrrole 12, while Cu catalyzed condensation with acetoacetate 13 gave the complementary pyrrole 14. Huan-Feng Jiang of South China University of Technology observed (Tetrahedron Lett. 2008, 49, 3805) that condensation of an acid chloride 15 with an alkyne 16, presumably to give the alkynyl ketone, followed by the addition of hydrazine delivered the pyrazole 17. Masanobu Uchiyama of RIKEN and Florence Mongin of the Université de Rennes 1 established (J. Org. Chem. 2008, 73, 177) that a pre-formed pyrazole 18 could be metalated and then iodinated, to give 19. Xiaohu Deng of Johnson & Johnson, San Diego reported (Organic Lett. 2008, 10, 1307; J. Org. Chem. 2008, 73, 2412) complementary routes to pyrazoles,

130

PREPARATION OF HETEROAROMATIC DERIVATIVES combining 20 and 21 under acidic conditions to give 22, and under basic conditions to give 23. H O

1. Pdcat/ Cu cat

Cl +

N N

2. H2N-NH2 15

N H

16

ZnCl2/ LiTMP;

N

18

19 Cl

NO2 CF3CH2OH N

N

N

N

22

Br

t-BuOK

+ H

Br

I

N

I2 17

Cl

N

N

Cl

20

N

Br 21

23

Mark Lautens of the University of Toronto demonstrated (J. Org. Chem. 2008, 73, 538) that dibromoalkenes such as 24, readily available from the corresponding aldehyde, could be condensed with an organoborane such as 25 to give the indole 26. Tao Pei and Cheng-yi Chen of Merck Process established (Angew. Chem. Int. Ed. 2008, 47, 4231) that the addition of an organometallic to the ketone 27 drove rearrangement to a homologated ketone, that on acid work-up gave the indole 28.

Br

O

O B O Pd cat

Br +

NH2 24

MgBr

N H

25

Cl NH2 Cl

26

27

H 28

O

CN OCH3 FeCl3 N

O

CN

30

O N

N 29

N Cl

CH3O

31 Ph

OCH3 ;

+ H O

N

HCl H

32

O 33

O

Ph

Each of these approaches depended on the availability of the ortho-substituted aniline starting materials. Junbiao Chang and Kang Zhao of Tianjin University devised (J. Org. Chem. 2008, 73, 2007) a complementary approach, the cyclization of 29 to 30, in the process directly aminating the benzene ring. Marijan Kocevar of the University of Ljubljana established (Tetrahedron 2008, 64, 45) an alternative Diels-Alder approach to indoles, combining 31 and 32 to give 33. The preparation of pyridines will be covered in the next column on heteroaromatic construction.

131

66. Preparation of Heteroaromatics July 13, 2009

Masahiro Yoshida of the University of Tokushima described (Tetrahedron Lett. 2008, 49, 5021) the Pt-mediated rearrangement of alkynyl oxiranes such as 1 to the furan 2. Roman Dembinski of Oakland University reported (J. Org. Chem. 2008, 73, 5881) a related zincmediated rearrangement of propargyl ketones to furans. The cyclization of aryloxy ketones such as 3 to the benzofuran 4 developed (Tetrahedron Lett. 2008, 49, 6579) by Ikyon Kim of the Korea Research Institute of Chemical Technology is likely proceeding by a FriedelCrafts mechanism. OH cat PtCl2

O

O

O

OH

O

CH3O 1

2

BCl3 O

CH3O 4

3

Sandro Cacchi and Giancarlo Fabrizi of Università degli Studi “La Sapienza”, Roma, observed (Organic Lett. 2008, 10, 2629) that base converted the enamine 5 to the pyrrole 6. Alternatively, oxidation of 5 with CuBr led to a pyridine. Zhuang-ping Zhuan of Xiamen University prepared (Adv. Synth. Cat. 2008, 350, 2778) pyrroles such as 9 by condensing an alkynyl carbinol 7 with a 1,3-dicarbonyl compound. Richard C. Larock of Iowa State University found (J. Org. Chem. 2008, 73, 6666) that combination of an alkynyl ketone 10 with 11 followed by oxidation with I-Cl led to the pyrazole 12.

N

O H

5

OH

O

Cs2CO3

6

H

CH3O CH3O CH3O

H

N 1. NH2 11 CH3O 2. I-Cl

10

CO2Et

8

cat InCl3 7

N H

9

O

O O

N H

O EtO2C

N N

OH

CO2Et N3 14

I CH3O 12 CH3O

Ru cat 13

HO N

N

N

EtO2C 15

The “click” condensation of azides with alkynes, leading to the 1,4-disubstituted 1,2,3triazole, has proven to be a powerful tool for combinatorial synthesis. Valery V. Fokin of Scripps/La Jolla and Zhenyang Lin and Guochen Jia of the Hong Kong University of Science and Technology have developed (J. Am. Chem. Soc. 2008, 130, 8923) a complementary approach, using Ru catalysts to prepare 1,5-disubstituted 1,2,3- triazoles. Remarkably, internal alkynes participate, and, as in the conversion of 13 to 15, propargylic alcohols direct the regioselectivity of the cycloaddition.

132

PREPARATION OF HETEROAROMATICS A variety of methods have been put forward for functionalizing pyridines. Sukbok Chang of KAIST described (J. Am. Chem. Soc. 2008, 130, 9254) the direct oxidative homologation of a pyridine N-oxide 16 to give the unsaturated ester 18. Jonathan Clayden of the University of Manchester observed (Organic Lett. 2008, 10, 3567) that metalation of 19 gave an anion that rearranged to 20 with complete retention of enantiomeric excess. O CO2t -Bu Ph 17

Ph N O

N N O

Pd cat 16

+ Bu3Sn

MsNH2 23 Pd cat;

H

DBU I

21

22

CO2Et

Ph LDA

N

N

20 Bn Rh cat; +

CO2Et

H

O

19 N

Ph

N

N

N

CO2t -Bu

18 O

Ph

Ph N

H2 / Pd-C Ph

Ph

24

25

N

26

27

Shigeo Katsumura of Kwansei Gakuin University developed (Tetrahedron Lett. 2008, 49, 4349) an intriguing three-component coupling, combining 21, 22, and methanesulonamide 23 to give the pyridine 24. Robert G. Bergman and Jonathan A. Ellman of the University of California, Berkeley established (J. Am. Chem. Soc. 2008, 130, 3645) a C-H activation based coupling, combining 25 and 26 to give, after debenzylation/aromatization, the pyridine 27. O

O O Rh cat + N3 28

N 29 H

30 O

N

31 N H Ts

H cat ZnCl2

HO N 32 H

N Ts

Tom G. Driver of the University of Illinois, Chicago found (Angew. Chem. Int. Ed. 2008, 47, 5056) that Rh octanoate catalyzed the well-known thermal conversion of an azide such as 28 to the indole 29. Valeriya S. Velezheva of the A. N. Nesmeyanov Institute of Organoelement Compounds uncovered (Tetrahedron Lett. 2008, 49, 7106) an improved protocol for the Nenitzescu synthesis, combining 30 and 31 to give 32. For an overview of the nine types of indole synthesis, see our upcoming review in Angewandte Chemie.

133

67. Heterocycle Construction: The Chang Synthesis of Louisianin C October 19, 2009

It has been known for some time that an acid chloride 1 can be added to an alkyne 2 to give the β-chloro enone. Yasushi Tsuji of Kyoto University found (J. Am. Chem. Soc. 2009, 131, 6668) that with an Ir catalyst, the condensation of 1 with 2 could be directed to the furan 3. Huanfeng Jiang of the South China University of Technology described (Organic Lett. 2009, 11, 1931) a complementary route to furans, Cu-mediated condensation of a propargyl alcohol 4 with the diester 5 to give 6. H

CH3 E

O

Ir cat

+

Ph

Ph

O

Cl

1

HO 4

3

E

E

5

O E

CuI DABCO

O 6

2 N

Bn

Cl

Ar O

H 7

CH3O

CN

O

Boc N H

CN

8 OEt

O N

DBU/TBAI Ph3P/CuI

Bn

9 OEt

10 H

Cl

I

11 O

N

Pd cat/CuI Et3N; NaI/H+

12

Boc

Bruce A. Arndtsen of McGill University developed (Organic Lett. 2009, 11, 1369) an approach to pyrroles such as 9, by condensation of an α,β-unsaturated α-cyano imine 7 with the acid chloride 8. Thomas J. J. Müller of Heinrich-Heine-Universität Düsseldorf observed (Organic Lett. 2009, 11, 2269) the condensation of an acid chloride 11 with a propargyl amine 10, leading to the iodo pyrrole 12. John A. Murphy of the University of Strathclyde uncovered (Tetrahedron Lett. 2009, 50, 3290) a new entry to the Fischer indole synthesis, by Petasis homologation of a hydrazide 13. Dali Yin of Peking Union Medical College took advantage (Organic Lett. 2009, 11, 637) of the easy sequential displacement of the ﬂuorides of 15, leading, after acid-catalyzed F

13

N

N

CN

18

O2 N

Cp2TiMe2

O

NH2

N 14

CN

1. PhI(OAc)2 2.

15 NO 2

H

OEt N 1. H 16 F 2.

N

OEt O2N

NH2

N 17

3. H+

O2N

O

N 19 H

20

134

N OH Boc

microwave 21

N H

HETEROCYCLE CONSTRUCTION cyclization, to the indole 17. Kang Zhao of Tianjin University extended (Organic Lett. 2009, 11, 2417; Organic Lett. 2009, 11, 2643) his studies of oxidation of an enamine 18 to the 2H-azirine, that on heating cyclized to the indole 19. Peter Wipf of the University of Pittsburgh established (Chem. Commun. 2009, 104) a microwave-promoted indole synthesis, illustrated by the intramolecular Diels-Alder cyclization of 20 to 21. A review delineating all nine types of indole syntheses will appear shortly in Angewandte Chemie. Fushun Liang and Qun Liu of Northeast Normal University demonstrated (J. Org. Chem. 2009, 74, 899) that the readily-prepared ketene thioacetal 22 condensed with NH3 to give the pyridine 23. Sundaresan Prabhakar and Ana M. Lobo of the New University of Lisbon observed (Tetrahedron Lett. 2009, 50, 3446) that the addition of the alkoxy propargyl amine to the alkyne 25 gave a Z alkene, that on warming rearranged to the pyridine 26. Yan-Guang Wang of Zhejiang University, Hangzhou developed (J. Org. Chem. 2009, 74, 903) a pyridine synthesis based on the Wolff rearrangement of a diazo ketone such as 28. The iminophosphorane derived from 27 added to the resulting ketene, leading, after by electrocyclic rearrangement, to the pyridine 29. CH3O

CH3O O

OR H N H

OH

NH4OAc

SO2Ar ;

25

SO2Ar

EtS

EtS

N

N

SEt 22

23

CH3

N

CH3 24

26

O CO2Et N3 27

N

CO2Et 28

N

N2

Ph3P

CO2Et

EtO2C

29

CN I

Br N

CO2CH3 31 Br Pd cat

30

CO2CH3

CN

N

32

O

N 33 Louisianin C

A great deal of work has been done on the selective metalation of pyridines. Ching-Yao Chang of Asia University, Taichung used this (Tetrahedron 2009, 65, 748; for another report on pyridine metalation, see Tetrahedron Lett. 2009, 50, 1768) to advantage in developing a synthetic route to the Streptomyces-derived Louisianin alkaloids. Lithiation of 4-cyanopyridine was followed by bromination. The product was again lithiated, then iodinated to give 30. A selective Heck reaction on 30 gave 32, that was carried on to Louisianin C 33.

135

68. Enantioselective Organocatalytic Construction of Carbocycles: The Nicolaou Synthesis of Biyouyanagin A August 11, 2008

One of the more powerful routes to enantiomerically-pure carbocycles is the desymmetrization of a prochiral ring. Karl Anker Jørgensen of Aarhus University has found (J. Am. Chem. Soc. 2007, 129, 441) that many cyclic β-ketoesters, including the vinylogous carbonate 1, can be homologated with 2 to the corresponding alkyne 3, in high ee. Sanzhong Luo of the Chinese Academy of Sciences, Beijing, and Jin-Pei Cheng, of the Chinese Academy of Sciences and Nankai University, have shown (J. Org. Chem. 2007, 72, 9350) that the catalyst 6 mediated the selective addition of 4-substituted cyclohexanones such as 4 to the nitroalkene 5, establishing three new stereogenic centers. O CO2t-Bu

CO2Allyl

CO2Allyl

O

cat Q*

+

CO2t -Bu

EtO

Cl

1

2

O

EtO O

NO2 +

93% ee

Ph

cat 6 NO2

Ph 4

3

7

5

6.5: 1 dr 97% ee

N H

N

N Bu

6

Organocatalysts, alone or complexed with activating metals, have also been used to effect enantioselective ring construction. E. J. Corey of Harvard University has established (J. Am. Chem. Soc. 2007, 129, 12686) that the proline-derived complex 10 will mediate the 2+2 addition of a cyclic enol ether with an acrylate to give the cyclobutane 11. Further elaboration led to the cyclohexenone 12. Armando Córdova of Stockholm University has described (Tetrahedron Lett. 2007, 48, 5835) a novel route to cyclopentanones such as 16, via tandem conjugate addition/intramolecular alkylation. Professor Jørgensen has reported (Angew. Chem. Int. Ed. 2007, 46, 9202) the double addition of 18 to the unsaturated aldehyde 17 to give 20. Earlier last year, Yujiro Hayashi of the Tokyo University of Science had shown (Angew. Chem. Int. Ed. 2007, 46, 4922) that the double addition of the inexpensive 21 to 5 could, depending on conditions, be directed selectively to 22, 23, or 24.

136

ENANTIOSELECTIVE ORGANOCATALYTIC CONSTRUCTION OF CARBOCYCLES H

NO2

cat 19

17

O

Ph

Ph

NO2 18

NO2 20

H NO2

+ O H 21

CF3

OH NO2

O +

Ar =

N 90% ee H

SiO2

H

Ph

OH Ph 23 NO 99% ee 2

5

CF3

19

O

O cat 16

Ar OTMS Ar

O DBU

H

H

Ph OH 24 NO 2

Ph OH 25 NO 2

As illustrated by the conversion of 8 to 13, organocatalysis can be used to effect the enantioselective construction of polycarbocyclic products. The initial ring prepared in enantiomerically-pure form by organocatalysis can also set the chirality of a polycyclic system. Professor Corey has reported (J. Am. Chem. Soc. 2007, 129, 10346) that ItsunoCorey reduction of the prochiral diketone 25 led to the ketone 27. Cyclization followed by oxidation and reduction then delivered estrone methyl ether 28. Ph

Ph

O

O

OH

N B 26 Bu

catecholborane

O CH3O

O

CH3O

25

O

1. HCl 2. IBX

cat

92% ee

27

3. H2 / Pd-C Et3SiH 4. Et3SiH / CF3CO2H

CH3O 28

Professor Hayashi, Professor Jørgensen and Samuel H. Gellman of the University of Wisconsin had established (OHL July 24, 2006) that an aldehyde could be added to a vinyl ketone in high ee. Building on these results, K. C. Nicolaou of Scripps/La Jolla has found (Angew. Chem. Int. Ed. 2007, 46, 4708) that the initial Michael adduct from the condensation of (R)-citronellal 29 with methyl vinyl ketone 30 can be converted into the Robinson annulation product 32 without epimerization at the gamma position. This led to 33, cycloaddition of which with 34 delivered (-)-biyouyanagin 35. Ph O

N

O

1.

H

H

OCH3 31 Ph cat

H

1. KHMDS; Tf2NH

+ 2. KOH 29

32

O

H

O UV

+ Ph 33

2. CH3MgI CuI

O

30

O

O O

O

H O Ph

34

(-)-Biyouyanagin A

137

O 35

69. Organocatalytic Ring Construction: The Corey Synthesis of Coraxeniolide A December 8, 2008

Armando Córdova of Stockholm University has found (Tetrahedron Lett. 2008, 49, 4209) that the organocatalyst 3a effected enantioselective conjugate addition of bromonitromethane 2 to the α,β-unsaturated aldehyde 1, to give the cyclopropane 4 as a ~ 1:1 diastereomeric mixture, both in high ee. Tomislav Rovis of Colorado State University has published (J. Org. Chem. 2008, 73, 2033) a detailed account of his development of catalysts such as 6, that effected enantioselective cyclization of 5 to 7 with excellent ee. Karl Anker Jørgensen of Aarhus University has employed (J. Am. Chem. Soc. 2008, 130, 4897) chiral quaternary salts derived from quinine that mediated the enantioselective addition of prochiral rings such as 8 to the allenoate ester 9 to give 10 with high ee. NO2 O

NO2 cat 3a

+ H

H

Br

1

O

4

2 O

O

91% ee

CO2Et

cat 6

H

N

Ph

7

O CO2tBu + 8

CO2Et cat Q*

N Ph

N

95% ee

CO2Et 5

Ar 3a Ar = Ph OTMS 3b Ar = 2-naphthyl Ar

N H

O

6

CO2tBu CO2Et

9

10

95% ee

Organocatalysts have also been used to prepare more highly substituted cyclohexane derivatives. Guofu Zhong of Nanyang Technological University used (Organic Lett. 2008, 10, 2437) a quinine-derived secondary amine to catalyze the Michael addition of 12 to 11 followed by intramolecular aldol (Henry) reaction, to give 13. When Professor Jørgensen attempted (Angew. Chem. Int. Ed. 2008, 47, 121) the related addition of 14 and 15 using catalyst 3a, he did not observe the expected Michael-Michael sequence. Rather, the initial Michael addition was followed by a Morita-Baylis-Hillman condensation, to give 16. The β-keto ester 16 existed primarily in its enol form. O O

NO2

EtO2C

CO2Et

cat Q*-NH2

+ O 11

OH

12 O

14

O

O H

NO2 95 : 5 dr 97% ee 13

CO2Et

+

CO2Et

cat 3a HO

15

138

16

6 : 1 dr 86% ee

ORGANOCATALYTIC RING CONSTRUCTION Organocatalysts can also be used to prepare polycyclic systems. Professor Jørgensen has found (Chem. Commun. 2008, 3016) that condensation of 14 with acetone dicarboxylate 17, again using catalyst 3a, gave the bicyclic β-keto ester 18. Matthew J. Gaunt of the University of Cambridge observed (J. Am. Chem. Soc. 2008, 130, 404) that for the cyclization of 19, catalyst 3b was superior to catalyst 3a. The power of desymmetrization of prochiral intermediates was illustrated by the report (J. Am. Chem. Soc. 2008, 130, 6737) from Benjamin List of the Max-Planck-Institute, Mülheim of the cyclization of 21 to 23. O

HO

O CO2CH3

H +

CO2CH3

H3CO2C

17

18

14

CO2CH3 CO2CH3

cat 3a HO

CO2CH3

99 : 1 dr 94% ee

F OH

O H

O

PhI(OAc)2 H

19

O

cat 3b CH3OH CH3O

H

CO2H N 22 H

O

H >20 : 1dr 20 99% ee

H 21

H

OH

H

O

O

96% ee

23

Organocatalysts can also be used to prepare larger rings. The Hajos-Parrish condensation of 2-methyl cyclopentane-1,3-dione with methyl vinyl ketone mediated by proline to give the aldol product 24 in high ee is one of the classic examples of enantioselective bicyclic construction directed by an organocatalyst. E. J. Corey of Harvard (J. Am. Chem. Soc. 2008, 130, 2954) effected Grob fragmenation on the derived diol 25 to give the cyclononadienone 26. While 26 might appear to be prochiral, in fact it was formed in the kinetically stable enantiomerically-pure conformation illustrated. With only one face of the enone open, conjugate addition to 26 proceeded with high diastereocontrol, leading to coraxenliolide A 27.

O

OH TsCl/py;

O

O

NaH/ HO 24

HO 25

H

O O

O

139

26

27 Coraxeniolide A

70. Enantioselective Organocatalyzed Construction of Carbocyclic Rings August 10, 2009

One of the most practical ways to construct enantiomerically-enriched carbocyclic systems is to effect asymmetric transformation of preformed prochiral rings. Choon-Hong Tan of the National University of Singapore observed (Chem. Commun. 2008, 5526) that allylic halides such as 1 coupled with malonates such as 2 to give the α-methylene ketone 3 in high ee. Xinmiao Liang of the Dalian Institute of Chemical Physics and Jinxing Ye of the East China University of Science and Technology reported (Chem. Commun. 2008, 3302) that nitromethane 5 could be added to enones such as 4 to construct cyclic quaternary stereogenic centers such as that of 6. The addition of the cyclohexanone 7 to the acceptor 8 described (Chem. Commun. 2008, 6315) by Yixin Lu, also of the National University of Singapore led to the creation of two new cyclic stereogenic centers. Polycarbocyclic prochiral rings are also of interest. Teck-Peng Loh of Nanyang Technological University devised (Tetrahedron Lett. 2008, 49, 5389) the steroid AB donor 10, that added to crotonaldehyde 1 to give the single enantiomerically-pure diastereomer 12. O Br

2

CO2St Bu CO2St Bu

O

O

organocat 94% ee 1

CO2St Bu CO2St Bu

3 SO2Ph

O

4

O

NO2 6 O

O NC

O

organocat 94% ee

SO2Ph 9

CN

NC

CN

H 11

SO2Ph

8 SO2Ph 7

CH3NO2 5 organocat 94% ee

organocat

CH3O

10

CH3O

12

H

87% ee

Nitro alkenes are excellent Michael acceptors. Dieter Enders of RWTH Aachen took advantage of this (Angew. Chem. Int. Ed. 2008, 47, 7539) in developing the addition of aldehydes such as 14 to the nitroalkene 13. Intramolecular alkylation ensued, to deliver the product 15 as a single diastereomer. Guofu Zhong, also of Nanyang Technological University, established (Organic Lett. 2008, 10, 3425; Organic Lett. 2008, 10, 3489) an approach to cyclopentane construction based on the Michael addition of β-ketoesters such as 16 and 19 to nitroalkenes such as 17 and 20. Intramolecular nitro aldol (Henry) addition led to 18, while an intramolecular Michael addition delivered 21. O H NO2 I 13

14 organocat 93% ee 99:1 dr

CH3O

H O NO2

EtO2C

Ph O

O 15

16

140

O EtO2C 17 NO2 organocat 92% ee HO

OCH3 NO2 18

ENANTIOSELECTIVE ORGANOCATALYZED CONSTRUCTION OF CARBOCYCLIC RINGS O EtO2C

EtO2C 20 O 19

H NO2

Ph

NO2

CO2Et organocat 95% ee

NO2 CO2Et

21

N O

O

MeO2C

22

23 organocat MeO2C 24 99% ee

O

O

Damien Bonne and Jean Rodriguez of Aix-Marseille Université employed (Organic Lett. 2008, 10, 5409) intramolecular dipolar cycloaddition to convert the initial adduct between 22 and 23 to the cyclopentane 24. They also prepared cyclohexane derivatives using this approach. The diketone 25 is prochiral. Benjamin List of the Max-Planck Institut, Mülheim devised (Angew. Chem. Int. Ed. 2008, 47, 7656) an organocatalyst that mediated the intramolecular aldol cyclization of 25 to 26 in high ee. Mark J. Kurth of the University of California, Davis developed (Angew. Chem. Int. Ed. 2008, 47, 6407) a resin bound organocatalyst that, inter alia, combined 27 with 28 to give the Robinson annulation product 29. Dawei Ma of the Shanghai Institute of Organic Chemistry reported (Organic Lett. 2008, 10, 5425) a related Robinson annulation, combining 30 and 14 to give 31. O

O

O 28 O organocat 93% ee 25

O

O H

O 26

PhMe2Si

14 MeO2C

30

organocat MeO2C 99% ee

organocat 91% ee

27

O O

CO2t Bu 32

31

O

H

H

O 33 organocat 99% ee

29

O

34

SiMe2Ph

The most powerful such Robinson annulation reported to date was by (Organic Lett. 2008, 10, 3753) Karl Anker Jørgensen of Aarhus University, Denmark, who showed that α-alkyl acetoacetates such as 32 could be combined with the silyl aldehyde 33 to give the 5-silyl cyclohexenones 34. Conjugate addition to such cyclohexenones is expected to proceed with high diastereocontrol, leading, for instance, after oxidative desilylation to the 5,6-dialkyl cyclohexenone.

141

71. Organocatalytic C-C Ring Construction: (+)-Ricciocarpin A (List) and (-)-Aromadendranediol (MacMillan) December 14, 2009

Yoshiji Takemoto of Kyoto University designed (Organic Lett. 2009, 11, 2425) an organocatalyst for the enantioselective conjugate addition of alkene boronic acids to γ-hydroxy enones, leading to 1 in high ee. Attempted Mitsunobu coupling led to the cyclopropane 2, while bromoetheriﬁcation followed by intramolecular alkylation delivered the cyclopropane 3. CH3O

CH3O

CH3O

1. NBS

PPh3

2

DIAD

Ph

94:6 dr O

O

o -NsNH2

HO

OH

EtO2C

O

O

OH

OH

5 H

DBU organocat

4

O 3

O O

Ph

O

Ph 1 95% ee

O O

Ph

2. t-BuOK

vs. 7:1 dr 99% ee

Ph 6

5:1 dr 99% ee CO2Et

Ph

CO2Et

7

Jeffrey W. Bode of the University of Pennsylvania demonstrated (Organic Lett. 2009, 11, 677) a remarkable dichotomy in the reactivity of N-heterocyclic carbenes. A triazolium precatalyst combined 4 and 5 to give 6, whereas an imidazolium precatalyst combined 4 and 5 to give 7. Xinmiao Liang of the Dalian Institute of Chemical Physics and Jinxing Ye of the East China University of Science and Technology devised (Organic Lett. 2009, 11, 753) a Cinchona-derived catalyst that converted the prochiral cyclohexenone 8 into the diester 10 in high ee. Rich G. Carter of Oregon State University found (J. Org. Chem. 2009, 74, 2246) a simple sulfonamide-based proline catalyst that effected the Mannich condensation of the prochiral ketone with ethyl glyoxalate 12 and the amine 13, leading to the amine 14. OCH3 H O 9

CO2Et CO2Et

O

organocat 8

10

O CO2Et 96% ee CO2Et

CO2Et O 12 organocat

O

H

N CO2Et

OCH3 11

13 H2N

142

14

2.4 : 1 dr 99% ee

ORGANOCATALYTIC C-C RING CONSTRUCTION In the ﬁrst pot of a concise, three-pot synthesis of (-)-oseltamivir, Yujiro Hayashi of the Tokyo University of Science combined (Angew. Chem. Int. Ed. 2009, 48, 1304) 15 and 16 in the presence of a catalytic amount of diphenyl prolinol TMS ether to give an intermediate nitro aldehyde. Addition of the phosphonate 17 led to a cyclohexenecarboxylate, that on the addition of the thiophenol 18 equilibrated to the ester 19. Ying-Chun Chen of Sichuan University used (Organic Lett. 2009, 11, 2848) a related diaryl prolinol TMS ether to direct the condensation of the readily-prepared phosphorane 20 with the unsaturated aldehyde 21 to give the cyclohexenone 22. Armando Córdova of Stockholm University also used (Tetrahedron Lett. 2009, 50, 3458) diphenyl prolinol TMS ether to mediate the addition of 24 to 23. The subsequent intramolecular aldol condensation proceeded with high diastereocontrol, leading to 25. SH

NO2 t-BuO2C 16 organocat; CO2Et O O 17 P /Cs2CO3;

O H 15

H O

SAr 18

t-BuO2C

O

CO2Et

O

Ph3P

19

O

20

EtO OEt H O CN

CO2CH3 CN 6:1 dr 95% ee

24 O organocat

25 H

O

93% ee 22

E

N H 27 organocat; Sm(OiPr)3

26 O

CO2t-Bu

O

Ot-Bu LiClO4 DABCO organocat

E O

OH

H

CO2CH3 23

H

21

O

O O 99% ee 28

O (+)-Ricciocarpin A

Benjamin List of the Max-Planck Institut, Mülheim employed (Nat. Chem. 2009, 1, 225) a MacMillan catalyst for the reductive cyclization of 26. Subsequent epimerization and Tishchenko hydride transfer then proceeded with high diastereoselectivity, leading directly to the liverwort-derived (+)-Ricciocarpin A 28. O H O

30 O cat G2

29

O 31

HO

O OTMS cat (S)-proline

H

organocat 32 O HO

5:1 dr 95% ee

H 33

OH

(-)-Aromadendranediol

David W. C. MacMillan of Princeton University devised (Angew. Chem. Int. Ed. 2009, 48, 4349) a remarkable one-pot three-component assembly of the lactone 32. Crossmetathesis of 29 with 30 gave a keto aldehyde. Direct addition of the furan 31 and an chiral imidazolidinone catalyst effected conjugate addition to the unsaturated aldehyde. A third catalyst, (S)-proline, then mediated intramolecular aldol condensation. The crystalline lactone 32 was readily carried on to (-)-Aromadendranediol 33.

143

72. Transition Metal-Mediated Construction of Carbocycles: Dimethyl Gloiosiphone A (Takahashi), Pasteurestin A (Mulzer), and Pentalenene (Fox) August 18, 2008

There continue to be new developments in transition metal- and lanthanide-mediated construction of carbocycles. Although a great deal has been published on the asymmetric cyclopropanation of styrene, relatively little had been reported for other classes of alkenes. Tae-Jeong Kim of Kyungpook National University has devised (Tetrahedron Lett. 2007, 48, 8014) a Ru catalyst for the cyclopropanation of simple α-oleﬁns such as 1. X. Peter Zhang of the University of South Florida has developed (J. Am. Chem. Soc. 2007, 129, 12074) a Co catalyst for the cyclopropanation of alkenes such as 5 having electronwithdrawing groups. CO2Et

+

Ru* cat

CO2Et

N2 1

2

3

CO2Et

+

94% ee 84 : 16

92% ee 4

O

O CO2 t -Bu Co* cat +

CO2 t -Bu 89% ee

N2

5

7

6

Alexandre Alexakis of the Université de Genève has reported(Angew. Chem. Int. Ed. 2007, 46, 7462) simple monophosphine ligands that enabled enantioselective conjugate addition to prochiral enones, even difﬁcult substrates such as 8. Seunghoon Shin of Hanyang University has found (Organic Lett. 2007, 9, 3539) an Au catalyst that effected the diastereoselective cyclization of 10 to the cyclohexene 11, and Radomir N. Saicic of the University of Belgrade has carried out (Organic Lett. 2007, 9, 5063), via transient enamine formation, the diastereoselective cyclization of 12 to the cyclohexane 13. Alois Fürstner of the Max-PlanckInstitut, Mülheim has devised (J. Am. Chem. Soc. 2007, 129, 14836) a Rh catalyst that cyclized the aldehyde 14 to the cycloheptenone 15. O

O

Boc

O

O

AlEt3

Au cat

Cu* cat 8 Br

H

8 : 1 dr

93% ee 9

BnO R3SiO 12

10 H

O N H Pd cat

O 11

H

O BnO

BnO 7 : 1 dr R3SiO 13

144

Rh cat H

BnO 14

O

BnO BnO O

15

TRANSITION METAL-MEDIATED CONSTRUCTION OF CARBOCYCLES Some of the most exciting investigations reported in recent months have been directed toward the direct diastereo- and enantioselective preparation of polycarbocyclic products. RaiShung Liu of National Tsing-Hua University has extended (J. Org. Chem. 2007, 72, 567) the intramolecular Pauson-Khand cyclization to the epoxy enyne 16, leading to the 5-5 product 17. Michel R. Gagné of the University of North Carolina has devised (J. Am. Chem. Soc. 2007, 129, 11880) a Pt catalyst that smoothly cyclized the polyene 18 to the 6-6 product 19. Yoshihiro Sato of Hokkaido University and Miwako Mori of the Health Science University of Hokkaido have described (J. Am. Chem. Soc. 2007, 129, 7730) a Ru catalyst for the cyclization of 20 to the 5-6-5 product 21. Each of these processes proceeded with high diastereocontrol. O

Me O

Co2(CO)8;

OH

Me O

CO /

O 17 H

16

18 O

O Ru cat O 20

O

Pt cat

O

19

O 21

O

Transition metal-mediated polycarbocyclic construction has also been applied to natural product synthesis. Takashi Takahashi of the Tokyo Institute of Technology has developed (J. Org. Chem. 2007, 72, 3667) the Pd-mediated spirocyclization of 22 to 23, leading to a formal synthesis of dimethyl gloiosiphone A 24. Johann Mulzer of the Universität Wien employed (Angew. Chem. Int. Ed. 2007, 46, 9320) the Vollhardt cyclization of 25 to 26 in an enantioselective synthesis of pasteurestin A 27. In a particularly straightforward approach, Joseph M. Fox of the University of Delaware used (Organic Lett. 2007, 9, 5625) Rh∗mediated enantioselective cyclopropanation of 28 to set the absolute conﬁguration of (-)-pentalenene 32. OMPM Pd cat

O

PhSO2 PhSO2

OCH3

OPMP

O HO

PhSO2 PhSO2

OAc

22

23

TBSO CoCp(CO)2

24

HO

TBSO H

25

26 CO2Et

H 28

SiR3

N2

EtO2C

EtO2C

29 H

Rh* cat 30

OCH3 OCH3 Dimethyl Gloiosiphone A

SiMe3

1. TMSCl

SiR3

O

2. Co2(CO)8 31

145

CO2H 27 OH Pasteurestin A

SiR3

32

H (-)-Pentalenene

73. Transition Metal-Mediated Ring Construction: The Yu Synthesis of 1-Desoxyhypnophilin December 15, 2008

Both 1 and 3 are inexpensive prochiral starting materials. Tae-Jong Kim of Kyungpook National University devised (Organomet. 2008, 27, 1026) a chiral Cu catalyst that efﬁciently converted 1 (other ring sizes worked as well) to the enantiomerically pure ester 2. Alexandre Alexakis of the University of Geneva found (Adv. Synth. Cat. 2008, 350, 1090) a chiral Cu catalyst that mediated the enantioselective coupling of 3 with Grignard reagents such as 4. The π-allyl Pd complex derived from 6 is also prochiral. Barry M. Trost of Stanford University showed (Angew. Chem. Int. Ed. 2008, 47, 3759) that with appropriate ligand substitution, coupling with the phthalimide 7 proceeded to give 8, readily convertible to (-)-oseltamivir (Tamiﬂu) 9, in high ee. PhCO3t-Bu

O

Cu* cat

97% ee

O 1

2

Cl 4

MgBr 95% ee

Cu* cat 5

3

O

O Pd* cat

+ O

H

N SiMe3 PhthN

6

O

7

8

O

CO2H

H2N 98% ee

racemic

O

N

9

CO2Et

Tamiflu

Jonathan W. Burton of the University of Oxford found (Chem Commun. 2008, 2559) that Mn(OAc)3-mediated cyclization of 10 delivered the lactone 12 with high diastereocontrol. John Montgomery of the University of Michigan observed (Organic Lett. 2008, 10, 811) that the Ni-catalyzed cyclization of 12 also proceeded with high diastereocontrol. Ken Tanaka of the Tokyo University of Agriculture and Technology combined (Angew. Chem. Int. Ed. 2008, 47, 1312) Rh-catalyzed ene-yne cyclization of 14 with catalytic ortho C-H functionalization, leading to 16 in high ee. H3CO2C

H3O2C

CO2CH3 Mn(OAc)3

R3SiO

R3SiO

10

146

O O

11

TRANSITION METAL-MEDIATED RING CONSTRUCTION MOMO

O

MOMO

SiMe3 O

O O

Et3SiH

MOMO

MOMO

Ni cat

O 12

SiMe3

OSiEt3

13

H OTBS

OTBS OCH3

CH3CH2O2C CH3CH2O2C

OCH3

CH3CH2O2C

Rh* cat

+

94% ee

CH3CH2O2C 14

15

O

16

O

Eric N. Jacobsen of Harvard University designed (Angew. Chem. Int. Ed. 2008, 47, 1469) a chiral Cr catalyst for the intramolecular carbonyl ene reaction, that converted 17 to 18 in high ee. Using a stoichiometric prochiral Cr carbene complex 20 and the enantiomerically-pure secondary propargylic ether 19, Willam D. Wulff of Michigan State University prepared (J. Am. Chem. Soc. 2008, 130, 2898) a facially-selective Cr-complexed o-quinone methide intermediate, that cyclized to 21 with high ee. CH3O

CH3O

Cr* cat

CH3O O

94% ee

HO

H

17

18 Cr(CO)5

OSiR3 + 19

CH3O

OCH3

CH3O 20

H

94% ee

O 21

Ph

Ph

A variety of methods have been put forward for the transition metal-mediated construction of polycarbocyclic systems. One of the more powerful is the enantioselective Rh-catalyzed stitching of the simple substrate 22 into the tricycle 23 devised (J. Am. Chem. Soc. 2008, 130, 3451) by Takanori Shibata of Waseda University. Inter alia, ozonolysis of 23 delivered the cyclopentane 24 containing two all-carbon quaternary centers. Zhi-Xiang Yu of Peking University has devised both carbonylative (J. Am. Chem. Soc. 2008, 130, 4421), illustrated, and non-carbonylative (J. Am. Chem. Soc. 2008, 130, 7178) Rh-catalyzed cylization of alkenyl cyclopropanes such as 26. Intramolecular aldol condensation followed by further functionalization converted 27 into 1-desoxyhypnophilin 28. Rh* cat Ts

N N Ts

22

O

O

O3 >99% ee

N

23

Ts O

24 O

Rh cat O

CO 25

O

R3SiO 26

27

147

OSiR3

28 1-Desoxyhypnophilin

74. Transition Metal Catalyzed Construction of Carbocyclic Rings: (-)-Hamigeran B August 17, 2009

Several elegant methods for the enantioselective transformation of preformed prochiral rings have been put forward. Derek R. Boyd of Queen’s University, Belfast devised (Chem. Commun. 2008, 5535) a Cu catalyst that effected allylic oxidation of cyclic alkenes such as 1 with high ee. Christoph Jaekel of the Ruprecht-Karls-Universität Heidelberg established (Adv. Synth. Cat. 2008, 350, 2708) conditions for the enantioselective hydrogenation of cyclic enones such as 3. Marc L. Snapper of Boston College developed (Angew. Chem. Int. Ed. 2008, 47, 5049) a Cu catalyst for the enantioselective allylation of activated cyclic enones such as 5. Alexandre Alexakis of the University of Geneva showed (Angew. Chem. Int. Ed. 2008, 47, 9122) that dienones such as 8 could be induced to undergo 1,4 addition, again with high ee. O

PhCO3t Bu Cu* cat 1

2

CO2CH3 O

6

SiMe3

O

O

O

H2

Ph 90% ee

Rh* cat 3

4

O

CH3MgBr O

90% ee

CO2CH3 O

Cu* cat

Cu* cat 5

7

90% ee

8

9

92% ee

Tsutomu Katsuki of Kyushu University originated (J. Am. Chem. Soc. 2008, 130, 10327) an Ir catalyst for the addition of diazoacetate 11 to alkenes such as 10 to give the cyclopropane 12 with high chemo-, enantio- and diastereoselectivity. Weiping Tang of the University of Wisconsin found (Angew. Chem. Int. Ed. 2008, 47, 8933) a silver catalyst that rearranged cyclopropyl diazo esters such as 13 to the cyclobutene 14 with high regioselectivity. CO2Et H

N2 11 Ir* cat 10

96% ee 91:9 dr

EtO2C 12

EtO2C CO2Et

Ag cat

EtO2C CO2Et

CO2Et

H 13

N2

14

CO2Et

Zhang-Jie Shi of Peking University demonstrated (J. Am. Chem. Soc. 2008, 130, 12901) that under oxidizing conditions, a Pd catalyst could cyclize 15 to 16. Sergio Castillón of the Universitat Rovira i Virgili, Tarragona devised (Organic Lett. 2008, 10, 4735) a Rh catalyst for the enantioselective cyclization of 17 to 18. Virginie Ratovelomanana-Vidal of the ENSCP Paris and Nakcheol Jeong of Korea University established (Adv. Synth. Cat. 2008, 350, 2695) conditions for the enantioselective intramolecular Pauson-Khand cyclization of 19 to give, after hydrolysis, the cyclopentenone 20. Quanrui Wang of Fudan University,

148

TRANSITION METAL CATALYZED CONSTRUCTION OF CARBOCYCLIC RINGS Cristina Nevado of the Universität Zurich and Andreas Goeke of Shanghai Givaudan described (Angew. Chem. Int. Ed. 2008, 47, 10110) the Au-mediated rearrangement of 21 to give, after hydrolysis, the cyclopentene 22 with minimal racemization. An alternative Au process converted 21 into the corresponding cyclohexenone with high ee. O

O

O

O O

Pd cat

Ph

Ph

O

H 2.H+ / H2O HO

O

AcO

O

1. Rh* cat/CO

1. Aucat

O

19

O > 95% ee

18

17

16

O

R3SiO Rh* cat

R3SiO

ox 15

H

99% ee 2. MeOH K2CO3 21

94% ee 20

89% ee 22

We developed (J. Org. Chem. 2008, 73, 8030) a general method for the conversion of an aliphatic aldehyde 23 to the cyclohexenone 25, condensation with the commercial phosphorane 24 followed by Fe-mediated cyclocarbonylation of the resulting alkenyl cyclopropane. Michel R. Gagné of the University of North Carolina devised (Angew. Chem. Int. Ed. 2008, 47, 6011) a Pt catalyst for the cyclization of polyalkenes such as 26 in high ee. Nicolai Cramer of ETH Zurich found (Angew. Chem. Int. Ed. 2008, 47, 9294) that ring expansion of the prochiral 28 to the cyclohexenone 29 could be effected with substantial enantioselectivity. Bruce H. Lipschutz of the University of California, Santa Barbara extended (J. Am. Chem. Soc. 2008, 130, 14378) his enantioselective conjugate reduction to substrates such as 30, leading, via aldol condensation, to the cyclohexane 31. O H 23

1.

PPh3

O Pt* cat

24 O

2. Fe cat / hν

OH

OH O

O Rh* cat

29

32

O

N2

O

O

OH 96% ee

(EtO)2MeSiH

30 OMe OBn

Rh cat.

MeO

27 Cu* cat

94% ee 28

87% ee

26

25

31 OH O O

Br

OBn 33

O

34

(-)-HamigeranB

Many methods for transition metal-mediated polycarbocyclic construction have also been reported. We showed (J. Org. Chem. 2008, 73, 7560) that cyclization of 32 gave 33, which we carried on to (-)-Hamigeran B 34.

149

75. Transition Metal-Mediated C-C Ring Construction: The Stoltz Synthesis of (-)-Cyanthiwigin F December 21, 2009

X. Peter Zhang of the University of South Florida extended (Organic Lett. 2009, 11, 2273) Co-catalyzed asymmetric cyclopropanation to the activated ester 2. The product 3 readily coupled with amines. André B. Charette of the Université de Montréal showed (J. Am. Chem. Soc. 2009, 131, 6970) that even α-oleﬁns such as 4 could be cyclopropanated in high ee with the diazo amide 5. Xue-Long Hou of the Shanghai Institute of Organic Chemistry established (J. Am. Chem. Soc. 2009, 131, 8734) conditions for the enantioselective coupling of 7 and 8 to give 9, in which sidechain chirality was also controlled. Tristan H. Lambert of Columbia University found (J. Am. Chem. Soc. 2009, 131, 7536) that “methylene” could be transferred in an intramolecular sense from the epoxide of 10 to the alkene, delivering the cyclopropane 11 in high ee. O

O NC

OSu N2 2

O

O

Co* cat

1

3

N2

CO2Su 91% ee

4

O OCO2Me Ph

9

Ph O

N

Rh* cat

6

CN OBn

La cat

O

12: 1 d 95% eer

93:7 dr > 90% ee

O

OBn

NPh2 Ph2N 8 Pd* cat LiHMDS

7

N 5

O

10

90% ee

11

Yuichi Kobayashi of the Tokyo Institute of Technology established (Organic Lett. 2009, 11, 1103) that the 2-picolinoxy leaving group worked well for the SN2' coupling with 13 to give 14. Chang Ho Oh of Hanyang University developed (J. Org. Chem. 2009, 74, 370) a new route to cyclopentenones such as 16, by gold-catalyzed cyclization of diynes such as 15. David J. Procter of the University of Manchester used (J. Am. Chem. Soc. 2009, 131, 7214; MgBr OTBS

OTBS Br 2-PyCO2

12

CuBr.Me2S ZnBr2

SmI2

O O 17

THF/H2O

O

Au cat

OAc 14

15

Br

O

O

O

OAc

13

HO HO2C

16 H

O

H

O

O

O

THF/t-BuOH 19

18

150

O

SmI2 OH OH 20

TRANSITION METAL-MEDIATED C-C RING CONSTRUCTION Tetrahedron Lett. 2009, 50, 3224) SmI2 to cyclize 17 to 18 and 19 to 20, each with high diastereocontrol. Yoshiaki Nishibayashi of the University of Tokyo devised (Angew. Chem. Int. Ed. 2009, 48, 2534) Ru catalysts for the cyclization of an enyne such as 21 to the cyclohexadiene 22. Laurel L. Schafer of the University of British Columbia developed (J. Am. Chem. Soc. 2009, 131, 2116) a Zr catalyst for the diastereocontrolled cyclization of amino alkenes such as 23. Hongbin Zhai of the Shangahi Institute of Organic Chemistry showed (J. Org. Chem. 2009, 74, 2592) that the Mo-mediated cyclization of 25 also proceeded with high diastereocontrol. Even more impressive was the selectivity Kozo Shishido of the University of Tokushima demonstrated (Tetrahedron Lett. 2009, 50, 1279) for the cyclization of 27. NH2

Ru cat Ph

Ph

Ph

Zr cat NH2 19:1 dr

Ph

21

23

22

24

TBSO Mo(CO)3DMF H

I

O O

O 25

26

TBSO Pd cat

OSiR3 95% de

OSiR3

27

28

Professor Lambert established (J. Am. Chem. Soc. 2009, 131, 2496) that the rearrangement of the vinyl cyclopropane 29 to the cyclopentene 30, usually a high temperature process, could be effected with MgI2. We (J. Org. Chem. 2009, 74, 2433) found that Fe-mediated cyclocarbonylation of 31 led to the cyclohexenone 32. O

O CO2Me

MgI2

CO2Me

O

Fe(CO)5/hν;

O

DBU

CH3CN 29

30 O

O O

O 33

31

32

O

O

O

O

O O

Pd* cat O

4.4:1 dr 34 99% ee

O 35 (-)-Cyanthiwigin F

Brian M. Stoltz of Caltech prepared (Nature 2008, 453, 1228) the diester 33 by dimerization of diallyl succinate followed by methylation. Pd-mediated rearrangement delivered 34, the central ring of (-)-Cyanthiwigin 35, in high de and ee.

151

76. Intermolecular and Intramolecular Diels-Alder Reactions: (-)-Oseltamivir (Fukuyama), Platensimycin (Yamamoto) and 11,12-Diacetoxydrimane (Jacobsen) August 25, 2008

Powerful methods for catalytic, enantioselective intermolecular Diels-Alder reactions have been developed. Ben L. Feringa and Gerard Roelfes of the University of Groningen have shown (Organic Lett. 2007, 9, 3647) that a catalyst prepared by combining salmon testes DNA with a Cu complex directed the absolute sense of the addition of 1 to cyclopentadiene 2. Mukund P. Sibi of North Dakota State University has reported (J. Am. Chem. Soc. 2007, 129, 395) related work with achiral pyrazolidinone dienophiles and chiral Cu catalysts. Tohru Fukuyama of the University of Tokyo found (Angew. Chem. Int. Ed. 2007, 46, 5734) that the MacMillan catalyst 5 was effective at mediating the addition of acrolein 4 to the pyridine-derived diene 3, enabling an enantioselective synthesis of the prominent antiviral (-)-oseltamivir (tamiﬂu) 7. Hisashi Yamamoto of the University of Chicago has demonstrated (J. Am. Chem. Soc. 2007, 129, 9534 and 9536) that the novel catalyst 10 effected addition of methyl acrylate 9 to the diene 8, leading to an elegant enantioselective synthesis of the tetracycle 12, the key intermediate in the Nicolaou synthesis of platensimycin. Ph O N

Ph

cat DNA.Cu

N

N

1

99:1 dr 98% ee

O 2

N

H

O 4

N 3 Cbz

O

Cbz

N

cat 5

H 6 H

CO2Et

N

Ph 7 (-)-Oseltamivir

O

O

NH2 O

CO2CH3 9 cat 10 8

N HCl

5

Ph Ph F O

N B H Ph

O

>99:1 dr 11 CO2CH3 99% ee

N

O

12

F

Tf

F 10

Tf

F F

New illustrations of the power of the intramolecular Diels-Alder reaction have been put forward. Demonstrating the inﬂuence of a single subsituent on the tether, William R. Roush of Scripps/Florida found (Organic Lett. 2007, 9, 2243) that cyclization of 13 led to the diastereomer 14, complementary to the result observed with an acyclic triene. Ryo Shintani and Tamio Hayashi of Kyoto University have extended (Angew. Chem. Int. Ed. 2007, 46, 7277) their studies of chiral diene-based Rh catalysts to the enantioselective cyclization of alkynyl dienes such as 16. Jonathan W. Burton of the University of Oxford and Andrew B. Holmes of the University of Melbourne employed (Chem. Commun. 2007, 3954) the 152

INTERMOLECULAR AND INTRAMOLECULAR DIELS-ALDER REACTIONS MacMillan catalyst 5 for the cyclization of 18 to 19. It is impressive that ent-5 catalyzed the cyclization of 18 cleanly into the diastereomer of 19 in which both of the newly-created stereogenic centers were inverted. CO2CH3

CO2CH3

SiMe2 140° O

20 h

H3CO2C

SiMe2 > 20:1 dr

O 13

OH

14

15 Ph

Ph

H3CO2C H3CO2C

Rh* cat

H3CO2C 94% ee

H3CO2C 16

17 PhMe2Si

PhMe2Si O

O

cat 5

OBn

OBn H H

O 18

19

H

O

Transannular intramolecular Diels-Alder (TADA) cyclizations have been widely employed. Although a great deal has been learned about relative stereocontrol, little progress had been made on asymmetric catalysis of the cyclization of prochiral trienes such as 20. Eric N. Jacobsen of Harvard University has now found (Science 2007, 317, 1736) that the o-ﬂuoro complex 21 served effectively. The power of this approach was illustrated by the conversion of the adduct 22 into the natural product 11,12-diacetoxydrimane 23.

O Si 20

O Si

O

O

Ph Ph

OAc

cat 21

OAc

N B H

83% ee 23 11, 12-Diacetoxydrimane

22

153

21

NTf2

O F

77. Intermolecular and Intramolecular Diels-Alder Reactions: Platencin (Banwell), Platensimycin (Matsuo), (-)-Halenaquinone (Trauner), (+)-Cassaine (Deslongchamps) August 24, 2009

José Barluenga of the Universidad de Oviedo described (Organic Lett. 2008, 10, 4469) a powerful route from lithiated arenes such as 1 to the benzocyclobutane 3, the immediate precursor to the powerful o-quinone methide Diels-Alder diene. Michael E. Jung of UCLA developed (Organic Lett. 2008, 10, 3647) a triﬂimide catalyst for the inverse electron demand coupling of the highly substituted diene 4 with the enol ether 5 to give 6 with high diastereocontrol. O CH3O Li

Cp2Zr(Me)Cl, Br ; Cl

1

O

CH3O +

cat Tf2NH

TESO

2

TESO

3

4

OTES TESO

5

6

Joseph M. Fox of the University of Delaware showed (J. Org. Chem. 2008, 73, 4283) that the cyclopropene carboxylate 8 was a powerful and selective dienophile. Richard P. Hsung and Kevin P. Cole of the University of Wisconsin ﬁnally (Adv. Synth. Cat. 2008, 350, 2885) reduced to practice the long-sought enantioselective Diels-Alder cycloaddition of a trisubstituted aldehyde, 11. Li Deng of Brandeis University devised (J. Am. Chem. Soc. 2008, 130, 2422) a Cinchona-derived catalyst for Diels-Alder cycloaddition to the diene 13 with high ee. Miguel Á. Sierra of the Universidad Complutense, Madrid, and Alejandra G. Suárez of the Universidad Nacional de Rosario described (Organic Lett. 2008, 10, 3389) a clever switchable chiral auxiliary 16 that favored diastereomer S-18 on thermal addition, but R-18 with EtAlCl2. O +

H

O

H O

N

Bn

N

CO2Me

RT N O

CH2Cl2

O

7

8

O OH 13

Q* cat

11

O O O

O 99% ee HO

15

H 12

16

13:87 dr

17 18

O PhO

90% ee OTBS

10

O O

14

Bn CO2Me O N

O

Cr* cat

TBSO

9 O

O

O

H

with EtAlCl2:

CO2R* 97:3 dr CO2R*

154

INTERMOLECULAR AND INTRAMOLECULAR DIELS-ALDER REACTIONS New approaches to the intramolecular Diels-Alder reaction continue to be introduced. Mathias Christmann, now at the TU Dortmund, showed (Angew. Chem. Int. Ed. 2008, 47, 1450) that a secondary amine organocatalyst converted the prochiral dialdehyde 19 into the bicyclic diene 20 with high de and ee. Martin G. Banwell of the Australian National University prepared (Organic Lett. 2008, 10, 4465) the triene 21 in high ee by microbiological oxidation of iodobenzene. On warming, 21 was converted smoothly into 22, which was carried on in a formal synthesis of platencin.

H

1. organocat

O

O

TBSO

2. NaBH4

O 19

O

OH

O

4:1 dr 98% ee

H

O 20

21

TBSO

22

Jun-ichi Matsuo of Kanazawa University was able (Organic Lett. 2008, 10, 4049) to induce (neat, 180 °C) the intermolecular Diels-Alder cycloaddition of 23 with 24, delivering the cycloadduct 25 with 11:1 diastereocontrol. This set the two rings and angular substitution of the key platensimycin intermediate 26. Dirk Trauner, now at the University of Munich, found (J. Am. Chem. Soc. 2008, 130, 8604) that the intramolecular Diels-Alder cyclization of 27 was most efﬁcient at high pressure. The product 28 was readily tautomerized and then oxidized to give (-)-Halenaquinone 29. Pierre Deslongchamps of the Université de Sherbrooke extensively investigated (J. Am. Chem. Soc. 2008, 130, 13989) the transannular Diels-Alder cyclization of 30 and derivatives. The adduct 31 was carried on to (+)-cassaine 32. OCH3 BzO

O

O

24 1.

OTBS BzO H O

2. H+/H2O

23 O

O 25

26

O O

O

27

O

O O

10 kbar

O

O O O

O

O 28

O

O

O O N O

O

N

O

OTBS HO

O 31

155

O N

123 °C

OTBS 30

O O 29 (-)-Halenaquinone

O 32 (+)-Cassaine

78. Stereocontrolled Carbocyclic Construction: The Trauner Synthesis of the Shimalactones December 22, 2008

Benjamin List of the Max Planck Institute, Mülheim devised (J. Am. Chem. Soc. 2008, 130, 6070) a chiral primary amine salt that catalyzed the enantioselective epoxidation of cyclohexenone 1. Larger ring and alkyl-substituted enones are also epoxidized with high ee. O

O cat* O 92% ee

50% H2O2 1

2

Three- and four-membered rings are versatile intermediates for further transformation. Tsutomu Katsuki of Kyushu University developed (Angew. Chem. Int. Ed. 2008, 47, 2450) an elegant Al(salalen) catalyst for the enantioselective Simmons-Smith cyclopropanation of allylic alcohols such as 3. Kazuaki Ishihara of Nagoya University found (J. Am. Chem. Soc. 2007, 129, 8930) chiral amine salts that effected enantioselective 2+2 cycloaddition of α-acyloxyacroleins such as 5 to alkenes to give the cyclobutane 7 with high enantio- and diastereocontrol. Al* cat

OH TrO

Et2Zn/CH2I2

3

OH TrO

87% ee 4 O

H +

5

O ArCO2

O

cat* O

H 7

6

Ar 93 : 7 dr 95% ee

Gideon Grogan of the University of York overexpressed (Adv. Synth. Cat. 2008, 349, 916) the enzyme 6-oxocamphor hydrolase in E. coli. The 6-OCH so prepared converted prochiral diketones such as 8 to the cyclopentane 9 in high ee. Richard P. Hsung of the University of Wisconsin found (Organic Lett. 2008, 10, 661) that the carbene produced by oxidation of the ynamide 10 cyclized to 11 with high de. Teck-Peng Loh of Nanyang Technological University extended (J. Am. Chem. Soc. 2008, 130, 7194) butane-2,3-diol directed cyclization to the preparation of the cyclopentane 15. Note that sidechain relative conﬁguration is also controlled. We established (J. Org. Chem. 2008, 73, 3467) that the thermal ene reaction of 17 delivered the tetrasubstituted cyclopentane 18 as a single diastereomer.

156

STEREOCONTROLLED CARBOCYCLIC CONSTRUCTION O

O

O

6-OCH; > 95% ee

TMSCH=N2 9

8 Ph

O

Ph

O O O

N

Ph

CO2CH3

CO2CH3

Ph O

11

10 TIPSO

Br H

TiBr4

Br H OH + TIPSO

O

TIPSO

O 13

> 95:5 de O CO2CH3

12

O

+

O N

14

15

10 : 1

R3SiO

OBn

R3SiO

200 °C

OBn

24 h

CO2Et

R3SiO

17

R3SiO

OH

O 16

18

CO2Et

Tony K. M. Shing of the Chinese University of Hong Kong devised (J. Org. Chem. 2007, 72, 6610) a simple protocol for the conversion of carbohydrate-derived lactones such as 19 to the highly-substituted, enantiomerically-pure cyclohexenone 21. Hiromichi Fujioka and Yasuyuki Kita of Osaka University established (Organic Lett. 2007, 9, 5605) a chiral diol-mediated conversion of the cyclohexadiene 22 to the diastereomerically pure cyclohexenone 24. O

OEt P OEt 20

O O

1.

O

O RO

O

2. TPAP NMO K2CO3

OR

O O RO

19

Ph

OR 21

O

CH3O

Ph

CH3O

Ph

O

Ph

O

O NBS

Ph O

CH3OH

Ph O

PDC

Br 22

BH3;

O

23

24

Dirk Trauner, now of the University of Munich, reported (Organic Lett. 2008, 10, 149) an elegant assembly of the neuritogenic polyketide shimalactone A 28. As anticipated, the polyene prepared by Stille coupling of the iodide 25 with the stannane 26 underwent 8 π cyclization to 27, that then spontaneously underwent 8 π cyclization to 28, with substantial diastereocontrol. OH

SnMe3

O

O + O

cat Pd

26

O

H HO

HO

I O

O 25

O

O

27

157

O

5:1 28 Shimalactone A

79. Stereocontrolled Carbocyclic Construction: (-)-Mintlactone (Bates), (-)-Gleenol (Kobayashi), (-)-Vibralactone C (Snider) August 31, 2009

Nigel S. Simpkins, now at the University of Birmingham, found (Chem. Commun. 2008, 5390) that the prochiral cyclopropane amide 1 could be deprotonated to give, after alkylation, the substituted cyclopropane 3 with high enanantio- and diastereocontrol. In the course of a synthesis of (+)-Lineatin, Ramon Alibés of the Universitat Autònoma de Barcelona optimized (J. Org. Chem. 2008, 73, 5944) the photochemical cycloaddition of 4 and 5 to give, after reductive dechlorination, the cyclobutene 6. O

O

PivO

O

LiNR*2; (iPr)2N

(i Pr)2N

Br

1

Cl PivO / hν;

O

Zn /MW

90% ee 3

2

Cl O 5

4

O 88:12 dr

6

In a related reaction, José L. García Ruano and M. Rosario Martín of the Universidad Autónoma de Madrid observed (J. Org. Chem. 2008, 73, 9366) that the cycloaddition of 8 to 7 proceeded with high regio- and diastereocontrol, to give the cyclopentene 9. Joseph M. Ready of UT Southwestern in Dallas developed (Angew. Chem. Int. Ed. 2008, 47, 7068) a powerful new cyclopentannulation, condensing the cyclopropane derived from the addition of 11 to 10 with the protected ynolate 12 to give 13, in the presence of a modiﬁed Lewis acid catalyst. Chun-Chen Liao of the National Tsing Hua University, Hsinchu described (Angew. Chem. Int. Ed. 2008, 47, 7325) the oxidative ring contraction of the o-alkoxy phenol 14 to the cyclopentenone 15. Stéphane Quideau of the Université de Bordeaux reported (Organic Lett. 2008, 10, 5211) a related ring contraction. We uncovered (J. Org. Chem. 2008, 73, 9479) a simple protocol for the in situ conversion of an ω-alkenyl ketone such as 16 to the corresponding diazo compound, leading, via dipolar cycloaddition, to the adduct 17.

Ph

O S

8 O

7

OH 14

OEt

10

O

OSiR3

2. EtO2C 9

CO2Et

OEt 1. N 11 2

O

Ph3P

OEt

OCH3

CO2Et

O CO2Et Ph S O

O

12 /Me AlCl 2 O2

13

CO2CH3

1. PhI(OAc)2 HO CH3OH

TsNH-NH2;

O

1

hν

K2CO3 /

2. O2 15

16

158

O

5:1 dr H 17

N

N

H 18

STEREOCONTROLLED CARBOCYCLIC CONSTRUCTION Ulrich Zutter of Roche Basel described (J. Org. Chem. 2008, 73, 4895), in a synthesis of Tamiﬂu, the hydrogenation of 19 to give the cyclohexane with all-cis diastereocontrol. Selective removal of the methyl ethers with trimethylsilyl iodide set the stage for enzymatic ester hydrolysis, delivering 20 in high ee. Jonathan Clayden of the University of Manchester developed (Angew. Chem. Int. Ed. 2008, 47, 5060) a complementary approach for converting benzene precursors to enantiomerically-pure cyclohexenones. In a synthesis of valiolamine, Tony K. M. Shing of the Chinese University of Hong Kong carried out (Organic Lett. 2008, 10, 4137) the direct aldol cyclization of 21 to 22. Catalysis with proline gave the alternative diastereomer. Bernhard Breit of Albert-Ludwigs-Universität, Freiburg developed (Organic Lett. 2008, 10, 5321) a chiral directing group for allylic alcohol hydroformylation. Subsequent carbonyl ene cyclization gave the cyclohexane 24. In pursuit of the complex polycyclic alkaloid gelsemine, Professor Simpkins reported (Organic Lett. 2008, 10, 4747) a remarkable double elimination-intramolecular Michael cyclization, converting 25 into the bridged cyclohexanone 26. O

OH CO2Et 1. H2/Rucat

O

O

2. Me3SiI

O

O

CO2Et

19

CH3O 21

20 OR*

1. Rhcat CO/H2

OR*

N

XX% de

23

O

24 OH

O

O O

O

O

CH3O

OCH3

OCH3

22 CN

O NC

2. SnCl4

O KHMDS

O

98% ee

HO

3. PLE

CO2Et

CO2H

OH

O

O

O

1. TMSOTf O Et3N

N

O 2. HCl 3. NaOCH3 CO2CH3 25

O CO2CH3 26

Roderick W. Bates of Nanyang Technological University found (J. Org. Chem. 2008, 73, 8104), in a synthesis of (-)-Mintlactone 29, that the diastereocontrolled reductive cyclization of 27 to 28 worked best in wet DMF. Susumu Kobayashi of the Tokyo University of Science showed (Chemistry Lett. 2008, 37, 770), en route to (-)-Gleenol 32, that the Claisen rearrangement of 30 delivered the cyclohexene 31 with high diastereocontrol. Barry B. Snider of Brandeis University prepared (J. Org. Chem. 2008, 73, 8049) (-)-Vibralactone C 36 from 33, available from o-anisic acid by the Schultz protocol.

O

H

cat Ru3CO12

DMF/H2O

100 psi CO O

HO

O OTES

O

SnCl2/NaI

OH

OTES 27

28

Br

O 29

30

31

32

(-)-Mintlactone

(-)-Gleenol

I O MOMO CH3O

33

HO

I

O O

2. Bn2NH.TFA

O

O

O

HO

1. O3

O

N

34

O

H 35

O

H

36

(-)-Vibralactone C

159

80. Stereocontrolled Carbocyclic Construction: The Mulzer Synthesis of (-)-Penifulvin A December 28, 2009

Tanmaya Pathak of the Indian Institute of Technology, Kharagpur devised (J. Org. Chem. 2009, 74, 2710) a preparation of enantiomerically-pure oxygenated cyclopropanes such as 3 from carbohydrate precursors. Andrei K. Yudin of the University of Toronto established (Organic Lett. 2009, 11, 1281) a route to aminated cyclobutanes such as 5 based on sigmatropic rearrangement of the β-lactam 4. O

BnO

CH3NO2 BnO 2 NaH BnO BnO 1 SO2Ar 3

O

OMs

CuI, Cs2CO3

N

SO2Ar

N

H

DMF, 4

NO2

5

Stephen C. Bergmeier of Ohio University reported (Tetrahedron 2009, 65, 741) a study of the balance between ﬁve- and six-membered ring formation in the cyclization of aziridines such as 6. Professor Bergmeier also described (Tetrahedron Lett. 2009, 50, 1261) the bridging additions of enones to cyclic allyl silanes such as 8. This is particularly interesting, as 8 is easily prepared by Birch reduction of the corresponding phenyl silane. O SiR3

BF3.OEt2 6

HO

SiMe3 N Ts

2.2:1 dr 7

H

N

11

10 N2

HO

CO2t Bu

SiR3

SnCl4 8

Ts

t -BuMgCl TBSO

O

9

CO2t Bu

O TMS 14 Li

O

O

LDA/HMPA TEMPO TBSO 12

13

15

OTMP

Ullrich Jahn of the Academy of Sciences of the Czech Republic observed (Chem. Eur. J. 2009, 15, 58) that the free-radical cyclization of 11 proceeded to give mainly the diastereomer 12 (~ 1:1 at the secondary allylic position). Daesung Lee of the University of Illinois at Chicago reasoned (J. Am. Chem. Soc. 2009, 131, 8413) that the stereochemical relationship between the O and the adjacent C-H of 13 was such that the C-H would be deactivated. The cyclization of the alkylidene carbene derived from 13 indeed proceeded to give 14, setting the stage for the synthesis of platensimycin. Marco A. Cufolini of the University of British Columbia found (Organic Lett. 2009, 11, 1539) an easy protocol for the generation of a nitrile oxide and subsequent dipolar cycloaddition, by oxidation of the oxime. In a related investigation, Adam J. M. Burrell and 160

STEREOCONTROLLED CARBOCYCLIC CONSTRUCTION Iain Coldham of the University of Shefﬁeld cyclized (Organic Lett. 2009, 11, 1515) the oxime derived from 18, by way of the intermediate nitrone, to give 19 with high diastereocontrol. O

H H 1. H NOH 2

H 3.8:1 dr

2. DIB/TFA

H

O N 17

16

N

i -Pr2NEt Cl

18

O

H2NOH.HCl

O

19

Me3Si O

O H ZnCl2

HO

O O

21

O

Me3Si

23

MeO OMe O CO t -Bu t -BuO2C O 2 Ph 24 Ph 22

SiMe3 20

Li

O O

25

CO2t-Bu 9:1 dr CO2t-Bu 92% ee

Toshio Honda of Hoshi University established (J. Org. Chem. 2009, 74, 3424) that the intramolecular Sakurai cyclization of 20 proceeded with high diastereocontrol, to give 21. Kiyoshi Tomioka of Kyoto University showed (Organic Lett. 2009, 11, 1631) that the chiral ligand 24 directed the absolute course of the cascade addition of 23 to 22. The product 25 was carried on to (-)-Lycorine. OH HO

O

O cat CH3Li

cat TESOTf O

O

OTES 26

27

HO

OH

2. Li/EtNH2 31

microwave CH3O 28 OCH3

29

O

91:9 dr 95% ee

OCH3

O O

1. IBX

1. hν

30

CH3O 95% ee

O

2. NaClO2 O 3. O3 32 4. PDC (-)-Penifulvin A

Pauline Chiu of the University of Hong Kong devised (J. Am. Chem. Soc. 2009, 131, 4556) conditions for the cyclization of the epoxide 26 to 27, with the enantiomerically-pure epoxide controlling the absolute conﬁguration of the tricyclic ring system. Timo V. Ovaska of Connecticut College set (Organic Lett. 2009, 11, 2715) the absolute conﬁguration of 28 by Itsuno-Corey reduction of the corresponding ketone. Cascade cyclization then delivered 29. Tanja Gaich and Johann Mulzer of the University of Vienna designed (J. Am. Chem. Soc. 2009, 131, 452) a short route to the dioxafenestrane insecticide (-)-Pentifulvin A 32. Photocyclization converted the alcohol 30 to a ~ 1:1 mixture of regioisomers. Reduction of one of them gave 31, which was oxidized to 32.

161

81. The Sammakia Synthesis of the Macrolide RK-397 January 7, 2008

The polyene macrolide RK-397 3, isolated from soil bacteria, has antifungal, antibacterial and anti-tumor activity. Tarek Sammakia of the University of Colorado has described (Angew. Chem. Int. Ed. 2007, 46, 1066) the highly convergent coupling of 1 with 2, leading to 3. OH

O

O

H

O

+ O

O

OH O

O

PMBO

1

O

OH

OTBS

2

3

OH OH OH OH OH OH

The preparation of 1 depended on the powerful methods that have been developed for acyclic stereocontrol. Beginning with the allylic alcohol 4, Sharpless asymmetric epoxidation established the absolute conﬁguration of 5. Following the Jung “non-aldol aldol” protocol, exposure of 5 to TMSOTf delivered the aldehyde 6 in high de. Condensation of 6 with the lithium enolate of acetone also proceeded with high de. The resulting alcohol was protected as the MOM ether, to direct the stereoselectivity of the subsequent aldol condensation with 8. Selective β-elimination followed by reduction and protecting group exchange then gave 1. OTMS

OTMS

O

O H OH 4

O

OH 5

6

OTMS

dr = 24:1

7

8

OH O

O HO O

9

O d.r. > 10:1

MOMO

OTMS O

MOMO

+

O H O

O HO O 10

O

O

O

1

anti/syn 4:1

The preparation of 2 took advantage of the power of Brown asymmetric allylation. Allylation of the symmetrical 11 led to the diol 12. This was desymmetrized by selective acetonide formation, to give 13. Ozonolysis, reductive work-up, and protection of the newly-formed 1,3-diol gave 14, setting the stage for oxidation and asymmetric allylation to give 15. Reductive deprotection and oxidation then delivered the acetonide 2.

162

THE SAMMAKIA SYNTHESIS OF THE MACROLIDE RK-397 H

O HO

H O

TBSO

OTBS 11

OH

HO

12

O

O

13 O

O

O

O

O

OH

O

PMB

O

O

O

OTBS

H

PMBO

O

O

OTBS

PMB 14

15

2

The tris acetonide 16 was assembled by addition of the enolate derived from 1 to the aldehyde 2, followed by reduction and protection. Kinetically-controlled metathesis with 17 established the triene 18. Phosphonate-mediated homologation to the pentaene 19 followed by hydrolysis and Yamaguchi macrolactonization then completed the synthesis of the macrolide RK-397 3. TBSO

TBSO O

O

O

OPMB O

H +

O

O 17

O

18

O

OPMB O

O

TBSO

O

G1

O OH O

O

4:1 E/Z

OH O

H O

OPMB

19

O O

OH O

OH

O OH OH OH OH OH OH OH

O O

20

3 MacrolideRK-397

RO2C

163

82. The Maier Synthesis of Cruentaren A February 4, 2008

Cruentaren A 3, isolated from the myxobacterium Byssovorax cruenta, is an inhibitor of mitochondrial F-ATPase. The synthesis of 3 (Organic Lett. 2007, 9, 655; Angew. Chem. Int. Ed. 2007, 46, 5209) by Martin E. Maier of the Universität Tübingen illustrates the power of alkyne metathesis as a tool for the synthesis of complex natural products. Very recently, Alois Fürstner of the Max-Planck-Institut, Mülheim, reported (Angew. Chem. Int. Ed. 2007, 46, 9275) an alternative synthesis, also based on alkyne metathesis, of cruentaren A 3. HO O ODMB

ODMB H

CH3O

O

CH3O

OTBS

O

O

OTBS O

CH3O

HO

O

CH3O TIPSO

OH O

TIPSO

1

N

CH3O

2

3 HO

The alcohol portion of 1 was prepared by Marshall homologation of 4 with 5, leading to 6. Homologation of the derived epoxide 7 then gave 8. Note that the homologation of 7 to 8 required three steps. This might have been accomplished more directly with the Li salt of 1-propyne, easily prepared from commercial 1- or 2-bromopropene. H

O

O

OTBS

+

O

H 4

ODMB

ODMB

MsO

HO

O H

5

OH

OTBS

O

O

6

7

8

Evans auxiliary-controlled homologation of 9 set the relative and absolute conﬁguration of 10, which was carried on to 12. To effect coupling, the acid of 12 was activated with carbonyl diimidazole, then condensed with the bis-alcoholate of 8. This acylation was highly regioselective, giving 1 as the only observed product.

164

THE MAIER SYNTHESIS OF CRUENTAREN A OCH3

CH3O

O

CH3O

O

CH3O

CH3O O

CH3O Ph

TIPSO

H 9

10

O

O

O

ODMB

ODMB OH

TIPSO 11

N O

CH3O

OCH3

CH3O

O

OCH3

CH3O

O O

OH

+

CH3O

OTBS

CH3O

HO

12 TIPSO

8

1

TIPSO

Cruentaren A 3 has two Z alkenes, so the authors chose a bis-alkyne strategy, with a partial hydrogenation of both alkynes at the end of the synthesis. To this end, alkyne metathesis was accomplished with the Schrock tungsten carbine catalyst 13. Homologation to 15 followed by deprotection and hydrogenation then gave enantiomerically pure cruentaren A 3. ODMB CH3O

O

OTBS

ODMB CH3O

CH3O

OTBS

O

cat 13

O

O

OH

CH3O TIPSO

1

OTBS O

CH3O TIPSO

CH3O

O

TIPSO

2

14

(t BuO)3WC(CH3)3)

HO

13

O N

H CH3O

O

N

OTBS

H HO

O

O

O

OTBS

CH3O

OH O

CH3O TIPSO

15

HO Cruentaren A

165

3

83. The Betzer and Ardisson Synthesis of (+)-Discodermolide March 3, 2008

(+)-Discodermolide 3, a potent anticancer agent that works synergistically with taxol, may yet prove to be clinically effective. For the synthetic material to be affordable, a highly convergent synthesis is required. Jean-François Betzer and Janick Ardisson of the Université de CergyPontoise have described (Angew. Chem. Int. Ed. 2007, 46, 1917) such a synthesis, coupling 1 and 2. A central feature of their approach was the repeated application of the inherently chiral secondary organometallic reagent 5. MOMO Ph

HO

I

O

O

O

O

OMOM + I

1 CH3O2C

O

HO

NH2

HO 3

HO TBSO

O

OTES 2

The ﬁrst use of 5 was the addition to the aldehyde 4. The product 6 was ozonized, and the resulting aldehyde was carried on to the α,β-unsaturated ester. Exposure of the hydroxy ester to benzaldehyde under basic conditions delivered, by intramolecular Michael addition, the acetal 7. Ti(Oi Pr)3 H + TBSO

O

O

O

4

1. O3

OCb

2. N

TBSO

O N

O OEt P OEt TBSO

N O 3. PhCH=O

OH 6

5

O

O

O 7

O

Ph

The next addition of the reagent 5 was to the aldehyde 10. The adduct 11 was deprotonated with t-BuLi to effect α-elimination, providing, after protection of the alcohol, the alkyne 12. Coupling of 12 with the amide 7 gave a ketone, enantioselective reduction of which under Itsuno-Corey conditions led, again after protection of the alcohol, to the alkyne 13. 1. t-BuLi; Br HO

Me2CuLi;

1. NaCN 2. Dibal

8

SnBu3 H

Bu3SnCl

O

O

9 2. ox

SnBu3

CbO 5 OH

10

2. MOM-Cl 11

Ph

O H

MOMO SnBu3

O

TBSO 1. t-BuLi;7

3. MOM-Cl

I

1. HF / py 2. TEMPO 3. NaClO2

OMOM

2. Itsuno-Corey 12 OMOM

1. t-BuLi

Ph

O O

SnBu3 4. TMSCH=N2 CH3O2C 5. catPtO2

13

OMOM

166

6. I2

OMOM 1

THE BETZER AND ARDISSON SYNTHESIS OF (+)-DISCODERMOLIDE Oxidation followed by selective hydrogenation and iodine-tin exchange then completed the assembly of 1. Note that PtO2, not typically used for partial hydrogenation, was the catalyst of choice for this congested alkyne. The third application of the enantiomerically-pure reagent 5 was addition to the aldehyde that had been prepared by ozonolysis of 15. Advantage was then taken of another property of the alkenyl carbamate, Ni-mediated Grignard coupling, to form the next carbon-carbon bond with high geometric control. Deprotection of the diene 17 so prepared followed by iodination then completed the synthesis of 2. SnBu3 PMBO

1. H PMBO

O 14

BF3.OEt2 2. TBS-Cl

TBSO OTES 17

PMBO

2. 5 3. TESOTf

TBSO 15

1. DDQ

PMBO

TBSO

2. I2 / Ph3P

Ni cat

Pd cat / 1

TBSO OTES 2

HO TBSO

O O 18

CH3O2C

OTES 16

t-BuLi; B-OMe-9-BBN;

I

MOMO Ph

MgBr

OCb 1. O3

OMOM

OTES 1.H+ / MeOH

O

2. Cl3CC(O)NCO 3. HCl

O

HO HO

HO

O

O NH2

3 (+)-Discodermolide

The convergent coupling of 1 with 2 was carried out under Suzuki conditions. Reduction of the iodide of 2 to the corresponding alkyl lithium followed by exchange with B-OMe-9BBN gave an intermediate organoborane, that smoothly coupled with 1 under Pd catalysis to give 18. Deprotection and carbamate formation then led to (+)-discodermolide 3. This synthesis clearly illustrates the power of 5 as an enantiomerically-deﬁned secondary organometallic reagent, and the synthetic versatility of the product alkenyl carbamates. The ready availability of the three enantiomerically-pure four-carbon fragments 4, 8, and 14 was also a key consideration in the design of this synthesis.

167

84. The Smith Synthesis of (+)-Lyconadin A April 7, 2008

The pentacyclic alkaloid (+)-lyconadin A 3, isolated from the club moss Lycopodium complanatum, showed modest in vitro cytotoxicity. A key step in the ﬁrst reported (J. Am. Chem. Soc. 2007, 129, 4148) total synthesis of 3, by Amos B. Smith III of the University of Pennsylvania, was the cyclization of 1 to 2. O

H

Cbz N

N O

N

Cbz N O

O

O 1

2

3

The pentacyclic skeleton of 3 was constructed around a central organizing piperidine ring 9. This was prepared from the known (and commercial) enantiomerically-pure lactone 4. The akylated stereogenic center of 9 was assembled by diastereoselective hydroxy methylation of the acyl oxazolidinone 5 with s-trioxane, followed by protection. Reduction of the imide to the alcohol led to the mesylate 7, which on reduction of the azide spontaneously cyclized to give, after protection, the piperidine 8. Selective desilylation of the primary alcohol then enabled the preparation of 9. O O

O

OH

Ph

O

O

N3

N OTBS

Ph

O 5

4

6 O

TBSO

N3 OTBS 7

N OTBS

TBSO

N3 OTBS OTBS

Cbz

Cbz N MsO

O

N

8

OTBS I

9

The plan was to assemble the ﬁrst carbocyclic ring of 3 by intramolecular aldol condensation of the keto aldehyde 15. The enantiomerically-pure secondary methyl substituent of 15 derived from the commercial monoester 10. Activation as the acid ﬂuoride followed by selective reduction led to the volatile lactone 11. Opening of the lactone with H3CONHCH3.HCl gave, after protection, the Weinreb amide 12. Alkylation of the derived hydrazone 13, selectively on the methyl group, led, after deprotection, to 15. The intramolecular aldol condensation of 15 did deliver the unstable cyclohexenone 1. Under the acidic conditions of the aldol condensation, the enol derived from the piperidone added in a Michael sense, from the axial direction on the newly-formed ring, to give the trans-fused bicyclic diketone 2.

168

THE SMITH SYNTHESIS OF (+)-LYCONADIN A OTBS

CO2H CO2CH3 10 OTBS

11 O

N

N

12 H

O

N

Cbz O

O

O O

N

13

OCH3

[1]

14

OTBS + 9

Cbz N

Cbz N OTBS

N

N

O

O

2

15

To move forward, it was necessary to epimerize 2 to the cis ring fusion, and also to differentiate the two ketones of 2. These two problems were solved simultaneously by deprotection and epimerization to the cis-fused hemiaminal 16. O H

Cbz N

2

OTBS

N

O H 16

O

17

N

N

N

OTBS

18

O OH

H

O

NH2

CO2CH3 +

19 I O N

H

20 O

O

H NH2

CO2CH3

21

N N (+)-Lyconadin A

22

3

Attempts to deoxygenate the tertiary alcohol of 16 failed, so instead, selective reduction followed by protection delivered 17. Reduction to the axial alcohol followed by dehydration with the Martin sulfurane then installed the trisubstituted alkene of 18. The C-N bond was re-established by exposure of 18 to NIS, leading to the crystalline 19. Activation of the derived ketone with Mander’s reagent followed by reductive deiodination (Et3SiH/Pd) gave 20, Michael addition of which with 21 led to 3.

169

85. The Rychnovsky Synthesis of Leucascandrolide A May 5, 2008

The macrolactone leucascandrolide A 4, isolated from the calcareous sponge L. caveolata, has both cytotoxic and antifungal activity. The key step in the synthesis of 4 reported (J. Org. Chem. 2007, 72, 5784) by Scott D. Rychnovsky of the University of California, Irvine, was the stereoselective condensation of the aldehyde 1 with the allyl vinyl ether 2 to give 3. H O

O

O

Br +

O HO

O

O

O

OMe O

OTIPS

OTIPS

1

O

2

N O

TBDPSO

TBDPSO

O

O

4

3

CH3O Leucascandrolide A

N

H

O

The cyclic ether of 1 was assembled from the crotyl addition product 5. Tandem Ru-catalyzed metathesis/hydrogenation converted 5 to the lactone 6. Reduction of 6 to the lactol followed by activation as the acetate gave 7, axial-selective condensation of which with the enol ether 8 delivered the enone 9. Diastereoselective Itsuno-Corey reduction of 9 followed by protecting group exchange and oxidation then gave 1, containing four of the eight stereogenic centers of leucascandrolide A 4.

G2 cat; O O

O

OTIPS H2 O

5

OSiMe3

Dibal; OTIPS Ac O 2

O OAc

6

+ OTIPS 7

8 H

ZnBr2

O O

OTIPS 1. ItsunoCorey

O

2. TIPSOTf

9

OTIPS 1. p-TsOH EtOH OTIPS 2. Dess-Martin

10

O

O OTIPS

1

The vinyl ether 2 was readily prepared from the corresponding homoallylic alcohol. Condensation of 1 with 2 involved Lewis acid activation of the aldehyde, addition of the resulting carbocation to the vinyl ether, and cyclization with trapping by bromide ion. In this process, the other four of the eight stereogenic centers were assembled. Three of those centers were formed in the course of the reaction. While stereocontrol was not perfect, the 170

THE RYCHNOVSKY SYNTHESIS OF LEUCASCANDROLIDE A route is pleasingly succinct, so practical quantities of diastereomerically pure 3 could be prepared. To complete the synthesis, the secondary alcohol of 3 was methylated. Selective desilyation of the primary alcohol followed by oxidation and desilylation then set the stage for the Mitsunobu macrolactonization. The intermediates in the Mitsunobu reaction are such that the lactonization can proceed with either inversion of absolute conﬁguration at the secondary center, or retention. While the usually-employed Ph3P gave the lactone with retention of absolute conﬁguration, Bu3P led to clean inversion. H O

O

O

O HO

TiBr4

+

OTIPS

Ti(Oi Pr)4

TBDPSO

TBDPSO 1

2

OMe O

12 SePh

OH

O O 13

CH3O

N

OMe O

O

O

N

O

CsO

O

11

O

O +

OMe O OH

O

PhSe O O

O

H

O

O

Br

3

1. DIAD Bu3P 2.

O

OTIPS

Br 1. CH3OTf 2. KOH 3. Jones 4. TBAF

14 H

N O 4

O

CH3O

Leucascandrolide A

O

N

H

O

The last challenge was the establishment of the (Z) alkene of the side chain. This was accomplished using the Toru protocol. Coupling of the secondary bromide with the Cs salt 12 proceeded with inversion of absolute conﬁguration, to give 13. The carboxylates of stronger acids were not sufﬁciently nucleophilic to displace the bromide. Aldol condensation of 13 with the aldehyde 14 gave a mixture of diastereomers, exposure of which to MsCl in pyridine delivered the requisite (Z) alkene 4.

171

86. The Burke Synthesis of (+)-Didemniserinolipid B June 2, 2008

The sulfate (+)-didemniserinolipid B 3, isolated from the tunicate Didemnum sp, has an intriguing spiroether core. A key step in the synthesis of 3 reported (Organic Lett. 2007, 9, 5357) by Steven D. Burke of the University of Wisconsin was the selective ring-closing metathesis of 1 to 2. OH Ph O

O

O

cat G1

O OMs

1

H

O

( )9

( )10

O O S O O

NaO

2

OMs

H

EtO2C

O 3

NH2

(+)-Didemniserinolipid B

The diol 6 that was used to prepare the ketal 1 was readily prepared from the inexpensive D-mannitol 4. Many other applications can be envisioned for the enantiomericallypure diol 6 and for the monoacetate and bis acetate that are precursors to it. HO

OH

AcO OH 1. AcBr

HO HO

Br

Br

2. Ac2O/py

OH

OAc

AcO

4

OAc 5

1. Zn

HO

2. NaOCH3 CH3OH

HO 6

To set up the metathesis, the β,γ-unsaturated ketone 10 was needed. To this end, the keto phosphonate derived from the addition of the phosphonate anion 8 to the lactone 7 was condensed with phenyl acetaldehyde 9. The derived enone 10 was a 5:1 mixture of β,γ- and α,β- regioisomers. O P(OEt)2 8

O 1.

O ( )12

Ph

Ph O

1. MsCl O

H

2.

2.

( )10

7

O

HO

10

/ H+

( )10 OMs

OH

9

HO

6

OH O O ( )9 OMs

O

N Boc 11

O ( )9

H

O

NaH 2

O

O N

Boc

172

cat G1

O

12

H

1

THE BURKE SYNTHESIS OF (+)-DIDEMNISERINOLIPID B The diol 6 is C2-symmetrical, but formation of the ketal 1 dissolved the symmetry, with one terminal vinyl group directed toward the styrene double bond, and the other directed away from it. On exposure to the ﬁrst generation Grubbs catalyst, ring formation proceeded efﬁciently, to give 2. Williamson coupling with the serine-derived alcohol 11 then gave 12. To establish the secondary alcohol of 13 and so of 3, the more electron rich alkene of 12 was selectively epoxidized, from the more open face. Diaxial opening with hydride then gave 13. OH CO2Et O 1. MCPBA 12 2. LiAlH4 O

O N

SePh

H +

O

( )9

cat G2

14

13

Boc OH

OH 1. TsNH-NH2 NaOAc

O H

O ( )9 N

Boc

N

PhSe

1. HCl 2. FMocOSu

O

O 15

H

( )9

2. MCPBA

O

O

O O

16

Boc

EtO2C

CO2Et OH

OH O O HO

NFmoc

O

1. Py.SO3 O

2. Piperidine

EtO2C

O H

H

NaO

17

O

O

O S

O

NH2

H

EtO2C

3 (+)-Didemniserinolipid B

With 13 in hand, another challenge of selectivity emerged. The plan had been to attach the ester-bearing sidechain to 13 using alkene metathesis, then hydrogenate. As the sidechain of 3 contained an additional alkene, this had to be present in masked form. To this end, the α-phenylselenyl ester 14 was prepared. Alkene metathesis with 13 proceeded smoothly, this time using the second generation Grubbs catalyst. The unwanted alkene was then removed by reduction with diimide, and the selenide was oxidized to deliver the α,βunsaturated ester.

173

87. The Kozmin Synthesis of Spirofungin A July 7, 2008

Often, 6,6-spiroketals such as Spirofungin A 3 have a strong anomeric bias. Spirofungin A does not, as the epimer favored by double anomeric stabilization suffers from destabilizing steric interactions. In his synthesis of 3, Sergey A. Kozmin of the University of Chicago took advantage (Angew. Chem. Int. Ed. 2007, 46, 8854) of the normally-destablizing spatial proximity of the two alkyl branches of 3, joining them with a siloxy linker to assure the anomeric preference of the spiroketal. The assembly of 1 showcased the power of asymmetric crotylation, and of Professor Kozmin’s linchpin cyclopropenone ketal cross metathesis. O

HO O

H2 BnO 1

BnO O O Si

OTBS

O

O O Si

O

Pd-C

O

O

CH3

OH OH

CH3

2

OTBS

O

3

To achieve the syn relative (and absolute) conﬁguration of 6, commercial cis-2-butene was metalated, then condensed with the Brown (+)-MeOB(Ipc)2 auxiliary. The accompanying Supporting Information, accessible via the online HTML version of the journal article, includes a succinct but detailed procedure for carrying out this homologation. For the anti relative (and absolute) conﬁguration of 9, it is more convenient to use the tartrate 8 introduced by Roush. 1.

O TBSO

BR*2

5 H 2. BnBr

4

6

iPrO2C O

O

O

+ H

7

BnO TBSO

CO2iPr

O B

HO

OBn

O TBSO 8

9

Driven by the release of the ring strain inherent in 10, ring opening cross metathesis with 6 proceeded to give the 1:1 adduct 11 in near quantitative yield. The derived cross-linked silyl ether 12 underwent smooth ring-closing metathesis to the dienone 1. On hydogenation, the now-ﬂexible ring system could fold into the spiro ketal. With the primary and secondary alcohols bridged by the linking silyl ether, only one anomeric form, 2, of the spiro ketal was energetically accessible.

174

THE KOZMIN SYNTHESIS OF SPIROFUNGIN A O

BnO

O

TBSO

+

O

O

1. TBAF

10

6

O

BnO

cat G2

11 TBSO

3. H

O

BnO 1

BnO O Si OTBS

OTBS

O

Pd-C

BnO O O Si

12

O

+

O

H2

cat G2

BnO

2. 9 (i Pr)2SiCl2

O

O Si

CH3 2

OTBS

A remaining challenge was the stereocontrolled construction of the trisubstituted alkene. To this end, the aldehyde 13 was homologated to the dibromide 14. Pd-mediated coupling of the alkenyl stannane 15 with 14 was selective for theE bromide. The residual Z bromide was then coupled with Zn(CH3)2 to give 16. These steps, and the ﬁnal steps to complete the construction of spirofungin A 3, could be carried out without exposure to equilibrating acid, so the carefully established spiro ketal conﬁguration was maintained. Br O O CH3

OTBS 1. TBAF O O Si

2. NaIO4

O 1. TBSCl 2. Ph3P=CBr2

OH

Br

O

O

O CH3

2

H

O

13

CH3

+ 14

Bu3Sn 15 HO

2. Zn(CH3)2

OTBS

O

O

OTBS CH3

O

O

O

1. Pdcat

O

OH OH

CH3

16

175

OTBS

OTBS

3 Spirofungin A

88. The Ley Synthesis of Rapamycin August 4, 2008

Rapamycin 3 is used clinically as an immunosuppressive agent. The synthesis of 3 (Angew. Chem. Int. Ed. 2007, 46, 591) by Steven V. Ley of the University of Cambridge was based on the assembly and subsequent coupling of the iododiene 1 and the stannyl alkene 2. HO

TBSO

CH3O

CH3O O

N O

O

Boc O OCH3

O

OTES O HO

O

CH3O +

O O

I 1

O

N

O

O

OH

CH3O

O

OCH3

Me3Sn 2

(-)-Rapamycin 3

The lactone of 1 was prepared by Fe-mediated cyclocarbonylation of the alkenyl epoxide 5, following the protocol developed in the Ley group. BnO

BnO OCH3 2. TPAP O 3. Ph3P=CH2 4

HO

O 7

OCH3 O

O OEt P OEt 1. CN

OCH3

O

3. LDA; CH3I

6

OBn

4. CH3MgBr 5. TPAP

O

OTBS O

1. Dibal; TBSCl 2. Pd / H2 3. TPAP

2. H2 / PtO2 5

OTBS

O

OCH3 1. Fe2CO9; CO

1. SAE

OCH3

O H

2. Dibal O

8

OCH3 I

1

The cyclohexane of 2 was constructed by SnCl4-mediated cyclization of the allyl stannane 9, again employing a procedure developed in the Ley group. Hydroboration delivered the aldehyde 11, which was crotylated with 12, following the H. C. Brown method. The alcohol so produced (not illustrated) was used to direct the diastereoselectivity of epoxidation, then removed, to give 13. Coupling with 14 then led to 2.

176

THE LEY SYNTHESIS OF RAPAMYCIN SiMe3 TBSO PhO2S CH3O

1. 9-BBN TBSO

SnCl4 TBSO

2. Swern CH3O

9

CH3O 11

10

TBSO S S +

OTES OPMB

CH3O

O 13

H 2. VO(acac) 2 t-BuOOH O 3. ClC(=S)OPh; Bu3SnH

CH3O

TBSO CH3O

BR*2 12

1.

O

N

O

Boc O

O

CH3O

2

14

OTES

PMBO Me3Sn

Combination of 1 with 2 led to 15, which was condensed with catechol to give the macrocycle 16. Exposure of 16 to base effected Dieckmann cyclization, to deliver the ringcontracted macrolactone 17, which was carried on to (-)-rapamycin 3. TBSO

TBSO

CH3O

CH3O OH O AllO

N Br OH

O

O

OTES O

CH3O

1. DCC

O

O

O

OTES

CH3O

O

OCH3

O O

OTES

OTES 16

15

TBSO

HO

CH3O

CH3O

OH

O

N

1. LiHMDS O 2. Pd cat

O

2. K2CO3

OCH3

O AllO

N OH

O

O TBSO

O

OH CH3O

OTES O

O O

OCH3

17

O

N O HO

O

O CH3O

OCH3

(-)-Rapamycin 3

177

OH O

89. The Toste Synthesis of (+)-Fawcettimine September 1, 2008

The tetracyclic Lycopodium alkaloid fawcettimine 3 and its derivatives are of interest as inhibitors of acetylcholine esterase. F. Dean Toste of the University of California, Berkeley recently reported (Angew. Chem. Int. Ed. 2007, 46, 7671) the ﬁrst enantioselective synthesis of 3. The key to the synthesis was the rapid assembly of the enantiomerically-enriched hydrindane 2. H

O

HO N I

O

O 1

2

3 (+)-Fawcettimine

The preparation of 2 began with the enantioselective Robinson annulation of the β-keto ester 4 with crotonaldehyde 5, mediated by the organocatalyst 6. In this protocol, originally developed by Karl Anker Jørgensen, the single stereogenic center was established by conjugate addition, presumably to the chiral iminium salt generated by the condensation of 5 with 6. Subsequent aldol (or more likely Mannich) cyclization followed by elimination gave 7. Hydrolysis and decarboxylation by heating with p-TsOH converted 7 to 1. This procedure was robust enough to allow preparation of a ten gram batch of 1. This Jørgensen annulation is the current method of choice for the enantioselective preparation of 2,5-dialkyl cyclohexenones. O H H+

5

t-BuO2C O

cat 6

t-BuO2C

4

7

O 88% ee

O

Ar OTMS Ar

N H 1

6

CF3

Ar =

CF3

Conjugate addition of the propargyl anion equivalent 8 to 1 proceeded with the expected > 95:5 axial diastereoselectivity, to give the silyl enol ether 9. Exposure of the derived iodide 10 to catalytic [Ph3PAu]Cl and AgBF4 induced smooth cyclization to the cis hydrindane 2. SnBu3 8

H NIS H AgNO 3

TBSOTf O

TBSO 1

Au cat I

10

178

I

O

TBSO 9

2

THE TOSTE SYNTHESIS OF (+)-FAWCETTIMINE Before constructing the nine-membered ring amine of fawcettimine 3, it was ﬁrst necessary to protect the ketone as the ketal. Pd-mediated coupling of the alkenyl iodide with the organoborane derived from 11 then proceeded smoothly, as did the subsequent hydroboration of the terminal alkene. H

H H

1. HO OH H /9-BBN; 11 Boc Pd cat

2.

N

I

O

1. PPh3 /I3 imidazole

2

O

H 2. t-BuOK N Boc

O

H

13

H

O /H O 2

1. BH3; ox

Boc

O

HO O

F3CCO2H

2. Dess-Martin

H+

O N

OH

12

3. 9-BBN; ox

O

N O

O 14

N

Boc

15

N

Boc

3 (+)-Fawcettimine

Neither the mesylate nor the tosylate derived from 12 could be induced to cyclize. In contrast, intramolecular displacement of the iodide proceeded well, to give 13. Hydroboration followed by oxidation then gave 15, which on deprotection cyclized to (+)-fawcettimine 3. Several aspects of this synthesis are attractive. While the stereochemical outcome of the hydroboration of 14 could not necessarily be predicted with conﬁdence, in fact it did not matter, as the stereogenic center adjacent to the ketone could be epimerized under the triﬂuoroacetic acid deprotection conditions, and only the desired diastereomer would be able to add in an intramolecular fashion to the cyclohexanone. The construction of 2 from 10 underscores the importance of the Au-catalyzed cyclizations developed by Professor Toste. The most important news from this synthesis is the validation in a second research group of the enantioselective Robinson annulation previously described by Professor Jørgensen. In the assembly of polycarbocycles, the central challenge is the enantioselective construction of the ﬁrst ring. The Jørgensen annulation is a powerful solution to that problem.

179

90. The Bergman-Ellman Synthesis of (-)-Incarvillateine October 6, 2008

The monoterpene alkaloid (-)-incarvillateine 3 has interesting symmetry properties. The central cyclobutane diacid core is not itself chiral, but the appended alkaloids are. The key step in the total synthesis of 3 recently (J. Am. Chem. Soc. 2008, 130, 6316) described by Robert G. Bergman and Jonathan A. Ellman of the University of California, Berkeley was the diastereoselective Rh-catalyzed cyclization of 1 to 2. H3CO

H

N

OH

O CO2Et

CO2Et

Rh cat

O

H

H

O

R3SiO

R3SiO

N CH3

N CH3 1

2

O

HO

3 OCH3

H

N

The cyclobutane diacid core 5 was assembled from ferulic acid 4 following the procedure of Kibayashi (J. Am. Chem. Soc. 2004, 126, 16553). H3CO OTs

O 1. TsCl

HO CO2H H3CO

HO OH

2. hν

4

O

TsO OCH3

5

The starting point for the preparation of 1 was the commercial aldehyde 6. Enantioselective allylation followed by silylation delivered 7, which on cross metathesis with methacrolein gave the diene aldehyde 8. Imine formation then completed the construction of 1. O

SnBu3 CO2Et CO2Et H O

6

1.

/ Binol

2. R3SiCl

1. R3SiO

H / G2

2. CH3NH2

7

CO2Et R3SiO N CH3 1

The cyclization of 1 was effected by warming (45 °C, 6 h) with 2.5 mol % [RhCl(coe)2]2 and 5.5 mol % (DMAPh)Pet2 ligand. While eight products were possible from the cyclization (four diastereomers, two geometric isomers of the exo alkene), only two were observed,

180

THE BERGMAN-ELLMAN SYNTHESIS OF (-)-INCARVILLATEINE with one predominating. Since the product mixture was easily susceptible to tautomerization, it was carried on directly to reduction and cyclization, to form the lactam 8. CO2Et

O CO2Et

Rh cat

NaBH4

R3SiO

R3SiO

N

R3SiO N dr = 83: 17 CH3

N CH3 1

2

8

O H2

1. LiAlH4

N

R3SiO

Pd / C

2. HCl

DEAD/Ph3P

9

10

H3CO

H

N

O

O 11

TsO OCH3

anthracene

H

H

OH

O Na

O

H3CO

H

N

OTs

O H

5

N

HO

O

H

O

HO

N

H

O

3 OCH3

H

N

(-)-Incarvillateine

Hydrogenation of 8 to 9 required high temperature and pressure, but delivered 9 as a single diastereomer. Reduction and desilylation then set the stage for Mitsunobu coupling with 5, to give 11. Dissolving metal conditions removed the tosyl groups from 5 to give (-)-incarvillateine 3. It will be interesting to see how general this Rh catalyzed cyclization will be. It will also be interesting to establish the mechanism. The authors described the cyclization of 1 as proceeding via initial metalation of the alkene C-H bond, followed by insertion of the ester-bearing alkene into the C-Rh bond to form a new C-Rh bond, and ﬁnally reductive elimination. Their previous observation of metalation of such an unsaturated imine with maintenance of the alkene geometry suppported this mechanism. The high diastereocontrol also suggested intramolecular C-C bond formation. Whatever the mechanism, the enantiomerically-pure cyclopentane 2, having four of its ﬁve carbons functionalized, is a versatile intermediate for further transformation.

181

91. The Roush Synthesis of (+)-Superstolide A November 3, 2008

(+)-Superstolide A 3, isolated from the New Caledonian sponge Neosiphonia superstes, shows interesting cytotoxicity against malignant cell lines at ~ 4 ng/mL concentration. The key transformation in the synthesis of 3 described (J. Am. Chem. Soc. 2008, 130, 2722) by William R. Roush of Scripps Florida was the transannular Diels-Alder cyclization of 2, which established, in one step with high diastereocontrol, both the cis decalin and the macrolactone of 3. R3SiO CH3O

CH3O

CH3O

O NH2

I

O

OSiR3

O B O

O

O

O

O

O

O

OH O

O

N Boc

N Boc

1

N

2

H

O

3

(+)-Superstolide A

The octaene 1 was assembled from four stereodeﬁned fragments. The ﬁrst, the linchpin 6, was prepared from the stannyl aldehyde 4. Homologation gave the enyne 5, which on hydroboration and oxidation gave 6. TMSCH=N2 H

H O 4

O O B

BH3 SnBu3

SnBu3

5

SnBu3 6

Earlier, Professor Roush had optimized the crotylation of the protected alaninal 7. In this case, the Brown reagent 8 delivered the desired Felkin product 9. Protection followed by ozonolysis gave the aldehyde 10. Crotylation with the Roush-developed tartrate 11 then gave the alkene 12, setting the stage for conversion to the iodide 13. Coupling of 13 with 6 completed the preparation of 14. CO2R O H

Ipc B Ipc

Boc N H 7

8

OH Boc N H

O

O N Boc

H

9

10

182

O B O 11

CO2R

THE ROUSH SYNTHESIS OF (+)-SUPERSTOLIDE A O B

HO I

O N Boc

HO

N Boc Pd cat

HO

12

O

6

O

O N Boc

13

14

The third component of (+)-superstolide A 3, the phosphonium salt 21, was assembled by Brown allylation of the aldehyde 15, to give 17. Protecting group interchange followed by ozonolysis delivered 18, which via Still-Gennari homologation was carried on to 21. Condensation with the fourth component, the aldehyde 22, and esteriﬁcation with 14 then gave 1.

O

Ipc

O H

Ipc

R3SiO

R3SiO

O

B

O

OTr

O

+ 17

16

CH3O

CH3O

HO

O 15

H

18 H

19

O

CO2Et

R3SiO

R3SiO

+

CH3O

CH3O OH

20

CO2TMSE

I

I

21

O

PBu3

22 H

R3SiO CH3O

CH3O

CH3O

O

I

O

OSiR3

O B O

NH2

Pd cat

O

O

O

O

O

O

OH O N Boc

O 1

N Boc

2

N H

O

3

(+)-Superstolide A

Under high dilution Suzuki conditions 1 was converted to 2. Storage in CDCl3 for ﬁve days, or brief warming, cyclized 2 to a single diastereomer of the transannular Diels-Alder product, that was carried on to (+)-superstolide A 3. While acyclic trienes comparable to 2 could be induced to cyclize, the transannular Diels-Alder reaction proceeded with much higher diastereocontrol.

183

92. The Takayama Synthesis of (-)-Cernuine December 1, 2008

(-)-Cernuine 3 falls in the subset of the Lycopodium alkaloids that feature a bicyclic aminal core. There had not been a total synthesis of this class of alkaloids until the recent (Organic Lett. 2008, 10, 1987) work of Hiromitsu Takayama of Chiba University. The key step in this synthesis was a diastereoselective intramolecular reductive amination, converting 1 to 2. As is apparent from the 3-D projection, (-)-cernuine 3 has a tricyclic trans-anti-trans aminal core, with an appended six-membered ring, both branches of which are axial on the core. While the branch that is part of the aminal could be expected to equilibrate, the other branch had to be deliberately installed.

N

N H2N

N NH

O 1

N

N N

O

axial O

3 (-)-Cernuine

2

The synthesis began with (+)-citronellal 4, each enantiomer of which is commercially available in bulk. After protection and ozonolysis, the ﬁrst singly-aminated stereogenic center was installed by enantioselective, and therefore diastereoselective, addition of 5 to the azodicarboxylate 6, mediated by the organocatalyst 7. Reductive cleavage of the N-N bond followed by acetal methanolysis converted 8 to 9. Ionization followed by allyl silane addition then delivered 11, having the requisite axial alkyl branch. O

O H

O H

4

O 5

OCH3 N 9

O

O

BnO2C CO2Bn N N 6

BnO2C N N H

Ph OTMS N Ph cat H 7

O 84% de O

8

O

SiMe3 10 N

O 11

O

O

The next two tasks were the assembly of the second of the four rings of 3, and the construction of the second single-aminated stereogenic center. The ring was assembled by deprotection of 11 followed by acylation with acryloyl chloride, to give 12. Grubbs cyclization followed by hydrogenation then led to 13. Homologation of 13 to the aldehyde 14 set the stage for condensation with the camphor-derived tertiary amine 15, following the protocol developed by Kobayashi. Sequential imine formation, aza-Cope rearrangement, and hydrolysis led to 1 in 94% de.

184

THE TAKAYAMA SYNTHESIS OF (-)-CERNUINE NH2

1. G1 cat

11

N HO

O

2. H2 /Pd-C 12

H

O 13

HO

+

N

N

O 14

15

O

O

TiCl4

N H2 N

NaBH4

N N

O 1

16

N

N

N

NH 2

O

17

One could envision reduction of the lactam carbonyl of 1 to an aldehyde equivalent, that would then, under acidic conditions, condense to form the desired aminal 2. This approach was, however, not successful. As an alternative, conditions were developed to convert 1 to the amidine 16. Reduction then proceeded with the expected high diastereocontrol, to give the cis 1,3-fused aminal 2. This was not isolated, but was directly acylated with acryloyl chloride, to 17. The synthesis of (-)-cernuine 3 was concluded by Grubbs cyclization of 17 to 3, followed again by hydrogenation. Note that there was a key difference between this cyclization and the Grubbs cyclization of 12 that led to 13, in that 17 contained a basic N, while 12 did not. For the cyclization of 12, the ﬁrst generation Grubbs catalyst was sufﬁcient, while for the cyclization of 17, the second generation catalyst was required.

N

N

1. G2cat N

O

N

2. H2 /Pd-C

O

3

17

(-)-Cernuine

This synthesis illustrates the efﬁcacy of the Grubbs cyclization for polycyclic construction. The approach outlined here also highlights the power of current methods for enantioselective allylation of imines for the construction of enantiomerically pure, and, in the context of this synthesis, diastereomerically pure, aminated secondary stereogenic centers.

185

93. The Wood Synthesis of Welwitindolinone A Isonitrile January 5, 2009

Welwitindolinone A Isonitrile 3 is the ﬁrst of a family of oxindole natural products isolated from the cyanobacteria Hapalosiphon welwischii and Westiella intricate on the basis of their activity for reversing multiple drug resistance (MDR). A key transformation in the total synthesis of 3 reported (J. Am. Chem. Soc. 2008, 130, 2087) by John L. Wood, now at Colorado State University, was the chlorination of 1, that in one step established both the axial secondary chloro substituent and the ﬂanking chiral quaternary center. O

OH

Cl

Cl

TIPSO

TIPSO

CN O

O O

O H

N

N

N H 1

O

H

3

2

The starting material for the synthesis of 3 was the diene acetonide 5, readily prepared from the Birch reduction product 4. Intermolecular ketene cycloaddition proceeded with high regio- and diastereoselectivity, to give the bicyclooctenone 6. O O

O

Cl

4

O

Et3N

O 5

6

O

The triazene-bearing Grignard reagent 7 added to the ketone 6 with the anticipated high diastereocontrol, to give, after reduction and protection, the cyclic urethane 8. Selective oxidation of the diol derived from 8 followed by silylation delivered the enone 9. Conjugate addition of hydride followed by enolate trapping gave the triﬂate 10. Pd-catalyzed methoxycarbonylation established the methyl ester 11. Addition of CH3MgBr to 11 gave 1, setting the stage for the establishment of the two key stereogenic centers of 2 and so of 3.

O

+ N

O MgBr

O O

7

TIPSO

TIPSO

O

O

O

O

O

O 6

TfO

O

O

N N

N H

8

186

N H

9

N H 10

THE WOOD SYNTHESIS OF WELWITINDOLINONE A ISONITRILE O

OH

Cl

CH3O2C TIPSO

TIPSO

TIPSO

NaOCl

O

O

O

O

O

O N H 11

N

N H

H

1

2

The transformation of 1 to 2 was envisioned as being initiated by formation of a bridging chloronium ion. Pinacol-like 1,2-methyl migration then proceeded to form the trans diaxial product, moving the ketone-bearing branch equatorial. In addition to being an elegant solution of the problem of how to establish the axial chloro substituent of 3, this strategy might have some generality for the stereocontrolled construction of other alkylated cyclic quaternary centers. Reduction of the ketone 2 and dehydration of the resulting alcohol led, after deprotection and oxidation, to the ketone 12. Protection followed by β-elimination gave the enone 13. Direct reductive amination of 13 failed, but reduction of the methoxime was successful, giving, after acylation, the formamide 14. Reductive N-O bond cleavage followed by deprotection and isonitrile formation then set the stage for the planned intramolecular acylation to complete the synthesis of Welwitindolinone A Isonitrile 3. Cl

O

Cl

Cl

Cl O

TIPSO

O O

(Boc)2O; O O

O

O N H

DBU

H N Boc 13

N H 12

2

H N CH3O

Cl

Cl

H N Boc 14

Cl

O 1. SmI2 2. HCO2H

H

N H

COCl2;

CN

CN

LiHMDS N

NH2 15

16

O

N O H 3 Welwitindolinone A Isonitrile

The starting diene 5 used in this synthesis was prochiral, leading to racemic 3. Now that the route to 3 is established, it would be interesting to devise a method for preparing enantiomerically-enriched 6. Enantiomerically-pure variants of 5 have been prepared, inter alia by fermentation of halogenated aromatics. Alternatively, an enantioselective version of the [2+2] cycloaddition to the prochiral 5 could be developed.

187

94. The Paquette Synthesis of Fomannosin February 2, 2009

The compact sesquiterpene (+)-fomannosin 3, isolated from the pathogenic fungus Fomes annonsus, presents an interesting set of challenges for the organic synthesis chemist, ranging from the strained cyclobutene to the easily epimerized cyclopentanone. In the synthesis of 3 developed (J. Org. Chem. 2008, 73, 4548) by Leo A. Paquette of Ohio State University, the cyclopentane was constructed by ring-closing metathesis of 1. The real challenge of the synthesis was the enantiospeciﬁc preparation of 1 from D-glucose.

cat G2

O

PMBO

OSiR3

1

O

OSiR3

OSiR3 PMBO

O

OSiR3

2

3

OH (+)-Fomannosin

The starting point for the preparation of 1 was the glucose derivative 4. Selective acetonide hydrolysis followed by oxidative cleavage gave the ester 5, which on base treatment followed by hydrogenation delivered the endo ester 6. Condensation of the enolate of 6 with formaldehyde proceeded with high diastereoselectivity, to give, after protection, the ester 7. Conversion of the ester to the vinyl group, exposure to methanolic acid and ether formation completed the preparation of 9. O O

4

H3CO2C

H

O OTs O

O 5

TBSO

H

O H3CO2C 7

O

H

O OTs O

O

H3CO2C 6

TBSO

H

O

O 8

H

O

O

O

O

TBSO O

OCH3

O 9

OPMB

The construction of the cyclobutane of 1 was effected by an interesting application of the Negishi reagent (Cp2ZrCl2/2 x BuLi). Complexation of Cp2Zr with the alkene followed by elimination generated an allylic organometallic 11, which added to the released aldehyde to give the cyclobutanes 12 and 13 in a 2.4:1 diastereomeric ratio.

188

THE PAQUETTE SYNTHESIS OF FOMANNOSIN TBSO

2 x BuLi OPMB

9

TBSO

OCH3 Cp ZrCl 2 2

O

O H

Cp2Zr OPMB

10

OSiR3 OH

PMBO

TBSO

OCH3

O

+ 2.4 : 1

12

Cp2Zr

11

OPMB

OSiR3 PMBO

OH 13

Homologation of the aldehyde 13 and subsequent oxidation were straightforward, but subsequent methylenation of the hindered carbonyl was not. At last, it was found that Peterson oleﬁnation worked well. Metathesis then delivered the cyclopentene 2. The last carbons of the skeleton were added by intramolecular aldol cyclization of the thioester 16.

H

O 12 PMBO

13

Li

1. 14 OSiR3

O

Me3SiCH2Li; OSiR3

2. PDC

OSiR3

PMBO

15

OSiR3

H+

OSiR3

PMBO

OSiR3

1

O cat G2

OSiR3

PMBO

O

O

OSiR3 O

PMBO

S

O

O

PMBO HO

16

2

17

OSiR3

The seemingly simple task of converting the alkene of 17 into a ketone proved challenging. Eventually, dihydroxylation followed by oxidation, and then SmI2 reduction, completed the transformation. This still left the challenge of controlling the cyclopentane stereogenic center. Remarkably, dehydration and epimerization led to (+)-Fomannosin 3 as a single dominant diastereomer.

O PMBO HO 17

1. OsO4

O

O 2. Swern PMBO HO 3. SmI2 OSiR3 18

H

O O

H O

O OSiR3

HO 19

1. Tf2O

O 2. DBU 3. TBAF OSiR3

O O O 3

OH

(+)-Fomannosin

189

95. The Zakarian Synthesis of (+)-Pinnatoxin A March 2, 2009

(+)-Pinnatoxin A 3, isolated from the shellﬁsh Pinna muricata, is thought to be a calcium channel activator. A key transformation in the synthesis of 3 reported (J. Am. Chem. Soc. 2008, 130, 3774) by Armen Zakarian, now at the University of California, Santa Barbara, was the diastereoselective Claisen rearrangement of 1 to 2. OTIPS O

OTIPS

MOMO

H N

Ph O

O MOMO

Ph O CO2H

O BnO

O

O

O O OBn

HO

O O

O

OH

O

PMBO PMBO 1

2

3 (+)-Pinnatoxin A

The alcohol portion of ester 1 was derived from the aldehyde 4, prepared from D-ribose. The absolute conﬁguration of the secondary allylic alcohol was established by chiral amino alcohol catalyzed addition of diethyl zinc to the unsaturated aldehyde 5.

ribose

O

Ph

Ph

Ph O

O

TIPSO

Et2Zn

O H

O TIPSO

H

MOMO 4

O OH

TIPSO

O

OMOM 5

O

cat* OMOM 6

The acid portion of the ester 1 was prepared from (S)-citronellic acid, by way of the Evans imide 7. Methylation proceeded with high diasterocontrol, to give 8. Functional group manipulation provided the imide 9. Alkylation then led to 10, again with high diastereocontrol. In each case, care had to be taken in the further processing of the α-chiral acyl oxazolidinones. Direct NaBH4 reduction of 8 delivered the primary alcohol. To prepare the acid 10, the alkylated acyl oxazolidinone was hydrolyzed with alkaline hydrogen peroxide. O

O N

7

O Ph

O

O N

8

OBn O

O

N

Ph

O Ph

190

OBn O

O 9

HO

OPMB 10

THE ZAKARIAN SYNTHESIS OF (+)-PINNATOXIN A On exposure of the ester 1 to the enantiomerically-pure base 11, rearrangement proceeded with high diastereocontrol, to give the acid 2. This outcome suggests that deprotonation proceeded to give the single geometric form of the enolate, that was then trapped to give speciﬁcally the ketene silyl acetal 12. This elegant approach is dependent on both the ester 1 and the base 11 being enantiomerically pure. OTIPS

OTIPS N

O MOMO

Ph O

Li

O

N

MOMO CF3 11

O MOMO

O BnO

O

OTIPS Ph

O

Ph O CO2H

OSiMe3 BnO

O

OBn

PMBO

PMBO

PMBO

1

12

2

The carbocyclic ring of pinnatoxin A 3 was assembled by intramolecular aldol condensation of the dialdehyde 11. This outcome was remarkable, in that 11 is readily epimerizable, and might also be susceptible to β-elimination. Note that the while the diol corresponding to 11 could be readily oxidized to 11 under Swern conditions, attempts to oxidize the corresponding hydroxy aldehyde were not fruitful. OTIPS

OTIPS

O MOMO

Ph O CO2H

OTIPS

O

OBn

O

Ph O OBz

MOMO O

OBn

H

Bn2NH2

MOMO

CF3CO2

O

H

PMBO 2

Ph O OBz OBn

H 11

O

12 H N

I O MOMO MOMO

Ph O + CH=O OBn TESO

O

O

O

O O

HO

O

O

O O

OTIPS 13

14

191

3 (+)-Pinnatoxin A

O OH

96. The Hoveyda Synthesis of (-)-Clavirolide C April 6, 2009

Conjugate addition-enolate trapping, a strategy originally developed by Gilbert Stork, has become a powerful method for stereocontrolled ring construction. A key step in the synthesis of (-)-Clavirolide C 3 reported (J. Am. Chem. Soc. 2008, 130, 12904) by Amir H. Hoveyda of Boston College occurred early on, with the enantioselective conjugate addition of Me3Al to 1 to give the silyl enol ether 2. Enantioselective conjugate addition to establish a quaternary center β on a cyclohexanone had been established (OHL August 18, 2008), but not yet on cyclopentanones. Professor Hoveyda found that a modiﬁed form of the Ag catalyst that they had published earlier, in combination with the Lewis acidic AlMe3, effected conjugate addition to 1 in 84% ee. Quenching of the reaction mixture led to the enol silyl ether 2. O O

Et3SiO

H

Me3Al

O O

Ag* cat; TESOTf

84% ee

1

2

3 (-)-Clavirolide C

The assembly of the 11-membered ring of 3 also began with an enantioselective conjugate methylation, of the lactone 4 with Me2Zn, again using a catalyst developed by Professor Hoveyda. Opening of the lactone 5 followed by Swern oxidation gave the Weinreb amide 6, that was homologated and reduced to give 7. O Me2Zn

O

1. MeONHMe.HCl

O

Cu* cat 4

5

O Me3Al

2. Swern >98% ee

MgBr

N CH3O

1.

6

3. Dibal

H

H

2. Et3SiCl O

O

Et3SiO

H

7

OSiEt3

OH

n-BuLi;

Ag* cat; TESOTf 1

O

O

O

OSiEt3

Et3B; 7 84% ee 2

8

1.5 : 1 dr

Addition of n-BuLi to 2 regenerated the enolate. There were two issues in the addition of that enolate to the aldehyde 7: syn vs. anti stereocontrol, and control of the conﬁguration of the newly formed ternary center on the ring relative to the already-established quaternary center. Inclusion of Et3B in the reaction mixture assured anti aldol formation, but there was 192

THE HOVEYDA SYNTHESIS OF (-)-CLAVIROLIDE C only a modest preference for the desired bond formation trans to the slightly more bulky butenyl group, to give 8. Medium rings are more strained than are larger rings. The diene 8 was reluctant to close with the second generation Grubbs catalyst, but the catalyst developed by Professor Hoveyda worked well. The δ-lactone of 3 was then constructed by acylation of 9 with 10 followed by reductive cyclization with SmI2. Conjugate addition to the derived enone 12 on the outside face of the medium ring alkene gave the desired 13 (9:1 dr). This reaction may be proceeding via the s-cis conformer, as the more stable s-trans conformer would have been expected to give the other diastereomer. Dehydration of 13 then delivered (-)-Clavirolide C 3. O

O O

H

OH

O OSiEt3

H2 cat

8

OH

H

HO

2. MnO2

O Me2CuLi

HO

H

H

O

2. SmI2

OSiEt3

11

O

O O

H

O

1. MsCl O

O 2. DBU

O 12

Br HO 1. Br 10 OSiEt3

9 O

1. H+

H

13

3 (-)-Clavirolide C

This concise synthesis of the dolabellane 3 showcases the power of the catalytic enantioselective methods for the construction of both ternary and quaternary, including cyclic quaternary, centers that Professor Hoveyda has developed. Clearly, asymmetric transformation of inexpensive prochiral ring precursors such as 1 and 4 will make advanced, high ee intermediates such as 2 and 5 much more readily available than they have been in the past.

193

97. The Carter Synthesis of (-)-Lycopodine May 4, 2009

Rich G. Carter of Oregon State University described (J. Am. Chem. Soc. 2008, 130, 9238) the ﬁrst enantioselective synthesis of the Lycopodium alkaloid (-)-lyopodine 3. A key step in the assembly of 3 was the diastereoselective intramolecular Michael addition of the keto sulfone of 1 to the enone, leading to the cyclohexanone 2.

O

O PhSO2

PhSO2

O

O 1

N3

N

O

3

2

N3

(-)-Lycopodine

The key cyclization substrate 1 bore a single secondary methyl group. While that could have been derived from a natural product, it was operationally easier to effect chiral auxiliary controlled conjugate addition to the crotonyl amide 4, leading, after methoxide exchange, to the ester 5. The authors reported that double deprotonation with LiTMP gave superior results, vs. LDA or BuLi, in the condensation of 6 with 5 to give 7. Metathesis with pentenone 8 gave the intramolecular Michael substrate 1.

O O S

MgBr CuBr

1.

N O

PhSO2 MeO

2. Mg(OMe)2

LiTMP x 2

+

PhSO2 O

O

4

5

6 N 3

N3

7

O

O

O

PhSO2 8 H2 cat

i-Pr2NH O N3

PhSO2 O

IPA 1

N3

O

PhSO2 O N3

2

The authors thought that they would need a chiral catalyst to drive the desired stereocontrol in the cyclization of 1 to 2. As a control, they tried an achiral base ﬁrst, and were pleased to observe the desired diastereomer crystallize from the reaction mixture in 89% yield. The structure of 2 was conﬁrmed by X-ray crystallography. To prepare for the intramolecular Mannich condensation, the azide was reduced to give the imine, and the methyl ketone was converted to the silyl enol ether. Under Lewis acid conditions, the sulfonyl group underwent an unanticipated 1,3-migration, to give 11.

194

THE CARTER SYNTHESIS OF (-)-LYCOPODINE Cyclization of 12 then delivered the crystalline 14. Reduction converted 14 to the known (in racemic form) ketone 15.

O PhSO2 O N3

OTBS

Ph3P; TBSOTf i-Pr2NEt

OTBS

Zn(OTf)2

PhSO2 N

N

2

ZnOTf 10

9

SO2Ph OTBS

SO2Ph OTBS N

PhSO2

SO2Ph O Na-Hg

N

ZnOTf 11

O N H

N H 12

14

15

To complete the synthesis, the amine 15 was alkylated with 16 to give the alcohol 17. Oppenauer oxidation followed by aldol condensation delivered the cyclized enone, that was reduced with the Stryker reagent to give (-)-Lycopodine 3.

O I N H 15

16 K2CO3

O

OH N

OH 17

O 1. t BuOK benzophenone 2. CuH

N 3 (-)-Lycopodine

Both the cyclization of 1 to 2 and the cyclization of 9 to 14 are striking. It may be that the steric demand of the phenylsulfonyl group destabilizes the competing transition state for the cyclization of 1.

195

98. The Johnson Synthesis of Zaragozic Acid C June 1, 2009

The zaragozic acids, exempliﬁed by Zaragozic Acid C 3, are picomolar inhibitors of cholesterol biosynthesis. Jeffrey S. Johnson of the University of North Carolina developed (J. Am. Chem. Soc. 2008, 130, 17281) an audacious silyl glyoxylate cascade approach to the oxygenated backbone fragment 1. Intramolecular aldol cyclization converted 1 to 2, setting the stage for the construction of 3. O TBSO t H BuO2C TBSO O t BuO2C t BuO2C O 1

TMSO OBn TBSO t BuO2C O TBSO O t BuO2C t BuO2C 2

OBn

O

Ph

OH

O OAc CO2H CO2H OH O

O HO2C

Ph

3 Zaragozic Acid C

The lactone 2 includes ﬁve stereogenic centers, two of which are quaternary. The authors were pleased to observe that exposure of 4 to vinyl magnesium bromide 5 led, via condensation, silyl transfer, condensation, and again silyl transfer, to a species that was trapped with t-butyl glyoxylate 6 to give 7 as a single diastereomer. This one step assembled three of the stereogenic centers of 2, including both of the quaternary centers. The alcohol 7 so prepared was racemic, so the wrong enantiomer was separated by selective oxidation. Intramolecular aldol condensation of the derived α-benzyloxy acetate 1 then completed the construction of 2. O t

BuO2C

Si t

4

TBSO t BuO2C t

BuO2C

1.

MgBr 5

2.

O

BuO2C

6 OTBS

6

TBSO

O t

BuO2C

SiR3

t

TBSO BuO2C

CO2tBu

H

TBSO t BuO2C TBSO t BuO2C t

t

OH

BuO2C 7

O TBSO H BuO2C TBSO O t BuO2C t BuO2C O 1

t

BuO2C O

t

OBn

SiR3

TMSO OBn TBSO BuO2C O TBSO O t BuO2C t

BuO2C

2

Addition of the alkyl lithium 8, again as a single enantiomerically-pure diasteromer, to 2 gave the hemiketal 9. Exposure of 9 to acid initially gave a mixture of products, but this could be induced to converge to the tricyclic ester 10. To convert 10 to 11, the diastereomer that was needed for the synthesis, two of the stereogenic centers had to be inverted. This was accomplished by exposure to t-BuOK/t-amyl alcohol, followed by re-esteriﬁcation. The inversion of the secondary hydroxyl group was thought to proceed by retro-aldol/re-aldol condensation.

196

THE JOHNSON SYNTHESIS OF ZARAGOZIC ACID C

t

TMSO OBn TBSO BuO2C O TBSO O t BuO2C t 2 BuO C

+

Ph 8

2

OBn O O OBn O O CO2CH3 CH3O2C TBSO 10

t

Li

OBn

TMSO OBn TBSO BuO2C OH TBSO O t BuO2C t

Ph

BuO2C

Ph

OAc AcO

HO O t BuO2C

TBSOTf OBn

9

Ph

OBn

Ph pTsOH/ CH3OH;

O HO

OBn CO2t Bu t CO2 Bu

t

O BuO2C

11

O HO 12

OAc CO2t Bu CO2t Bu

Debenzylation of 11 followed by acetylation delivered 12, an intermediate in the Carreira synthesis of the zaragozic acids. Following that precedent, the ring acetates of 12 were selectively removed, leaving the acetate on the side chain. Boc protection was selective for the endo ring secondary hydroxyl, leaving the exo ring secondary hydroxyl available for condensation with the enantiomerically-pure acid 13. Global deprotection then completed the synthesis of Zaragozic Acid C 3. OAc AcO t

O BuO2C

HO

OAc O CO2t Bu CO2t Bu 12

O

Ph 1. MeOH/ K2CO3

Ph

O HO2C

3. 13 / DCC Ph

O OH

O

2. Boc2O 4. TFA

OH OAc CO2H CO2H

O OH

3 Zaragozic Acid C

Ph

13

The key to the success of this synthesis of the complex spiroketal 3 was the assembly of 7 in one step as a single diastereomer from the readily-available building blocks 4, 5, and 6. This process, reminiscent of group transfer polymerization, will be a useful complement to the cascade organocatalyzed aldol condensations that have recently been developed.

197

99. The Keck Synthesis of Epothilone B July 6, 2009

The total synthesis of Epothilone B 4, the ﬁrst natural product (with Epothilone A) to show the same microtubule-stabilizing activity as paclitaxel (Taxol®), has attracted a great deal of attention since that activity was ﬁrst reported in 1995. The total synthesis of 4 devised (J. Org. Chem. 2008, 73, 9675) by Gary E. Keck of the University of Utah was based in large part on the stereoselective allyl stannane additions (e.g. 1 + 2 → 3) that his group originated. O Bu3Sn

CO2Et BF .OEt

H

3

+ TBSO

O

HO

2

N O

OH

TBSO

1

S

CO2Et

2

4 O HO O Epothilone B

3

The allyl stannane 2 was prepared from the acid chloride 5. Exposure of 5 to Et3N generated the ketene, that was homologated with the phosphorane 6 to give the allene ester 7. Cu-mediated conjugate addition of the stannylmethyl anion 8 then delivered 2. CO2Et

O

1. Et3N Cl

2.

O

Ph3P

5

CO2Me TBSO

7

OEt

6

9

2

CO2Et

1. Dibal 2. 2 / BF3.OEt2

TBSO

O

H

CO2CH3

B

O

CO2Et

1. O3 2. SmI2 H2O

OH 3

H O

CO2Et

Bu3Sn

Bu3SnCH2Li 8 CuI

TBSO

OH OH 10

O

TBSO

CO2CH3

+ 11

O

O

O 12

O 13

The silyloxy aldehyde 1 was prepared from the ester 9 by reduction with Dibal. Felkincontrolled 1,2-addition of the allyl stannane 2 established the relative conﬁguration of the secondary alcohol of 3, that was then used to control the relative conﬁguration of the new alcohol in 10. Addition of the crotyl borane 12 to the derived aldehyde 11 also proceeded with high diastereocontrol. The other component of 4 was prepared from the aldehyde 14. Enantioselective allylation, by the method the authors developed, delivered the alcohol 16. The Z trisubstituted 198

THE KECK SYNTHESIS OF EPOTHILONE B alkene was then assembled by condensing the aldehyde 17 with the phosphorane 18. Dibal reduction of the product lactone 19 gave a diol, the allylic alcohol of which was selectively converted to the chloride with the Corey-Kim reagent. Hydride reduction then delivered the desired homoallylic alcohol, that was converted to the phosphonium salt 21. Condensation of 21 with 13 gave the diene, that was carried on to Epothilone B 4. S H

15

N O

O

N

HO S

Cl S

TBSO

19

1. LiEt3BH

N

2. NCS/DMS H

2. Ph3P/I2

20

3. Ph3P

O

O S

TBSO S

17

1. Dibal

N

Ph3P

S

TBSO

O

TBSO

H

N 16

HO

PPh3 18

CO2CH3

HO

N

+

O

N TBSO

O

S

(S)-BINOL Ti(O-i Pr)4

14 O

O

SnBu3

O

21

O

13

O HO O 4 Epothilone B

The synthesis of Epothilone B 4 as originally conceived by the authors depended on ring-closing metathesis of the triene 22. They prepared 22, but on exposure to the secondgeneration Grubbs catalyst it was converted only to 23. The authors concluded that the trans acetonide kept 22 in a conformation that did not allow the desired macrocyclization. S O

TBSO

N G2

O

O

TBSO

22 O

O 23

O

O

199

O

100. The Overman Syntheses of Nankakurines A and B August 3, 2009

The tetracyclic alkaloids Nankakurine A and Nankakurine B were isolated from the club moss Lycopodium hamiltonii. A preliminary study of the biological activity of Nankakurine A suggested that it could induce secretion of neurotrophic factors and promote neuronal differentiation. The key step in the ﬁrst syntheses of Nankakurine A and of Nankakurine B, reported (J. Am. Chem. Soc. 2008, 130, 11297) by Larry E. Overman of the University of California, Irvine was the intriguing intramolecular aza-Prins cyclization of 1 to 2. Ph

O BnO

H

N

N

O

H CH2=O

R N

OBn

1

N

N

N

Ph

2

3 R = H: Nankakurine A R = Me: Nankakurine B

The starting material for the synthesis was 5-methyl cyclohexenone 6, prepared from (R)-pulegone. The diene 5 was prepared from the alkyne 4, following the procedure developed by Diver. There were two issues in developing the Diels-Alder addition of the enone 4 to the diene 6. The ﬁrst was the relative lack of reactivity of 4 as a dienophile. The other issue was the ready epimerization of the product ketone 9. Both of these problems were solved using the activation method devised by Gassman. Condensation of 4 with 7 in the presence of the bis-silyl ether 7 and the diene 6 at cryogenic temperatures led to the ketal 8. It is thought that the active dienophile was the cation 11. O

BnO

BnO

BnO

CH2=CH2

O

4 / TMSOTf

O

cat G2 4

5

TMSO OTMS 7

6

8 Ph

O O BnO

O

FeCl3 SiO2 9

HN Ph 1. NH2 10 2. NaBH3CN

BnO

H

N

N

1

H

OTMS O

11

Gentle hydrolysis of the ketal 8 was effected with minimal epimerization. Reductive amination with the hydrazide 10 proceeded with high diastereocontrol, to give the precursor 1. The intramolecular aza-Prins cyclization of 1 to 2 proceeded well, though the desired tetracyclic 2 was only observed when base was included in the reaction medium. In the absence of base, tricyclic alkenes dominated. 200

THE OVERMAN SYNTHESES OF NANKAKURINES A AND B O BnO

H

Ph N

N

O

H CH2=O

Ph

N

N

Ph 1. SmI2

EtN(i -Pr)2 OBn

1

1. H2 /Pdcat 2. AlH3

2

N

Ph

MsCl

H

N

13

OH

2. CH2=O NaBH3CN

Et3N -40 °C

H

O

N

N OBn 12

N

N

Ph

1. H2/Pdcat

N 14

R N

2. CH2=O NaBH3CN

3 R = H: Nankakurine A R = Me: Nankakurine B

Reduction of the N-N bond of 2 proceeded smoothly with freshly prepared SmI2. After reductive methylation, hydrogenation removed the benzyl ether, and AlH3 converted the benzamide to the benzyl amine. At low temperature, mesylation of the alcohol was apparently faster than mesylation of the secondary amine, enabling cyclization to 14. Removal of the benzyl protecting group gave Nankakurine A, which was successfully methylated to give Nankakurine B. The completion of a total synthesis is an anxious moment, as for the ﬁrst time it is possible to compare spectra of the synthetic material with those reported for the natural product. There is always a concern as to whether or not the spectra are being acquired under precisely the same conditions employed by those who did the initial isolation. This is particularly true for very polar molecules such as these diamines. In fact, the spectra in CD3OD did not initially match, but on the addition of small amounts of CF3CO2H they were brought into congruence. Although in this synthesis the starting enantiomerically-pure cyclohexenone 4 was derived from natural sources, one could imagine that enantioselective conjugate methylation of cyclohexenone or a derivative could get one into the same manifold.

201

101. The Trost Synthesis of (-)-Ushikulide A September 7, 2009

(-)-Ushikolide A 4, isolated from a culture broth of Streptomyces sp. IUK-102, showed powerful activity against murine splenic lymphocyte proliferation (IC50= 70 nM). The most important player in the synthesis of 4 described (J. Am. Chem. Soc. 2008, 130, 16190) by Barry M. Trost of Stanford University was the ProPhenol ligand 1. O

Ph Ph HO

+

OPMB

O

O

HO

TBSO

OH

O

OH

O

PMBO

N

O OH

O

O

OH

O N HO 1 Ph

O

O 2

I

Ph

O

4

3

PMBO

(-)-Ushikulide A

HO

The precursor 2 was prepared by coupling the mesylate 7, the alkyne 12, and the aldehyde 13. The ﬁrst role of catalyst 1 was in mediating the enantioselective coupling of commercial 5 with 6 to give, after saponiﬁcation and CuCl decarboxylation, the mesylate 7. The preparation of 12 began with the Noyori hydrogenation of the ester 8 to the alcohol 9 in the expected high ee. Note that although this transformation was carried out at 1800 psi, such reductions proceed well and in similar ee at 60°C and 60 psi. Brown crotylation of the derived aldehyde 10 delivered 11, that was homologated to the alkyne 12. O H 5

6

OMs

CO2CH3

H cat 1/Me2Zn

7

OBn

O

O 95% ee H

CH3O

TBSO

8

O

O

Ru BINAP H2

CH3O

OBn

OH 99% ee

9

TBSO

OBn

H 11

10

12 H

The third fragment 13 was prepared by chiral auxiliary directed aldol condensation. Combination of 12 with 13 was followed by Au-mediated cyclization, converting the internal alkyne of 14 to the spiroketal of 15. Pd-catalyzed coupling of 15 with 7 then led to 2 with high diastereocontrol.

202

THE TROST SYNTHESIS OF (-)-USHIKULIDE A TBSO

H S

OBz

HO

O 12

Au cat

S

S

13

OPMB

S 14

OH

O O

OH

O OBz

PMBO

15

OBz

O

PMBO

7

O

O TBSO

Pd cat /Et2Zn

H

PMBO

HO

16

2

O I

H

The aldol addition of the enolate of 17 to 18 proved elusive under the usual conditions, but with 30 mol % of the Zn catalyst 1 the reaction proceeded smoothly, to deliver 19 with high diastereocontrol. O PMBO H OTBS O

OPMB 17

18

O

PMBO

OH

OPMB

O

O

cat 1/Me2Zn

OH

19 OTBS

OPMB 3

O

PMBO

To complete the synthesis, hydroboration with 9-BBN was effected on the free carboxylic acid 3, and Pd-mediated coupling of the derived borane was carried out with the free iodo alcohol 2. As a result, the product hydroxy acid 20 could be taken directly to the subsequent macrolactonization. O

CO2H

O

O OH

PMBO 9-BBN;

OPMB

O

O

OH

O

HO

O

OPMB TBSO

O

OH

O

2 / Pd cat

O

O O O PMBO

3

PMBO

203

20

O 4 (-)-Ushikulide A

HO

102. The Castle Synthesis of (-)-Acutumine October 5, 2009

The complex tetracyclic alkaloid (-)-acutumine 3, isolated from the Asian vine Menispermum dauricum, shows selective T-cell toxicity. The two adjacent cyclic all-carbon quaternary centers of 3 offered a particular challenge. Steven L. Castle of Brigham Young University solved (J. Am. Chem. Soc. 2009, 131, 6674) this problem by effecting net enantioselective conjugate allylation of the enantiomerically pure substrate 1 to give 2 with high diastereocontrol. OCH3

O OTBS TBSO O

OTBS TBSO O

OBn Cl

CH3O CH3O

Cl OBn Cl

CH3O CH3O

1

OCH3

OH O CH3O

2

3

N OCH3 CH3

The starting coupling partners (Organic Lett. 2006, 8, 3757; Organic Lett. 2007, 9, 4033) for the synthesis were the Weinreb amide 4, prepared over several steps from 2,3dimethoxyphenol, and the diastereomerically- and enantiomerically-pure cyclopentenyl iodide 5, prepared by singlet oxygenation of cyclopentadiene followed by enzymatic hydrolysis. Transmetalation of 5 by the Knochel protocol, addition of the resulting organometallic to 4 and enantioselective (and therefore diastereoselective) reduction of the resulting ketone delivered the alcohol 6. Methods for installing cyclic halogenated stereogenic centers are not well developed. Exposure of the allylic alcohol to mesyl chloride gave the chloride 7 with inversion of absolute conﬁguration. Remarkably, this chlorinated center was carried through the rest of the synthesis without being disturbed. OTBS

O

N OCH3 I

O

OTBS

I

OCH3 + BnO

5

Et3Al oxaziridine

TBSO 1. MsCl

I

OH

TBSO BnO

OH Cl

CH3O OCH3

8

OCH3

1. L-Selectride 2. TBS-Cl 3. H2 / Pd-C 4. PhI(OAc)2 5. BnBr/NaH

I

Cl

2. HF

OCH3 BnO

O (Bu3Sn)2 hν

TBSO

2. ItsunoOTES Corey

OCH3 4

MgCl LiCl

1.

OCH3

3. PCC

6

BnO

OCH3

7

OTBS TBSO O CH3O CH3O

OBn Cl

OCH3 1

A central step in the synthesis of 3 was the spirocyclization of 7 to 8. Initially, iodine atom abstraction generated the aryl radical. The diastereoselectivity of the radical addition to the

204

THE CASTLE SYNTHESIS OF (-)-ACUTUMINE cyclopentene was set by the adjacent silyloxy group. The α-keto radical so generated reacted with the Et3Al to give a species that was oxidized by the oxaziridine to the α-keto alcohol, again with remarkable diastereocontrol. Conjugate addition to the cyclohexenone 1 failed, so an alternative strategy was developed, diastereoselective 1,2-allylation of the ketone followed by oxy-Cope rearrangement. The stereogenic centers of 1 are remote from the cyclohexenone carbonyl, so could not be used to control the facial selectivity of the addition. Fortunately, the stoichiometric enantiomerically-pure Nakamura reagent delivered the allyl group preferentially to one face of the ketone 1, to give 9. The subsequent sigmatropic rearrangement to establish the very congested second quaternary center of 2 then proceeded with remarkable facility, at 0°C for one hour. OTBS TBSO O CH3O CH3O

OBn t-BuOK Cl

CH3O

OCH3 1

TBSO O CH3O

2. MeNH2 CH3O NaBH3CN OCH3

OTBS TBSO O

OCH3 2

OTBS

TBSO

OBn Cl

CH3O CH3O

OCH3 9

OTBS 1. O3

OTBS

TBSO HO

OBn Nakamura Cl CH3O

OBn Cl NH

OH

10

Cl

Cl

BCl3 O CH3O

N 11 OCH3 CH3

OCH3

O

OBn O CH3O

N 3 OCH3 CH3

(-)-Acutumine

Oxidative cleavage to the aldehyde followed by reductive amination gave 10, that looks as though it could be poised for intramolecular displacement of the secondary chloride. Nonetheless, Lewis acid mediated ionization followed by cyclization proceeded smoothly, to establish the fourth ring of the natural product. Oxidation state adjustment then completed the synthesis of (-)-Acutumine 3. The face selective enone allylation followed by oxy-Cope rearrangement (1 → 2), a highlight of the approach presented here, will have many applications in target-directed synthesis.

205

103. The Kobayashi Synthesis of (-)-Norzoanthamine November 2, 2009

The Zoanthus alkaloids, exempliﬁed by (-)-norzoanthamine 3a and zoanthamine 3b, show promising activity against osteoporosis. Susumu Kobayashi of the Tokyo University of Science assembled (Angew. Chem. Int. Ed. 2009, 48, 1400; Angew. Chem. Int. Ed. 2009, 48, 1404) the challenging tricyclic core of 3a employing the intramolecular Diels-Alder cyclization of 1 to 2. The cyclopentane of 1 served as useful scaffolding, even though it was cleaved en route to 3a. O OTBS

MOMO

OTBS

MOMO

N O O

O

TBSO

TBSO

O

OTBS 1

O R 3a R = H Norzoanthamine 3b R = Me Zoanthamine

2

The cyclohexane ring of 1 has ﬁve of its six positions substituted, including three that are alkylated quaternary centers. The starting point for the preparation of 1 was the enantiomerically-pure Hajos-Parrish ketone 4, containing the ﬁrst of the those quaternary centers. Conjugate addition of MeLi established the second quaternary center. The less stable endo alkyl branch of 1 was installed by conjugate addition to the more reactive α-methylene ketone of the cross-conjugated 5, followed by kinetic quench. Addition of vinyl cuprate across the open face of the enone 7 then established the ﬁnal quaternary center, setting the stage for the intramolecular Diels-Alder reaction. The silyl enol ether from the cyclization of 1 was not stable, so it was directly oxidized to the enone 2. TBSO

TBSO

O

TBSO

O

PhMe2SiLi CuCN

O

O 4

O

5

6

MOMO

OTBS

TBSO

TESO

OTBS

Li

7

SiPhMe2

MOMO

OTES

OTBS

1. 210 °C

+

2. cat Pd TBSO

TBSO 8

H

O

9

1

206

OTES

2

O

THE KOBAYASHI SYNTHESIS OF (-)-NORZOANTHAMINE The keto phosphonate 16 for the last two rings of 3a was prepared from the previouslyreported crystalline glutamic acid-derived mesylate 12. Reduction and homologation delivered the ester 14, that was condensed with the phosphonate anion 15 to give 16. 1. H+

LDA; CH3I O

O

O

EtO EtO

N O H

Boc P O

15

EtO EtO

14

CH3O2C

N

Li

O Boc

3. Boc2O

12

Boc

13

OMs

11

N

2. H2/Pd-C

O

OTBS

10

O

O

2. MsCl

O

OTBS

1. NaN3

O P

O

O

16

The congested cyclopentanone 17, derived from 2, was most efﬁciently deprotonated with n-BuLi. Exposure of the resulting silyl enol ether to ozone led to the α-hydroxylated product 18. Unexpectedly but happily, oxidative cleavage of 18 delivered, after deprotection and reprotection, the more congested aldehyde 19. This cleavage may be proceeding by tautomerization of 18 to the regioisomeric keto alcohol. The aldehyde 19 was condensed with the keto phosphonate 16, to give, after hydrogenation, the keto lactone 20. A series of oxidation state adjustments then completed the synthesis of (-)-norzoanthamine 3a. OTBS

MOMO

OTBS

O

OTBS

O 1. BuLi; TMSCl HO 2. O3

2

17

O

H O

O 16; H2-Pd/C

OTBS O N

O

O O

O

TESO

TESO

18

OTBS

O

Boc N

O O

TBSO

TBSO

TBSO

O

19 OTES

20 OTES

3a O (-)-Norzoanthamine

The preparation of 3a outlined here underlines the importance of developing new methods for concise stereocontrolled carbocyclic construction. The utility of an enantiomerically-pure bicyclic scaffold such as 4 for subsequent relative stereocontrol is particularly apparent.

207

104. The Davies / Williams Synthesis of (-)-5-epi-Vibsanin E December 7, 2009

There are currently 61 known vibsane-type diterpenes, as exempliﬁed by (-)-5-epi-Vibsanin E 3. The ﬁrst synthesis of 3, described (J. Am. Chem. Soc. 2009, 131, 8329) by Huw M. L. Davies of Emory University and Craig M. Williams of the University of Queensland, was based on the enantioselective seven-membered ring construction developed by the Davies group and the end game established by the Williams group. A key step in the synthesis was the intramolecular hetero Diels-Alder cyclization of 1 to 2.

O

O

O

O

H O O 1

2

3

O

(-)-5-epi-Vibsanin E

The absolute conﬁguration of 1 was set by the Rh-mediated cyclopropanation of 4 with the diazo ester 5. Though closely related to the α-diazo β-keto ester 6, the alkene of 5 donates electron density to the intermediate Rh carbene, making it more susceptible to the inﬂuence of the chiral ligands. The alkene of the enol ether then participated in the Cope rearrangement, delivering 8. Routine functional group transformation then converted 8 to 1, that cyclized smoothly to 2. N2 TBSO 5 4

OTBS CO2CH3

CO2CH3

OTBS

Rh* cat

N2 O 6

CO2CH3

7

90% ee

8

CO2CH3

O CO2CH3

H BF3.OEt2

9

1

208

O

2

THE DAVIES / WILLIAMS SYNTHESIS OF (-)-5-EPI-VIBSANIN E The enol ether of 2 was reduced with high diastereocontrol to give 10. The ketone was installed by allylic oxidation, setting the stage for attachment of the two pendant sidechains of 3 by conjugate addition followed by enolate trapping. Cu-catalyzed addition of the α-oxygenated organolithium 12 proceeded well in the presence of TMS-Cl, to establish the silyl enol ether 13. Allylation of the regenerated enolate proceeded at oxygen, but the enol ether 14 so prepared rearranged to the desired C-alkylated product 15 on microwave heating. O H+ O

NaBH3CN

2

MOMO

MOMO CH3Li; OTMS

O

CuCl / TMSCl

11 O

O

MOMO

Li

O

PCC

10

O 12

SeO2;

microwave O

Br

O O

13

O

14

15

The synthesis endgame was based on an unusual transformation, the addition to the keto aldehyde 16 of the phosphonium salt 17, developed (Tetrahedron 2008, 64, 6482) by the Williams group. This allowed the introduction of the complete vinyl ester array of (-)-5-epiVibsanin E 3.

O MOMO O O O

15

O O

O

O

H

1. H+/H2O 2. Swern 3. Wacker

O

O 17 O

PPh3

O O

16

3

(-)-5-epi-Vibsanin E

This synthesis illustrates the power of the elegant enantioselective seven-membered ring construction developed by the Davies group. The Williams phosphonium salt will also have general applicability. In a simpler manifestation, conversion of an aldehyde to, e.g., the enol benzoate, followed by exposure to dilute methoxide, will allow the conversion of an aldehyde to the aldehyde one carbon longer, without the acidic hydrolysis usually required for such a transformation.

209

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Author Index

Ackermann, Lutz, 2: 82 Adjiman, Claire S., 3: 48 Aggarwal, Varinder, 1: 82 2: 136 Akamanchi, Krishnacharya G., 2: 190 3: 7 Akhrem, Irena S., 3: 26 Alajarín, Mateo, 2: 159 Albericio, Fernando, 3: 20 Alexakis, Alexandre, 1: 179, 204 2: 5, 6, 73 3: 73, 144, 146, 148 Alfonso, Carlos A. M., 1: 88 Alibés, Ramon, 3: 158 Alonso-Moreno, Carlos, 3: 16 Alper, Howard, 2: 178 Altmann, Karl-Heinz, 3: 59 Alvarez-Manzaneda, Enrique, 3: 127 Amat, Mercedes, 1: 192 An, Duk Keun, 3: 8 An, Gwangil, 3: 3 Anabha, E. R., 3: 129 Anderson, James C., 2: 62 3: 15 Andrade, Rodrigo B., 3: 46 Andrus, Merritt B., 2: 4 Antilla, Jon C., 3: 62 Aora, Paramjit, 3: 129 Aoyama, Toyohiko, 3: 37 Aponick, Aaron, 3: 88 Arai, Takayoshi, 3: 80 Arcadi, Antonio, 1: 49 Ardisson, Janick, 3: 166 Aribi-Zouioueche, Louisa, 1: 34 Arimoto, Hirakazu, 1: 140 Arndt, Hans-Dieter, 2: 187 Arndtsen, Bruce A., 3: 134 Arora, Paramjit, 2: 151 Arseniyadis, Stellios, 3: 45 Asao, Naoki, 3: 22 Asokan, C. V., 3: 129 Aubé, Jeff, 1: 112, 139 2: 37 Aucagne, Vincent, 3: 90 Augé, Jacques, 3: 90 Aurrecoechea, José M., 3: 130

Baba, Akio, 1: 26 3: 35 Bäckvall, Jan-E., 2: 8 3: 108 Badía, Dolores, 2: 122 Baldwin, Jack E., 2: 169 Bandyopadhyay, Debkumar, 2: 179 Bangdar, B. P., 3: 3 Banwell, Martin G., 1: 170 3: 155 Baran, Phil S., 2: 63 3: 26, 29 Barbas, Carlos F., III, 1: 152 2: 7, 121 3: 63, 80, 82 Barluenga, José, 2: 75 3: 154 Barrett, Anthony G. M., 2: 156 3: 125 Barua, Nabin C., 3: 15 Baskaran, Sundarababu, 1: 8 Basu, Amit, 1: 40 Bates, Roderick W., 3: 159 Bavetsias, V., 1: 100 Bechara, William S., 3: 75 Becht, Jean-Michel, 2: 185 Bedford, Robin B., 3: 124 Bélanger, Guillaume, 3: 107 Beller, Matthias, 3: 42, 126 Bennasar, M.-Lluïsa, 3: 117 Bergman, Robert G., 1: 122 2: 41, 126, 178 3: 19, 37, 133, 180 Bergmeier, Stephen C., 2: 192 3: 160 Bernardi, Luca, 2: 58 Bernini, Roberta, 1: 20 Bertozzi, Carolyn R., 3: 20 Bertrand, Michèle P., 3: 63 Bettinger, Holger F., 3: 26 Betzer, Jean-François, 3: 166 Bhanage, Balchandra M., 3: 12, 122 Bhattacharyya, Ramgopal, 3: 42 Bieber, Lothar, 2: 55 Bifﬁs, Andrea, 3: 18 Bischoff, Laurent, 2: 159 Blagg, Brian S. J., 3: 33 Blakey, Simon, 3: 68 Blanchet, Jérôme, 3: 82 Blay, Gonzalo, 3: 68 Blazejewski, Jean-Claude, 2: 55 211

AUTHOR INDEX Blechert, Siegfried, 1: 134 2: 109, 111, 152, 153, 205 3: 51 Bochet, Christian G., 3: 17 Bode, Jeffrey W., 1: 114 2: 166 3: 85, 142 Boger, Dale L., 2: 45 Bolm, Carsten, 3: 5, 33, 76 Bonne, Damien, 3: 141 Borhan, Babak, 2: 196 3: 99 Bornscheuer, Uwe T., 2: 48 Bosch, Joan, 1: 192 Boukouvalas, John, 2: 189 Bowden, Ned B., 2: 151 Boyd, Derek R., 3: 148 Braun, Manifred, 1: 178 Breit, Bernhard, 1: 148 2: 86 3: 41, 80, 108, 159 Brewer, Matthias, 3: 33 Brookhart, Maurice, 3: 25, 39 Brovetto, Margarita, 3: 90 Brückner, Reinhard, 3: 64 Buchwald, Stephen L., 1: 164 2: 187 3: 32, 128, 129 Buono, Frederic G., 3: 125 Burgos, Alain, 3: 60 Burke, Steven D., 2: 56 3: 172–73 Burkhardt, Elizabeth R., 3: 14 Burrell, Adam J. M., 3: 160 Burton, Jonathan W., 3: 146, 152 Buszek, Keith R., 3: 38

Chakraborty, Tushar Kanti, 2: 128 3: 86, 108 Chan, Albert S. C., 1: 65 Chan, Johann, 3: 7 Chandra Roy, Subhas, 2: 93 Chandrasekhar, Srivari, 1: 86 3: 64 Chang, Ching-Yao, 3: 135 Chang, Ho Oh, 3: 150 Chang, Junbiao, 3: 131 Chang, Maosheng, 3: 22 Chang, Sukbok, 2: 43, 190 3: 122, 133 Charette, André B., 1: 192 2: 58, 69 3: 12, 34, 59, 72, 75, 150 Chatani, Naoto, 3: 126 Chauvin, Remi, 2: 110 Che, Chi-Ming, 1: 175 2: 146 3: 102, 104 Chemler, Sherry R., 3: 106 Chen, Cheng-Yi, 3: 131 Chen, Chien-Tien, 2: 47, 127 Chen, Jihua, 1: 201 2: 186 Chen, Ying-Chun, 3: 107, 143 Cheng, Jin-Pei, 3: 136 Chiba, Shunsuke, 3: 130 Chiu, Pauline, 3: 161 Chong, J. Michael, 2: 140 3: 72 Christmann, Mathias, 3: 155 Ciufolini, Marco A., 1: 48 3: 160 Clapés, Pere, 2: 165 Clark, J. Stephen, 2: 201 3: 88 Clark, James H., 3: 17 Clavier, Hervé, 3: 48, 50 Clayden, Jonathan, 2: 37 3: 63, 133, 159 Clive, Derrick L. J., 1: 74 3: 57 Coates, Geoffrey W., 2: 59 3: 32 Coldham, Iain, 3: 161 Cole, Kevin P., 3: 154 Cole-Hamilton, David J., 1: 148 Coleman, Robert S., 2: 62 Coltart, Don M., 2: 147 3: 31 Compain, Philippe, 3: 14 Concellón, José M., 3: 31 Córdova, Armando, 1: 118, 151 2: 8, 68, 121 3: 64, 78, 79, 82, 83, 84, 102, 136, 138, 143 Corey, E. J., 1: 168, 196, 197 2: 71, 100, 180, 208 3: 136, 137, 139 Cossy, Janine, 1: 109 2: 10 3: 31, 45 Cox, Liam R., 3: 23, 98 Craig, Donald, 3: 110 Crich, David, 2: 33, 179, 191 3: 17

Cabral, Shawn, 3: 9 Cacchi, Sandro, 3: 132 Caffyn, Andrew J. M., 3: 124 Cahiez, Gérard, 3: 31 Cammidge, Andrew M., 1: 174 Campagne, Jean-Marc, 3: 49 Campos, Kevin R., 2: 91 Cárdenas, Diego J., 2: 125 Cardierno, Victoria, 2: 145 Carreira, Erick, 1: 98, 150 2: 6, 17, 53, 118, 161, 181 3: 9, 42 Carretero, Juan C., 2: 92, 195 3: 70, 72 Carter, Rich G., 3: 121, 142, 194 Casey, Charles P., 3: 2 Casiraghi, Giovanni, 1: 152 Castarlenas, Ricardo, 2: 110 Castillón Sergio, 2: 94 3: 148 Castle, Steven L., 3: 204 Catellani, Marta, 3: 26 Çetinkaya, Bekir, 2: 22 212

AUTHOR INDEX Dujardin, Gilles, 3: 43 Dussault, Patrick H., 3: 41

Crimmins, Michael, 1: 134 2: 30, 95, 115 Crooks, Peter A., 3: 12 Csuk, René, 2: 144 Cuerva, Juan M., 2: 125, 174 Cumpstey, Ian, 3: 88 Cunico, Robert, 1: 126 Curci, Ruggero, 1: 176 3: 24, 28, 29 Curran, Dennis P., 1: 183 2: 50 3: 44

Earle, Martyn, 1: 21 Eberlin, Marcos N., 1: 202 Ellman, Jonathan A., 1: 122 2: 41, 126, 178 3: 80, 133, 180 Enders, Dieter, 1: 185 2: 7, 62, 171, 203 3: 140 Ermolenko, Mikhail S., 1: 186 Estévez, Ramon J., 1: 9 Eustache, Jacques, 3: 49 Evano, Gwilherm, 3: 110 Evans, David A., 2: 38 3: 72 Evans, P. Andrew, 1: 140 2: 73

Dai, Wei-Min, 3: 53 Dake, Gregory R., 2: 206 3: 114 Daly, John W., 3: 113 Danheiser, Rick L., 2: 40 Danishefsky, Samuel, 1: 73, 197 2: 156 Darcel, Christophe, 3: 16 Das, Biswanath, 3: 4 Dauban, Phillipe, 2: 179 3: 67 Daugulis, Olafs, 3: 121 David, Michèle, 3: 43 Davies, Huw M. L., 1: 169 2: 61, 105 3: 28, 103, 208 Davis, Benjamin G., 3: 50 Davis, Franklin A., 1: 188 Deiters, Alexander, 2: 83 3: 23 Dembinski, Roman, 3: 132 Deng, Li, 1: 153 2: 4, 23, 101, 139, 164 3: 62, 63, 71, 154 Deng, Xiaohu, 3: 130 Deng, Youquan, 1: 45 Denmark, Scott, 1: 22, 154 2: 117 Désaubry, Laurent, 3: 124 Deslongchamps, Pierre, 3: 155 de Vries, Johannes G., 3: 74 Diaz, Yolanda, 2: 94 Dieter, R. Karl, 3: 85 Diver, Steven T., 3: 45 Dixneuf, Pierre, 1: 182 2: 110 Dixon, Darren J., 3: 21 Doctorovich, Fabio, 3: 41 Dodd, Robert H., 2: 179 3: 67 Doi, Takayuki, 2: 66 Donsbach, Kai, 2: 152 Dore, Timothy M., 2: 88 Doyle, Michael P., 1: 177 2: 127, 192 3: 26 Driver, Tom G., 3: 133 Duan, Wenhu, 3: 20 Du Bois, Justin, 1: 8, 137, 153 2: 118, 210 3: 25, 28, 29 Dudley, Gregory B., 2: 47, 87, 91 3: 33

Faber, Kurt, 1: 158 Fabrizi, Giancarlo, 3: 132 Fagnoni, Maurizio, 2: 181 3: 25 Fagnou, Keith, 2: 25, 41, 156 Fairlamb, Ian J. S., 2: 104 Falck, J. R., 2: 129 3: 66, 68, 99 Fan, Renhua, 3: 25 Fañanás, Francisco J., 3: 100 Fang, Jim-Min, 1: 17 Farina, Vittorio, 2: 152 Faucher, Anne-Marie, 1: 132, 161 Feng, Xiaoming, 2: 93 3: 68 Feringa, Ben L., 1: 151, 164, 192, 204 2: 6, 60, 100, 162 3: 50, 71, 74, 77, 152 Fernández, Roberto, 3: 96 Ferraz, Helena M. C., 1: 202 2: 198 Ferroud, Clotilde, 3: 21 Fiaud, Jean-Claude, 1: 34 Fillion, Eric, 3: 92 Finn, M. G., 1: 145 Firouzabadi, Habib, 1: 106, 156 3: 15 Fleet, George W. J., 3: 20 Floreancig, Paul, 1: 195 2: 198 3: 89 Fogg, Deryn E., 2: 50 3: 45 Fokin, Valery V., 2: 86 3: 132 Forbes, David C., 1: 44 Fox, Joseph M., 2: 70 3: 145, 154 Fox, Martin E., 1: 194 Fringuelli, Francesco, 2: 99 Frontier, Alison J., 3: 102 Fu, Gregory C., 1: 38, 60, 61, 104 2: 5, 24, 83, 101, 128 3: 30, 37, 75, 76, 92 213

AUTHOR INDEX Fu, Hua, 3: 26 Fujii, Nobutaka, 3: 117, 126 Fujioka, Hiromichi, 2: 107 3: 157 Fujita, Ken-ichi, 2: 55 Fujiwara, Kenshu, 1: 195 3: 93 Fukumoto, Yoshiya, 2: 146 3: 5 Fukuyama, Tohru, 1: 142 2: 141 3: 14, 52, 98, 152 Funk, Raymond L., 2: 84, 136, 169 Furket, Daniel P., 3: 103 Fürstner, Alois, 1: 126 2: 52 3: 33, 35, 55, 144, 164 Fustero, Santos, 3: 23, 102 Futjes, Floris, 1: 92 Fuwa, Haruhiko, 3: 89

Grainger, Richard S., 3: 4 Greaney, Michael F., 3: 120 Greenberg, William E., 3: 103 Grela, Karol, 1: 126 2: 110 3: 47, 48 Griengl, Herfried, 3: 65 Grimme, Stefan, 3: 38 Grogan, Gideon, 3: 156 Gröger, Harald, 2: 143 Grotjahn, Douglas B., 3: 40 Grubbs, Robert H., 1: 28 2: 49, 110, 151 3: 45, 47, 48, 50 Grützmacher, Hansjörg, 3: 2 Guant, Matthew J., 1: 167 Guo, Qing-Xiang, 3: 121 Gürtler, C., 1: 100

Gaffney, Piers R. J., 3: 20 Gagné, Michel R., 2: 198 3: 92, 98, 145, 149 Gagosz, Fabien L., 2: 49, 173 3: 130 Gaich, Tanja, 3: 161 Gais, Hans-Joachim, 2: 128 Gallagher, Timothy, 1: 106 Ganesan, A., 1: 174 Garcia Fernandez, José M., 2: 91 Garg, Neil K., 3: 127 Garner, Charles M., 2: 129 Gastaldi, Stéphane, 3: 63 Gau, Han-Mou, 2: 162 Gaunt, Matthew J., 3: 114, 126, 139 Gellman, Samuel H., 2: 60, 119, 190 3: 70, 75, 137 Georg, Gunda, 1: 70 Georgiadis, Dimitris, 2: 66 Gervay-Hague, Jacquelyn, 2: 133 Gevorgyan, Vladimir, 3: 130 Ghosh, Arun, 1: 50 2: 199 Ghosh, Subrata, 2: 178 Gil, Gérard, 3: 63 Gimeno, José, 2: 145 Gin, David Y., 2: 140 Gleason, James L., 1: 114 2: 167 Glorius, Frank, 1: 18, 139 2: 128 Gnaim, Jallal M., 1: 174 Goeke, Andreas, 3: 149 Goel, Atul, 3: 127 Gómez Arrayás, Ramón, 2: 195 Gong, Liu-Zhu, 2: 74 3: 78, 86 Goossen, Lukas. J., 1: 156 2: 185 Gracias, Vijaya, 2: 41

Hajipour, Abdoul Reza, 2: 85 Hajra, Saumen, 3: 88 Halcomb, Randall, 1: 32 Hall, Dennis G., 1: 62 2: 197 3: 11, 65 Hamada, Hiroki, 3: 79 Hamada, Yasamusa, 1: 78 Hammond, Gerald B., 3: 16, 36 Han, Hyunsoo, 3: 65 Han, Li-Biao, 3: 39 Hanazawa, Yuji, 2: 81, 188 Hanessian, Stephen, 2: 51, 177 Hansen, Trond Vidar, 3: 124 Hanson, Paul, 1: 40 2: 109 Hanzawa, Yuji, 3: 129 Harada, Tadao, 3: 41 Harada, Toshiro, 1: 151 3: 67 Harder, Sjoerd, 2: 125 Harman, W. D., 2: 65, 99 Harris, Thomas, 3: 125 Harrity, Joseph P. A., 1: 53, 193 2: 205 Harrowven, David C., 2: 26 Hartley, Ricard C., 3: 91, 102 Hartwig, John F., 1: 157, 160 2: 60, 92, 155 3: 23, 39, 66, 120, 122, 123, 124 Harvey, Joanne, 3: 101 Hasegawa, Masayuki, 3: 77 Hashimoto, Shunichi, 3: 100 Hatakeyama, Susumi, 1: 196 3: 94 Hatanaka, Minoru, 3: 5 Hayashi, Tamio, 1: 64, 66 2: 120, 129 3: 33, 107, 152 Hayashi, Yujiro, 1: 4 2: 60, 68, 172 3: 12, 58, 72, 74, 136, 137, 143 214

AUTHOR INDEX He, Chuan, 1: 122, 175 2: 17, 177 3: 24 He, Ren, 3: 44 Heinrich, Markus R., 3: 125 Helmchen, Günter, 1: 138, 179, 202 2: 113, 161 Helquist, Paul, 3: 106 Heravi, Majid, 2: 75 Herrera, Antonio J., 3: 27 Herrera, Raquel, 2: 58 Hiemstra, Henk, 1: 92 Hiersmann, Martin, 1: 96 2: 61 3: 81 Hiller, Michael C., 2: 41 Hilmersson, Göran, 3: 9 Hilt, Gerhard, 2: 156 3: 25, 127 Hinkle, Kevin, 1: 106 Hintermann, Lukas, 2: 146 3: 5 Hirama, Masahiro, 2: 198 Hiroya, Kuo, 2: 159 Hiyama, Tamejiro, 3: 116 Hodgson, David M., 1: 81, 149 2: 137 3: 36 Hoerrner, Scott, 1: 40 Hoffman, Reinhard W., 2: 135 Holmes, Andrew B., 3: 152 Hon, Yung-Son, 2: 78 Honda, Toshio, 1: 75 3: 161 Horni, Osmo E. O., 1: 88 Hosomi, Akira, 3: 88 Hosseini-Sarvari, Mona, 2: 130 Hou, Duen-Ren, 2: 153 Hou, Xue-Long, 3: 150 Houk, K. N., 2: 198 Houpis, Joannis N., 3: 125 Hoveyda, Amir H., 1: 96, 141, 182 2: 24, 29, 48, 50, 94, 164, 196, 207 3: 71, 192, 193 Hoye, Thomas, 1: 130 2: 154 Hoz, Shmaryahu, 1: 18 Hsung, Richard P., 1: 187 2: 101 3: 154, 156 Hu, Longqin, 3: 18 Hu, Qiao-Sheng, 1: 110 Hu, Xinquan, 3: 3 Hudson, Richard A., 2: 15 Hue, Xue-Long, 3: 84 Hultzsch, Kai C., 2: 92 Hung, Shang-Cheng, 1: 16 Hunson, Mo, 2: 13

Iguchi, Kazuo, 1: 102 Ikariya, Takao, 2: 192 Ila, Hiriyakkanavar, 3: 33 Imada, Yasushi, 2: 77 Imahori, Tatsushi, 3: 56 Inoue, Masayuki, 2: 198 Inoue, Yoshio, 1: 98 Iqbal, Javed, 3: 46 Iranpoor, Nasser, 1: 106, 156 3: 15 Ishibashi, Hiroyuki, 2: 145, 210 3: 109 117 Ishihara, Kazuaki, 2: 44, 65, 76, 100 3: 156 Ishii, Yasutaka, 1: 22 3: 128 Isobe, Minoru, 1: 136 2: 130 Ito, Hajime, 3: 65, 85 Ito, Hisanaka, 1: 102 3: 22 Ito, Katsuji, 2: 58 Ito, Yukishige, 3: 22 Iwabuchi, Yoshiharu, 2: 204 3: 13 Jackson, James E., 3: 23 Jacobi, Peter A., 3: 85 Jacobsen, Eric N., 1: 84, 138, 150, 160, 177, 205 2: 108 3: 71, 74, 115, 147, 153 Jaekel, Christoph, 3: 148 Jahn, Ullrich, 3: 160 Jamison, Timothy F., 1: 94 2: 78, 126, 136, 198 3: 39, 93, 112 Jang, Doo Ok, 2: 182 Jennings, Michael P., 1: 187 3: 22, 58 Jeon, Heung Bae, 1: 188 Jeong, Nakcheol, 3: 148 Jew, Sang-sup, 2: 163 Jia, Guochen, 3: 132 Jia, Xueshun, 2: 189 Jiang, Biao, 3: 33 Jiang, Huan-Feng, 3: 130, 134 Joglar, Jesús, 2: 165 Johnson, Jeffrey S., 2: 29 3: 196 Johnson, Marc J. A., 2: 148 3: 31 Johnston, Jeffrey N., 1: 38 3: 119 Jones, Christopher, 3: 60 Jones, Paul B., 1: 176 Jørgensen, Karl Anker, 1: 119, 166, 205 2: 4, 14, 23, 60, 102, 121, 172, 203 3: 62, 64, 77, 85, 136, 137, 138, 139, 141, 178 Joshi, N. N., 1: 64 215

AUTHOR INDEX Juhász, Zsuzsa, 3: 87 Jun, Chul-Ho, 2: 178 3: 42 Jung, Kyung Woon, 3: 112 Jung, Michael E., 2: 70 3: 154

Kobayashi, Shu, 1: 111 2: 39, 60, 162, 196 3: 34, 83, 104 Kobayashi, Susumu, 3: 159, 206 Kobayashi, Yoshihisa, 3: 19 Kobayashi, Yuichi, 3: 150 Kocevar, Marijan, 3: 131 Koert, Ulrich, 2: 135 3: 54 Koide, Kazunori, 3: 33, 46 Kokotos, George, 2: 48 Komatsu, Mitsuo, 2: 137 Kondo, Yoshinori, 1: 10 Kotaki, Yoshihiko, 3: 52 Kotsuki, Hiyoshuzi, 1: 153 Kowalski, Conrad, 1: 107 Kozlowski, Marisa C., 2: 185 Kozmin, Sergey A., 3: 174 Krafft, Marie E., 2: 173 Krause, Norbert, 2: 197 Krische, Michael J., 2: 195 3: 68, 82 Kroutil, Wolfgang, 1: 2 3: 66, 69 Kudo, Kazuaki, 3: 74 Kuhakarn, Chutima, 3: 14 Kulkarni, Mukund G., 2: 127 Kunai, Atsutaka, 2: 185 Kündig, E. Peter, 1: 137 Kunz, Horst, 3: 109 Kurth, Mark J., 3: 141 Kuwahara, Shigefumi, 1: 200 3: 44 Kuwano, Ryoichi, 3: 104 Kwong, Fuk Yee, 3: 124

Kakiuchi, Fumitoshi, 2: 209 Kalesse, Markus, 3: 65 Kambe, Nobuaki, 3: 36 Kamimura, Akio, 3: 78 Kaminski, Zbigniew J., 2: 44 Kamitanaka, Takashi, 3: 41 Kan, Toshiyuki, 3: 98 Kanai, Motomu, 1: 98 2: 3, 52, 87 3: 61, 74 Kaneda, Kiyotomi, 1: 104, 107 Kanemasha, Shuji, 3: 77 Kappe, C. Oliver, 2: 155, 187 Karoyan, Philippe, 3: 77, 106 Katsuki, Tsutomu, 2: 13, 58 3: 6, 40, 66, 148, 156 Katsumora, Shigeo, 2: 152 3: 133 Kawabata, Takeo, 1: 38 3: 105, 107 Kawatsura, Motoi, 2: 62 Keck, Gary E., 2: 9, 32 3: 198 Kelly, T. Ross, 1: 108 Kempe, Rhett, 2: 209 Kerr, Michael A., 3: 119 Kerr, William J., 2: 147 Khaksar, Samad, 3: 21 Kigoshi, Hideo, 1: 134 Kim, Deukjoon, 2: 32, 170 Kim, Ikyon, 3: 132 Kim, Jae Nyoung, 2: 41, 187 Kim, Kwan Soo, 1: 188 Kim, Mahn-Joo, 1: 88 Kim, Sanghee, 2: 107 Kim, Sunggak, 3: 85 Kim, Tae-Jeong, 3: 144, 146 Kim, Young Gyu, 1: 108 Kirsch, Stefan F., 2: 206 Kirschning, Andreas, 1: 189 2: 151 3: 21, 177 Kishi, Yoshito, 1: 178 2: 191 3: 68 Kita, Yasuyuki, 2: 13, 18, 107 3: 24, 157 Kitazume, Tomoya, 2: 85 Klosin, Jerzy, 2: 59 Knight, David W., 2: 145 3: 128 Knochel, Paul, 1: 81, 110, 127, 149 2: 39 3: 129

Lakouraj, M. M., 1: 86 Lambert, Tristan H., 3: 92, 150, 151 Landais, Yannick, 3: 86 Larock, Richard C., 2: 82 3: 128, 132 Lautens, Mark, 1: 74 3: 129, 131 Lavigne, Guy, 2: 151 Leadbeater, Nicholas, 1: 54 2: 22 Lebel, Hélène, 2: 43, 210 Lectka, Thomas, 1: 62, 119 2: 161 Lee, Chulbom, 2: 138, 173 Lee, Daesung, 1: 132 3: 56, 160 Lee, Eun, 1: 72 2: 199 Lee, Hee-Yoon, 1: 36 Lee, Nathan K., 2: 152 Lee, Su Seong, 3: 51 Lee, Victor, 2: 169 Lee, Yoon-Silk, 3: 3 Lefenfeld, Michael, 3: 23 Legzdins, Peter, 3: 24 216

AUTHOR INDEX Leighton, James L., 2: 62, 89, 162 Lendsell, W. Edward, 2: 43 Lepore, Salvatore D., 3: 15 Lesma, Giordano, 1: 70 Levacher, Vincent, 2: 44 Ley, Steven V., 2: 19, 67 3: 176 Li, Bryan, 2: 130 Li, Chao-Jun, 2: 144 3: 3, 28 Li, Chaozhong, 2: 173 3: 43, 106 Li, Jin-Heng, 2: 155, 185 Li, Shun-Jun, 3: 72 Li, Zhong, 3: 114 Liang, Fushun, 3: 135 Liang, Xinmiao, 2: 144 3: 140, 142 Liang, Yong-Min, 3: 128 Liao, Chun-Chen, 3: 158 Lièvre, Catherine, 1: 75 Lin, Chung-Cheng, 2: 47 Lin, Guo-Qiang, 2: 62 3: 63 Lin, Zhenyang, 3: 132 Linclau, Bruno, 1: 156 Linker, Torsten, 3: 91 Liotta, Dennis C., 3: 83 Lipshutz, Bruce H., 3: 13, 48, 72, 149 List, Benjamin, 1: 78, 166 2: 68, 203 3: 62, 73, 75, 76, 84, 139, 141, 143, 156 Little, R. Daniel, 1: 194 Liu, David R., 3: 39 Liu, Guoshen, 3: 29, 40 Liu, Hong, 3: 125 Liu, Kevin G., 2: 160 Liu, Lei, 3: 121 Liu, Qun, 3: 135 Liu, Rai-Shung, 1: 171 3: 145 Livingstone, Tom, 2: 33 Lobo, Ana M., 3: 135 Loh, Teck-Peng, 1: 150, 178 2: 30, 96 3: 69, 73, 140, 156 Love, Jennifer, 3: 36 Lu, Yixin, 3: 140 Lubell, William D., 2: 87 Lubin-Germain, Nadège, 3: 88 Luo, Sanzhong, 3: 136 Luo, Shi-Wei, 3: 86 Lyapkalo, Ilya M., 2: 146 3: 16

MacMillan, David W. C., 1: 4, 119, 124 2: 1, 6 3: 70, 75, 76, 143 Mäeorg, Uno, 3: 21 Mafﬁoli, Sonia I., 2: 43 Maier, Martin E., 3: 122, 164 Makosza, Mieczyslaw, 2: 29 Malachowski, William P., 2: 208 Maleczka, Robert E., Jr., 2: 160 3: 8 Manabe, Kei, 3: 120 Manabe, Shino, 3: 22 Mancini, Pedro, 2: 188 Mander, Lewis N., 1: 12, 198 Mann, André, 3: 108 Marciniec, Bogdan, 2: 17 Marco, J. Alberto, 1: 29 Marek, Ilan, 1: 47 Mariano, Patrick, 1: 139 Markó, István, 2: 22, 93, 148 3: 49, 74 Marks, Tobin, 1: 30 3: 13, 92 Marque, Sylvain, 3: 123 Marquis, Robert W., 1: 184 Marshall, James A., 2: 122, 134 3: 91 Martín, Angeles, 3: 90 Martín, M. Rosario, 3: 158 Martin, Stephen, 1: 29, 83 2: 34, 51, 70 Martín, Victor S., 2: 96 3: 104 Maruoka, Keiji, 1: 90, 152, 170 2: 23, 117 3: 78, 82, 85, 109 Masson, Géraldine, 3: 69, 105 Mata, Ernesto G., 3: 48 Matsuo, Jun-ichi, 2: 14, 145, 210 3: 155 Mauduit, Marc, 3: 47, 48 May, Oliver, 2: 143 May, Scott A., 2: 82 Mazurkiewicz, Roman, 2: 85 McCluskey, Adam, 3: 23 McDonald, Frank E., 1: 30, 70 3: 93 McMurray, John S., 3: 9 Meek, Graham, 1: 174 Mehta, Goverdhan, 2: 113 Melchiorre, Paolo, 3: 84 Mellet, Carmen Ortiz, 2: 88, 91 Menzel, Karsten, 3: 122 Metz, Peter, 2: 66 Micalizio, Glenn A., 2: 122, 195 3: 36 Michael, Forrest E., 3: 108 Mihovilovic, Marko D., 2: 134 Militzer, H.-Christian, 1: 191 Miller, Stephen A., 2: 143 Milstein, David, 2: 86 3: 7

Ma, Dawei, 1: 143 2: 164 3: 83, 112, 141 Ma, Shengming, 1: 132 2: 34 217

AUTHOR INDEX Nakata, Masaya, 2: 186 Naota, Takeshi, 2: 77 Narasaka, Koichi, 1: 128 2: 188 3: 130 Naso, Francesco, 3: 19 Nay, Bastien, 1: 186 Negishi, Ei-chi, 3: 76 Nelson, Scott G., 1: 116, 201 2: 122, 140 3: 80 Neumann, Ronny, 1: 86 2: 77 Nevado, Cristina, 3: 149 Nguyen, SonBinh T., 2: 117, 143 3: 51 Ni, Raney, 3: 15, 67 Nichols, Paul J., 2: 120 Nicolaou, K. C., 1: 120 2: 44, 74, 76, 112, 131, 170 3: 137 Nihsikawa, Toshio, 2: 130 Nishibayashi, Yoshiaki, 3: 151 Nishimura, Takahiro, 3: 74 Nishiyama, Hisao, 2: 7 Nishiyama, Shigeru, 1: 145, 157 Njardarson, Jon T., 3: 106 Node, Manabu, 3: 69 Nokami, Junzo, 1: 96 2: 57 Nolan, Steven P., 2: 15 3: 48, 50 Novick, Scott J., 2: 162 Novikov, Alexei, 2: 209 Nozaki, Kyoko, 2: 39 Nugent, Thomas C., 3: 67 Nugent, Willam A., 2: 122

Minakata, Satoshi, 2: 137 Minnaard, Adriaan J., 1: 164, 204 2: 60 3: 50, 94 Mioskowski, Charles, 2: 190 3: 99 Miura, Katsukiyo, 3: 88 Miura, Masahiru, 1: 19 3: 37 Miyashita, Masaaki, 1: 146 2: 103 Mizuno, Noritaka, 2: 77 3: 7 Moberg, Christina, 1: 64 Moeller, Kevin, 1: 80 Mohapatra, Debendra K., 3: 45 Molander, Gary A., 1: 76 3: 122 Mongin, Florence, 3: 130 Montgomery, John, 2: 30 3: 31, 146 Moody, Christopher, 3: 121 Moore, Jeffrey S., 2: 110 3: 49 Mori, Atsunori, 2: 25 Mori, Miwako, 1: 58, 83 3: 145 Morimoto, Yoshiki, 2: 93 3: 94 Morken, James P., 1: 6 2: 58, 119 Morris, Robert H., 1: 204 Mortier, Jacques, 2: 186 Mortreux, André, 3: 47 Morvan, François, 3: 10 Mottaghinejad, Enayatollah, 1: 176 Moutevelis-Minakakis, Panagiota, 3: 8 Movassaghi, Mohammad, 2: 79, 154, 188 3: 14 Moyano, Albert, 3: 108 Mukai, Chisato, 2: 92 Mukaiyama, Teruaki, 3: 5, 12, 36, 70 Müller, Paul, 1: 168 2: 179 3: 67 Müller, Thomas J. J., 2: 41 3: 134 Mulzer, Johann, 1: 183 2: 174 3: 145, 161 Murahashi, Shun-Ichi, 3: 10 Murakami, Masahiro, 1: 123 2: 69, 205 Murphy, John A., 1: 10 3: 134 Murphy, Paul V., 3: 107 Murray, William V., 2: 49 Myers, Andrew G., 1: 87, 190 2: 11 3: 77

O’Brien, Peter, 1: 89 Ochiai, Masahito, 3: 38, 126 O’Doherty, George A., 3: 84 89 Odom, Aaron L., 1: 170 Ogoshi, Sensuke, 3: 116 Ogura, Katsuyuki, 3: 123 Oguri, Hiroki, 3: 91 Ohira, Susumu, 1: 168 2: 31 Ohno, Hiroaki, 3: 117, 126 Oi, Shuichi, 1: 98 Oii, Takashi, 2: 118 Oikawa, Hideaki, 3: 91 Ojima, Iwao, 2: 108 Okamoto, Sentaro, 2: 16 Olah, George A., 2: 86 Olivo, Horacio F., 2: 107 Ollivier, Jean, 3: 102 Oltra, J. Enrique, 2: 125, 174 Ooi, Takashi, 3: 80 Organ, Michael G., 3: 41

Nagao, Yoshimitsu, 2: 59 Nagaoka, Hiroto, 1: 36 Nagashima, Hideo, 3: 8 Nájera, Carmen, 2: 56 Nakada, Masahisa, 1: 4, 52, 165 2: 183 Nakamura, Eiichi, 3: 126 Nakamura, Shinji, 3: 38 Nakanishi, Koji, 2: 198 Nakao, Yoshiaki, 3: 116 218

AUTHOR INDEX Poulsen, Sally-Ann, 2: 49 Poupon, Erwan, 3: 118 Powell, David A., 2: 180 Prabhakar, Sundaresan, 3: 135 Prashar, Sanjiv, 3: 124 Prati, Fabio, 1: 144 Preston, Peter N., 2: 43 Prim, Damien, 3: 123 Proctor, David J., 3: 12, 150 Punniyamurthy, T., 1: 26 3: 2 Punta, Carlo, 3: 34 Pyne, Stephen G., 2: 165

Oriyama, Takeshi, 3: 2 Oshima, Koichiro, 2: 88 3: 38, 125 Otero, Antonio, 3: 16 Ouchi, Akihiko, 3: 23 Ouellet, Stéphane G., 3: 14 Ovaska, Timo V., 3: 161 Overhand, Mark, 1: 83 Overman, Larry E., 1: 56, 143, 160 2: 27, 149, 174, 191 3: 24, 200 Ozerov, Oleg V., 2: 16, 56 Padwa, Albert, 1: 22 2: 100, 157 3: 111, 115 Pagenkopof, Brian, 1: 5 3: 81 Pale, Patrick, 3: 18 Palomo, Claudio, 2: 57, 166 3: 65, 72 Panek, James, 1: 73 Papini, Anna Maria, 2: 44 Paquette, Leo A., 1: 24 2: 189 3: 188 Park, Hyeung-geun, 2: 163 Park, Jaiwook, 1: 88 2: 13 3: 8 Parker, Kathlyn A., 2: 10 3: 83 Parkinson, Christopher J., 2: 185 Parsons, Andrew F., 2: 21 Parsons, Philip J., 3: 46 Partridge, Ashton C., 3: 36 Patel, Bhisma K., 2: 75 Paterson, Ian, 3: 97, 99 Pathak, Tanmaya, 2: 86 3: 160 Pedro, José R., 3: 68 Pei, Tao, 3: 131 Pelletier, Jeffrey C., 3: 4 Perchyonok, V. T., 3: 14 Petasis, Nicos A., 2: 165 Peters, René, 3: 65, 84 Pettus, Thomas R. R., 2: 175 Petursson, Sigthur, 3: 20 Pfaltz, Andreas, 2: 69, 119 Phillips, Andrew J., 1: 180 2: 121 3: 41, 87 Piers, Warren, 1: 131 Pihko, Petri M., 2: 99 3: 90 Pineschi, Mauro, 1: 80 Pizzo, Fernando, 2: 99 Plietker, Bernd, 3: 82 Popik, Vladimir, 2: 129 Porco, John, 1: 131 Porta, Ombretta, 3: 34 Postema, Maarten H. D., 1: 194 Potts, Barbara C. M., 1: 196

Quan, Junmin, 2: 186 Que, Lawrence, Jr., 3: 82 Quideau, Stéphane, 3: 158 Quinn, Kevin J., 1: 186 Radivoy, Gabriel, 2: 15 Raghavan, Sadagopan, 3: 32 Raines, Ronald T., 3: 47 Rainier, Jon D., 3: 46 Rajan-Babu, T. V., 2: 120 Ram, N. Ram, 3: 34 Ramachandran, P. Veeraghavan, 2: 33 Rama Rao, K., 2: 18 Ranier, Jon D., 2: 50 Rao, J. Madhusudana, 2: 44 Rassu, Gloria, 1: 52 Ratovelomanana-Vidal, Virginie, 3: 148 Rawal, Viresh H., 2: 166 Ray, Jayanta K., 3: 27 Raymond, Kenneth N., 3: 19, 37 Ready, Joseph M., 2: 62, 97 3: 67 Reetz, Manfred T., 2: 91 Reeves, Jonathan, 2: 187 Reiser, Oliver, 3: 55 Reissig, Hans-Ulrich, 3: 129 Renaud, Phillipe, 2: 126 3: 25, 40 Rhee, Hakjune, 3: 3 Richardson, David E., 3: 13 Riera, Antoni, 1: 193 Rios, Ramon, 3: 108 Robbins, Morris, 1: 175 Roberts, Stanley, 1: 191 Robichaud, Joël, 2: 114 Rodríguez, Félix, 3: 100 Rodriguez, Jean, 3: 141 Roelfes, Gerard, 2: 100 3: 152 Roesky, Peter W., 2: 125 219

AUTHOR INDEX Seitz, Oliver, 2: 133 Sekar, G., 3: 10, 13 Selvakumar, N., 3: 54 Sestelo, José Pérez, 2: 209 Severin, Kay, 2: 178 Shair, Matthew D., 2: 7 Sharghi, Hashem, 2: 130 Sharma, G. V. M., 1: 144 Sharma, Pawan K., 3: 10 Sherburn, Michael, 1: 68 Shi, Xiaodong, 3: 108 Shi, Yian, 1: 5, 158 2: 77, 171, 210 3: 80 Shi, Zhang-Jie, 2: 81, 186 3: 127, 148 Shibasaki, Masakatsu, 1: 56, 90, 98, 159 2: 3, 52, 57, 74, 87, 111, 166 3: 61, 74 Shibata, Takanori, 3: 147 Shih, Tzenge-Lien, 1: 56 Shiina, Isamu, 2: 57, 136 3: 99 Shin, Seunghoon, 3: 144 Shindo, Mitsuro, 2: 187 Shing, Tony K. M., 2: 177, 207 3: 157, 159 Shintani, Ryo, 3: 107 Shipman, Michael, 3: 104 Shiraishi, Yasuhiro, 3: 42 Shirakawa, Eiji, 3: 33 Shishido, Kozo, 3: 151 Sibi, Mukund P., 1: 52, 116 2: 9 3: 60, 62, 65, 71, 152 Sierra, Miguel Á., 3: 154 Silvani, Alessandra, 1: 70 Simpkins, Nigel S., 3: 158, 159 Singaram, Bakthan, 3: 40 Singer, Robert A., 2: 155 Singh, Vinod K., 3: 6 Sirkecioglu, Okan, 1: 16 Skrydstrup, Troels, 3: 31, 32 Slater, Martin J., 3: 104 Smith, Amos B., III, 2: 48, 111, 114, 135 3: 168 Smith, Milton R., 2: 40, 160 Snapper, Marc L., 2: 48, 178, 206 3: 44, 57, 148 Snider, Barry B., 2: 102, 169 3: 101, 159 Snowden, Timothy S., 3: 34 Solladié-Cavallo, Arlette, 1: 92 Soltani, Mohammad Navid, 2: 189 3: 30 Somfai, Peter, 3: 108, 123 Somsák, László, 3: 87

Rojas, Christian M., 3: 92 Rokach, Joshua, 3: 17 Romo, Daniel, 1: 202 3: 86 Roush, William R., 1: 174 2: 31, 62 3: 152, 182 Rovis, Tomislav, 1: 78, 203 2: 139 3: 88, 105, 138 Rowlands, Gareth, 1: 92 Rozen, Shlomo, 2: 13 3: 4 Ruano, José Luis García, 3: 16, 76, 158 Rueping, Magnus, 3: 82 Rutjes, Floris P. J. T., 2: 130 3: 74 Rychnovsky, Scott D., 1: 162 2: 30, 96, 191, 200 3: 30, 87, 170 Saá, Carlos, 2: 103 Saicic, Radomir N., 1: 74 2: 153 3: 144 Saikawa, Yoko, 2: 186 Saito, Akio, 2: 81, 188 3: 129 Saito, Susumu, 3: 16 Sajiki, Hironao, 2: 86 3: 20 Sakai, Norio, 3: 8 Samant, Shriniwas D., 2: 39 Sames, Dalibor, 2: 25 3: 29 Sammakia, Tarek, 1: 203 2: 198 3: 162 Sammis, Glenn M., 3: 90, 92 Sanford, Melanie S., 1: 157 2: 82 3: 41, 124 Santillo-Piscil, Fernando, 2: 48 Sarandeses, Luis A., 2: 209 Sarkar, Tarun, 1: 140 Sarpong, Richmond, 2: 187 Sasaki, Makato, 3: 89 Sataki, Masayuki, 3: 100 Sato, Fumie, 1: 44 Sato, Ken-ichi, 2: 191 Sato, Yoshiro, 3: 145 Satoh, Tsuyoshi, 1: 110 Saudan, Lionel A., 3: 8 Sawamura, Masaya, 3: 65, 84 Schafer, Laurel L., 1: 1 2: 195 3: 151 Schafmeister, Christian E., 3: 15 Schaus, Scott E., 1: 66 2: 62, 133, 172 3: 80 Scheidt, Karl A., 2: 117, 203 3: 14 Schmalz, Hans-Günther, 3: 72 Schmid, Andreas, 1: 35 Schmidt, Bernd, 2: 109 Schrekker, Henri S., 2: 181 Schrodi, Yann, 3: 45 220

AUTHOR INDEX Soós, Tibor, 3: 75 Sordo, José A., 2: 145 Sorenson, Erik J., 2: 65, 123 Spanevello, Rolando A., 3: 40 Spino, Claude, 1: 46 Spring, David R., 3: 96 Stahl, Shannon S., 2: 190 3: 40 Standen, Michael C., 1: 44 Steel, Patrick, 1: 54 Steinke, Joachim H. G., 2: 49 Stoltz, Brian M., 1: 164 3: 57, 68, 113, 116, 151 Stork, Gilbert, 2: 35, 3: 192 Strukul Giorgio, 2: 177 Studer, Armido, 3: 38, 67 Suárez, Alejandra G., 3: 154 Suárez, Ernesto, 3: 27, 90 Suda, Kohji, 1: 159 Sudalai, Arumugam, 3: 28, 64, 78 Sugai, Takeshi, 3: 38 Suginome, Michinori, 3: 126 Sun, Wei, 3: 37 Sun, Zhaolin, 1: 20 Surya Prakash, G. K., 2: 86 Suzuki, Keisuke, 2: 101 Suzuki, Ken, 3: 10 Szabó, Kálmán J., 3: 25, 34, 81

Tanaka, Masato, 2: 181 Tanaka, Tetsuaki, 1: 46, 166 3: 24 Taneja, Subhash Chandra, 3: 86 Tang, Weiping, 3: 148 Tang, Yun, 2: 203 Tanino, Keiji, 1: 14 2: 103 Taylor, Paul C., 3: 48 Taylor, Richard E., 3: 87 Taylor, Richard J. K., 3: 96 Tedrow, Jason S., 3: 8 Terada, Masahiro, 2: 120 Terao, Jun, 3: 36 Tevelkar, Vikas N., 3: 10 Theodorou, Vassiliki, 3: 20 Thomson, Regan J., 3: 35 Tietze, Lutz, 1: 142 Tius, Marcus A., 3: 40 Tobisu, Mamoru, 3: 127 Tokunaga, Makoto, 3: 6 Tomioka, Kiyoshi, 1: 200 2: 5 3: 161 Tomooka, Katsuhiko, 3: 116 Toshima, Kazunobu, 2: 47 Toste, F. Dean, 2: 41, 73, 84, 93, 159, 195 3: 106, 178 Trauner, Dirk, 1: 1 2: 26 3: 155, 157 Trost, Barry M., 2: 32, 108, 139, 146, 163, 193 3: 82, 95, 103, 113, 146, 202 Trudell, Mark, 1: 41 Tsuji, Yasushi, 3: 6, 134 Tsukamoto, Hirokazu, 3: 18 Tu, Yong Qiang, 2: 138 Tuck, Kellie L., 3: 14 Tudge, Matthew, 3: 12

Taber, Douglass F., 1: 28, 57, 141, 165 2: 34, 84, 104, 207 3: 33, 36, 69, 149, 156, 158 Tachibana, Kazuo, 3: 100 Taddei, Maurizio, 3: 41 Takacs, James M., 3: 66 Takahashi, Takashi, 2: 66 3: 145 Takahata, Hiroki, 3: 56 Takamura, Norio, 2: 160 Takayama, Hiromitsu, 3: 184–85 Takeda, Takeshi, 1: 11 2: 21, 205 Takemoto, Yoshiji, 1: 63 2: 163 3: 43, 142 Talbakksh, M., 1: 86 Tamooka, Katsuhiko, 2: 92 Tamura, Osamu, 3: 43, 109 Tan, Choon-Hong, 3: 140 Tan, Derek S., 2: 94 Tan, Kian L., 3: 42 Tanabe, Yoo, 2: 148 Tanaka, Fujie, 1: 152 3: 63 Tanaka, Ken, 2: 73, 103 3: 123, 146

Uchiyama, Masanobu, 1: 101 2: 78 3: 38, 130 Uedo, Ikao, 1: 34 Uenishi, Jun’ichi, 2: 130 Uozumi, Yasuhiro, 3: 2 Uriac, Philippe, 3: 120 Urpí, Fèlix, 3: 58 Uziel, Jacques, 3: 88 Vakulya, Benedek, 3: 75 Vanderwal, Christopher D., 3: 109 van de Weghe, Pierre, 3: 120 Vankar, Yashwanl D., 2: 130 Vederas, John, 1: 54 2: 38 Velezheva, Valeriya S., 3: 133 Verkade, John K., 2: 155 221

AUTHOR INDEX Vesely, Jan, 3: 108 Vidal-Ferran, A., 2: 77 Vilarrasa, Jaume, 3: 16, 58 Villar, Ramón, 2: 49 Vincent, Jean-Marc, 3: 86 Vinod, Thottumakara K., 2: 76 Vogel, Pierre, 1: 60, 144 Vogt, Dieter, 3: 41

Woerpel, Keith A., 3: 4 Wolf, Christian, 2: 144 Wolfe, John, 1: 138 2: 134 Wong, Chi-Huey, 3: 103 Wong, Man-Kin, 2: 146 Wood, John L., 3: 186 Wood, Mark E., 3: 28 Woodward, R. B., 2: 35 Woodward, Simon, 1: 204 2: 3 Wu, Jie, 3: 120 Wu, Yun-Dong, 1: 114 3: 84 Wulff, William D., 2: 195 3: 147

Walsh, Patrick J., 1: 66, 152 2: 3, 61, 69 3: 130 Walters, Iain A. S., 2: 83 Wang, Chun-Jiang, 3: 108 Wang, Ge, 3: 6 Wang, Mei-Xiang, 3: 66 Wang, N. Jianbo, 3: 104 Wang, Pengfei, 3: 19 Wang, Quanrui, 3: 148 Wang, Wei, 2: 9, 203 3: 20, 79, 106 Wang, Xiaolai, 2: 75 Wang, Yan-Guang, 3: 135 Wardrop, Duncan J., 2: 135 Weck, Marcus, 3: 60 Wee, Andrew G. H., 2: 180 Wei, Xudong, 2: 152, 182 Weissman A., Steven, 2: 21 Weller, Andrew S., 2: 178 Wendeborn, Sebastian, 2: 147 Wender, Paul A., 2: 104 Wennemers, Helma, 3: 75 Wessjohan, Ludger A., 2: 181 West, Frederick G., 3: 106 Westermann, Bernhard, 2: 62 White, James D., 3: 97 White, M. Christina, 2: 18, 134, 210 3: 24, 40 Whitehead, Roger C., 1: 200 Wicha, Jerzy, 2: 102 Widenhoefer, Ross A., 2: 92, 137 Widlanski, Theodore S., 1: 144 Williams, Craig M., 3: 208–09 Williams, David, 1: 42 2: 208 Williams, Jonathan M. J., 1: 26, 156 2: 189 3: 2, 10, 16 Williams, Lawrence J., 1: 172 Williard, PauI G., 1: 176 2: 210 Willis, Christine, 2: 135 Willis, Michael C., 2: 178 3: 76 Winssinger, Nicolas, 2: 112, 192 Wipf, Peter, 3: 135

Xia, Chungu, 3: 37 Xiao, Jianliang, 3: 35 Xiao, Wen-Jing, 1: 184 2: 67 Xie, Shiping, 3: 104 Xu, Bo, 3: 16 Xu, Jian-He, 2: 161 Xu, Ming-Hua, 2: 62 3: 63 Xu, Zhen-Jiang, 3: 104 Yadav, J. S., 2: 18, 197 3: 1, 4, 11, 30, 31, 36, 92, 122, 123 Yamaguchi, Masahiko, 2: 125 Yamaguchi, Ryohei, 2: 55 Yamamoto, Hisashi, 1: 62, 118, 158 2: 61, 76, 117, 165, 171, 198 3: 61, 78, 152 Yamamoto, Yoshinori, 2: 37, 40, 137 Yan, Tu-Hsin, 1: 148 Yanagisawa, Akira, 3: 127 Yang, Dan, 2: 172 Yang, Zhen, 1: 201 2: 186 Yao, Ching-Fa, 1: 108 Ye, Jinxing, 3: 140, 142 Yin, Dali, 3: 134 Ying, Jackie Y., 3: 51 Yoon, Tehshik P., 3: 38 Yorimitsu, Hideki, 2: 88 3: 15, 38, 125 Yoshida, Hiroto, 2: 185 Yoshida, Hisao, 3: 124 Yoshida, Jun-ichi, 2: 104 Yoshida, Kasuhiro, 3: 127 Yoshida, Masanori, 3: 77 Yoshida, Mashiro, 3: 132 Yoshimi, Yasuharu, 3: 5 Yoshimitsu, Takehiko, 3: 24 Yu, Biao, 3: 104 Yu, Chan-Mo, 1: 150 2: 95 3: 89 222

AUTHOR INDEX Zhang, X. Peter, 3: 144, 150 Zhang, Xumu, 1: 88 2: 59 3: 42 Zhang, Zhaoguo, 3: 64 Zhao, Cong-Gui, 3: 86 Zhao, Kang, 2: 160 3: 131, 135 Zhao, Matthew M., 2: 56 Zhdankin, Viktor V., 1: 176 2: 185 3: 16 Zheng, Zhuo, 2: 163 Zhong, Guofu, 1: 152 3: 84, 138, 140 Zhou, Gang, 3: 123 Zhou, Qi-Lin, 2: 120 3: 118 Zhou, Yong-Gui, 1: 48 2: 91 3: 67 Zhu, Jieping, 2: 21 3: 66, 69, 105 Zhuan, Zhuang-ping, 3: 132 Zoghlami, H., 3: 40 Zutter, Ulrich, 3: 159

Yu, Jin-Quan, 1: 1 3: 26, 121, 124 Yu, Xiao-Qi, 2: 189 Yu, Zhengkun, 1: 184 Yu, Zhi-Xiang, 3: 147 Yudin, Andrei K., 3: 160 Yus, Miguel, 2: 15 Zacuto, Michael J., 3: 18 Zakarian, Armen, 3: 81, 190 Zard, Samir, 1: 23 3: 34, 39 Zeitler, Kirsten, 2: 146 Zercher, Charles K., 2: 207 Zhai, Hongbin, 3: 105, 114, 151 Zhang, Li, 3: 17 Zhang, Liming, 2: 103, 182, 206 3: 11, 90, 118 Zhang, Weige, 3: 22

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Reaction Index

To amide 3: 5, 12 To amine 2: 21 To amine (loss of carbon) 1: 100 2: 27, 44 To epoxy ketone (homologation) 1: 149 To ester, one carbon homologation 1: 106 To ether 3: 9 To hydride (one carbon loss) 2: 26, 29, 158 3: 5 To ketone, homologation 1: 11, 109, 163 2: 117 To β-keto ester 2: 148 To nitrile 1: 12 2: 43 To nitrile (one carbon loss) 2: 190 To nitrile (homologation) 3: 32 To nitro alkene (loss of carbon) 2: 44 Unsaturated, enantioselective conjugate addition 3: 73, 74 Unsaturated, enantioselective nitrile addition 1: 150 Unsaturated, enantioselective OH addition 1: 177 Unsaturated, from alkynyl aldehyde 2: 146 Unsaturated, enantioselective reduction 3: 42, 72, 74 Acyl anion 1: 26 2: 68 Alcohol Allylation, enantioselective 3: 68 Allylic, from halide, enantioselective 2: 162 Allylic, to aldehyde 2: 146 Allylic, to alkene 3: 14, 36 Allylic, to allylic alcohol, enantioselective 2: 161 Allylic, to amino alcohol 3: 134 Allylic, to enone 3: 13, 34 Benzylic, enantioselective allylation 1: 178 Dehydration 1: 25 From allylic sulﬁde 2: 4 From alkene 2: 10

Acid (Amide, Ester) Aldol, intramolecular 1: 202 Aldol, with thioester 2: 147 Alkylation Intermolecular, enantioselective 3: 77 Intramolecular 1: 14, 39, 201 Amide from acid 3: 5, 11, 15, 16, 17 Amide from aldehyde 2: 190 3: 14 Amide from amide 2: 76, 190 Amide from ester 2: 190 Amide from azide 3: 17 Anhydride, enantioselective opening 2: 59 Ester from alcohol 3: 15 Ester from alcohol, homologation 3: 32 From alcohol 1: 26, 75, 76 From aldehyde (oxidation) 1: 17 2: 21, 144 3: 4, 12, 15 From aldehyde (one carbon addition) 2: 21 From alkene (one carbon addition) 1: 148 3: 41 From alkene (two carbon addition) 1: 122 3: 41 From alkyne 2: 43, 86, 146, 190 3: 5 From amine 2: 44 3: 11 From aryl mesylate 3: 32 From ketone 1: 20, 113, 139 2: 76 From nitrile 2: 43 Halo, to alkyl amide, enantioselective 2: 6 Halogenation, enantioselective 1: 119 Halolactonization, selective 2: 97 Hydrolysis, enzymatic 2: 48 α-Hydroxylation, enantioselective 2: 161 protection (see protection) To alcohol 2: 86 3: 8, 12, 14 To aldehyde 2: 53, 189 3: 8 To alkene (loss of carbon) 1: 157 To alkyne (one carbon added) 1: 107 3: 31 To allyl silane 1: 195 225

REACTION INDEX α-Hydroxylation, enantioselective 1: 152 2: 1 3: 61, 64, 84 Homologation 2: 178, 181 3: 34-37 Single center, enantioselective 1: 4, 62, 65, 66, 95, 96, 114, 150, 178 2: 56, 57, 59, 89, 117, 118, 119, 162, 197, 198 3: 30, 61-71, 73-78, 86, 95 Multiple centers, enantioselective 1: 6, 42, 47, 51, 55, 63, 64, 92, 95, 114, 116, 117, 124, 125, 152, 153, 163, 166, 189, 200 2: 2, 7, 8, 9, 10, 19, 20, 31, 61, 62, 67, 89, 121, 122, 165, 166, 196, 197, 199, 203, 204 3: 78, 89, 95 α-Methylenation 2: 99 α-Sulﬁnylation, enantioselective 2: 4 To acid 3: 3, 10 To acid (one carbon addition) 2: 21 3: 34 To alkene 2: 22, 56 To alkyne (same carbon count) 2: 146 To alkyne (homologation) 1: 82 2: 148 3: 37 To allylic alcohol (two carbons added) 2: 147 To amide 2: 190 3: 7, 13, 14 To amine 3: 12 To amine, with homologation 1: 26 2: 8, 21, 58, 62, 118, 195, 196 To amine, one carbon loss 3: 7 To amino alcohol, homologation 3: 34 To α-bromo unsaturated ester, homologation 3: 33 To 1,1-diiodide 1: 87 To epoxide 1: 44 To ester 3: 11, 14 To ether 1: 16, 86 3: 2 To halide 3: 4 To iodoalkene, homologation 3: 36 To ketone 2: 56, 147 3: 34 To nitrile 3: 7, 11 To unsaturated ester 3: 36 To unsaturated ketone 3: 31, 36 Unsaturated, conjugate addition 3: 57 Unsaturated, conjugate amination 3: 84 Unsaturated, enantioselective conjugate addition 3: 73 Unsaturated, enantioselective homologation to epoxy alcohol 1: 152

Alcohol (continued ) From epoxide 3: 8 From ester 3: 12 From ketone 3: 2 From ketone, enantioselective 1: 2, 88 3: 60, 64 From nitro 3: 85 From oxazoline 3: 14 Homologation 2: 55 Oxidative cleavage 2: 198 protection (see protection) To acid 1: 26 2: 2, 75, 76, 143, 144 3: 13 To acid, homologation 3: 32 To aldehyde 1: 41 2: 13, 75, 95 3: 3, 6 To amide 3: 7 To amine 1: 56, 136, 156, 160, 161, 188 2: 34, 63, 145, 161, 189, 195 3: 4, 16 To aryl ketone 3: 35 To azide 2: 189 3: 15 To halide 1: 156 2: 85, 189 To hydride 1: 195, 198 2: 16, 55, 133 3: 10 To ketone 1: 26, 41, 86, 176 2: 13, 143 3: 2, 6 To ketone, enantioselective 1: 89 To mercaptan 3: 12 To nitrile 3: 30 To phosphonium salt 2: 85 Aldehyde Aldol, enantioselective 3: 79, 81, 88, 104 α-Allylation 3: 35 α-Allylation, enantioselective 3: 71, 73 α-Alkenylation, enantioselective 3: 75 α-Amination, enantioselective 3: 65, 67, 78 Decarbonylation 3: 111 From acid 2: 53, 189 From alcohol 1: 41 3: 3, 6 From alkene 1: 146 2: 59, 78, 126 3: 42 From alkyne 2: 86 3: 16 From allylic alcohol 2: 146 From allylic alcohol (one carbon homologation) 1: 148 From epoxide 1: 159 From halide 3: 14 α-Halogenation, enantioselective 1: 119 3: 82 226

REACTION INDEX Oxidation, to enone 1: 177 2: 177, 184 3: 115 Oxidative cleavage 1: 129 2: 194 3: 38, 41 Ozonolysis 1: 77 Reduction 3: 10 To acid (one carbon homologation) 1: 122 To aldehyde (one carbon homologation) 1: 146 2: 59, 126, 127 3: 42, 108 To alkenyl silane 3: 39 To allyl silane 2: 78 To allylic amine 2: 210 To amide, one carbon homologation 3: 41 To amine, one carbon homologation 3: 41 To azide 2: 17 To diol, enantioselective 3: 13, 67 To epoxide 3: 38 To epoxide, enantioselective 1: 159 3: 40, 60 To ester (oxidation) 2: 144 To ester (one carbon homologation) 1: 146 To ether 2: 17 To ketone 2: 178 3: 41, 43, 99 To methyl ketone (Wacker) 1: 120 2: 90 3: 209 To phosphine oxide 3: 39 To silane 2: 125, 3: 39 To unsaturated acid, one carbon homologation 3: 41 Alkyne Addition to aldehyde 1: 47, 65 3: 31 Addition to epoxide 1: 5 Addition to unsaturated amide 1: 98 Amination, intramolecular 3: 106 From acid 3: 31 From aldehyde, one carbon homologation 1: 82 3: 37 From aldehyde (same carbon count) 2: 146 From aldehyde, homologation 1: 150 2: 126, 182 From epoxy ketone 1: 13 From ketone 3: 16 From ketone, homologation 3: 33, 37 From nitrile, homologation 2: 148 3: 31

Unsaturated, enantioselective epoxidation 2: 14, 121 Unsaturated, enantioselective reduction 2: 6 Unsaturated, from propargylic alcohol 2: 146 Alkaloid synthesis 1: 8, 9, 12, 58, 82, 84, 112, 134, 136, 146, 188, 190 2: 11, 26, 27, 35, 37, 38, 45, 48, 63, 74, 79, 91, 97, 100, 107, 108, 111, 139, 140, 141, 149, 153, 157, 159, 167, 169, 170, 188 3: 52, 56, 59, 94, 98, 109-119, 121, 135, 155, 169, 170, 172, 178, 180, 190, 194, 198, 200, 204, 206 Alkene Acylation 3: 41 Aminoalkoxylation 3: 92, 98, 106 Diamination, enantioselective 3: 80 Dihydroxylation 3: 113 epoxidation 1: 35 2: 77, 98 3: 42, 60 (see also epoxidation, enantioselective) from acid, one carbon loss 1: 157 2: 44 From alkene 2: 177 From enol triﬂate 3: 32 From halide 3: 15 From ketone 2: 16, 22, 150, 174 Haloamination 2: 137 Haloarylation 3: 41 Homologation 2: 78, 120, 126, 178 3: 39, 41, 59 Homologation, branching, enantioselective 3: 76, 81 Hydroamination (see hydroamination) Hydroboration, diastereoselective 2: 10 Hydroboration, enantioselective 3: 66, 72 Hydroformylation 3: 42, 108 Hydrogenation 2: 77 3: 9, 20, 38, 42 Hydrogenation, enantioselective 1: 161, 164, 174 2: 59, 119 3: 70, 72, 74, 76, 79, 102, 104 Hydrohalogenation 3: 42 Hydroxyamination 3: 39 Hydrosilylation 3: 39 metathesis (see Grubbs reaction) Metathesis with ester 2: 50 Oxidation, to allylic alcohol 1: 25, 137 2: 18, 168 227

REACTION INDEX From alcohol 1: 156 2: 34, 64, 145, 189, 195 3: 4, 16 From aldehyde 3: 15 From aldehyde, enantioselective 3: 62, 67 From alkyne 1: 1 From allylic halide, enantioselective 2: 4 From allylic alcohol 1: 136, 188 2: 161 From allylic alcohol, enantioselective 1: 56, 160, 161 2: 161 3: 65 From amide 2: 158, 168 3: 9, 12 From amide, with homologation 2: 21 From aryl halide 1: 110 2: 87, 155 From ketone 2: 16, 3: 14 From ketone, enantioselective 2: 16, 117, 162, 204 3: 62, 67 From nitrile 2: 4, 15 From nitro 2: 15 From unsaturated amide, enantioselective 3: 62, 65 Propargyl, to allenyl aldehyde 3: 37 protection (see protection) Reductive methylation 3: 108, 201 To acid 2: 76 To amide 3: 5, 11, 12, 13, 15 To ketone (oxime) 3: 10 To nitrile 3: 14 To nitro 3: 4 Amino acid from hydroxy acid 1: 40 α-Amino acid (nitrile) synthesis 2: 23, 162 3: 43, 63, 70 β-Amino acid (nitrile) synthesis 3: 62, 63 Aromatic ring construction 1: 171, 191 2: 40, 81, 84, 105, 176, 186, 188 3: 121, 123, 125, 127, 131 Aromatic ring substitution 1: 10, 18, 19, 21, 48, 54, 65, 69, 104, 108, 110, 111, 120, 122, 138, 149, 164, 171, 174, 175, 190, 205 2: 11, 12, 15, 22, 25, 26, 28, 39, 40, 58, 75, 81, 82, 84, 86, 87, 91, 108, 128, 132, 134, 141, 155, 156, 157, 160, 175, 176, 179, 180, 185, 186, 206, 208, 209 3: 25, 27, 32, 33, 35, 63, 110, 114, 116, 118, 120-127, 129, 131-134 Aza-Cope: 2: 27 Azide Addition to epoxide 1: 8

Alkyne (continued ) Homologation 2: 90, 93, 101, 182 3: 25, 37, 39 Hydroamination 1: 13 Hydrostannylation 1: 6 Hydrozirconation 1: 32 Metathesis Intermolecular 1: 126 2: 110 3: 47 Intramolecular 1: 83, 126, 127 3: 49, 55 Metathesis with aldehyde to alkene 2: 103 Reduction, to trans alkene 1: 127 Reductive homologation 1: 104 2: 20, 122 3: 37 To acid 2: 43, 86, 146, 190 3: 5 To aldehyde 1: 1 2: 146 3: 5, 16 To alkene, homologation 3: 36, 39 To alkyne, alkyne migration 1: 127 To allylic alcohol 3: 31, 39 To amine 1: 1 To diene 1: 44 To 1,4-diyne 2: 147 To enone 3: 36 To iodoalkene 3: 33 To ketone 3: 16 To ketone, homologation 3: 37, 39 To nitrile 2: 146 Zirconation 2: 98 Allene homologation 2: 13, 95 3: 37 Allene homologation, enantioselective 3: 76 Allylic coupling 1: 46, 58, 60, 64, 66, 78, 97, 128, 129, 160, 179, 192, 193 2: 5, 12, 20, 24, 33, 60, 62, 70, 74, 97, 108, 122, 139, 140, 155, 161, 162, 163, 193, 194, 197, 198, 205 3: 4, 13, 14, 18, 19, 22, 25, 28, 29, 33-36, 66-69, 70, 73, 77, 80, 81, 83-85, 88, 90, 92, 93, 98, 99, 101, 103, 106, 107, 144-146, 150 Amination, of C-H Intramolecular 2: 10, 118 3: 25, 29 Intermolecular 2: 180, 210 3: 26, 28 Amine Allylic, to hydride 2: 65 α-Amination of aldehyde, enantioselective 3: 65 From acid (loss of one carbon) 1: 100, 184 2: 23, 44 228

REACTION INDEX Addition to ketone 1: 113, 139 2: 38 From alcohol 2: 189 3: 15 To amide 3: 16 To nitrile 2: 14 Aziridine From alkene 2: 18 From haloaziridine, homologation 1: 160 Opening 1: 92, 193 2: 18, 34, 121, 140, 166, 188, 196 3: 105-107, 110 Synthesis, enantioselective 1: 92 3: 78, 105 Aziridine aldehyde to amino ester 1: 115

C-H Insertion Intermolecular 2: 61, 106, 210 3: 25 Intramolecular By carbene 1: 110, 142, 168 2: 31, 135, 180, 207 3: 25, 29, 88, 93, 98, 100, 104, 112, 149, 157, 160 By nitrene 1: 8, 153, 175 2: 10, 180, 189, 209 3: 25, 29, 133, 134 C-H to ketone 2: 179 3: 21 Claisen rearrangement 1: 27, 96, 195, 203 2: 62, 107, 122, 163, 182, 193, 194 3: 97, 121, 191, 209 Claisen rearrangement, enantioselective 3: 81, 83, 85, 116, 159 C-O ring 4 construction 1: 116 2: 124 C-O ring 5 construction 1: 50, 51, 56, 69, 78, 95, 130, 140, 141, 142, 154, 168, 186, 189, 194 2: 29, 31, 32, 49, 66, 88, 95, 97, 111, 133, 134, 135, 154, 158, 184, 197, 200, 202 3: 24, 42-44, 54, 55, 86-101, 197 C-O ring 6 construction 1: 29, 33, 42, 43, 108, 124, 130, 140, 141, 142, 187, 189, 194, 195, 203 2: 10, 29, 30, 32, 50, 88, 93, 94, 96, 111, 114, 116, 133, 135, 136, 153, 156, 197, 198, 199, 200, 201 3: 11, 27, 29, 43, 46, 49, 51, 52, 54, 61, 86, 87, 89-97, 99-101, 197 C-O ring 6 construction 1: 155, 195 2: 20, 133 3: 45, 49, 51, 53, 55, 58, 197 Conjugate addition 3: 30, 52, 90-93, 96, 105, 107, 160 Conjugate addition, enantioselective 1: 57, 84, 98, 150, 151, 153, 166, 167, 192, 204, 205 2: 60, 67, 68, 73, 74, 131, 149, 163, 166, 203, 204, 207 3: 75, 77, 79, 83, 85, 86, 92, 101, 103, 104, 106, 107, 109, 136-144, 148, 161, 178, 192 Cope rearrangement 1: 24 2: 208 3: 127, 157, 204 Cycloalkane C7 synthesis: 1: 23, 24, 25, 33, 43, 45, 72, 73, 75, 77, 86, 135, 2: 16, 71, 72, 98, 100, 114, 153, 156, 170, 193, 202, 208 3: 59, 105, 139, 147, 153, 157, 160, 193 Cyclobutane cleavage 2: 113, 124 3: 57, 149

Baeyer-Villiger 1: 20 2: 124, 133 3: 79 Baylis-Hillman reaction, intramolecular 1: 196 Beckmann rearrangement 1: 20 2: 76 Benzofuran synthesis 3: 132 Benzyne substitution 2: 185 3: 120, 125, 154 Biotransformation (see enzyme) Biphenyl synthesis 1: 19, 54, 60, 110, 171 2: 39, 42 3: 25, 97, 120, 121, 123-125, 127, Birch reduction 1: 12 2: 168, 184, 208 Blaise reaction 3: 94 Carbene cyclization 1: 36, 142, 168 2: 31, 69, 70, 106, 135 3: 88, 93, 98, 100, 104, 112, 149, 157, 160 Carvone (starting material) 1: 33, 148 2: 63, 123 C-H Activation 1: 59, 110, 122, 157, 175 2: 10, 18, 22, 25, 40, 78, 81, 82, 85, 105, 127, 134, 135, 140, 156, 180, 188, 210 3: 24-29, 63, 67, 69, 70, 88, 93, 98, 100, 104, 121, 122, 112, 133, 134, 149, 157, 160 C-H to alcohol 1: 157 2: 18, 134, 168, 179, 210 3: 24, 26, 28, 29 C-H to alkene 3: 25, 26 C-H to amine 2: 10, 118, 180, 210 C-H to amine 2: 10, 118, 180, 210 3: 25, 26, 28 C-H to amine, enantioselective 3: 29, 67, 69, 70 C-H to C-borane 1: 157 2: 40 3: 121, 122 C-H to halide 3: 24, 28 C-H Homologation 3: 25, 27, 28, 29 229

REACTION INDEX Intramolecular 1: 22, 120, 135, 146, 191, 199, 203 2: 66, 79, 81, 101, 105, 168, 169, 170 3: 11, 109, 111, 115, 153-155, 206 Intermolecular 1: 13, 52, 112, 136, 139, 168, 180, 198 2: 65, 99, 100, 123, 171, 176, 186, 188, 202, 208 3: 131, 152, 154, 155, 200 Retro 1: 198 2: 186 Transannular 3: 155 1,1-Dihalide, from halide, homologation 3: 34 Diimide generation 2: 77 3: 38 Diol from epoxide 1: 160 2: 161 Dipolar cycloaddition 2: 34, 53, 54, 140, 158, 199, 202 3: 39, 103, 107, 108, 132 Diastereoselective cycloheptane construction 1: 76 2: 207 3: 161 Diastereoselective cyclohexane construction 1: 22, 23 2: 46, 158 3: 161 Diastereoselective cyclopentane construction 3: 47, 141, 158

Cyclobutane synthesis 1: 76, 102 2: 64, 71, 113, 206 3: 27, 49, 136, 137, 145, 148, 156-158, 181, 186, 189 Cycloheptane synthesis 1: 53, 165, 169, 180, 204 2: 51, 70, 104, 124, 206 3: 45, 51, 55, 144, 161, 169 Cyclohexane synthesis 1: 12, 14, 22, 23, 25, 32, 37, 53, 57, 58, 66, 68, 75, 78, 80, 81, 128, 136, 143, 165, 166, 167, 180, 188, 190, 198, 200, 201, 202, 204, 205 2: 12, 20, 24, 27, 34, 35, 36, 52, 60, 63, 64, 65, 66, 67, 68, 70, 73, 74, 100, 102, 104, 124, 156, 158, 159, 164, 166, 167, 169, 171, 172, 173, 174, 184, 204, 206, 207, 208 3: 11, 57, 59, 109, 111, 115, 117-119, 136-139, 141-145, 147, 149, 151-155, 167, 161, 169, 177, 183, 191, 194, 200, 201 Cyclopentane synthesis 1: 9, 12, 23, 24, 36, 37, 42, 43, 52, 66, 74, 77, 79, 80, 112, 128, 165, 166, 167, 168, 180, 183, 189, 198, 200, 201, 202, 203, 205 2: 1, 28, 68, 70, 72, 73, 97, 101, 102, 103, 104, 113, 123, 124, 159, 164, 167, 169, 170, 171, 172, 173, 174, 180, 183, 184, 193, 203, 205, 206, 207, 208 3: 27, 47, 48, 50, 109, 136-138, 140-143, 149, 150, 152-155, 157-160, 178, 181, 189, 204 Cyclopropane cleavage 2: 10, 70, 71, 104, 184 3: 55, 102, 138, 142-145, 147, 148, 150, 156-158, 160, 208 Cyclopropane synthesis 1: 52, 81, 167, 203 2: 69, 70, 184, 205 3: 102, 138, 142-145, 147, 148, 150, 156, 157, 158, 160, 208

Ene reaction, intramolecular 1: 24 3: 157, 159, 177 Ene reaction, intermolecular, enantioselective 3: 68 Enone Allyl addition 3: 30 Conjugate addition 3: 30, 96 Conjugate addition, enantioselective 3: 73, 74, 137, 138, 140-142, 144, 148, 192 Cyanide addition 1: 199 Cyanide addition, enantioselective 3: 74 Conjugate amination, enantioselective 3: 69 Conjugate reduction 1: 25 3: 13 Enantioselective reduction to allylic alcohol 1: 103 2: 12 Epoxidation, enantioselective 3: 84, 156 From alkene 3: 41, 115 Enzyme Aldol condensation 2: 165 Arene oxidation 1: 190 Epoxide hydrolysis, enantioselective 2: 161

Dieckmann cyclization 1: 37 Diels-Alder Catalyst 1: 52, 168 2: 100 3: 152-155 Diene 1: 189 2: 65, 99 Dienophile 1: 112, 136, 189 2: 65, 99, 100 Hetero 2: 94, 165, 166, 188, 195 3: 105 Hetero, intramolecular 2: 2, 45 3: 106, 129 230

REACTION INDEX with azide 1: 173 with dithiane 1: 51 with organometallic 1: 46, 80, 165 2: 58, 63, 133 3: 81, 82, 164 Reduction 2: 125, 178 Reductive cyclization 3: 87, 112, 130, 145 To aldehyde 3: 162 To allylic alcohol 1: 137 To amino alcohol 1: 160 To diol 1: 160 2: 161 To propargylic alcohol 3: 33 Epoxy alcohol to silyloxy aldehyde 3: 162 Epoxy aldehyde to hydroxy ester 1: 115 3: 65 Epoxy amide to hydroxyamide 1: 159 Epoxy ether to ether aldehyde 1: 159 Eschenmoser cleavage 1: 13 Ether, enantioselective allylic from allylic alcohol 3: 66 Ether cleavage 2: 189 Ether formation Fragmentation 3: 33 From aldehyde or ketone 1: 16, 86 2: 15 3: 2 From alkene 2: 17 From ester 3: 9

Ester hydrolysis 2: 48 Glucosidase 3: 23 Henry reaction 3: 65 Reduction of ketone 1: 1, 34 2: 143, 183 Reductive amination 2: 161 3: 69 Reduction of unsaturated lactone 3: 879 Resolution of alcohol 1: 34, 88, 158 3: 65, 76, 108 Resolution of amine 3: 63 Ring cleavage, enantioselective 3: 156 Epoxidation (see also sharpless asymmetric epoxidation) Of enone, enantioselective 1: 90, 91 3: 84, 156 Of unsaturated amide, enantioselective 1: 90 Epoxide Addition by azide 1: 8 Alkenyl, carbonylation 3: 176 Carbene donor 3: 150 Enantioselective, from halo ketone 1: 3 From aldehyde 1: 44 From alkene 1: 35 2: 77, 98 3: 38, 40, From alkene, enantioselective 1: 32, 159 2: 14, 58, 61, 77, 98, 112, 134, 156, 171, 177, 198 3: 40, 60, 84, 156 From allylic alcohol (Sharpless) 1: 32, 46, 67, 115, 141, 168, 172, 193 2: 58, 61, 77, 112, 156, 197, 198 3: 94, 162, 176 From α, β-unsaturated aldehyde, enantioselective 2: 14, 121 From α, β-unsaturated amide, enantioselective 1: 90, 159 From α, β-unsaturated sulfone, enantioselective 1: 91 Homologation, reductive 2: 128 Homologation (one carbon) to allylic alcohol 2: 95 Homologation to epoxy ketone 1: 149 Homologation to β-lactone 2: 59 Hydrogenolysis 1: 1 2: 102 3: 8 Opening intramolecular 2: 173 3: 87, 90, 91, 93, 94, 99 with alcohol 2: 93, 202 3: 54 with alkyne 1: 5, 94 3: 3, 33, 81, 82,164

Fragmentation 2: 198 3: 139, 156 Furan synthesis 1: 175 2: 41 3: 19, 128, 130, 132, 134 Gold catalysis Aldol condensation 2: 104, 173 Alkene activation 2: 17 Alkene hydroamination 2: 92, 137, 140, 196 3: 102 Alkyne activation 1: 122 3: 107, 118 Allylic hydration 3: 8 Arene alkylation 1: 175 Cyclohexane synthesis 3: 144 Cyclopentane synthesis 2: 206 3: 149, 150, 178 Dihydrofuran formation 2: 197 Enone from propargyl alcohol 2: 182 3: 11 Furan synthesis 3: 130 Pyrrole synthesis 2: 41 3: 130 Spiroketal formation 3: 203 231

REACTION INDEX Hetero Diels-Alder (see Diels-Alder, hetero) Horner-Emmons, intramolecular 3: 157 Hydride from alcohol 3: 10 Hydroamination Intermolecular Alkene 1: 30 2: 177 Alkyne 1: 1 2: 37 Intramolecular Alkene 1: 30 2: 92, 137, 196 Alkyne 1: 13, 170 2: 37 Allene 2: 137, 196 3: 102 Hydrogen peroxide Epoxidation 3: 40, 42 Oxidation of alcohols 1: 26, 86

Grubbs reaction Ene-yne 1: 75, 82, 83, 130 2: 154 3: 56, 200 Intramolecular 1: 29, 42, 70, 72, 73, 74, 93, 103, 112, 131, 132, 133, 139, 141, 154, 161, 181, 182, 183, 184, 185, 186, 187, 188, 189, 194, 195, 200 202 2: 20, 49, 51, 52, 90, 93, 94, 95, 96, 109, 110, 111, 113, 114, 116, 150, 151, 152, 153, 154, 193, 195 3: 45, 46, 48-59, 89, 93, 95, 101, 103, 105, 170, 172, 189 Intermolecular 1: 28, 50, 70, 71, 74, 141 2: 17, 49, 51, 79, 95, 109, 110, 112, 132, 152, 154, 178, 196 3: 44, 46-51, 53, 163, 173, 175, 180, 193, 194, 199 New catalysts 1: 131, 141, 182, 183 2: 49, 49 (Au), 50, 151 3: 44-48, 50, 51

Indole synthesis 2: 25, 35, 36, 41, 42, 45, 63, 84, 91, 140, 157, 160 3: 106, 115-118, 129, 131, 133, 134 Indoline synthesis 1: 38, 48 143 2: 40, 45, 46, 108, 139 3: 109, 113, 115, 116 Indolizidine synthesis 1: 8, 31, 182 2: 34, 37, 111 3: 25, 105, 106, 107, 109, 111, 112, 114, 118, 119 Ionic Liquid Alkane nitration 2: 85 Aromatic substitution 1: 21 Baeyer-Villiger 1: 20 Beckmann rearrangement 1: 20 Carbocyclization 2: 45 Henry reaction 1: 21 Friedel-Crafts 1: 21 Heck reaction 1: 21 Osmylation 1: 89 Iridium Catalyst Alcohol oxidation 3: 3 Alcohol allylation, enantioselective 3: 68 Aldol condensation 2: 55 Allylation 1: 63 Allylic coupling 1: 138, 160, 179, 202 2: 113, 161 3: 65, 66 Borylation of C-H 2: 40, 160 3: 25, 121, 122 Claisen rearrangement 2: 122, 163 Cyclopropanation 3: 148 Dihydrofuran synthesis 3: 90 Ester aldol condensation, enantioselective 1: 6 Ether cyclization 3: 88

Halide Alkenyl, homologation 1: 149, 157 Allylic, to aldehyde 1: 177 Alkyl, homologation 2: 19, 55, 56, 127, 128, 181 Alkyl, homologation, enantioselective 2: 6, 23, Allylic, homologation, enantioselective 3: 71 Aryl, homologation 1: 149 2: 12 3: 35 From alcohol 2: 85, 189 From aldehyde 3: 4 From ketone 1: 26 Propargylic, homologation 3: 37 Propargylic, homologation, enantioselective 3: 76 To aldehyde 3: 14 To alkene 3: 15 To alkyl 3: 30 To amine (one carbon added) 2: 55 α To carbonyl, homologation, enantioselective 3: 75, 77 To ester (one carbon added) 2: 43 To hydride 2: 16 3: 14 Haloalkene 3: 36 Heck Reaction (see Pd) Henry reaction, enantioselective 2: 57 3: 65, 68 232

REACTION INDEX Furan synthesis 3: 134 Hydrogenation, enantioselective 1: 49 2: 91, 119 3: 76, 118 Iron Catalyst Aldehyde hydroxylation 3: 61 Aldehyde reductive amination 3: 12 Alkene acylation 3: 41 Alkene dihydroxylation, enantioselective 3: 82 Alkene reduction 3: 2, 42 Alkyne hydration 3: 16 Allylic acetate carbonylation 3: 93 Allylic epoxide carbonylation 3: 176 Arene coupling 3: 126 C-H oxidation 2: 179, 210 Cyclohexane synthesis 3: 149, 151 Halide coupling 3: 30, 35 Haloarene amination 3: 125 Indole synthesis 3: 131 Ketal deprotection 3: 200 Sulﬁde to sulfoxide 3: 6 Isoxazole synthesis 3: 128

Reduction, enantioselective 1: 2, 43, 162, 165 2: 42, 143 3: 60, 64, 85, 89, 102, 103, 166, 170, 202 Reduction to alcohol 3: 5 Reduction to alkene 2: 16, 22 Reduction to amine 1: 16, 117 3: 9, 14, 109 Reduction to amine, enantioselective 2: 162, 204 3: 62, 69 Reduction to ether 1: 16 2: 15 Silyl enol ether coupling 3: 35 To alkene 2: 16, 158, 174 3: 31 To alkyne 3: 16 To amide 1: 20, 113, 147 2: 38, 76 To enone 3: 7, 11 To iodoalkene 1: 87 to methylene 1: 87 2: 86 3: 9 Unsaturated, conjugate addition (see enone, conjugate addition) Unsaturated, epoxidation, enantioselective 3: 84, 156 Unsaturated, from aldehyde 3: 31 Unsaturated, from propargylic alcohol 2: 173, 182 Kulinkovich reaction 1: 197 2: 71 3: 102

Julia synthesis 3: 95 Ketone α−cylation 3: 30 Aldol, enantioselective 3: 79, 80, 83, 86, 103 α−lkenylation 2: 128 3: 115 α−llylation, enantioselective 3: 68, 151 α−rylation 1: 165 2: 156, 173 Alkylation with aldehyde 1: 107 Alkylation, enantioselective 1: 165 Alkylation, intramolecular 1: 134, 167 Enantioselective Mannich 1: 151 From alcohol 1: 26, 41, 86, 176 2: 85 From aldehyde 2: 56, 147 From alkene 1: 120 2: 90, 178 3: 41, 43, 99, 209 From alkyne 3: 16 From amide 1: 11, 109, 163 2: 117 From nitrile 2: 82 From thiol 3: 5 Halogenation, enantioselective 1: 158 Hydroxylation, enantioselective 1: 4, 118 Oxidation to enone 2: 131, 142 Protection (see protection) Reduction 1: 86 2: 15, 16

Lactam hydroxylation 2: 46 Lactam synthesis 1: 10, 20, 22, 59, 113, 147, 182, 193, 196, 197 2: 11, 12, 26, 28, 33, 37, 38, 46, 100, 120, 210 3: 29, 106, 107 Lactone, to α,β-unsaturated lactone 2: 14 β-Lactone homologation 2: 59 Macroether synthesis 1: 183 2: 26, 170, 202 Macrolactam synthesis 1: 72, 74, 83, 124, 132, 133, 142, 161, 185 2: 20, 26, 38, 134, 138, 152 3: 98 Macrolactone synthesis 1: 6, 51, 71, 72, 94, 126, 131, 163, 187, 195 2: 20, 30, 32, 51, 52, 54, 66, 90, 112, 116, 136, 153, 156, 198, 199 3: 59, 97, 99, 101, 196 Mannich Intermolecular 2: 55, 127 3: 34, 35 Intermolecular, enantioselective 1: 65 2: 58, 62, 92, 118, 119, 121 3: 63, 69, 70, 77, 79-85, 142 Intramolecular 2: 28, 34, 35, 142, 149 3: 110, 119, 195 233

REACTION INDEX Cephalotaxine 3: 117 Cermizine A 3: 118 Cernunine 3: 184 Chimonanthine 2: 188 Citlalitrione 1: 24 (6E)-Cladiella-6,11-dien-3-ol 2: 170 Cladospolide C 2: 153 Clavilactone B 2: 156 Clavirolide A 3: 192 Colombiasin A synthesis 2: 105 β-Conhydrine 3: 15 Conocarpan 3: 100 Coraxeniolide A 3: 139 Coryantheidol 2: 140 Crispine A 3: 118 Cyanthiwigin 1: 180 Cyanthiwigin F 3: 151 Cytotrienin A 3: 59 Cruentaren A 3: 164 Dactylolide 3: 59 Dasycarpidone 3: 117 Deacetoxyalcyonin acetate 1: 76 Dendrobatid alkaloid 251F 1: 112 Deoxyharringtonine 2: 140 Deoxyneodolabelline 1: 42 7-Deoxypancriastatin 3: 111 1-Desoxyhypnophillin 3: 147 11, 12-Diacetoxydrimane 3: 153 Didemniserinolipid B 3: 172 Digitoxigen 2: 183 Dihydroxyeudesmane 3: 29 Dimethyl Gloiosiphone A 3: 145 Discodermolide 3: 166 Dolabelide D 2: 89 Dolabellane 1: 42 Dolabellatrienone 2: 100 Drupacine 3: 113 Dumetorine 2: 153 Dysiherbaine 3: 94 Elatol 3: 57 Elisapterosin B 2: 105 Ephedradine 1: 142 Epothilone B 3: 198 Epoxomycin 1: 172 β-Erythrodine 2: 169 Erythronolide A 2: 53 Esermethole 2: 108, 139 3: 116 Ethyl Deoxymonate B 3: 96 Eunicillin 1: 76, 135 D-Fagoamine 2: 165

McMurry coupling 1: 43 2: 71 Mercaptan from alcohol 3: 12 Metathesis, Alkene (see Grubbs) Metathesis with ketone 3: 46 metathesis, alkyne (see alkyne metathesis) Michael addition Intramolecular 1: 166, 166, 167, 201 2: 38, 68, 73, 101, 102 3: 47, 52, 79, 76, 119, 142 Intermolecular 1: 57, 84, 153, 166, 204 2: 23, 38, 60, 67, 74, 92, 101, 108, 120, 163 3: 136, 137-143, 178 Mitsunobu reaction, improved 2: 145 3: 70 Natural product synthesis Abyssomycin C 2: 170 Acutiphycin 2: 136 Agelastatin 1: 188 Aigialomycin D 2: 112 3: 101 Alkaloid 205B 2: 111 Alkaloid 223AB 3: 112 Alliacol 1: 80 Amphidinolide 1: 50, 94 Amphidinolide V 3: 55 Amphidinolide X 3: 58 Amphidinolide Y 3: 53 Anatoxin 1: 82 Antasomycin 2: 19 β-Araneosene 2: 71 Arglabine 3: 55 Arnebinol 2: 186 Aromadendranediol 3: 143 Aspidophytidine 2: 157 Attenol A 2: 200 Aurantioclavine 3: 116 Aureonitol 3: 98 Avrainvillamide 2: 11 Acutumine 3: 204 Berkelic Acid 3: 101 Biyouyanagin A 3: 137 Blepharocalyxin D 2: 199 Botcinin F 3: 99 Brasilenyne 1: 154 Blumiolide C 3: 59 Brevisamide 3: 100 Bruguierol A 3: 101 Calvosolide A 2: 136 Cassaine 3: 155 Centrolobine 2: 11 234

REACTION INDEX Macrolide RK 397 3: 163 Magnofargesin 2: 135 Majusculone 2: 207 Merrilactone 2: 113 Methyl 7-Dihydro-trioxaacarcinoside B 3: 54 Morphine 2: 141 Nanakurines A and B 3: 200 Nigellamine A2 2: 97 Nomine 2: 167 Norﬂuorocarine 3: 109 Norzoanthamine 1: 146 3: 206 NP25302 2: 139 Omaezakianol 3: 93 Omuralide 1: 196 Ophirin 1: 134 Ottelione B 3: 57 Paeonilactone B 3: 97 Panaxtriol 3: 56 Pasteurestin A 3: 145 Pauliurine F 3: 110 Pentalenene 3: 145 9-epi-Pentazocine 3: 114 Penifulvin A 3: 161 Periplanone C 2: 153 Phaseolinic Acid 3: 54 Phenserine 1: 142 Phomactin A 1: 32 Pinnotoxin A 3: 190 Pladienolide D 3: 53 Platensimycin 2: 131 Pleocarpenone 2: 206 Podophyllotoxin 1: 68 Pumiliotoxin 251D 3: 112 Quinidine 1: 84 Quinine 1: 84 Rapamycin 3: 176 Rhazinicine 3: 114 Rhazinilam 2: 26, 140 Rhishirilide B 2: 175 Ricciocarpin A 3: 143 Rimocidinolide 1: 162 Saliniketal B 3: 99 Salinosporamide 1: 196 Salmochelin SX 3: 99 Sanguline H-5 3: 97 Sarain A 2: 149 SCH 351448 2: 115 Serotobenine 3: 98 Serratezomine A 3: 119

Fawcettidine 3: 115 Fawcettimine 3: 178 Ferrugine 1: 82 Floriesolide B 2: 112 Fomannosin 3: 188 FR901483 3: 119 Fusicoauritone 2: 208 Galubima alkaloid 1: 12 2: 79 Garsubellin A 2: 51 Gigantecin 2: 154 Gleenol 3: 159 Guanacastepene E 2: 123 Guanacastepene N 2: 174 Incarvillateine 3: 180 Halenaquinone 3: 155 Hamigeran B 1: 120 3: 149 Haterumalide NA 3: 99 (+)-6’-Hydroxyarenarol 3: 15 Ingenol 1: 14, 134 5-F2t-Isoprostane 3: 57 Irofulven 2: 157 Isoedunol 2: 71 Isofagomine 3: 56 Jatrophatrione 1: 24 Jerangolid D 3: 95 Jimenezin 2: 135 Juvabione 2: 204 Kainic Acid 3: 52, 112, 116 Kendomycin 2: 114 Lactacystin 1: 196 2: 108 Lasalocid A 3: 91 Lasonolide A 2: 199 Lasubine 1: 134 Lasubine II 2: 139 Latrunculin 2: 51 Lepadiformine 2: 107 Lepadin 1: 142 Lepadin B 3: 59 Lepadiformine 3: 111 Leucascandrolide A 3: 170 Littoralisone 2: 1 Longicin 2: 51 Louisianin C 3: 135 Lyconadin A 3: 168 Lycopladine A 2: 159 Lycopodine 3: 194 Lycoramine 2: 208 γ -Lycorane 2: 108 Lycoricidine 2: 100 Lysergic Acid 3: 117 235

REACTION INDEX From aryl halide 2: 21 From nitro alkane 2: 6 From unsaturated amide, enantioselective 1: 150 Reductive cleavage 1: 13 To alkene 3: 33 To alkyl 2: 200 To alkyne, by metathesis 2: 148 3: 31 To amide 2: 43 To ketone 2: 82 Nitro From amine 3: 4 To alcohol 3: 85 To amine 3: 4, 15 Nitro alkane to hydride 3: 9 Nitro alkene Enantioselective conjugate alkoxylation 3: 64 Enantioselective conjugate addition 1: 153 3: 73 Enantioselective reduction 1: 150 From unsaturated acid (one-carbon loss) 2: 44 Radical homologation 1: 108 Reduction to amine 3: 9

Natural product synthesis (continued ) Shimalactone A 3: 157 Siamenol 3: 119 Solandelactone E 3: 97 Sordaricin 1: 128, 198 Spiculoic Acid A 2: 169 Spirastrellolide A Me Ester 3: 97 Spirofungin A 3: 174 Spirolaxine Methyl Ether 3: 95 Spirotryprostatin B 3: 113 Stemoamide 2: 107 Stephacidin B 2: 11 Strychnine 1: 58 3: 115 Superstolide A 3: 182 Symbioimine 2: 170 Taiwaniaquinone G 3: 127 Tangutorine 3: 118 Terpestacin 2: 193 Tetracyclin 1: 190 Tetrodotoxin 1: 136 Tocopherol 1: 142 Tonantzitlolone 1: 188 Tremulenolide A 2: 70 Triclavulone 1: 102 Ushikulide A 3: 202 Valienamine 1: 188 Vibralactone C 3: 159 Vigulariol 2: 201 Vindoline 2: 45 Welwitindolinone A Isonitrile 3: 186 8-epi Xanthatin 2: 51 Xestodecalactone A 2: 201 Yangonine 3: 43 Yohimbine 3: 115 Zaragozic Acid 3: 196 Zoapatanol 1: 109

Organocatalysis 1: 4, 62, 91, 114, 115, 116, 118, 119, 124, 125, 151-153, 166, 167, 202, 205 2: 1, 2, 4, 6, 8, 9, 14, 60, 61, 67, 68, 100, 101, 102, 118, 119, 139, 166, 171-173, 195, 203, 204 3: 61-66, 68-71, 73, 75-86, 88, 136-143, 154-156 Osmylation (see also sharpless asymmetric dihydroxylation) Of alkene 1: 8, 21 3: 79 Of diene 1: 15 Oxamination Of ketone, enantioselective 1: 4, 118 Oxazole synthesis 3: 128 Oxy-Cope rearrangement 1: 24 3: 204

Nazarov cyclization 2: 208 Negishi coupling (see Pd) Nitrene cyclization 2: 84, 118 3: 26, 30, 134, 135 Nitrile Alkylation 1: 199 From alcohol 3: 30 From alcohol, with inversion 1: 106 From aldehyde 1: 17 From alkene 2: 181 From alkyne 2: 146 From amide 1: 12 2: 43 From amine 3: 14

Palladium catalysis Alcohol silylation 2: 130 Alkene alkoxy arylation 1: 142 2: 134 Alkene alkylation 3: 39 Alkene amination 3: 40, 80, 108 Alkene amino arylation 2: 138 Alkene carbonylation 1: 148, 178 3: 38, 42 236

REACTION INDEX Alkene chloroarylation 3: 41 Alkene diamination, enantioselective 3: 80 Alkene reduction 3: 9, 20 Alkyne addition 2: 73 Allene diborylation 2: 48 Allene stannylation 2: 95 Allyl ether cleavage 3: 18 Allylic rearrangement/coupling 1: 56, 58, 78, 128, 164,165, 192, 193 2: 32, 62, 70, 97, 108, 122, 193, 194, 205 3: 14, 18, 25, 29, 34, 35, 103, 107, 113, 117, 144-146, 150, 151 Amide reduction 3: 9 Amide to nitrile (reversible) 2: 43 Arene acylation 2: 82 Arene borylation 2: 40 Arene carboxylation 2: 40 Arene halogenation 2: 81 3: 124, 125 Aryl mesylate carbonylation 3: 32 Aryl substitution 1: 19, 171 2: 22, 25, 26, 42, 156, 180, 185, 209 3: 27, 31, 123, 124, 125, 127, 134 Borane coupling 3: 41 Carbonylation of halide 2: 43 3: 120 C-H hydroxylation 1: 157 2: 18, 82, 134 Conjugate addition 2: 73 Cope rearrangement 3: 116 Cyclobutane synthesis 3: 157 Cyclohexane synthesis 3: 151, 157 Cyclopentane synthesis 3: 145, 149 Cyclopropane synthesis 3: 150 Cyclooctane synthesis 3: 157 Decarboxylation of acid to alkene 1: 157 Enol phosphate coupling 3: 89 Enol triﬂate carbonylation 2: 28 Ether oxidation 3: 89 Furan synthesis 2: 41 3: 128, 130 Haloarene amination 2: 87, 155 Haloarene cyanation 3: 120 Haloarene hydrolysis 3: 127 Heck Intermolecular 1: 18, 21, 20, 105, 122, 142, 174, 175 2: 39, 104, 178, 186 3: 36, 44, 121-123, 176 Intramolecular 1: 1, 18, 58, 59 2: 28, 114, 141, 157, 174 3: 110, 114, 115, 118, 152 Hydroamination of alkyne 2: 37 Hydrogenolysis of benzylic amine 2: 186

Hydrogenolysis of benzylic nitro 3: 10 Hydrogenolysis of epoxide 1: 1 Imine reduction 3: 67 In ionic liquid 1: 21 Indole synthesis 3: 129, 13 Ketone α-allylation, enantioselective 3: 68, 73 Ketone α-arylation 1: 165 2: 156, 173 Ketone to enone 2: 131, 142 3: 206 Kumada coupling 3: 120 Negishi coupling 1: 61, 164, 192 2: 91 3: 106 Nitrile homologation to ketone 2: 82 Nitrile from aryl halide 2: 21 Organotin coupling 3: 31 Organozirconium coupling 1: 104 Oxidation of alcohol 2: 13, 122, 128 Phenol to hydride 2: 86 Polycarbocyclic construction 3: 145, 157 Pyrazole synthesis 3: 131 Pyridine substitution 3: 133, 135 Pyrrole synthesis 3: 134 Reductive amination 3: 108 Sonogashira coupling 1: 60, 175 2: 155, 185 (Cu only) 3: 33 (Fe only) Spiroketal from alkene 3: 99 Spiroketal from alkyne 3: 95 Stille coupling 1: 7, 60, 155 2: 100, 150 3: 32, 111, 183 Suzuki Intermolecular 1: 54, 85 2: 22, 39, 62, 79, 83, 126, 159, 188 3: 120, 122, 167, 179, 203 Intramolecular 1: 33 Wacker oxidation of alkene 1: 120 2: 90 3: 99, 209 Pauson-Khand cyclization 1: 201 2: 70 Phenol protection 1: 145 2: 112 Phosphine oxide, from alkene 3: 39 Phosponium salt From alcohol 2: 85 From alkene 2: 125 Pinacol coupling 1: 64 2: 71 Piperidine synthesis 1: 13, 30, 39, 49, 59, 70, 92, 93, 132, 134, 138, 139, 143, 164, 182, 192, 193 2: 33, 34, 65, 79, 80, 109, 111,137, 138, 153, 165, 166, 168, 195, 196, 206 3: 56, 59, 160, 168, 169, 181, 184, 195, 201 237

REACTION INDEX Polyene synthesis 1: 162 Prins cyclization 2: 32, 96, 136, 197, 199 3: 88, 89 Propargyl coupling 1: 53 3: 76, 83, 85, 104, 164 Protection Of acid (ester, amide) 1: 46, 100, 144, 156, 172 2: 7, 43, 48, 59, 89 3: 17, 19, 20, 22, 23 Of alcohol 1: 4, 16, 34, 40, 86, 144, 145, 155, 156, 158, 177 2: 10, 47, 48, 87, 90, 91, 129, 130, 191 3: 18, 20, 21 Of aldehyde 3: 23 Of alkyne 2: 129 3: 23 Of amine: 1: 40, 56, 59, 100, 101, 144, 170, 193 2: 10, 48, 83, 130, 149 3: 19, 21-23, 116 Of ketone 2: 80, 129 3: 19, 21 Of phenol 1: 145 2: 112 3: 21 Pyridine synthesis 1: 10, 49, 123, 139, 171 2: 25, 42, 159, 188, 209 3: 102, 103, 105, 107-109, 111, 112, 114, 115, 117, 119, 129, 133, 135, Pyrrole synthesis 1: 170, 189 2: 41, 159, 187 3: 128, 130, 132, 134 Pyrrolidine synthesis 1: 11, 31, 48, 59, 82, 83, 84, 92, 106, 138, 139, 143, 182, 184, 196 2: 33, 34, 37, 73, 74, 91, 92, 107, 108, 110, 111, 137, 138, 168, 196 3: 25, 48, 52, 102-113, 115-119, 147, 159, 187

Cyclic, aminated 1: 136, 196 2: 46, 138, 139, 140, 149, 196 3: 25, 28, 195, 201, Cyclic, oxygenated 1: 14, 24, 32, 33, 43, 67, 80, 102, 121, 135, 137, 196 2: 34, 46, 65, 66, 71, 80, 88, 93, 94, 98, 100, 102, 104, 113, 119, 132, 134, 138, 154, 156, 158, 170, 175, 176, 184, 196, 200, 202, 206, 208, 210 3: 27, 59, 61, 90, 138, 139, 140, 142-144, 149, 156, 159, 161, 186, 188, 189, 193, Acylic, alkylated 1: 114, 196 2: 23, 24, 128, 164 3: 71, 73, 77, 81, 83, 85, 191, Acyclic, aminated 2: 23, 62, 69, 87, 107, 118, 163 3: 28, 63, 133 Acyclic, oxygenated 2: 53, 54, 61, 71, 72 3: 54, 61, 68, 203, Quinolizidine synthesis 3: 118, 185 Radical coupling 1: 54 2: 56, 79, 127, 128, 188 Radical cyclization 1: 10, 23, 36, 48, 69, 108, 196, 200 2: 12, 34, 172, 174, 201 3: 90, 92, 108, 117, 119, 160 Ramberg-Backlund 3: 101, 115 Resolution Of alcohols 1: 34, 88, 158 2: 124 3: 66 Of amines 3: 63 Rh catalysis Aldehyde homologation 2: 7 Aldehyde to amide 1: 132 3: 7 Alkene acylation 3: 43 Alkene aminoalkylation 3: 41 Alkene aminohydroxylation 3: 92 Alkene borylation 3: 72 Alkene carboxylation 3: 41 Alkene epoxidation 1: 35 Alkene homologation 1: 122, 178 3: 39 Alkene hydroamination 2: 92 Alkene hydroformylation 3: 42, 108 Alkene hydroformylation/aldol, enantioselective 3: 81 Alkene to aldehyde 3: 5, 16 Alkyne addition 3: 105 Alkyne cyclization 2: 138 3: 123 Alkyne homologation 2: 90, 195 3: 37 Alkyne to enamine 3: 5 Alkyne to alkynyl thioether 3: 36

Quaternary center, stereocontrolled Cyclic, alkylated 1: 1, 5, 13, 15, 23, 24, 33, 43, 46, 47, 58, 67, 68, 78, 80, 97, 102, 121, 128, 134, 153, 165, 169, 176, 181, 197, 199, 205 2: 24, 26, 27, 34, 38, 45, 52, 60, 63, 65, 67, 68, 70, 71, 73, 97, 100, 101, 102, 104, 105, 108, 113, 120, 123, 125, 128, 131, 157, 159, 164, 167, 169, 172, 174, 183, 184, 196, 199, 204, 205, 206, 207, 208 3: 136-141, 143, 144, 148-155, 157, 158, 159, 160, 161, 178, 183, 189, 192, 205, 206, 208 238

REACTION INDEX Ring contraction 1: 12 2: 72, 100 Ru catalysis (see also Grubbs reaction) Alcohol to amide 3: 7 Alcohol to amine 3: 16 Aldehyde allylation, enantioselective 3: 77 Aldehyde oxidation, to ester 3: 11 Aldol condensation 1: 107 Alkene addition 2: 178 Alkene aminohydroxylation 3: 92 Alkene dihydroxylation, enantioselective 3: 82 Alkene migration 3: 40 Alkyne activation 1: 123 Alkyne cyclization 3: 127 Alkyne hydration 2: 86, 103, 146 Allene carbonylation 3: 159 Amide reduction 3: 9 Arene construction 2: 40 Arene coupling 2: 82 Arene hydrogenation 3: 159 Borylation 2: 17 Carbene insertion 3: 104 Conjugate addition 1: 204 Cyclohexane synthesis 3: 145, 151 Cyclopentane synthesis 3: 145 Cyclopropane synthesis 3: 144 Enantioselective hydrogenation 3: 104 Ester reduction 2: 86 3: 8 Ketone from alkene 2: 178 Nitrene insertion 3: 69 Nitrile from alkyne 2: 146 Oxidation 1: 88, 2: 13, 78 3: 3, 40 Oxidative fragmentation 2: 198 Phthalimide reduction 2: 192 Polycarbocyclic construction 3: 145 Propargyl alcohol isomerization 2: 146 Reduction of alkene 3: 9 Reduction of ketone 1: 88, 162 3: 3 Reduction of ketone, enantioselective 3: 4, 85, 89, 202 Ring construction 2: 103, 104 Triazole synthesis 3: 132

Allene hydroacylation, enantioselective 3: 76 Allylic amination, enantioselective 3: 67 Allylic coupling 1: 66, 141 2: 74, 198 3: 67 Allylic oxidation 1: 177 Amine oxidation 2: 127 Arene coupling 3: 120 C-H activation 2: 41 Conjugate addition 1: 98 2: 74, 120, 205 3: 72 Conjugate addition, enantioselective 3: 74 Conjugate borylation 3: 66 Cycloheptane synthesis 3: 144, 208 Cyclohexane synthesis 3: 147, 149, 153 Cyclopentane synthesis 3: 147, 149, 153, 181 Cyclopropane synthesis 3: 145 Cyclooctane synthesis 3: 147 Decarbonylation 3: 111 Diazo cyclization 1: 22, 142 Diels-Alder 2: 81 Dipolar cycloaddition 3: 103 Enantioselective hydrogenation 1: 161, 174 2: 59, 119, 163 3: 74 Enyne cyclization 2: 70, 73, 74 139 Hydroacylation 2: 103, 178 Hydroformylation 1: 148 2: 59 Indole synthesis 2: 188 3: 133 Intermolecular C-H insertion 2: 61, 106, 209 3: 29 Intramolecular C-H insertion 1: 8, 142, 15 2: 173, 188, 209 3: 25, 88, 98, 99, 112, 149 Intermolecular cyclopropanation 2: 106 3: 150, 208 Intramolecular cyclopropanation 2: 70 Mannich 3: 63 Nitrene insertion 1: 8 Phthalimide reduction 2: 192 Polycarbocyclic construction 3: 147, 151 Propargylic oxidation 3: 26 Pyridine synthesis 3: 129, 132 Reductive aldol, enantioselective 3: 83 Ring expansion 3: 148, 149, 189 Silylation 3: 18

Schmidt reaction, intramolecular 1: 113, 147 2: 38 Selenide Alkylation 2: 112 Elimination to alkene 2: 112 Oxidation, to aldehyde 239

REACTION INDEX To sulfoxide 3: 6 Sulfonate, aryl to hydride 2: 86 Sulfone Alkylation, intramolecular 3: 87 Displacement 3: 87 To hydride 2: 86, 140, 193 Unsaturated, conjugate addition, enantioselective 3: 72 Sulfoxide Homologation 3: 32 To alkene 2: 22 Suzuki reaction (see Pd)

sharpless asymmetric dihydroxylation (see also osmylation, alkene dihydroxylation) 1: 84, 89, 141, 189 2: 54, 165, 194 3: 13, 67, 84, 97 Sharpless asymmetric epoxidation 1: 32, 46, 67, 115, 141, 168, 172, 193 2: 58, 61, 77, 112, 156, 197, 198 3: 94, 162, 176 Silane, allylic synthesis 1: 43 2: 78 Silane From alkene 2: 125 3: 39 From ether 3: 4 To alcohol 2: 36 Sonogashira coupling (see Pd) Spiroketal construction 1: 187 2: 88, 94, 200, 204 3: 89, 91, 95, 97, 99, 101, 172, 174, 190, 202 Stannane, α-alkoxy, from aldehyde, enantioselective 3: 68 Stille coupling (see Pd) Strecker synthesis 1: 26 enantioselective 1: 99 2: 118 3: 62 Sulfamate synthesis, cyclic, by Rh-mediated intramolecular nitrene C-H insertion 1: 8, 153 3: 29 Sulﬁde Alkenyl, homologation 2: 200 Allylic, to alcohol 2: 4 To alkene 2: 145 To hydride 3: 15 To ketone, homologation 3: 30

Tebbe reaction 1: 148 2: 50 3: 91, 97, 102 Tetrazole synthesis 1: 17 Thioketal desulfurization 3: 18 Thiol To alcohol 3: 5 To ketone 3: 5 Thiocyanate α to ketone 3: 5 Triazine synthesis 1: 17 Triazole synthesis 3: 128, 132 Ullmann coupling 3: 110 Vinyl cyclopropane rearrangement 1: 203 3: 151 Wacker reaction (see Pd) Wittig reaction E-selective 1: 108 Wittig reaction intramolecular 3: 143 Wolf-Kishner reduction (see ketone to methylene)

240