The Alkaloids: Chemistry and Pharmacology, Volume 51

THE ALKALOIDS Chemistry and Biology VOLUME 51

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THE ALKALOIDS Chemistry and Biology Edited by Geoffrey A. Cordell College of Pharmacy University of Illinois at Chicago Chicago, Illinois

VOLUME 51

Academic Press San Diego London Boston New York Sydney Tokyo Toronto

This book is printed on acid-free paper.

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Copyright 0 1998 by ACADEMIC PRESS All Rights Reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the Publisher. The appearance of the code at the bottom of the first page of a chapter in this book indicates the Publisher’s consent that copies of the chapter may be made for personal or internal use of specific clients. This consent is given on the condition, however, that the copier pay the stated per copy fee through the Copyright Clearance Center, Inc. (222 Rosewood Drive, Danvers, Massachusetts 01923), for copying beyond that permitted by Sections 107 or 108 of the U S . Copyright Law. This consent does not extend to other kinds of copying, such as copying for general distribution, for advertising or promotional purposes, for creating new collective works, or for resale. Copy fees for pre-1998 chapters are as shown on the title pages. If no fee code appears on the title page, the copy fee is the same as for current chapters. 0099-9598198 $25.00

Academic Press a division of Harcourt Brace & Company 525 B Street, Suite 1900, San Diego, California 92101-4495, USA http:Ilwww.apnet.com Academic Press Limited 24-28 Oval Road, London NWI 7DX, UK http:llwww.hbuk.co.uklapl International Standard Book Number: 0-12-469551-5 PRINTED IN THE UNITEDSTATES OF AMERICA 98 9 9 0 0 01 02 0 3 Q W 9 8 7 6

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CONTENTS

CONTRIBUTORS. ... PREFACE.........

...................................................

...................................................

vii ix

Alkaloids of the Aspidospermine Group J. E. SAXTON I. Introduction ........................................................ 11. Isolation and Structure Determination of New Alkaloids of Aspidospermine Group ........................................... 111. Rearrangements and Transformations of the Aspidospermine Alkaloids ... IV. Total Synthesis of the Aspidospermine Alkaloids ....................... V. Alkaloids of the Pseudoaspidospermidine-PandolineGroup ............. References .........................................................

2 21 56 92 163 186

Cephalotarus Alkaloids I. 11. 111. IV. V. VI. VII. VIII.

M. A. JALILMIAH,TOMAS HUDLICKY, A N D JOSEPHINE W. REED Introduction. . . . . . . . . . . .... ...................... Isolation and Structural Studies of Cephalotaxus Alkaloids. .............. .......................... Synthesis of Cephaloraxus Alkaloids. . Synthesis of Cephalotaxine Esters.. . . ............ .. Model Studies toward the Synthesis of the Cephalotaxine Ring System. . .. Unnatural Cephalotaxus Esters and Their Antitumor Activity ............ Analytical and Spectroscopic Studies .................................. Pharmacological and Clinical Studies .................................. References. ........................................................

199 200 208 224 236 254 261 262 264

The Ipecac Alkaloids and Related Bases I. 11. 111. IV. V. VI. VII.

Tozo FUJIIAND MASASHIOHBA Introduction. ....................................................... ............ Occurrence.. ....... Chemistry and Synth Related Compounds ................................................ Analytical Methods .. . ......................................... Biosynthesis. ......... ......................................... .................. Biological Activity . . References ......................................................... V

271 279 281 296 299 300 305 308

vi

CONTENTS

The Amaryllidaceae Alkaloids OSAMU HOSHINO I. Introduction and Botanical Sources ................................... 11. Lycorine-Type Alkaloids. ............................................ 111. Crinine-Type Alkaloids. ............................................. IV. Narciclasine (Lycoricidine)-TypeAlkaloids. ............................ V. Galanthamine-Type Alkaloids . . . . . . . . . . . VI. Tazettine-Type Alkaloids ............................................ VII. Lycorenine-Type Alkaloids .......................................... VIII. Montanine-Type Alkaloids. .......................................... IX. Mesembrine-Type Alkaloids ........ ............................. X. Miscellaneous .......................................... References .........................................................

324 342 362 369 382 387 391 393 402 410 417

.............................................. CUMULATIVE INDEXOF TITLES INDEX...................................................................

425 435

CONTRIBUTORS

Numbers in parentheses indicate the pages on which the authors’ contributions begin.

Tozo FUJII(271), Faculty of Pharmaceutical Sciences, Kanazawa University, Takara-machi, Kanazawa 920, Japan (323), Faculty of Pharmaceutical Sciences, Science UniOSAMU HOSHINO versity of Tokyo, Shinjuku-ku, Tokyo 162, Japan (199), Department of Chemistry, University of Florida, TOMAS HUDLICKY Gainesville, Florida 3261 1-7200

M. A. JALILMIAH(199), Department of Chemistry, University of Florida, Gainesville, Florida 32611-7200 MASASHI OHBA(271), Faculty of Pharmaceutical Sciences,Kanazawa University, Takara-machi, Kanazawa 920, Japan

W. REED(199), Department of Chemistry, University of FlorJOSEPHINE ida, Gainesville, Florida 3261 1-7200 J. E. SAXTON (l), School of Chemistry, The University, Leeds LS2 9JT, United Kingdom

vii

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PREFACE

This volume of The Alkaloids: Chemistry and Biology series returns to a more traditional motif, updating the very substantial isolation, structure elucidation, and synthetic studies that have been conducted on some of the major, classical groups of alkaloids, each of which has members noted for their clinical significance. A significant theme that runs through all of the chapters is the substantial number of new alkaloids characterized and the increasing emphasis that is being placed on the enantioselective synthesis of various key alkaloids in these important groups. Saxton reviews the isolation and synthesis of the aspidospermine alkaloids in Chapter 1,thereby updating the last review, which appeared in this series over 20 years ago. The chapter complements a contribution (also by Saxton) in Volume 50 that specifically focused on the synthetic highlights of this intensely studied aspect of indole alkaloid chemistry. The Cephalotaxus alkaloids, which were last reviewed in this series in 1984, are discussed by Miah, Hudlicky, and Reed. This chapter is a very thorough review of all of the approaches that have been described for synthesis of these alkaloids, the efforts to explore structure-activity relationships, and the biological and clinical aspects of the Cephalotaxus alkaloids. Chapter 3 by Fujii and Ohba reviews the progress that has been made since 1983 on the ipecac alkaloids and related bases. In particular, the very substantial progress made in the isolation of more polar alkaloids lacking the methyl groups of the well-established alkaloids and the tetrahydroisoquinoline monoterpene glucoside derivatives is discussed. In addition, there has been substantial progress in developing new and innovative synthetic procedures for both the established and the new alkaloids. Interest in the many diverse classes of Amaryllidaceae alkaloids has increased since the last review in 1987. The many recent isolations of new and known alkaloids, the multitude of efficient synthetic approaches to many of the alkaloids, and some of the biological aspects of these alkaloids are reviewed by Hoshino. Geoffrey A. Cordell University of Illinois at Chicago ix

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-CHAPTER 1-

ALKALOIDS OF THE ASPIDOSPERMINE GROUP J . E. SAXTON School of Chemistry The University Leeds LS2 9JT. United Kingdom

I . Introduction ........................................................................................ 2 I1. Isolation and Structure Determination of New Alkaloids of the Aspidospermine Group ............................................................................................... 21 21 A . Secodine Derivatives .................................................................... 21 B. The Quebrachamine Group ............................................................ C. The Aspidospermidine Group ......................................................... 24 D . Rearranged Aspidospermidine Derivatives ........ ........................... 28 E. Oxidized (2.7-seco) Aspidospermidine Derivatives .............................. 28 F. Degraded Aspidospermidine Derivatives ........................................... 30 30 G . The Vincadifformine-Tabersonine Group ......................................... H. Oxidized and/or Rearranged Vincadifformine Derivatives .................... 38 I . The Vindolinine Group ............................................... ..........40 J . The Aspidofractinine Group ........................................................... 41 K . Seco-Aspidofractinine Alkaloids, with or without Subsequent Cyclization ................................................................................. 49 L. Biogenetically Related Quinoline Alkaloids ............... M. Kopsine/Fruticosine Derivatives .............................. N. Seco-Kopsine/Fruticosine Alkaloids ................................................. 55 I11 Rearrangements and Transformations of the Aspidospermine Alkaloids .........56 56 A . Rearrangements of Quebrachamine and Aspidospermine ..................... B. Transformations of Vindoline and Its Derivatives ............................... 57 C Reactions of Leuconolam .............................................................. 60 D . Fragmentation of Vindolinine and Solvolysis of 19-Iodotabersonine ....... 61 E.1. Reactions and Rearrangements of the Vincadifformine Group ..............63 E.2. Formation of Vicarnine and Its Derivatives ...................................... 63 E.3. Partial Synthesis of Minovincine, Vincoline, Kitraline, and Kitramine ..... 68 E.4. Functionalization in Rings D and E ................................................. 71 E.5. Miscellaneous Reactions of Vincadifformine and Tabersonine ...............76 76 F. Structure and Stereochemistry of Vincatine ....................................... G Conversion of Vincadifformine into the Goniomitine Ring System ......... 78 H. Partial Synthesis of Baloxine .......................................................... 79 I. Partial Synthesis of Meloscine and Scandine ...................................... 80 J . Partial Synthesis of Vindorosine and Vindoline .................................. 85 K . Partial Synthesis of Pachysiphine ..................................................... 88 L. Synthesis and Absolute Configuration of Strempeliopine ...................... 89 M. Enlargement of Ring C ................................................................. 92 92 IV . Total Synthesis of the Aspidospermine Alkaloids ....................................... A. Synthesis of Secodine and Its Relatives ............................................ 94

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THE ALKALOIDS. VOL. 51 0099-9598/98$25.00

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Copyright 0 1998 by Academic Press. All rights of reproduction in any form reserved.

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J. E. SAXTON B. Quebrachamine . .......................................................... 102 C. Aspidospermidine mple Derivatives .................................. 110 D. Vindorosine and Vindoline .......................................................... 127 E. The Vincadifformine Group ......................................................... 132 F. The Vindolinine Group ............................................... 150 G. Vallesamidine ........................................................................... 152 H. The Aspidofractinine Group ........................................................ 152 I. The Meloscine Group ................................................................. 159 J. The Kopsine Group ................................................... V. Alkaloids of the Pseudoaspidospermidine-Pandoline Group ..... A. Occurrence and Structure ............................................................ 163 B. Ibophyllidine and Iboxyphylline Group .......................................... 168 C. Chemistry of the Pseudoaspidospermidine-IbophyllidineGroup .......... 169 D. Synthesis of the Pseudovincadifformine-Pandoline Group .................. 169 E. Synthesis of the Ibophyllidine-Iboxyphylline Group .......................... 180 References ....................................................................................... 186

I. Introduction

The alkaloids of the aspidospermine group have not been surveyed in this series since Cordell’s review in Volume 17 (I),which covered the area up to 1977. The present chapter covers the 19-year period from 1977 to the end of 1996. The change of title is deliberate and reflects the fact that the emphasis here is on alkaloids based on the pentacyclic aspidospermidine and vincadifformine skeletons, together with the closely related quinoline alkaloids (e.g., scandine, meloscine, and their relatives), as well as other minor groups of alkaloids that can be derived from the aspidospermidine or vincadifformine skeleton by simple oxidation and rearrangement reactions, followed in some cases by further cyclization to give less easily recognizable ring systems. The present survey also includes the pseudoaspidosperminepandoline group, together with their derivatives and variations such as ibophyllidine, iboxyphylline, and dichomine. However, in contrast to the chapter in Volume 17, ellipticine, uleine, and their congeners are not discussed-the syntheses of ellipticine were surveyed in Volume 39 (2)neither are those bisindole alkaloids that are composed of one or two aspidospermidine-derived units included, since they merit treatment together with all the other bisindole alkaloids in a separate chapter. This area was last covered in Volume 20 (3). Interest in this area has been considerable in recent years and shows few signs of abating. The intensity of activity can be gauged by inspection of Table I, which lists all the isolations of alkaloids, both new and previously

TABLE I ASPIDOSPERMINE ALKALOIDS: ISOLATIONS SINCE1976 ~~

Alkaloid Tetrahydrosecodine Demethoxycarbonyl-tetrahydrosecodine

2-Ethyl-3-[2-(3-ethyl-N-piperidino) ethyllindole Crooksidhe 2-Ethyl-3-[2-(3-acetyl-N-pipendino) ethyllindole (-)-Quebrachamine

14/3-Hydroxy-quebrachamine Strictanol (Quebrachamine 7hydroxyindolenine) Rhazidine Voaphylline (conoflorine)

Plant Source Serodine derivatives Aspidosperma marcgravianum Rhazya stricta Aspidosperma marcgravianum Haplophyton crooksii Rhazya stricta

Haplophyton crooksii Aspidosperma marcgravianum QUA' e derivatives Aspidosperma album Hunteria elliottii Kopsin officinalis Melodinus morsei Stemmadenia grandiflora Stemmadenia grandiflora Rhazya stricta

Melodinus morsei Ervatamia coronaria Ervatamia polyneura Hazunta modesta spp. modesta var. divaricata Pagiantha macrocarpa Peschiera buchtieni Stemmadenia grandiflora Stemmadenia tomentosa Stenosolen heterophyllus Tabemaemontana chippii

Plant Part"

RB

Structure

1

5

2

5

C

RB

6

AP

7,8 9

R

AP

4

RB

3

Sd L, Tl3, SB, RB R

5

9

L SB

6

Sd SB L, s C L

RB

13 10-12

I5 15 11

AP L

7,8 5

14 16

AP L, Sd L, Sd Fr, L

Ref.

15 42.43 38 18 33 19 17 34 15 26 29 30

(continues)

TABLE I (continued) Alkaloid

N-Methylvoaphylline (hecubine) 12-Methoxyvoaphylline P

Voaphylline hydroxyindolenine

Stapfinine (5-hydroxyvoaphylline) Voafinine N-Methylvoafinhe Ervatinine Alkaloid TC-A Alkaloid TC-B Alkaloid TC-C Hyderabadine Ervayunine Vincadine

14,lS-Didehydro-epivincadine

Plant Part"

Plant Source

Tabernaemontanacimfolia Tabemaemontana dichotoma Tabemaemontana divaricata Tabemaemontana eglandulosa Tabemaemontana undulata Tabemanthe iboga Tabemanthe pubescens Trachelospennwnjarminoides Ervatamia coronaria Tabemaemontana divaricata Pagiantha cerifera Tabemaemoniana dichotoma Peschiera buchtieni Tabernaemontanadichotoma Tabemaemontana divaricata Tabemanthe pubescens Ervatamia coronaria Tabernaemontanadivaricata Tabernaemontanadivaricata ENatamia coronaria Tabernaemontanachippii Tabemannontana chippii Tabemaemontana chippii E ~ o t a m i acoronaria ENatamia yunnanensis Amsonia tabemaemontana Rhazya stricta Catharanthus roseus

Structure

L Sd C, L, DF L, T, SB S C L

L,s L

14

L (var. Df) L L SB Sd, L C L L L (var. Df) L (var. Df) L

RB RB RB L R L

L

10

u

17a 1% 17c 16 18 20 19 21

13 7 8

Ref. 32 27 21-25 28 I9 21 20 31 18 24,25 41 39,40 34 27,44 22 20 43

49 49 47 30 30 30

52 45 36 35 37

Voaharine Aspidochibine (+)-Aspidospermidhe

N-Methylaspidospermidine N-A&tylaspidospermidine (desmethoxyaspidospermine)

Demethoxypalosine (Npropionylaspidospermidine) ( + )-lJ-Didehydroaspidospermidine ( -)-1,2-Didehydroaspidospermidine

v,

oxidizedlreprrangedq u e b r a c h d e derivatives Tabernaemontana divaricata L, DF Aspidospenna quebrachoblunco C Aspidospennidine derivatives Aspidospenna album Sd Aspidosperma rhombeosignatum B Melodinus morsei AP Ervatamia peduncularis L,SB Aspidosperma excekurn RB Rhazya stricta R Aspidospenna album Sd Geissospermum argenteum L, BrB Aspidospenna rhombeosignatum B

Rhazya stricta Hunteria elliottii Melodinus morsei ( +)-1,2-DidehydroaspidospermidineN-oxide Rhazya stricta N-Methyl-14,15-didehydro-aspidospermidine Vinca herbacea (+)-Mehanine Ewatamia coronaria (-)-Mehranine Tabernaemontana divaricata enr-N-Methyl-14.15-ddehydroVinca sardoa aspidospermidine Aspidospermidose Rhazya stricta Aspidospermiose Rhazya sm'cta ( +)-Desmethylaspidospennine Aspidosperrna excekurn Geissospermum argenteum Strempeliopsis strempelioides Aspidosine Strempeliopsis strempelioides ( +)-Deacetylaspidospermine Strempeliopsis strempelioides Vallesine Strempeliopsis strempelioides Vallesia glabra

C L AP R L DF R L L RB L, BrB L, SB L SB L L, s

22 23

24,25 53

24

13 71 38 54 55 9 13 56 71

25

26a

26b

27a 27b 51 28 60 61 52 53 54

29 32 30 31

6 10 38 66 57 73 25 67 43 70 55 56 58 58 58 58 59

(continues)

TABLE I (continued) Alkaloid (- )-Aspidospermhe

01

Plant Part'

Plant Source

Aspidospem rhom beosignaium Geissospermum argenteum Strempeliopsis strempelioides Vallesia glabra Aspidospenna pyrifoIiurpl (+)-Aspidospermhe Rhazya stncta Strictanine Aspidospenna murcgravianum Aspidocarpine Geissospennum argenteum Microplumeria anomala A n o d e Microplumeria anomala Demethoxyanomaline Microplumeria anomala 12-0-Methylanomaline Aspidosperma rhombeosignaium Limaspermidine Limaspermine Aspidospenna album Aspidospenna album 11-Methoxylimaspermine Aspidospenna marcgravianum Limapodine Aspidospenna album Aspidolimidine Aspidospenna marcgravianum (+)-Fendlerine A s p i d o s p e m album Aspidospenna marcgravianum Haplocidine Vallesia glabra Aspidospem marcgravianum 18-Oxohaplocidine Vallesia glabra Cicine Haplophyton crooksii Haplophyton crooksii Cicidine 10,11,12-Trimethoxy-18-oxo-aspidoalbidine Aspidospenna rhombeosignaturn Aspidospenna album (+)-0-Methyl-18-0x0-aspidoalbine Alalakine Aspidospenna album Aspidosperma cruenta Obscurinervine Aspidospenna cruenta Obscurinervidine

Structure

B L, BrB SB L, s

33

RB,L

55 56

Fr B, RB L, BrB B B B B Sd Sd B, RB Sd B, RB Sd

34 57 58 59 35a 3 s 36 37 38

39

RB

40

L, s RB L, s

41a

AFAF-

41b 41c

B

42s

Sd

42b 64 49

Sd L L

50

Ref. 71 56 58 59 68 42 5 56

72 72 72 71 13 13 5 13 5 13 5 59 5 59 8 8 71 13 13

65 65

Vindorosine

Cathovaline Deacetylcathovaline 14-Hydroxycathovaline Vindoline

Deacetylvindoline Deacetoxyvindoline Bannucine

21

(+)-Melonine Melonine N-oxide Rhazinilam

5,221-Dihydro-rhaziniam

3-0~0-14,15-didehydro-rhazinilam Leuconolam

21-Epileuconolam 21-0-Methylleuconolam N-Methylleuconolam Leuconoxhe Unnamed alkaloid

Catharanthus ovalis AP Catharanthuspusillus (Vinca pusilla) L,R Catharanthus roseus F Catharanthus ovalis AP Catharanthus roseus L Catharanthusovalis AP Catharanthus ovalis AP Catharanthus ovalis AP Catharanthus roseus C, R,F, Sdl Melodinus fusiformis Catharanthus roseus Sdl Catharanthus roseus Sdl Catharanthus roseus L Rearranged aspidospermidhe derivatives Melodinus cehtroides Br, L Melodinus celastroides Br, L Oxidized (2,7-seeo) aspidospermidine derivatives Aspidosperma marcgravianum BB Leuconotis eugenifolius DC. Kopsia teoi SB, L Vallesia glabra s, L Leuconotis eugenifolius Aspidosperma quebrachoblanco C Alstonia scholaris Leuconotis eugenifolius L, s Leuconotis grifjithii WP Leuconotis eugenifolius Leuconotis eugenifolius L, s Rhazya stricta R Leuconotis eugenifolius L,s Degraded aspidospermidhe derivatives Voacanga ajiicaw L

43

46 47 48 44

45 62 63

63 60,61 62 63 64 63 63 63 62,74-77 78 77 77 79

65

80,81 80,81

67

5 82 83,84 59 82 53 87

68 69 70

82,86 71 72 73 74

85 82 86 89 86

75

90 (continues)

TABLE I (continued)

Alkaloid (-)-Vincadifformine

(?)-Vincadifformine oo

(+)-Vincadifformine

Plant Source

Plant Part"

The vincadif€ormine-trsonine group Amsonia sinensis L Bonafousia tetrastachya Hunteria congolana Sd Hunterin elliottii L, s, RJ3 Melodinus morsei P Melodinus scandens Melodinus suaveolens Tr Rhazya stricta C Stemmndenia grandiflora L, Sd Vallesia glabra L, s Vinca herbacea AP Vinca minor Sd Aspidosperma album Hwueria congolana Sd Hunteria elliom'i TB Kopsia officinalis Fr Melodinus aeneus L,s Melodinus polyadenus L, s Strempeliopsis strempelioides L, SB Stemmadenia grandiflora L, Sd Pterotabema inconspicua L Melodinus hemsleyanus Ap Bonufousia tetrastachya L Rhazya stricta L Amsonia sinensis Catharanthus roseus C Catharanthus trichophyllus C C Stemmadenia tomentosa Vinca erecta Voacanga africana C

Structure 76

94 91 92 1412 16 93 95 6 I5 59

96

n

-7

3-Oxovincadifformine 5-Oxovincadiffonnine(ervinidinine?) 1 1-Hydroxyvincadifformhe ( -)-12-Hydroxyvincadirmine 15P-Hydroxyvincadifformine (-)-Minovincinine

Ref.

97 13 I1 I1 100

98

99 97 84 98 99

100 80

58 15 130 I14 91 133 94 117 112 26 124 26

(-)-Echitoveniline 11-Methoxyechitoveniline

11-Methoxyechitovenidine (+)-Minovincinine (-)-Echitovenine 19-Epi-(+ )-echitoveniline 11-Methoxyvincadifformine

Tabersonine

W

Alstonia venenata Aktonia venenata Alstonia venenata Ervatamia yunnanensis Catharanthus trichophyllus Alstonia venemta Melodinus suaveolens Vinca herbacea Vinca minor Hazunta modesta var. modesta subvar. montana Amsonia brevifolia Amsonia elliptica Amsonia sinensis Catharanthus roseus Catharanthus roseus Catharanthus trichophyllus Hazunta modesta var. modesta subvar. montana Melodinus aeneus Melodinus cehtroides Melodinus fusiformis Melodinus hemsleyanus Melodinus henryi Melodinus polyadenus Melodinus reticulatus Melodinus scandens Melodinus suaveolens Rhazya stricta Sarcopharyngia crassa Stemmadenia grandijlora Stemmadenia tomentosa

Fr, L Fr, L Fr, L

R

102 103 104 85

C L Tr AP

86 105 87

L

101

WP Sd C Sdl C L

L, s Br,L, AP

AP R,Fr L, s Fr,S, L P Tr C Sd L, s C

78

135J36 135,136 135,136 45 112 I38 95 96 97 103 111 I01 94 103,106 77

112 103 98 81,102,110 78 114 113 99 I08 93 95 6 I09 15 26 (continues)

TABLE I (continued) Alkaloid

Tabersonine N-oxide 3-Oxotabersonine

(-)-Lochnericine

Pachysiphine

Plant Source

Tabernaemontana citrifolia Tabernaemontana dichotoma Tabernaemontana macrocalyx Voacanga africana Voacanga schweinfurthii var. puberula Voacanga thowrsii Amsonia elliptica Amsonia elliptica Hazunta modesta var. modesta subvar. montana Melodinus scandens Sarcopharyngio crassa Stemmadenia grandiflora Alstonia lenormandii var. lenormandii Aktonia l e n o m n d i i var. minutifolia Aktonia lanceolifera Amsonia sinensk Catharanthus pusillus (Vinca pusilla) Catharanthus roseus Catharanthus trichophyllus Hazunta modesta var. rnodesta subvar. modesta Melodinus aeneus Melodinus scandens Petchia ceylanica Tabewemontana citrifolia Tabernaemontana pachysiphon Voacanga africana Sarcopharyngia crassa

Plant ParP Fr, L Sd Sd C Sd C Sd Sd L

Structure

107

E, Sd Sd L, Sd L, SB L, SB SB

32,105 27 19 26 I04 107 I01 I01 103 93 109

79

R,L C, R C

L L, s P

s, L Fr B

C Sd

Ref.

90

15 122 122 120 94 60,61 74,116-1I9 112 103 98 93 I23 105 121 26 109

19R-Hydroxypachysiphe (19R-epimisiline) 19s-Hydroxrpachysiphine (19Sepimisiline) 3-Oxopachysiphine 14,15-Epoxy-3-oxovincadiffonnine Rosicine 11-Hydroxytabersonine

1l-Hydroxy-14,15a-epoxytabersonine e @

19R-Hydroxytabersonine

19s-Hydroxytabersonine 19s-Acetoxytabersonine 19s-Acetoxy-3-oxotabersonine Hoerhammericine Hoerhammerinine Cathovalinine 11-Methoxytabersonine

Stemmadenia grandiflora Tabernaemontana divaricata Petchia ceylanica Petchia ceylanica Stemmadenia grandiflora Amsonia elliptica Catharanthus roseus Catharanthus roseus Melodinus fusiformis Melodinus guillauminii Melodinus hemsleyanus Melodinus morsei Melodinus suaveolens Melodinus tenuicaudatus Tabernanthe pubescens Melodinus fusiformis Melodinus hemsleyanus Catharanthus ovalis Catharanthus roseus Melodinus celastroides Melodinus scandens Melodinus suaveolens Catharanthus ovalis Melodinus celastroides Melodinus scandens Melodinus scandens Catharanthus roseus Catharanthus trichophyllus Catharanthus roseus Catharanthus ovalis Melodinus suaveolens Catharanthus roseus Melodinus aeneus

L, Sd DF L L L, Sd Sd L Sdl

119

m

l21 118 I25 81

SB, AP

AP AP Tr SB L

117

AP AP

114

88

C Br, L E, Sd, P Tr

AP Br, L E, Sd, P E, Sd C C C

AP

108 110 111 91a 92 91b

Tr

F, Sdl L, s

15 25 142 142 15 101 37 77 78 125 114 38 95 126 20 78

82

63 117 81 93 95 63 81 93 93 115-118 112 115,116,118 63 95 62,77,127 98

(continues)

TABLE I (continued) ~

Alkaloid

11-Methoxy-3-oxotabersonine (-)-Lochnerinine (hazuntine)

11,19R-Dihydroxytabersonine

10-Hydroxy-11-methoxy-tabersonine 19-Acetoxy-11-hydroxy-tabersonine 19R-Hydroxy-l l-methoxy-tabersonhe (vandrikidine) 19-Acetoxy-11-methoxy-tabersonine Petchicine Buxomeline Apodine Modestanine (deoxoapodine)

Plant Pa&

Plant source Melodinus fusformis Melodinus guilhuminii Meloahus hemsleyanus Melodinus henryi Melodinus polyadenus Melodinus reticuhtus Melodinus suaveolens Melodinus tenuicaudntus Alstonia y u n m n s i s Alstonia y u n m n s i s Catharanthus roseus Melodinus aeneus Melodinus henryi Melodinus suaveolens Melodinus tenuicaMelodinus fusformir Melodinus hemsleyanus Melodinus suaveolens Hazunta modesta var. brevintba Catharanthus roseus Alstonia yunnanensk Catharanthus roseus Melodinus suaveolens Catharanthus roseus Petchia ceyhica Melodinus celastroides Peschiera buchtieni Peschiera van heurckii Ewatamia corymbosa

Structure 78 125 114 113 99 108 95 126

SB, AP

AP R, Fr L, L,

s s

Tr SB s, L

R

1U 83

C

L,s R, Fr

Tr SB

ll3

AP Tr L C R C

114 115 89

Tr C SB Br, L L L, SB L, SB

Ref.

116 122

123 93 94

140 128 118,119 98 113 95 126 78 114 95 141 115,116 128 115,116 95 115,116 143 81 34 131 132

Hedrantherine Vandrikine Apodinine (14-hydroxyapodine)

14,15-Epoxy-16-hydroxy-l6methoxycarbonyl-3-oxo-l,2didehydroaspidospermidine Vincoline

w

Kitraline Kitramine Suaveolenine Trichophylline Goniomitine Vidolinine (19R-vindoliine)

19-Epivindolinine(19s-vindolinine)

Hazunta modesta var. modesta subvar. L montana Peschiera van heurckii L, SB Ervatamia corymbosa L, SB Tabernaemontana apoda Oxidized endlor rearranged vincadiffonnine derivatives Amsonia elliptica Sd Melodinus morsei Melodinus suaveolens Catharanthus ovalis Catharanthus ovalis Melodinus suaveolens Catharanthus trichophyllus Gonioma malagasy Vindolinine group Catharanthus ovalis Catharanthus roseus Catharanthus trichophyllus Melodinus celastroides Melodinus hemsleyanus Melodinus rnorsei Melodinus phylliraeoides Melodinus suaveolens Melodinus tenuicaudatus Catharanthus ovalis Catharanthus roseus Catharanthus trichophyllus Melodinus celastroides Melodinus morsei Melodinus phylliraeoides

103 % 95

131 132

124

144

u7

101

AP

128

Tr AP

129

AP

wo

Tr R RB

l34 l31

38 95 63,139 63,139 95 145

l35

I46

AP

109

63 115,116,118 112 81 114 16

C C Br, L

AP L,s

148

Tr SB AP c, L C Br, L

95 126 63 115-118,149,150 112 81 16

L,s

137

148 (continues)

TABLE I (continued) Alkaloid Vindolinine N-oxide

19-Epivindolinine N-oxide

* f,

Dihydrovindolinine (Pseudokopsinine) Tuboxenine N-Methyl-14,15-didehydro-tuboxenine 16&Hydroxy-19R-vindolinine 16/3-Hydroxy-19S-vindolinine 15a-Hydroxy-14,15dihydro-vindolinine

15a-Hydroxy-14,15-dihydro-16-

Plant Source Catharanthus roseus Melodinus morsei Melodinus phylliraeoides Melodinus tenuicaudatus Catharanthus roseus Melodinus morsei Melodinus phylliraeoides Melodinus tenuicaudam Vinca erecta Hunteria zeylanica Vinca sardoa Melodinus hemsleyanus Melodinus hemsleyanus Melodinus morsei Melodinus morsei

PlantPart"

Structure

L, c

117,149

16

L, s SB L, CF

148 126 117,149 16 148

L, s

SB L,B R AP Ap

AP

AP

Ref.

126

139 144 145 140 141 142 143

124 153

67 114 114

16,38 1438

epivindolinine Aspidofractinine N-Methylaspidofractinine N-Methyl-14.15-didehydro-aspidofractinine Kopsinginol (-)-Kopsinine

Aspidofmetinine group Hunteria elliottii Vinca sardoa Vinca sardoa Kopsia teoi Hunteria elliottii Hunteria zeylanica Kopsia hainanensis Kopsia larutensis Kopsia officinalis Kopsia pauciflora Melodinus fusiformis Melodinus guillauminii Melodinus morsei

SB, RB R R SB L, RB,s SB SB S, B R,Fr S

SB, AP

146 147 148 161 149

12 67 67

163,164 10-12 154 155 156 14,100 183 78 125 16

(-)-Kopsininic acid Kopsinoline (kopsinine N-oxide) 15a-Hydroxykopsinine

19P-Hydroxykopsinine 14,15-Didehydro-17a-hydroxykopsinine 14,15-Didehydro-17a-hydroxy-16epikopsinine 14,15-Didehydro-3-oxo-kopsinine N-oxide (+)-Kopsinone 10-Methoxykopsinone 12-Methoxykopsinone 14,15-Dihydro-l0-rnethoxy-kopsinone 3-Oxohydroxykopsinine ( -)-17P-Hydroxy-Na-methoxycarbonylkopsinine ( -)-14,15-Didehydro-17/3-hydroxy-Narnethoxycarbonylkopsinine 16,17-Didehydro-N,-rnethoxycarbonyl-11,12methylenedioxykopsinine 16,17-Didehydro-Na-methoxycarbonyl-ll ,12methylenedioxykopsinineN-oxide 16,17-Didehydro-12-rnethoxy-Narnethoxycarbonykopsinine 16,17-Didehydro-12-methoxy-NarnethoxycarbonykopsinineN-oxide

Melodinus reticulatus Kopsia hainanensis Kopsia hainanensis Catharanthus longiolius Catharanthus ovalis Melodinus fusiformis Melodinus guillauminii Melodinus insulae-pinorum Melodinus morsei Melodinus insuhe-pinorum Kopsia teoi Kopsia teoi

L, s SB SB

108

152 153

w

AP SB, AP SB, AP SB, AP SB

155

155

I55 157 63 78 I25 158 16 158 163,164

s, L

162 163

Vinca erecta Kopsia deverrei Kopsia deverrei Kopsia deverrei Kopsia deverrei Melodinus guillauminii Kopsia deverrei

SB L L L SB, AP SB

164 165 166 167 168 174 169

166 I67 168 168 168

Kopsia deverrei

SB

170

I67

Kopsia profunah

s, L

175

169,170

Kopsia profunda

s, L

Kopsia profunda Kopsia pauciflora Kopsia profunah

s, L S

s, L

83

125 167

170 176

169,170 I83 I70 (continues)

TABLE I (continued) Alkaloid

16,17-Didehydro-12-hydroxy-Namethoxycarbonykopsinine (-)-Venalstonhe

3-(hrovenalstonine 19~-Hydroxyvenalstonine ( -)-Venalstonidine

Plant Source

Plant Part"

Structure

Ref.

Kopsia profkndn

s. L

177

170

Catharanthus ovalis Catharanthus roseus Kopsia lapidelecta Melodinus balonsae var. paucivenosus Melodinus cehtroides Melodinus fusiformis Melodinus guillawninii Melodinus hemsleyanus Melodinus insulae-pinorum Melodinus phylliraeoides Melodinus polyadenus Melodinus reticulatus Melodinus scandens Melodinus guillauminii Melodinus reticulatus Melodinus guillauminii Melodinus insulae-pinorwn Melodinus reticularus Catharanthus ovalis Melodinus balansae var. paucivenosus Melodinus cehtroides Melodinus guillauminii Melodinus hemsleyanus Melodinus insulae-pinorum Melodinus phylliraeoides Melodinus polyadenus Melodinus reticulatus

AP

150

63 74 I60 159 81 78 125 114 I58 I48 99

R B, L L Br, L SB, AP

AP SB, AP L, s L, s L, s

108

P SB, AP s, L SB, AF' SB, AP s, L

AP L

AP SB, AP

AP SB, AP L, s L, s

L, s

156

93 I25 108

178

125

I58 108

lS1

63 159 102,110 125 114 158

148 99 108

Melodinus scandens Melodinus reticulatus 19B-Hy droxyvenalstonidine Melodinus reticulatus 15-Demethoxypyrifoline Aspidosperma pyrifolium Pleiocarpine Hunteria ellwttii Kopsia officinalis Kopsijasmine Kopsia jasminiflora Kopsia dasyrachis Kopsidasine Kopsidasine N-oxide Kopsia dasyrachis (-)-12-Methoxykopsinaline Kopsia officinalis (-)-11,12-Methylenedioxy-kopsinaline Kopsia officinalis (-)-12-Methoxy-N-methoxyKopsia deverrei carbonykopsinaline Kopsia officinalis Kopsia pauciflora Kopsia deverrei (-)-N-Methoxycarbonyl-11,12methylenedioxy-kopsinaline (kopsamine) Kopsia officinalis Kopsia pauciflora (-)-11,12-Dimethoxy-N-methoxycarbonyl- Kopsia officinalis kopsinaline Kopsia pauciflora 1l-Hydroxy-12-methoxy-NKopsia officinalis methoxycarbony1-kopsinaline Kopsia officinalis 12-Hydroxy-ll-methoxy-Nmethoxycarbonyl-kopsinaline Kopsamine N-oxide Kopsia officinalis Kopsia pauciflora Kopsinginine Kopsia teoi Kopsinol Kopsia teoi Kopsinginol Kopsia teoi Kopsia teoi Kopsaporine 11,12-Methylenedioxy-kopsaporine Kopsia teoi Kopsia singapurensis Kopsingine Kopsia teoi Kopsia singapurensis

3-Oxovenalstonidine

r

4

P

L,s

L, s

=, L Sd Fr L L L

R R SB R, Fr S SB R, Fr S R S Fr

Fr Fr S SB SB SB SB L TrB SB, L L

179 180

ms ls7 183 181 182 185 186

188 158

187

93 108 108 68 161 100 172 171 171 14 14 167 14,100,162 183 167 14,100,162 183 14 183

189

100

190

100

191 192 161 159

198 160

100 183 163,164 163,164 84 163,164 83 176 83,163,164 83

(continues)

TABLE I (continued) Alkaloid

Plant ParP

Kopsia teoi SB Kopsia teoi SB Kopsia teoi SB Kopsia teoi Kopsia singapurensis TrB Kopsia singapurensis TrB Kopsia singapurensis TrB Kopsia singapurensis TrB Kopsia paucijlora Kopsia paucijlora seco-Aspidohctinine alkaloids, with or withoat subsequent cydization 3-0xo-14,15-secokopsinal Melodinus guillauminii SB,A P Kopsia jasminiflora L Kopsijasminilam Kopsia jasminijlora L 20-Deoxykopsijasminilam 14,15-Didehydro-kopsiJasminilam Kopsin jasminiflora L Kopsia dasyrachis L Kopsidasinine Kopsia jasminijlora L 10-Demethoxy -kopsidasinine 12-Methoxy-10-demethoxy-kopsidasinine Kopsia paucijlora S (-)-Lapidledine A Kopsia lapidilecta B, L Kopsia lapidilecta B, L (+)-Lapidilectine B Kopsia lapidilecta B, L Isolapidilectine Lapidilectam Kopsia lapidilecta B, L Kopsia lapidilecta B,L Lapidilectinol Epilapidilectinol Kopsia lapidilecta B,L 10-Methoxy-3-0x0-lapidilectineB Kopsia tenuis Lundurine A Kopsia tenuis Lundurine B Kopsia tenuis Lundurine C Kopsia tenuis L Paudorine A Kopsia pauciflora L Kopsia pauciflora Pauciflorine B Kopsinganol Kopsidine A Kopsidine B Kopsidine C Singapurensine A Sigapurensine B Singapurensine C Singapurensine D Paucidactine A Paucidactine B

O0

Plant Source

~

Structure 193 194 195

Ref.

m

163,164 163 163 175 176 176

201

I 76

24x2

176 177 177

w 199

203 204

u16

m 208 209

210 21h 211b 2x4 214 215 216 217 218 219 220

221 222 223 224

125 172,179 172,179 172.179 171 172,179 183 160,180 160,180

160 160 160 160 181 181 181 181 182 182

Meloscine 16-Epimeloscine

9-Hydroxy-16-epimeloscine Meloscandine (+)-Scandine

Scandine N-oxide 10-Hydroxyscandine CI

14,15-Epoxyscandine Meloscandonine 19-Epimeloscandonine Kopsan-22-one 522-Dioxokopsane

Kopsinilam Jasminiflorine Kopsinitarine A Kopsinitarine B

Biogenetidy related qoinoline alkaloids Melodinus scandens P Ap Melodinus hemsleyanus Melodinus scandens E, SD, P Melodinus scandens L Melodinus fusiformis Kopsia sp. Melodinus fusiformis AP Melodinus hemsleyanus Fr, R Melodinus henryi E, Sd, P Melodinus scandens SB Melodinus tenuicaudam Melodinus fusiformis Melodinus fusiformis AP Melodinus hemsleyanus SB Melodinus tenuicaudatus Melodinus hemsleyanus AP Melodinus hemsleyanus AP P Melodinus scandens AP Melodinus hemsleyanus Kopsindfruticosine derivatives Kopsia hainanensis SB Fr Kopsia officinalis Alstonia venenata RB SB Kopsia hainanensis B Kopsia macrophylla R, Fr Kopsia officinalis Kopsia hainanensis SB Fr Kopsia officinalis Kopsia jasminijlora L Kopsia teoi L Kopsia teoi L

225

226 233 227 228

232

231 229

234 235 236

237

238 239 240

93 114 93 186 78 184 78 114 185 93 126 78 78 114 126 114 114 93 114 155 100 152 155 178 14,100 155 100 172,179 187,188 187,188

(continues)

TABLE I (continued) Alkaloid Kopsinitarine C Kopsinitarine D Mersingine A Mersingine B Methyl chanofruticosinate Methyl Ndemethoxycarbonylchanofrutiminate Methyl 11,12-methylenedioxychanofrutiminate Methyl 11,12-methylenedioxy-Ndemethoxycarbonylchanofruticosinate Methyl 11,12-methylenedioxy-Ndemethoxycarbonyl-14,lSdidehvdrochanofruticsinate

Plant source Kopsin teoi Kopsia teoi Kopsia teoi Kopsia teoi S e m Kopsia officinaris Kopsia arborea Kopsia offkinulis Kopsia arborea Kopsia offkinalis Kopsia arborea Kopsia arborea

Plantpart"

L L K. W 'eallmloids

Structure

241

L

242 243a

L

243b 244 245

187,188 188 188,189 188,189

247

190 191 190 191 190 191

248

191

246

L

Ref.

L, leaves; SB, stem bark; RB,root bark R, roots; S, stems; WP,whole plant; C, cell cultures; F, flowers; P, pericarp; E, endocarp; Sd, seeds; AP,aerial parts; TB,trunk bark T, twigs; DF, double flowers; Fr, fruits; Sdl, seedlings; BB, branch bark Tr, trunk; B, bark Br, branches.

1. ALKALOIDS

OF THE ASPIDOSPERMINE GROUP

21

known, reported during the period under review; more than 240 alkaloids are included. In the discussion that follows, the structures of the new alkaloids are described; there then follows an account of the various transformations and rearrangement reactions that are characteristic of these alkaloids, particularly those related to vincadifformine. Finally, the many elegant and ingenious syntheses of these alkaloids are summarized. This last topic is necessarily not covered in exhaustive detail, because it has recently been surveyed in the celebratory Volume 50 of this series (4).

11. Isolation and Structure Determination of New Alkaloids of the

Aspidospermine Group A. SECODINE DERIVATIVES Since oxidized derivatives of secodine appear to be involved as late intermediates in the biosynthesis of the aspidospermidine and pseudoaspidospermidine alkaloids, it is logical to begin with those secodine derivatives that have been found to occur naturally. Tetrahydrosecodine (1)occurs in the root bark of Aspidosperma marcgravianum Woodson ( 5 ) and has been detected in cell-suspension cultures of Rhazya stricta Decaisne ( 6 ) ; its demethoxycarbonyl derivative (2) also occurs in A . marcgravianum (9,and in Hapfophyton crooksii L. Benson (7,8) and the roots of R. stricta (9).The two isomeric carbonyl derivatives, 2-ethyl-3-[2-(3-acetylN-piperidino)ethyl]indole (3) and crooksidine (4), occur, respectively, in A . marcgravianum (5) and H. crooksii (7,8). B. THEQUEBRACHAMINE GROUP Several new sources of quebrachamine (5) (10-16) and, particularly, voaphylline (conoflorine, 6 ) (25,27-34) have been found in recent years. Other known alkaloids encountered in recent extractions include vincadine (7) (35,36), 14J5-didehydro-epivincadine (8) (37), rhazidine (9) (38), and 12-methoxyvoaphylline(10) (39-41). New alkaloids include quebrachamine hydroxyindolenine (strictanol, 11),which has been found in the fruits (42) and leaves (43) of R. stricta, and voaphylline hydroxyindolenine (U), for which five sources have been reported (20,22,27,34,44). In common with many other hydroxyindolenine derivatives of easily oxidized alkaloids, these may well prove to be artifacts of the extraction process. Ervayunine (U), the enantiomer of voaphylline, occurs in the roots of Ervatarnia yunnanensis

22

J. E. SAXTON

Tsiang (45). N-Methylvoaphylline (hecubine, 14) is a constituent of the leaves of E. coronaria Stapf (18) and Tubernuernontuna divaricuta (L.) R. Br. ex Roem. et Schult. (24), and of the double flowers of a variety of this same plant (25). 14P-Hydroxyquebrachamine (l5)has been isolated from the leaves and seeds of Stemmadenia grandifloru (Jacq.) Miers (15). It was recognized from its mass spectrum as a quebrachamine-type alkaloid containing a hydroxyl group in ring D. The position of the hydroxyl group was deduced from an analysis of the spin systems involved in the splitting of the protons, and particularly the C-14 proton in ring D; the pconfiguration of the hydroxyl group was established by the reduction of voaphylline (conoflorine, 6) by means of lithium aluminum hydride, which gave a 1:5 mixture of 14P-hydroxyquebrachamine (15) and its 15P-hydroxy isomer, a reaction that had been used earlier during the initial structure determination of conoflorine (46). Two new alkaloids, ervatinine and stapfinine, have been extracted from the leaves of E. coronaria, a species endemic in Pakistan, which is used in the indigenous system of medicine for the treatment of ophthalmia, in the treatment of wounds, and as an anthelmintic. The structures of both alkaloids were deduced from their mass and nuclear magnetic resonance (NMR) spectra. Ervatinine (16) is an 11-hydroxy-5-oxovoaphyllineof unknown stereochemistry (47), and stapfinine (17a) appears to have the relative stereochemistry of 5-hydroxyvoaphylline. Again, the configuration of the hydroxyl group is unknown (48). Two further relatives of voaphylline have been obtained from the leaves of the double-flowering variety of T. divaricata (49). These are voafinine (17b) and N,-methylvoafinine (17c), whose structures were deduced mainly from an examination of their NMR spectra. Three incompletely characterized alkaloids in the quebrachamine group are among the 45 alkaloids isolated from the root bark of T. chippii Stapf (30). Alkaloids TC-A and TC-C gave identical mass spectra, which were in turn identical with that exhibited by synthetically prepared (14S,15s)voaphyllinediol(l8) (50,52).Alkaloids TC-A and TC-C are therefore regarded as (14R,15S)-voaphyllinediol and (14S,15S)-voaphyllinediol (19 and l8), but in view of the trace amounts of alkaloid isolated, it was not possible to determine which was which. Alkaloid TC-B contains an additional oxygen atom (mass spectrum), probably as a hydroxyl group attached to C19, the most frequently substituted position in this group of alkaloids. It is therefore tentatively formulated as 20 (30). The remaining alkaloid in this group, hyderabadine, is similarly oxidized at positions 14 and 15, and also at C-18. It occurs in the leaves of E. coronaria (52) and is formulated as the pentacyclic ether 21 of undetermined stereochemistry, on the basis of its NMR and mass spectra.

COMe

1. Tetriihydrosecodine

El

2

4. Crooksidine

2.

H

Et

3.

H

Ac

5.

7.

(-)-Quebrachemine

R 1= H. R 2= H

Vincadine R1 =C02Me,

R2=H

15. 14&Hydroxyquebracharnine R1=H, R 2 = OH

”

6.

1 2 Voaphylline R = R = H

1 10. 12-Methoxyvoaphylline R = H. R2= 14.

N-Methylvoaphylline R1 = Me, R2= H

-a

H

8. (+)-14,15-Dklehyd-M1~XdiW

11. strictand

9.

Rhazidine

12. Voaphylline hydroxyindolenine

Et H 13. E~ayunine

16

OM

Enratlnine

24

J. E. SAXTON

Two new structural variants in the quebrachamine group have been encountered recently. Voaharine (22), a constituent of T. divaricutu, is clearly obtained by oxidation of voaphylline (6),followed by rearrangement. Its structure was established by X-ray crystallographic analysis (24). Aspidochibine (23), which has so far only been isolated from cellsuspension cultures of A. quebruchoblunco Schlecht (53),rather than intact plants, is the product of the oxidation of quebrachamine at C-3, C-5,and C-14,followed by lactone formation between a carboxyl group generated at C-5and a hydroxyl group at C-14.Structure 23 indicates the relative stereochemistry of aspidochibine. The absolute configuration is presently unknown. C. THEASPIDOSPERMIDINE GROUP

A number of new sources of the known aspidospermidine derivatives (24-50) have been revealed in recent years (5,6,9,10,13,38,54-65,71,74-78) and are listed in Table 1.Fourteen new alkaloids have been isolated including (+)-1,2-didehydroaspidospermidineN-oxide (51), which is a constituent of the roots of R. stricta (66).Its structure was deduced from its spectroscopic properties, but an attempt to assign the absolute stereochemistry by removal of the N-oxide function by reduction or reaction with phosphorus trichloride met with failure, the product obtained being an unidentified indole derivative. In contrast, ent-N-methyl-14,15-didehydroaspidospermidine (52), which was extracted from the roots of Vincu sardou (Stearn) Pignatti ( 6 3 , was unequivocally shown to belong to the less familiar stereochemical series related to (-)-aspidospermidine. The same applies to ( +)-aspidospermine ( 5 9 , the enantiomer of the long-known (-)-aspidospermine (33), which occurs in the root bark of A. pyrifolium Mart. (68). Not surprisingly, it belongs to the same stereochemical series as the major alkaloid of this plant, pyrifoline. Aspidospermidose (53) (69) and aspidospermiose (54) (70), two derivatives of aspidospermidine isolated from the leaves of R. stricta, contain a carbohydrate unit attached to the indoline nitrogen. In the case of aspidospermidose this is a glucose unit, but in aspidospermiose it is an unidentified pentose. Both alkaloids are depicted as being derivatives of (-)aspidospermidine, apparently without supporting evidence. Strictanine (56) is another aspidospermidine derivative obtained from R. stricta; this alkaloid occurs in the fruits (42). Isolated in insufficient quantity for complete study, strictanine appears, from its mass and proton NMR spectra, to be N-formyl-l6a-hydroxyaspidospermidine. The coupling constant for H-2 (52.16 = 7.03 Hz) is appropriate for a trans-diaxial coupling,

Me

H

R2

1

17b VoeRnlne R ’ = R 3 = H , # = O H 17c N.-Methyhroafinine

R’ = H, R2=OH, R3 = Me

2

3

R

R

R

18. Alkaloid TC-A

OH

H

H

19.

Alkaloid TC-C

H

OH

H

20.

Alkaloid TC-B

OH

H

OH

17a Stapfinine R’ = OH, R2 = R3 = H

21. Hyderabadine

aEt

0

22. Voaharine

&NH 0 Et

H 23. Aspidochiblne

0

6

R

1

R

29 (+)-DrNnethylaspidospmine H 30. (+)-Deacetylaspidosperrnlne Me

31. Valleslne 32. Aspidosine 33. (-)-A~pldosperml~~

Me

25. N-MethylaspidosperrnidineR = Me R

268. N-Acetylaspidosperrnidine R = Ac

2

26b. Demethoxypalosine R = COEt 27a. (+)-1.2-Dklehydroaspid~rmidi~R = H. A I , ~

Ac H

28. N-Methyl-14.15didehydroaspidosperrnidine R = Me,

CHO

H

H

Me

H

24. (+)-Aspidospermidire R = H

0

R2

I

A14,15 51.(+)-1.2-DidehydroaspidosperrnidineN-oxide. R = H. dl .2,

Ac

N-oxide

P!JY HO

Ac

34. Aspidocarpine 1

358. umaspennidina

H

R2 R3 R 4 H H O H

35b. Limasperrnine H OH COEt OH 36.11-Methoxylimasperrnlne O W OH COEt OH

37. Umepodine

H

OH

Ac

OH

n

R1

R2

R3

428. 10,11,12-Trimethoxy-l8-oxoaspidoalbidine, R=H 42b. (+)-O-Methyl-18-oxoaspidoalbine,R = COEt

38. Aspidolirnidine

OMe

Ac

H,H

39. Fendlerine

OW

COEt

H,H

40. Haplocidine

H

Ac

H,H

Ac

0

41a. 18-Oxohaplocidine H 41b. Cimicine 41c. Cirnickline

H

COEt

OMe

COEt

0 0

OR

*-R2

..^

H '

1 2 43. Vindorosine, R = H, R = OAc 1 2 44. Vindoline, R = OMe, R =OAc 1 2 45 Deacelylvindoiine, R =OMe. R =OH 1 62 Deacetoxyvindoline, R =OMe, R 2= h

1 2 46 Cathowline, R =Ac,R = H 2 47 Deacetylcathovaline, R1= R = H 1 48 14-Hydroxycathowline, R = Ac, RC OH

49 Obscurinenrine, R = E t

52 ent-N-Methyl-l4,15-didehydroaspldospermidine

50 Obscurinervidine, R = Me

$ O H '. H

0

1.

ALKALOIDS OF THE ASPIDOSPERMINE GROUP

27

and therefore H-2 is cis with respect to the hydroxyl group. The absolute configuration of strictanine is unknown. Two new alkaloids from the bark of Venezuelan A. rhombeosignatum Mgf. have been identified as the depropionyl derivative of limaspermine (limaspermidine, 35a) and 10,11,12-trimethoxy-18-oxo-aspidoalbidine (42a) (72). Anomaline (57),demethoxyanomaline (58), and 12-O-methylanomaline (59) are three new alkaloids related to aspidocarpine, which have been extracted from the bark of Microplumeria anomala (M. Arg.) Mgf., collected from the banks of the Rio Negro (72). These structures were deduced mainly by analysis of their proton and 13C NMR spectra, and by comparison of their NMR data with those of appropriate models; again, structures 57-59 show only the relative stereochemistry. The situation is rather different in the case of mehranine. Isolated in 1983from the leaves of E. coronaria, (+)-mehranine was assigned the gross structure 60,with unspecified stereochemistry (73), i.e., it is an epoxide of 14,15-didehydro-N-methylaspidospermidine.In 1995, its enantiomer (-)-mehranine (61)was discovered in the leaves of the double-flowering variety of T. divaricata, grown in Petaling Jaya (Malaysia) (25).The stereochemistry of the ring system and the configuration of the epoxide function in (-)-mehranine were assigned on the assumption that this alkaloid has a common biogenetic origin with the other alkaloids from this source; the configuration of the epoxide function was also supported by the excellent agreement observed between the C-3,14,15,19,20, and 21 resonances and those exhibited by tabersonine /3-epoxide and several bisindole alkaloids found in this plant. If this falls below a rigid proof of absolute configuration, the balance of probability nevertheless favors the view that (-)-mehranine is a derivative of (-)-aspidospermidine. (+)-Mehranine (60) thus belongs to the (+)-aspidospermidine series. New derivatives of vindoline include deacetoxyvindoline (62), which was found in seedlings of Catharanthus roseus G . Don. (77), and bannucine (63), which was found in the leaves of this same species (79). Bannucine is at present unique among the aspidospermine group of alkaloids in having a pyrrolidone ring attached (at C-10) to the pentacyclic framework. Its structure was deduced from an examination of its mass, proton, and 13C NMR spectra, all of which indicated a close similarity between the nonaromatic portion of bannucine and that of vindoline. The presence of singlets owing to H-9 and H-12 in the proton NMR spectrum pointed to substitution at C-10, this substituent being a fragment of composition C4H6N0(mass spectrum), most likely a pyrrolidone ring. Since the UV spectrum of bannucine was almost identical to that of vindoline the pyrrolidone ring was not attached via its nitrogen atom to C-10; analysis of its proton NMR spectrum

28

J. E. SAXTON

then revealed that it was attached via C-5’. The complete structure of bannucine is therefore 63. The final new alkaloid in this group is alalakine (64), which was obtained, together with 24 other alkaloids, from the seeds of A. album (Vahl) R. Bent. (13). Alalakine exhibits a UV spectrum reminiscent of that of obscurinervine (49), but its IR and mass spectra reveal, in its hydroaromatic portion, a resemblance to O-methy1-18-oxoaspidoa1bine (42b). On this basis, alalakine (64) is formulated as an isomer of 14,15-dihydroobscurinervine, with the lactone oxygen attached to C-21 instead of C-17. D. REARRANGED ASPIDOSPERMIDINE DERIVATIVES (+)-Melonine (65) and its Nb-oxide, isolated from the branches and leaves of Melodinus celastroides Baill. (80,81), contain a ring system that is at present unique. The three quaternary bisindole alkaloids containing this system, which were simultaneously extracted from M . celusfroides, are almost certainly artifacts, the result of using dichloromethane in the extraction process. The ring system in melonine can be regarded as intermediate between that of (+)-aspidospermidine (24) and ( -)-Nanorvallesamidine (66) and can in principle be formed by migration of C-6 from C-7 to C-2 in aspidospermidine. In consonance with this, and in confirmation of its absolute configuration, melonine is converted into 24 and 66 by thermal rearrangement at 200°C in vucuo.

E. OXIDIZED (2,7-SECO) ASPIDOSPERMIDINE DERIVATIVES These bases may well be artifacts of the isolation process, derived by the oxidation of a precursor, possibly 1,2-didehydroaspidospermidine(27). New sources of rhazinilam (67) have been reported (5,59,82-84), and its 5,21-dihydro derivative 68 has been found in Leuconotis eugenifolius A. DC (82). The latter suffers oxidation on prolonged exposure to air, with formation of rhazinilam. Further oxidation of rhazinilam affords 3oxo-14,15-didehydrorhazinilam(69), which has been obtained from cell suspension cultures of A. quebruchoblanco (53),and further oxidation of 5,21-dihydrorhazinilam affords leuconolam (70), which has been isolated following extractions of L. grifithii Hook. (85), L. eugenifolius (82,86),and Alstoniu scholaris R. Br. (87). Its epimer, 21-epileuconolam (71), was also obtained from L. eugenifolius (82). Structure 70 for leuconolam is not in doubt, since it was established by X-ray crystallography (85,238).Other close relatives that have been encountered include 21-O-methyl-leuconolam(72), which was obtained during extractions of L. eugenifolius (86);N-methylleuconolam (73), from the roots of R. sfrictu (89); and leuconoxine (74), another product of the extraction of L. eugenifolius (86). This last artifact

55 (+)-Aspidospermine

58 Strictanine

2 1 57 Anomaiine, R = OMe, R = H 1 2 58 DemethoxyanomaHne, R = R = H

59 12QMethylet~1~line, R1= O M .R2=

60 (+)-Mehranine

Me

0 p 0

N

Me

61 (-)-Meh&ne

66 (-)-Nonrellssamidine

63 Bannucine

67 Rhazinilam, R=H,H 68 5,21-Dlhyd~inilam,R = H,H; 5,21dihydm 69 3-0xo-l4,15didehydr~wt1azwhgzinilam,R = 0, A14,15

30

J. E. SAXTON

contains a novel ring system, which has previously been generated by the reaction of hydrogen chloride in methanol on leuconolam (82). F. DEGRADED ASPIDOSPERMIDINE DERIVATIVES A pentacyclic alkaloid, so far unnamed, isolated (90) from the leaves of Voacanga africana Stapf, is the epoxide 75 of a degraded aspidospermane base in which C-5 and C-6 of the original tryptamine ethanamine chain have been lost; this is the first recorded occurrence of this ring system.

GROUP G. THEVINCADIFFORMINE-TABERSONINE The major anilinoacrylate alkaloids, (-)-vincadifformine (76), (%)vincadifformine, (+)-vincadifformine (77), tabersonine (78), (-) lochnericine (79), (-)-minovincinine (80), ll-hydroxytabersonine (81), 11methoxytabersonine (82), and (-)-lochnerinine (hazuntine, 83), occur widely, and several new sources have been revealed in recent years (see Table I). Tabersonine appears to be particularly widespread, which is not surprising, in view of its presumed position in the biogenetic sequence. Other known alkaloids for which new occurrences have been reported include 5-oxovincadifformine (ervinidinine, 84), which was isolated from the leaves and seeds of Pterotaberna inconspicua Stapf (230); (+)-minovincinine (85), from Ervatamiu yunnunensis Tsiang (45);(-)-echitovenine (86), which is produced in in vitro cultures of Catharanthus trichophyllus (Baker) Pichon (122); 11-methoxyvincadifformine (87), a constituent of Vinca minor L. ( 9 3 ,V. herbacea Waldst. et Kit. (96),and Melodinussuaveowhich occurs in fens Champ. ex Benth. (95); 19R-hydroxytabersonine (a), several Catharanthus and Melodinus species (63,82,93,95,127);and 19Rhydroxy-ll-methoxytabersonine(vandrikidine, 89), which has been found in the roots of Afstonia yunnanensis Diels (228) and in cell suspension cultures of C. roseus (126). The configuration of C-19 in vandrikidine, previously unknown, has been established following an analysis of its 400 MHz NMR spectrum (229). Pachysiphine (90) occurs in Sarcopharyngiu c r a m (Benth.) Boiteau et Allorge (209),in Stemmadeniu grandijlora (25), and in the double-flowering variety of Tabernaemontana divaricata (25). Horhammericine (918) is produced in cultures of C. roseus (225-227) and C. trichophyllus (222), cathovalinine (91b) has been found in the aerial parts of C. ovalis Mgf. (63) and the trunk of M . suaveofens (95), and hihhammerinine (92) in cultures of C. rosew (215,226). Horhammericine and cathovalinine are stereoisomers based on (-)+incadifformine with the gross structure 91; of the four possibilities cathovalinine is 91b, with a 19s configuration, according to X-ray crystal structure analysis (I). Since the two C-19 epimers containing a P-epoxide function are represented by 19R-

u

0

70

Leuoono(am.

1

2

R = R =H. $OH

74 Lelmnmh

1 71 Pl-EpHeuCondam. R =R2=H, a O H 1 2 72 21-Q-MethyHeucondam. R = Me. R = H, N M e 1 2 73 N-MethyI-leucondam, R =H, R =Me,$ O H

H 75 Unnamedbase

'Et

78 (-)-Tabersonine, R = H 77 (+)-vincadiiormine

H

I co2M" 79 Lochnericine, R = H 83 Lochnarinine, R = OMe

81 11-Hydroxytabersonine, R = OH

82 ll-Methoxytabersonine, R = OMe

\

/

m2Me

80 (-)-Minovindnine, R = H, 19R 86 Echiiovenine, R = Ac, 19R

0

eco2Me 84 5-Oxovincadinormine

19

H

85 (+)-Minovincinine

32

J. E. SAXTON

epimisiline and 19s-epimisiline (vide infra), horhammericine must be the 19R-epimer (91a). Apodine (93) has been obtained from Peschiera van heurckii (Muell.Arg.) L. Allorge (232) and P. buchtieni (Tabernaemontuna buchtieni Mgf.) (34).Deoxapodine (modestanine, 94) occurs in Hazunta modesta var. modesra subvar. montana (203)and Ervatamia coryrnbosa Roxb. ex Wall. (232). Vandrikine (95) occurs in E. corymbosa (232), and hedrantherine (96) in P. van heurckii (232). Among the new alkaloids, the structure deduced for 3-oxovincadifformine (97), an alkaloid from the leaves and seeds of Colombian Stemmadenia grandij7ora, was confirmed by identifying it with the hydrogenation product of the long-known 3-oxotabersonine (25). Three new hydroxyl derivatives of vincadifformine have been isolated recently; these are 11hydroxyvincadifformine (98), which occurs in the aerial parts of Melodinus hemsleyanus Diels (124), from the Sichuan province of China, (-)-12hydroxyvincadifformine (99), from the leaves of Bonafousia tetrastachya (Humboldt, Bonpland, et Kunth) Mgf. (92), and 15P-hydroxyvincadifformine (loo), from the leaves of Rhazya stricta (233). The structure of 98 was deduced from the proton NMR spectrum of its methylation product, 11-methoxyvincadifformine,and confirmed by comparison of 98 with the hydrogenation product of 11-hydroxytabersonine (86),which occurs in the same plant (224). (-)-12-Hydroxyvincadifformine (99) exhibits a molecular ion appropriate to C21H24N203,and in its mass spectrum exhibits fragment ions characteristic of the hydroaromatic portion of vincadifformine (76) (92). The presence of a vincadifformine skeleton is confirmed by the perfect correspondence between the chemical shifts of the saturated carbons, and the anilinoacrylate function, in 76 and 99. The additional oxygen atom must therefore be attached to the aromatic ring, confirmed by the observation of a bathochromic shift of the UV spectrum in alkaline solution. The position of the phenolic hydroxyl group could not be established from the proton NMR spectrum, but when the ipso, ortho, meta, and para effects of the hydroxyl group on the aromatic nucleus were taken into account, it was deduced that the hydroxyl group was situated at position 12, as in 99. The very high negative rotation, [aD]-427", indicates clearly the absolute configuration of 99. The situation with regard to 15P-hydroxyvincadifformine (100) is rather different. Its structure was deduced (133)from its spectroscopic properties, mainly its proton and I3C NMR spectra; some critical chemical shifts, such as H-15 and C-15, were compared with those reported (234) for 15ahydroxyvincadifformineand 1SP-hydroxyvincadifformine (loo),which had earlier been prepared in racemic form as intermediates in a synthesis of

1.

ALKALOIDS OF THE ASPIDOSPERMINE GROUP

‘ a#@ M e

R’

R2

R3

88 19RHYdmxYtatmoniw

H

H

H.H; 19R

89 Vandrikldlne

H

OMe H,H; 19R

@LOR1 ’N

33

&: HC4Me

1

90 pachysiphine

R = H,R2= H,H R1 = OH, R 2= H,H; 19R

108 19SHydrox)4abersonim

H

H

H.H; 19s

119 19REpimisiiine

110 19SAcetoxytabersonine

Ac

H

H,H; 19s

111 19SAcetoxy-3-oxotalWrsonine Ac H

. O ; 19s

120 19SEpimlsiline R1= OH, R2= H,H; 19s 1 2 121 3-Oxopechysiphin8 R = H.R = 0

918 tloerhemmerichw, l9R

92 m m m e r i n i n e

91b Cathovalinine 19s

1 93 ~podhw,, R = O . R ~ = H 1 94 -nine, R = H,H; R ~ H = 1 95 Vandrikine, R = H.H; R2=

96 Hedrantherine

tabersonine. Although formulated as a member of the (- )-vincadifformine (76) series, there appears to be no proof of the absolute configuration of 100, and the reported rotation, [aD]+24O0,is not helpful.

34

J. E. SAXTON

A dihydroxy derivative of vincadifformine, formulated as 1 4 ~ 5 dihydroxyvincadifformine (101), has been isolated from Hazunta modesta var. modesta subvar. monfana (203).Unfortunately, the paucity of alkaloid obtained precluded determination of its stereochemistry. Echitoveniline (102), ll-methoxyechitoveniline (103), and 11methoxyechitovenidine (104) are three new alkaloids from the fruits of Alstoniu venenutu R. Br. (235,136),although the leaves are a better source of 103. In consonance with these structures, ester exchange with sodium methoxide affords (-)-19R-minovincinine (80) from 102, and (-)-19R-11methoxyminovincinine, a minor alkaloid of Vinca minor (237), from 103 and 104. 19-Epi-(+)-echitoveniline (105) [aD]+462" is yet another alkaloid from the leaves of A. venenufa (138).The UV spectrum of 105 indicates that it is composed of P-anilinoacrylate and trimethoxybenzoate chromophores, and hence the alkaloid must bear a close resemblance to echitoveniline (102). The high positive rotation suggests that it is related to (+)-vincadifformine; the two alkaloids, 102 and 105, however, are not enantiomers, and they must therefore have the same configuration at C-19. This was confirmed by hydrolysis, decarboxylation, and reduction (sodium borohydride) of 19-epi-(+ )-echitoveniline (105) and (-)-echitoveniline (102), which gave, respectively, the diastereoisomeric 19R-19-hydroxy-(-)quebrachamine (106) and its 20-epimer. Similarly, methanolysis of 105 gave a base 85 that exhibited spectral properties closely similar to those of (-)19R-minovincinine (HO), prepared by methanolysis of (-)-echitoveniline. However, the two bases are not enantiomers, because, although they exhibit Cotton effects of opposite sign, the CD curves are not enantiomeric. Since the absolute configuration of the parent vincadifformine skeleton dictates the sign of the Cotton effect, the two bases must be based on enantiomeric vincadifformine skeletons, but possess the same ( R ) configuration at C-19. Hence, the new base is 19-epi-(+)-echitoveniline (105), and the identification of the methanolysis product 85 and its O-acetyl derivative with the (+)-minovincinine (85) and its O-acetate establishes the R configuration at C-19 in both these alkaloids. The Nb-oxide of tabersonine (78) is reported to occur in the seeds of Amsoniu ellipfica Roem. et Schult. (ZOZ),in which it is accompanied by 3oxotabersonine (107). Four other sources of 3-oxotabersonine have also been recorded (15,93,203,209).The structure of this alkaloid was established (202)by hydrogenation to 3-oxovincadifformine, which was identified by comparison with a (racemic) synthetic sample ( I ) ,and by its preparation by oxidation of tabersonine by means of potassium permanganate (102). 19s-Hydroxytabersonine (108) is a constituent of the aerial parts of Catharanthus ovalis Mgf. (63) and the branches and leaves of Melodinus

1.

ALKALOIDS OF THE ASPIDOSPERMINE GROUP

35

celustroides (81).Its structure was confirmed by its partial synthesis, together with 19R-hydroxytabersonine (88), from vindolinine (109) (139), by reaction with iodine, which gave a mixture of the epimeric 19-iodotabersonines, followed by hydrolysis. The configuration at C-19 in 108 was then determined by the method of Horeau. 19s-Acetoxytabersonine (110) and its 30x0 derivative 111 occur in the endocarp and seeds of M . scundens Forster (93). Again, these structures were confirmed by partial synthesis from vindolinine. The mixture of epimeric 19-acetoxytabersonines obtained was oxidized by means of osmium tetroxide to the corresponding 3-OX0 derivatives, and the 19R and 19s epimers were identified from their proton and I3C NMR spectra. 11-Methoxy-3-oxotabersonine (112) is the only new alkaloid among the eight found in the stems and leaves of Alstoniu yunnunensis (240). 11,19RDihydroxytabersonine (113) has been extracted from Melodinus fusiformis Champ. ex Benth. (78), a plant used in Chinese folk medicine for the treatment of rheumatic heart disease, and it has also been isolated from the trunk of M . suuveolens (95),which is also used in Chinese folk medicine. Extracts of this plant, collected in Hainan Province, are used for the treatment of hernia, infantile malnutrition, dyspepsia, and testitis. A third source of this alkaloid is the aerial parts of M . hemsleyunus (214). 10Hydroxy-11-methoxytabersonine (114) occurs in Huzuntu modestu var. brevitubu (242), and 19-acetoxy-11-hydroxytabersonine(115) and 19-acetoxy11-methoxytabersonine (116, the acetate of vandrikidine) are produced along with vandrikidine in the suspension culture of the 943 cell line of Cutharunthus roseus (215,216). Among the new alkaloids that contain an epoxide grouping, 1l-hydroxy14,15a-epoxytabersonine (117) is a constituent of Melodinus fusiformis (78) and the aerial parts of M . hemsleyunus (214), and 14,15-epoxy-3-oxotabersonine (118) occurs in the seeds of Amsoniu ellipticu (201). 29R-Hydroxypachysiphine (19R-epimisiline, 119) and 19s-hydroxypachysiphine (19sepimisiline, 120) are two new alkaloids of the leaves of Sri Lankan Petchiu ceylunicu Wight (242).Their structures and relative stereochemistry were deduced from an examination of their NMR spectra, which revealed that they are most likely 19-epimers. This was confirmed by oxidation of the alkaloids, which gave the same ketone. The optical rotation values (119, [aID -382"; 120, [a],-399") indicate that they belong to the (-)-vincadifformine series; the configuration at C-19 was then deduced by the application of Horeau's method. It then follows that 3-oxopachysiphine, an alkaloid from Stemmudeniu grundifloru, has the structure 121 (25). Petchicine (122), the third alkaloid of Petchiu ceylunicu, contains two more oxygen atoms than tabersonine (143). Its spectroscopic properties indicate that it is a member of the anilinoacrylate group, and its optical

36

J. E. SAXTON

101 14,15-Dlhydroxyvl~cadlffonnine

105 19-Epl-(+).echltovenillne

OH

H

106 19RHydroxy-(-)quebrachamlne

Me02C

R3

109 10fFVlndolinlne

112 -ll

H

113 11.19R-Dlhydroxyiabytebersonlne H

OMe 0

H

OH

OH; l9R

H2

114 l O M y d m x y - l l - t W h o ~ n eOH OMe H2 115 19-A&O~ll-hvdroxytsawsonlne H 116 19-Acetoxy-ll-IhW

‘Et

H

H

OH

H2

OAC

OW

&

OF-&

1. ALKALOIDS

OF THE ASPIDOSPERMINE GROUP

37

rotation, [a],-380", that it is related to (-)-vincadifformine, The presence of a 3H doublet at 1.02 ppm coupled with a downfield quartet for one proton at 4.12 ppm suggested the presence of a hydroxyethyl group attached to C-20, as in minovincinine (80). There were no olefinic protons in the molecule; instead, a downfield multiplet at 4.11 pprn (C-14aH) and signals at 3.09 and 2.95 ppm (C-15aH and 15pH) indicated the presence of a poxygen substituent at C-14. These resonances, together with a singlet at 3.42 ppm (C-17aH) and appropriate cross-peaks in the COSY-45 spectrum and interactions in the NOESY spectrum, established the presence of an ether link between C-14 and C-17, and the a-orientation of the C-14, C17, and C-21 protons. The absence of a double bond was also apparent from the 13CNMR spectrum, in which the signals for C-14 and C-17 in the vincadifformine spectrum were replaced by signals for two oxymethine carbons at 80.0 and 79.4 ppm, which are the points of attachment of an ether oxygen atom. The configuration at C-19 was deduced by application of Horeau's procedure. Consequently, the complete structure and stereochemistry of petchicine is as given in 122. Buxomeline (123),a new alkaloid from Melodinus celastroides, is an anilinoacrylate alkaloid belonging to the (-)-vincadifformine series (UV and mass spectra, and optical rotation) (81).The presence of a 3H doublet at 1.05 pprn and a low-field quartet at 3.98 pprn indicates that buxomeline contains a MeCH-0-group; this presumably accounts for C-18 and C-19. The pattern of protons in ring D was deduced from their chemical shifts and coupling constants, and a methylene group at C-17 was apparent from an AB system, otherwise not coupled with any other protons. A hydroxyl group was placed at C-21, since the signal for H-21 was missing in the NMR spectrum. This was confirmed by proton exchange with D20,and the failure of the hydroxyl group to respond to attempts at acetylation. These results only allow for the oxygen attached to C-19 to be contained in an ether grouping, and since C-6 is not substituted (peak at m/z 214 in the mass spectrum) this oxygen must be attached to C-5, as shown in 123. Buxomeline is thus both a carbinolamine and a carbinolamine ether, which is unusual. The configuration at C-19 is unknown. Little is known about apodinine, an alkaloid from the leaves of Tubernaernontunu apodu Wr. ex Sauv. (244). Its UV spectrum is that of an anilinoacrylate alkaloid, and its IR and mass spectra suggest that it is a hydroxyapodine. The hydroxyl group is not attached to the aromatic ring (NMR spectrum) and it is not a carbinolamine, since it does not exhibit mild reducing properties. On this basis, and on that of an analysis of its mass spectrum, it is formulated as 14-hydroxyapodine (124). However, since the optical rotation was not recorded, it is not known whether it belongs to the (+)- or (-)-vincadifformine series, and there is no information concerning the configuration of the hydroxyl group.

38

J. E. SAXTON

Finally in this group, the structure assigned to rosicine (129, another alkaloid from the leaves of Catharanthus roseus, on the basis of an extensive analysis of its mass and NMR spectra, is that of the P-epoxide of desethyltabersonine (37). It is thus one of the few Aspidosperma alkaloids that lacks the angular ethyl group, and it may well arise by fragmentation of an iminium ion (e.g., 126)derived by oxidation of 19-hydroxytabersonine (88), which occurs in the same plant. The absolute configuration implied in 125 is based on this presumed biogenetic relationship; there appears to be no independent evidence.

H. OXIDIZED AND/OR REARRANGED VINCADIFFORMINE DERIVATIVES 14,15-Epoxy-16-hydroxy-16-methoxycarbonyl-3-oxo-1,2-didehydroaspidospermidine (127) has been extracted from the seeds of Amsonia elliptica (101). However, this is almost certainly an artifact, derived by aerial oxidation of 3-oxotabersonine (107), which occurs in the same plant, or its epoxide. Vincoline (128)has recently been found in Melodinus suaveolens (95) and M. morsei (38),and the alkaloids 129 and WO, from Carharanthus ovalis (63,139),whose structures were elucidated earlier (l), are now referred to as kitraline (19s) and kitramine (19R), respectively (63). Trichophylline, a novel alkaloid isolated from the roots of Catharanthus trichophyllus, has the structure 131, according to X-ray crystal structure analysis (145). Reduction of trichophylline with sodium borohydride gives an unsaturated lactone, formulated as 132. Oxidative fission of the C/D ring system in vincadifformine derivatives has been observed previously; hence, trichophylline may arise by oxidation at C-21 of an appropriate precursor, such as a 19-hydroxytabersonine (88)or 108,to the hydroperoxide 133, followed by fission of the 20,21-bond and simultaneous migration of C-18. In suaveolenine (134),an alkaloid from the trunk of Melodinus suaveolens, oxidation of the vincadifformine ring system has occurred between C-7 and C-21. The structure and stereochemistry of suaveolenine, also established by X-ray crystallography, show that it is very closely related structurally, but not stereochemically, to vincoline, with which it occurs in M . suaveolens (95). Goniomitine (135),an alkaloid of a new structural type from the root bark of Gonioma malagasy E. May, is apparently the result of a much more far-reaching transformation of a vincadifformine precursor (146).Its structure was deduced on the basis of an analysis of its NMR spectra, including a comparison of its I3Cchemical shift data with those of tryptophol and guettardine (136).It is included in this group on the basis of its presumed derivation from vincadifformine (77)by a series of plausible, unexceptional

123 B u m i n e

124 Apodinine?

126

125 Rosidne

0

Ho CON 127 14,lfi-Epo~-l6-hydroxy-l li-methoxycahonyl128 W n c d i t ~ . R = H, 19s

3-0m-l m i3? -i

129 Klbalhre. R=Me, 19s

130 Kitrarnine, R = Me. 19R

H 133

/

N H 132

\

131 Trichophylline

w

40

J. E. SAXTON

steps. Initially (146), the enantiomeric stereochemistry was tentatively proposed for goniomitine on the assumption that it was derived from (-)vincadifformine (76).However, the enantioselective synthesis ( qv.), later contributed by Takano et al. (147), established the absolute stereochemistry shown in 135.Goniomitine must therefore be derived from (+)-vincadifformine (77). I. THEVINDOLININE GROUP This group is dominated by vindolinine (19R-vindolinine, 109), 19epivindolinine (19S-vindolinine, 137), and their &-oxides, new sources for which are listed in Table I. The alkaloids isolated from the leaves of Catharanthus roseus and formulated as 16-epi-19s-vindolinine (150) and its N-oxide (149) were later shown to be 19s-vindolinine (137)and its Noxide, and the apparently puzzling features in the NMR spectrum of the base 137 were explained (151). If kept in chloroform or deuterochloroform at room temperature, 19s-vindolinine (137)isomerizes to 19R-vindolinine (109)via a mechanism that must involve a series of equilibria in which Nb is first protonated and then the 7,21-bond is broken to give an iminium ion 138 in which proton exchange and inversion of C-19 are possible. Accordingly, the NMR spectrum of 19S-vindolinine, if recorded within 2 h of dissolution in chloroform, is consistent with that of structure 137. But after 36 h the isomerization is more or less complete, and the spectrum of 19R-vindolinine (109) is obtained. The 13C NMR spectrum naturally undergoes similar changes. Dihydrovindolinine (pseudokopsinine, 139) has been reported to occur in Vinca erecta (124). Two new alkaloids from the aerial parts of Melodinus hemsleyanus have been shown to be 16p-hydroxy-19R-vindolinine(140)and its epimer, 16phydroxy-19s-vindolinine(141)(114). Their UV spectra are superimposable and characteristic of a dihydroindole system, and their NMR spectra reveal that they are epimers based on a vindolinine skeleton. The absence of a signal owing to H-16 and the presence in both spectra of an AB system for the C-17 protons, with an additional, small coupling of the 17a proton of 140 with H-21 (W-coupling), was a clear indication that the unplaced hydroxyl group was situated at C-16. The chemical shift of the protons of the ester methoxyl group was closer to that of 16-epi-l9R-vindolinine than to those of 19R- (109)and 19s-vindolinine (137);hence, the 16-hydroxyl group in the new alkaloids 140 and 141 has the p-configuration (114). Two new alkaloids, which contain two more hydrogen atoms than the preceding ones, have been found in Melodinus morsei (16,152). These were shown, from an examination of their spectroscopic data, to be 15a-hydroxy-14,15-dihydrovindolinine(142)and its 16-epimer 143. NOE

1.

ALKALOIDS OF THE ASPIDOSPERMINE GROUP

41

experiments on the former indicated that this alkaloid contained a pmethoxycarbonyl group. Thus, irradiation of H-21 resulted in enhancement of the H-19 signal, which is consistent with an a-hydrogen at C-19. Similarly, irradiation of the 18-Me signal caused enhancement of the H-16 signal, but not the H-21 signal; thus, H-16 has the a-configuration. Irradiation of the H-15 signal led to NOE enhancements in the H-14p and H-17a signals; hence, H-15 has the p-configuration, and this alkaloid is 15a-hydroxy-14,15dihydrovindolinine (142).By similar means, the structure of its 16-epimer 143 was deduced. Irradiation of the H-16 signal caused enhancement of the H-17p signal, but not that of the 18-Me signal. Tuboxenine (144) has been shown to occur in the leaves and bark of Hunteria zeylanica Gardn. (153),and N-methyl-14,15-didehydrotuboxenine (145),a new alkaloid, occurs in the roots of Vinca sardoa (67). J. THEASPIDOFRACTININE GROUP

Aspidofractinine (146),the parent member of this third large subgroup of alkaloids of the aspidospermine group, does not occur widely, and the only recent report of its occurrence is in the stem bark and root bark of Hunteria elliottii Pichon (22). Its Na-methyl (147) and N,-methyl-14,15didehydro (148)derivatives are new alkaloids, which have been found in the roots of Vinca sardoa (67).The ester alkaloids occur much more widely, and several new sources have been reported for (-)-kopsinine (149),(-)venalstonine (150),(-)-venalstonidine (El), and several minor alkaloids (152-160)(Table I). Of the six reported isolations of 1%-hydroxykopsinine (154), one (26) does not specify the configuration of the hydroxyl group. Since it is described as a known alkaloid, it is presumed to be 15ahydroxykopsinine, because 15p-hydroxykopsinine is unknown as a natural product. The structure of kopsamine (158),previously unknown, has been revealed by X-ray crystallography (165). Of the new alkaloids, kopsinginol(161), from the stem bark of a relatively new Malaysian species, Kopsia teoi L. Allorge et RCmy, is simply 14,15didehydro-17p-hydroxyaspidofractinine (84,163,164) and is the only new alkaloid in this subgroup, apart from 147 and 148, that does not contain an ester group either on C-16 or as part of a urethane group on N,. A range of new kopsinine and venalstonine relatives (162-170,174-177)have been encountered, almost entirely from Kopsia and Melodinus species. The only exception is 14,15-didehydro-3-oxokopsinineN-oxide (164),from V. erecta (266);however, complete evidence for this structure is lacking. 14,15-Didehydro-17a-hydroxykopsinine (162)is one of several new bases from Kopsia teoi (84,163,264).Its presumed 16-epimer 163was later isolated from the stem bark of the same plant, but the relationship between the

% O H

Et

.* Et

135 (-)-Goniomitlne

136 Guettardine

139 Mhydmvinddinlne 140 16&Hydmxy-l9Rvinddinine 141 Is&Hydroxy19Svinddinine

R =H

142 l ! j a - ~ ~ l 4 , 1 5 d l ~ ~ ~ ~

144 Tuboxenine,

143 15Cr-Hydmxy-14,lMihydro-1BepMndolinlne a-C02Me

145 Na-Methyi-l4,15ddehydrotuboxenine, R = Me,

1.

ALKALOIDS OF THE ASPIDOSPERMINE GROUP

43

two alkaloids is not entirely clear. Kam et al. (264)deduced the stereochemistry of their alkaloid 162 from the absence of a W-coupling between H16 and H-18, and the magnitude of the coupling constant between H-16 and H-17. In contrast, there is a W-coupling between H-16 and H-18 of 2.1 Hz in the alkaloid isolated by Varea er al. (83) and formulated as 163. In other respects the spectra of these two alkaloids appear to be identical; hence, their identity as two distinct epimers remains to be firmly established. The new alkaloids of Kopsia deverrei L. Allorge, a large Malaysian tree, are (+)-kopsinone (165) (167) and its 10-methoxy- (166) and 12-methoxy(167) derivatives, 14,15-dihydro-l0-methoxykopsinone(168) (168), (-)17~-hydroxy-Na-methoxycarbonylkopsinine (169), and its 14J5-didehydro derivative 170 (167). (+)-Kopsinone (165) exhibits a dihydroindole UV spectrum, has the molecular formula C21H22N203 (mass spectrum), and contains both urethane and ketone carbonyl groups (IR spectrum). Two olefinic protons, coupled with a methylene group, reveal the presence of a 14J5-double bond, and an AA’BB’ system indicates that the ethanamine chain (C-5 and C-6) is intact. The I3C NMR spectrum, which contains signals owing to six tertiary carbons, suggests that the aromatic ring is unsubstituted, and a signal at 212.9 ppm confirms the presence of a carbonyl group. These data can only be interpreted by a structure based on kopsinine, but containing a carbonyl group at C-17 or C-19; this is confirmed by the deshielding of the signal owing to C-20. Which of the two possibilities is the correct one was established by reduction to the corresponding alcohol 171, the mass spectrum of which contained a fragment at m/z 123, owing to the ion 172. The carbonyl group in (+)-kopsinone is thus situated at C-17, and the complete structure is 165 (167). The structures of the substituted kopsinone derivatives 166 and 167 were revealed by the close similarity of the nonaromatic portions of their NMR spectra with that of kopsinone (165). Analysis of their proton and 13C NMR spectra then allowed the positions of the methoxyl groups in 10methoxykopsinone (166) and 12-methoxykopsinone (167) to be identified (268). Conversion of 10-methoxykopsinone (166) into the fourth alkaloid by hydrogenation established its structure as 14,15-dihydro-l0methoxykopsinone (168) (168). The 13CNMR spectrum of ( -)-17~-hydroxy-Na-methoxycarbonylkopsinine (169) reveals close similarities to that of kopsinine (149), except that a tertiary carbon signal at 67.7 ppm in the spectrum of 169 replaces one of the secondary carbon signals of kopsinine. Also observed is a deshielding of the signals owing to C-16 and C-20, which establishes the position of the hydroxyl group as C-17. The configuration of this hydroxyl group was determined by reduction to the related alcohol 173, in which H-17 was

44

J. E. SAXTON

coupled with H-16. The magnitude of the coupling constant and the absence of a W-coupling with protons on either C-18 or C-19 was consistent with pseudoaxial protons at both C-16 and C-17 in a boat-shaped ring F. This alkaloid therefore has the structure 169, and its congener, which can be hydrogenated to 169,is its 14,15-didehydro derivative 170 (267). Another kopsinine derivative, described as 3-0x0-hydroxykopsinine (174),has been isolated from Melodinus guillauminii (225), but owing to lack of material it proved impossible to determine the position and configuration of the hydroxyl group. Five new alkaloids from the leaves and stems of Kopsia profundu Mgf., another Malaysian species, have been shown to be 16,17didehydro-N,-methoxycarbonyl-ll,l2-methylenedioxykopsinine (175)[the dehydration product of kopsamine (US)], 16,17-didehydro-12-methoxyN,-methoxycarbonylkopsinine (176), 16,17-didehydro-12-hydroxy-N,methoxycarbonylkopsinine (177), and the N-oxides of 175 and 176 (269,170).19P-Hydroxyvenalstonine(178),not previously known as a natural product, has been reported to occur in Melodinus guilluuminii (225), M. reticulatus Boiteau (208), and M. insulae-pinorum Boiteau (158). Its structure was deduced from its mass spectrum and comparison with that of venalstonine, and confirmed by its hydrogenation to 19P-hydroxykopsinine (108). Both 3-oxovenalstonidine (179) and 19P-hydroxyvenalstonidine (180)have been found in the leaves and stems of M. reticulatus (108).Their structures were deduced from their mass and NMR spectra, and that of the former was confirmed by its preparation through the oxidation of venalstonidine (108). The first extractions of the leaves of Kopsiu dusyruchis Ridl., which is endemic to North Borneo, have yielded three new alkaloids, of which kopsidasine (181)and its N-oxide contain the aspidofractinine ring system (2 72). Kopsidasine &-oxide contains a carbinolamine N-oxide function, an @unsaturated ester, and a urethane grouping. Its structure and relative configuration were established by the conversion of both 181 and its Nboxide into the hexacyclic ester 182,and by comparison of its mass spectrum with that of pleiocarpine (157).The absolute configuration of these alkaloids is not yet known, but they have been provisionally formulated as shown in 18U182,since all of the alkaloids of this group known to date belong to the same stereochemical series. The NMR spectroscopic data for kopsijasmine (183),a new alkaloid from the leaves of Thai Kopsia jasminij?oru Pitard (172),strongly resemble those exhibited by deoxykopsidasine (184),and on this basis the alkaloid is formulated as 10-demethoxy-21-deoxykopsidasine, Kopsiu oflcinulis Tsiang et P. T. Li enjoys a reputation in popular Chinese medicine for the alleviation of gout and rheumatism, and as an analgesic

1.

ALKALOIDS OF THE ASPIDOSPERMINE GROUP

45

in pharyngitis and tonsillitis. The roots and fruits of this species have yielded a number of alkaloids of the aspidospermine group, including, notably, several derivatives of kopsinine which have undergone further oxidation at C-16.The roots contain (-)-12-methoxykopsinaline (185), (-)-11,12methylenedioxykopsinaline (186), (-)-11,12-dimethoxy-N-methoxycarbonylkopsinaline (187), (-)-12-methoxy-N-methoxycarbonylkopsinaline (188), and (-)-N-methoxycarbonyl-ll,l2-methylenedioxykopsinaline (kopsamine, 158) (24). The last two alkaloids are also present in the fruits, together with kopsamine N-oxide, 1l-hydroxy-12-methoxy-N-methoxycarbonylkopsinaline (189), and 12-hydroxy-ll-methoxy-N-methoxycarbonylkopsinaline (190)(ZOO). It seems likely that (-)-12-methoxy-N-methoxycarbonylkopsinaline (188) is identical with kopsilongine, an alkaloid of Kopsia 1ongiJora Merrill (273), but this identity has not yet been firmly established. The structure of 12-hydroxy-ll-methoxy-N-methoxycarbonylkopsinaline (190) has also been established by X-ray crystallographic analysis (265). The stem bark of Kopsia teoi contains kopsinginine (191) (84,263,164), which is also oxidized at C-16, together with four alkaloids that are oxidized at both C-16and C-17. These are kopsinol(192), kopsaporine (159),kopsinand kopsinganol (193).Comparison of the I3CNMR spectrum gine (la), of kopsinginine, which contains one oxygen atom less than kopsingine (la)with , that of kopsingine showed that the carbon resonances of these two alkaloids are essentially similar, except that for C-17, which in kopsinginine is appropriate to a methylene group, and is at higher field than the methine carbon resonance exhibited by kopsingine. Kopsinginine (191)is thus 17-deoxykopsingine.During the course of this investigation the structure of kopsingine (160)was confirmed by X-ray crystal structure analysis (164). Two new alkaloids from the stem bark of Kopsia teoi are the result of even further oxidation, at C-3 and C-15,followed by carbinolamine ether formation between the hydroxyl group generated at C-3 and that at C-17. Kopsidine A has the structure 194 and kopsidine B is 195 (263). These structures have been confirmed by two partial syntheses from kopsingine (160). The method adopted by Husson and co-workers (174) involved the generation of the enaminium salt 196 by a Polonovski-Potier reaction on kopsingine N-oxide. Reaction of 196 with methanol or ethanol then gave kopsidine A (194)or kopsidine B (195).Tan et al. (275)oxidized kopsingine electrochemically in the presence of lutidine as a proton scavenger to generate 196. Workup with methanol, ethanol, or aqueous acetonitrile then gave, respectively, kopsidine A (194),kopsidine B (195),or the related 15alcohol, kopsidine C (l97),which had also been isolated from K. teoi in minute amounts. Finally, reduction of kopsidine C by means of sodium borohydride gave kopsinganol (193).

@; 12

16 146 Aspidofractinine, R = H 147 N.-MethylaspldotractInlne, R =

Me

148 Nn-Methyl-l4.15dldehydroaspidofractinine, R

= Me,A1'.15

H H M e H H H H H Me Nb-OXide OH H Me H OH Me

149 Kopsinine 152 (-)-Kopsininic acid 153 Kopsinoline 154 15a-Hydroxykopsinir1e 155 19pHydroxykopsinine

4 Q-V

150 (-)- Venaktonine

MzMe 2

R' Hz

R2 H

H2

H

O

178 19p-Hydroxpnaktonine

H2

H OH

179 3-Oxovenalstonidine 180 19pHydroxyvenalstonidine

0 HZ

OH 14,15a-epoxide

0

NH

151 (-)-Venalstonidine

156 3-Oxovenalstonlne

14,15a-epoxide

m02C

co2m

H 14,15a+poXide

157 Pleiocarpine

158 Kopsamine

R'

R2

R3

159 Kopsaporine

H

H

CO2Me

180 Kopsingine

H

OMe

192 Kopsinol

H H 198 11,12-MethyleWixykopsaporine OCH@

H 161 Kopsinginol

46

C09.40 , H C02Me

173

CHDH

C0;OzMe 175 16.17 - D i d e h y d r o - N a - m e t h o ~ M1~,lZ*thylenediWl kopsinine. R’R2 = OCHP

176 1 6 , 1 7 - D i d e h y d ~ l 2 - ~ ~ N ~ ~ ~ ~ ~ R’ = H, R2 = OMe 177 16,17-Diehydro-12-hydroxy-Na-mtho~M~k~nine. R’ = H . R ~=OH

47

194 KopsldineA, R =

Me

195 KopsMbB. R = El 197 KopsidlmC, R = H

t

196

R'

R3

199 shgapmmm ' A

H

H

H

200 SlnaepurensmeB

H

H

Me

201 singapwensinec

OCHg

H

202 SingapurensineD

CCHg

Me

t Kopsinglne (160)

1. ALKALOIDS

OF THE ASPIDOSPERMINE GROUP

49

11,12-Methylenedioxykopsaporine(198) has been isolated from the leaves of Kopsiu teoi (83) and from the trunk bark of K. singupurensis Ridley ( I 76),in which it occurs together with four alkaloids closely related to the kopsidines; these are the singapurensines A-D (199-202). Two alkaloids containing a novel ring system, which incorporates a lactone function in a previously unknown position, have been found in Kopsiu puucifEoru Hook. f, a species endemic to North Borneo (177).The structure of paucidactine A (203) was deduced from its spectroscopic data and confirmed by X-ray crystal structure analysis. Its congener, paucidactine B, is deoxypaucidactine A, and since it lacks a hydroxyl group, but contains a signal at 3.64 ppm appropriate to H-21~2,which exhibits W-coupling with H-17a, it is clearly 21-deoxypaucidactine A (204). Finally, 15-demethoxypyrifoline (205)has been shown to be a constituent of the root bark and leaves of Aspidospermu pyrifolium (68). This alkaloid appears to be the only representative of the enantiomeric series in this subgroup encountered in recent years from natural sources. ALKALOIDS, WITH OR WITHOUT K. SECO-ASPIDOFRACTININE SUBSEQUENT CYCLIZATION In view of the fact that the aspidofractinine ring system is susceptible to oxidation at no fewer than 10 positions, that is, carbon atoms 3, 5, 6, 10, 11, 12, 15, 16, 17, and 21, it is not surprising to find that in some instances oxidation is followed by ring fission, and occasionally recyclization to afford new ring systems. Possibly the simplest of these is exemplified by 3-0x014,15-secokopsina1(206), from the stem bark and aerial parts of M. guilluuminii, in which oxidation at postions 3, 14,and 15 is followed by fission of ring D (225).The structure of 206 was deduced mainly from its proton and mass spectra and comparison of the latter with appropriate models in the tabersonine and venalstonine series. The alternative structure, in which the formyl and acetyl groups are transposed, was eliminated by the chemical shift of the formyl proton, and by the resistance of the acetyl group to reduction by means of sodium borohydride. In kopsijasminilam (207), from K . jusminifloru (272,279), the C/D ring junction has been severed. The structure of 207 was established by X-ray crystal structure analysis ( I 79),from which it was deduced, by comparison of spectroscopic data, that its congeners are 20-deoxykopsijasminilam(208) and 14,15-didehydrokopsijasminilam (209). Kopsidasinine (210),from K. dusyruchis ( I 72), and 10-demethoxykopsidasinine (211a),from K. jusminifloru (I72), share a ring system in which oxidation at C-21 is followed by fission of the &,21 bond and formation of a bond between Nb and C-17. Kopsidasinine contains an aromatic methoxyl

50

J. E. SAXTON

group, a tertiary base and urethane functions, together with an ester group and a ketone function in an unstrained ring system. Its structure was elegantly established by reaction with methyl iodide, followed by Hofmann decomposition of the methofluoride, which gave the same tertiary aminoketone 212 as did methylation of kopsidasine (181) (272). The structure of 10-demethoxykopsidasinine(211a) was then deduced from a detailed examination of its proton and I3C NMR spectra (272). More recently (283), 12-methoxy-lO-demethoxykopsidasinine (211b), the 12-methoxy isomer of kopsidasinine, has been isolated from the stems of Kopsia pauciporu Hook. f., from Sabah (North Borneo). The ring system present in lapidilectine A (213), from the bark of Malaysian Kopsia lapidifectaVan der Sleesen (280), can, in principle, be generated by hydrolysis of the lactqm function in an intermediate with the gross structure of kopsijasminilam (207), followed by formation of the Nb,20 bond. Alternatively, it may be derived biogenetically from venalstonine (150), which occurs in the same plant. Such a provenance leads inevitably to the revised stereochemistry (260)shown in 213. Initially (280),the structure postulated had the 18,19and 16,17 two-carbon chains transposed. Lapidilectine B (214), from the leaves of the same plant, has suffered oxidative removal of C-21, followed by lactonization of a hydroxyl group generated at C-7 with the C-16 carboxyl group. Four more new alkaloids, from the same plant, are closely related structurally; these are isolapidilectine (16epilapidilectine A, 215), lapidilectam (3-oxolapidilectine A, 216), and the lapidilectinol(217) and epiepimeric 15-hydroxy-14,15-dihydro-derivatives, lapidilectinol (218) (260).Another lapidilectine derivative, lO-methoxy-3oxolapidilectine B (219), is a constituent alkaloid of Kopsia tenuis Leenh. and Steenis, a previously uninvestigated species from North Borneo (281). The major alkaloids of K. tenuis are lundurines A-C (220-222), which contain a novel ring system incorporating a cyclopropyl unit. These alkaloids are obviously closely related biogenetically to the lapidilectines and may well be derived from an intermediate such as 10-methoxy-3-oxolapidilectine B (282). Lundurine A has the molecular formula, C21H22N204 (mass spectrum), is a dihydroindole (UV spectrum), and contains a 10-methoxyl group, an N,-methoxycarbonyl group, a 14,15-double bond, and a C-3 carbonyl group (proton and 13CNMR data). The double bond was deduced to be part of a five-membered ring, since JI4,,5was 6 Hz instead of the 10 Hz usually observed in six-membered rings. The remaining protons were shown by 2D COSY and HMQC experiments to be contained in two CH2CH2groups and one CH2CH group. One of the CH2CH2 groups was assigned to C-5 and C-6 (low-field protons on C-5) and the other to C-18 and C-19. One notable feature in the proton spectrum was the presence of a high-field

203 PauddactineA. R = OH

204 PauddadineB , R = H

4 ' N

H

207 Kopsijaminitam. R = OH

208 2o-Deoxyjasminihm. R = H

209 14,15-Didehydr~opsi~smini$m, R = OH,

210 Kopsidasinim, R' =

O M . R2 = H

1. AmberliteIRA400F

211a 10-Demethoxykopsidasinine,R' = R2 = H

2. 200%

21l b 12-MethoXy-lD&emethoXykopsidasinine, R' =H. F? = OMe

213 LapidilectineA 215 lsolapidiledine

216 Lapidiledam

CO2Me H

H

CO2M

C02Me

H

Hz H2

0

Kwidasine (181)

52

J. E. SAXTON

doublet at 1.12 ppm (also observed in lundurines B and C), which was shown to be the methine proton in the remaining CH&H unit and which is appropriate for a proton in a cyclopropyl or cyclobutyl ring. On this basis, the structure 220 was deduced for lundurine A. The alternative structure containing a cyclobutyl ring was eliminated by the observation of a long-range (3J) heteronuclear correlation between the H-17 methylene and (2-15. If a cyclobutyl ring were present, the methylene hydrogens (now on C-16) would be separated from C-15 by four bonds. Lundurine A is thus 220, and the structures of lundurine B (221) and lundarine C (222) follow from the spectral data (182). Pauciflorines A and B, two alkaloids from the leaves of Kopsiu paucgura, are the most recently isolated alkaloids that result from the fission of the 20,21-bond in an aspidofractinine-type precursor (Z82).Pauciflorine A has the molecular formula C24H26N208 (mass spectrum), is a dihydroindole derivative (UV spectrum), and contains a methylenedioxy group at positions 11 and 12, an N,-methoxycarbonyl group, a methyl ester function and a hydroxyl group at C-16, a lactam carbonyl group, and a trisubstituted double bond (proton and I3C NMR spectra). COSY and HMQC experiments revealed the presence of an isolated methylene group, a CH2CH2 unit, and a CH2CH2CH2unit. This limits the position of the lactam carbonyl group to C-21 and allows the structure of pauciflorine to be defined as 223. The presence of the lactam carbonyl group at C-21 accounts for the unusual deshielding of H-3a (4.03 ppm) and is also supported by the observed 3J correlation between C-21 and H-6. The pattern of substitution on C-16 is consistent with a long-range W-coupling between the intramolecularly-bonded 16-hydroxyl proton and H-17@, as well as the observed 3J (C-17 to 16-OH) and 'J (C-16 to 16-OH) interactions. These and other key HMBC correlations and NOE interactions serve to establish structure 223 for pauciflorine A unequivocally, and a further comparison of NMR data allows the structure of pauciflorine B to be defined as the 11,12-dimethoxyanalog 224. These alkaloids inhibit melanin biosynthesis in B16 melanoma cells; this represents a rare example of such inhibition by indole alkaloids.

L. BIOGENETICALLY RELATED QUINOLINE ALKALOIDS Several new isolations of known alkaloids in this relatively small subgroup have been noted (Table I). These include (+)-scandine (228), which has been extracted from a hitherto unidentified Fijian Melodinus species, and whose structure and absolute configuration have been confirmed by X-ray crystal structure analysis (184). Five new alkaloids have been reported. These are scandine N-oxide (230), which occurs in Melodinus fusiformis

217 Lapidilectinol 218 Epilapidilectinol

MeO$

R’

R2

OH H

H OH

-=

220 LundurineA, R = 0 221 LUndurlneB, R = H2 222 LundurineC, R = He, 14.15dihydro

@I. /

N

H

O

225 Mekscine, R = H, 16&H

226 16-EpimlrnCim, R = H, 16a-H R = OH, 16a-H

233 9Hydmay-lBepim&dne,

R’

R2

a!! 223 PauMbrineA

0ch20

224 Paucifbrine B

OMe OMe

0

HO

N H

O

227 Meloscandine 7

co2Me

235 Kopsen-22-on8, R = H2 236 5,22-Dioxokopsane, R = 0

237 Kopsinilam

6H OH 238 Jasrniniflorine

R2

~1

239 KopsinitarineA

C02Me A14*15

240 KopsinitarineB

H

241 KopsinitarineC

H

242 KopsinitarineD

~14.15

15a-OH

C02Me 1%-OH

kH2

R1

24% MersingineA, R =

2-

MersingineB, R = 15a-OH

R2

R3

244 Methyl chanofruticosinate

C02Me H

H

245 Methyl N,-demethoxycarbonylchanofrutiosinate

H

H

H

246 Methyl 11,12-t~~thylenedbxychanofruticosinate CO2Me 247 Methyl 11,lZ-methvlenedioxv-Na-demethoxycarbonylchanofrutkosinate

OCHD

H

OCH20

H

OCH&

248 Methyl 11,12-methylenedbxy-N,-demethoxycarbonyl14,15didehydrochanofruticosinate

1. ALKALOIDS

OF THE ASPIDOSPERMINE GROUP

55

(78);14,15-epoxyscandine (231), a constituent of the aerial parts of M. hemsleyanus (224); and the first two phenolic alkaloids of this series, 10hydroxyscandine (232),from three Melodinus species, and 9-hydroxy-16epimeloscine (233),recently found in the leaves of M. scandens Forst. (286). The only other new base is 19-epimeloscandonine (234),which has been found in the aerial parts of M . hemsieyanus (224). M. KOPSINE/FRUTICOSINE DERIVATIVES

There are a few new reports of the occurrence of the known alkaloids 235-237 in this subgroup, and six new ones have been isolated. These include jasminiflorine (238),a constituent of the leaves of K.jasminiflora (272,179),whose structure as 12-methoxyfruticosinewas deduced by analysis of its proton NMR spectrum. Yet another new ring system has been encountered among the alkaloids of Kopsia teoi (287,288).In the minor alkaloids kopsinitarines A-D (239242) the 6,22-bond characteristic of kopsine is present, and there is also a 5,17-oxygen bridge resulting from oxidation at C-5, followed by cyclization with a 17-hydroxyl group. The nonindolic portion of these molecules thus constitutes a cagelike system that contains two five-membered rings and three six-membered rings. Kopsinitarine A has the structure 239,kopsinitarine B (240) has lost the Na-methoxycarbonyl group, and kopsinitarine C (241)is the 15a-hydroxydihydro derivative of kopsinitarine B, the result of hydration of the 14,15-double bond. The fourth alkaloid, kopsinitarine D (242),is the Na-methoxycarbonyl derivative of kopsinitarine C, whose structure, and in consequence the structures of kopsinitarines A-C, was established by X-ray crystallographic analysis (288).This paper also reports revised assignments of the I3C NMR signals for the kopsinitarines (288). The remaining two alkaloids in this group, mersingines A (243a) and B (243b),also from Kopsia teoi (288,289), are regarded as artifacts, the consequence of using ammonia in the extraction process. They are presumably derived from kopsinitarines B (240)and C (241),via ammonolysis of the isomeric a-ketols. N. SECO-KOPSINEFRUTICOSINE ALKALOIDS

Five alkaloids, 244-248,have been isolated that contain a new ring system resulting from the fission of the 16,17-bond in fruticosine. The structure of methyl 11,12-methylenedioxy-chanofruticosinate(Alkaloid C, 246), a constituent of the leaves of Kopsia officinalis (290) and K. arborea B1. (291), was established by X-ray crystallographic analysis (290). Alkaloids A and B lack the methylenedioxy group, and it was deduced, on the basis

56

J. E. SAXTON

of their 13CNMR spectra, that they are methyl chanofruticosinate (244) and its de-N,-methoxycarbonyl derivative 245 (190). Two further alkaloids from Kopsia arboreu were shown to be methyl 11,12-methylenedioxyN,-demethoxycarbonylchanofruticosinate (247) and its 14J5-didehydroderivative 248 (192).

111. Rearrangements and Transformations of the

Aspidospermine Alkaloids Alkaloids of the aspidospermine group undergo a variety of rearrangements and transformations that have continued to provide a rich field for investigators during the past two decades. Vincadifformine and tabersonine have proved to be particularly versatile substrates; in addition to their intrinsic interest, these rearrangement reactions have stimulated numerous investigations,since the end products are vincamine and its relatives, which are of considerable interest clinically. Other investigations have been aimed at the partial synthesis of other alkaloids in the aspidospermine group, either with the intention of confirming their structure, or to provide alternative routes to inaccessible alkaloids from the relatively abundant vincadifformine and tabersonine. The earliest of these investigations were discussed in Volume 17 of this series ( I ) , and the more recent experiments are summarized here. OF QUEBRACHAMINE AND ASPIDOSPERMINE A. REARRANGEMENTS

(-)-Quebrachamine (S), on irradiation, gives the 16-hydroxy derivative 249 of an ibogamine-like ring system, which is the result of the formation of a 3,16-bond (192). In contrast, deacetylaspidospermine (30) simply gives a 10,lO’-dimer (193). 1,2-Didehydroaspidospermidine(27), on deamination with nitrous acid, gives a hemiacetal 250, an unexceptional result that can be explained by any one of three mechanisms (194). Pyrolysis of (-)-1,2-didehydroaspidospermidine (27) at 200°C affords (-)-aspidospermidine (251) and (-)-eburnamenine (252). This is interpreted as proceeding via a dimeric species, which undergoes two 1J-sigmatropic shifts to give an intermediate 253 that then fragments to (-)aspidosperrnidine (251) and (-)-eburnamenine (252) (195).At much higher temperatures, under flow thermolysis conditions, several products are formed. At 580°C the only product is vincane (254), which presumably

1.

ALKALOIDS OF THE ASPIDOSPERMINE GROUP

57

arises via two consecutive sigmatropic shifts, involving the shift of C-21 to C-2 to give the transient intermediate 255, followed by the shift of C-16 to N , (295). At 620-630°C several other sigmatropic shifts occur, and four products, the indolenines 256 and 257 and the indoles 254 (vincane) and 258 (isovincane) are obtained (296).The ring systems represented by compounds 256-258 have not yet been encountered in nature, but it is of interest to note that those possessed by the intermediates 255 and 259 are found in vallesamidine [cf. (-)-N,-norvallesamidine, 661 and melonine (65), respectively (Scheme 1). B. TRANSFORMATIONS OF VINDOLINE

AND

ITS DERIVATIVES

The oxidation of vindoline (44)by means of Sarett’s reagent (297) gives a mixture of lactams 260-262, but with Attenburrow’s active manganese dioxide a more complex reaction occurs (298,299). With short reaction times the N-formyl analog 263 of vindoline is formed (298), but with longer reaction times the major product is the ether lactam 264 (299). Also obtained were the unsaturated ether lactam 265 and the dimer 266. However, the most interesting product was the rearranged vincinederivative 267, which presumably arises by oxidative N-demethylation of vindoline followed by a rearrangement analogous to that involved in the rearrangement of vincadifformine to vincamine. Such a rearrangement has not previously been observed in this series. The structure of 267 is not in doubt, since it was established by X-ray crystal structure analysis (299) (Scheme 2). When treated with sodium hydride, 17-oxo-17-deacetoxyvindoline (268) undergoes rearrangement and the product, also studied by the X-ray method, is the carbonate ester 269. This product may well be formed via an intermediate epoxide (200) (Scheme 3). The microbial transformations of vindoline and its derivatives have been further examined. Human caeruloplasmin and laccases of Pofyporus anceps and Rhus vernicifera converted vindoline (44) into the known enamine 270 and the dimer 266 (202), which have been encountered in previous microbiological studies on vindoline. The dimer 266 is also formed by the action of horseradish peroxidase on vindoline (202). The oxidation of 16-O-acetylvindoline(271) by means of enzymic (laccase and human caeruloplasmin), microbiological (Streptomyces griseus), or chemical (DDQ) reagents gives the 3,Nb-iminium derivative 272 (203). Hydrolysis of the 16-O-acetyl group in 272 again gives the dimer 266. On the other hand, the microbiological oxidation of dihydrovindoline (273) by means of S. griseus UI 1158 gives four products, which are 3oxo-dihydrovindoline; 3-hydroxy-dihydrovindoline, and the phenol that is

58

J. E. SAXTON

OAc 02Me

260, X =

H2

261, X = 0

262, X = H,OH

263 ii

44 Vindoline

267

Reagents: i s

ii, Mn02, CH&l2, 40 h.

SCHEME 2

60

J. E. SAXTON

249

250

268 1 7 - 0 ~ ~'I-deacetoxyvindoline -1

269

Reagent: I, NaH,THF

SCHEME 3

obtained by demethylation of its 11-methoxyl group; and 14-acetyl-17-0deacetyl-14,15-dihydro-3,14-didehydrovindoline (274) (204). The dimer, 10,lO'-bisvindoline,is the major product (60%yield) obtained when vindoline is oxidized electrochemically with the addition of trifluoroacetic acid to the anodic compartment using a platinum anode and a graphite cathode, followed by controlled potential cathodic reduction. Two minor products, so far unidentified, were also obtained (205).

C. REACTIONS OF LEUCONOLAM When treated with hydrochloric acid in methanol, leuconolam (70) affords the two epimeric pentacyclic chlorolactams 275 and 276, which are presumably formed by nucleophilic attack by N , on C-21 in the iminium ion derived from leuconolam, followed by a nonstereospecific, anti-

1.

ALKALOIDS OF THE ASPIDOSPERMINE GROUP

61

Markownikov addition of HCl to the 6,7-double bond (82,206).The resulting chlorolactams possess the same ring system as leuconoxine (74), from Leuconotis eugenifolius. The structure of 275 was confirmed by X-ray crystal structure determination (207). A second reaction of considerable interest is that of leuconolam with potassium hydroxide in methanol, which involves the removal of a proton from C-16, followed by internal Michael addition to the 6,7-double bond. The product is the pentacyclic dilactam 277, which contains the meloscine ring system (82). D. FRAGMENTATION OF VINDOLININE AND SOLVOLYSIS OF 19-IODOTABERSONINE When heated with diazabicycloundecene in DMSO, 19-iodotabersonine (278), prepared from 19R-vindolinine (lW),gives mainly the expected 18J9-didehydrotabersonine (279), together with the cyclobutane derivative 280, and an optically inactive, nonbasic indole derivative, for which the structure 281 has been proposed (208).A much improved yield of 281 can be obtained if the reaction is conducted in DMF in the presence of sodium acetate. The formation of the cyclobutane derivative 280 would seem to involve a straightforward elimination of hydrogen iodide from 278, with assistance from the anilinoacrylate function, followed by hydration of an

N,Zdouble bond. The alternative fission of the 7,21- and 20,21-bonds to give the neutral product 281 may well proceed via an iminium ion 282, as illustrated in Scheme 4 (208). If correct, this mechanism requires the

OAc

CO2OnMe 270 271 lM)-ACetyMnddine, R = AC 273 Dihydrovindollne. R = H, 14.15dihydro

62

J. E. SAXTON

’

Et Et

C- Leucornlam (70)

__t

0 275 a-CI

277

276 $-Cl

I

282; R = H W A C

H 281

Reagents: I, 12, N a 0 3 , THF, Hfl; it, diazabicycloundscene,DMSO; ill, NaOAc, DMF. heat; iv, Pb(OAc),, PhH. heat.

SCHEME 4

1. ALKALOIDS OF THE ASPIDOSPERMINE GROUP

63

presence of water in the reaction mixture. Subsequently (209,210),the same neutral product 281 was obtained by the oxidative fragmentation of 19svindolinine (137) by means of lead tetra-acetate, or by solvolysis of 19iodotabersonine (278)with sodium acetate in DMF. Of the various possible mechanisms for the course of the oxidation by lead tetra-acetate, that illustrated in Scheme 4 is the one favored by Atta-ur-Rahman et al. A similar structural unit to that contained in 281, that is, an N-formyl group in an ll-membered ring, is known in some bisindole alkaloids, such as vinamidine. A possible mode of generation of this unit may thus be via the fragmentation of ring D in a precursor in which an appropriate leaving group is situated in the y-position to Nb.

E.1. REACTIONS AND REARRANGEMENTS OF THE VINCADIFFORMINE GROUP Although not strictly a rearrangement reaction, the behavior of (-)vincadifformine (76)when heated in a sealed tube in a microwave oven is of interest. Almost quantitative racemization occurs, presumably via reversible Diels-Alder fission of ring C and the related achiral secodine intermediate (211). The structure of oxymetavincadifformine (283), the name now given (212) to the oxidative rearrangement product of vincadifformine ( I ) , has been confirmed by X-ray crystal structure analysis. E.2. FORMATION OF VINCAMINE AND ITSDERIVATIVES Of all the rearrangement reactions of vincadifformine, the one that has been the subject of the most intensive investigations is the rearrangement to vincamine. The earliest studies were summarized in Volume 17 (1). These include the oxidation of vincadifformine (76)by means of p-nitroperbenzoic acid, followed by treatment of the intermediate 16-hydroxyindolenine &oxide (284) so formed with triphenylphosphine and acetic acid. The N oxide function in 284 was thereby reduced, and the resulting hydroxyindolenine 285 rearranged to a mixture of vincamine (286) and 16-epivincamine (213). Analogous processes allowed the conversion of tabersonine (78)into 14,15-didehydrovincamine (287)and its C-16 epimer, and of 11methoxyvincadifformine (87)into vincine (288a),16-epivincine, and apovincine (288b) (214). A minor product in this sequence of reactions on tabersonine (78)was formulated as 289a. since hydrogenation, hydrolysis, and decarboxylation afforded a hydroxylactam 289b, which on reduction gave rhazinilam (67).Proof of the intermediacy of 16-hydroxyindolenine derivatives such as 284 and 285 and the configuration of C-16 in these compounds comes from a study of the rearrangement of tabersonine (78)

64

J. E. SAXTON

into 14,15-didehydrovincamine(287)(214). The intermediate 290, proved by simple correlation to have the same stereochemistry as 285, can be converted by reductive methylation into 291, in which the ring D double bond is retained. Reaction of 291 with iodine and potassium iodate gives a lactam 292a,together with an aromatic iodo derivative 292b,on prolonged reaction. Alternatively, oxidation of 291 by means of chromium trioxide in pyridine affords a small yield of the lactam ether 293, which retains the six-membered ring D. Obviously, the products 292 and 293 can only be obtained if the C-16 hydroxyl group is trans with respect to the CID ring junction substituents (215) (Scheme 5). In recent years some alternative, more refined, and higher yielding processes have been developed. One method that employs milder conditions than the earlier ones and avoids the formation of the &-oxide involves ozonization of vincadifformine (76)in 0.43 M sulfuric acid in methanol at 60"C, which gives a 74% yield of a 7:3 mixture of vincamine (286) and 16-epivincamine in a one-pot reaction (226). Here again the 16hydroxyindolenine derivative 285 is an intermediate, since it can be isolated if the ozonization reaction is conducted at 20°C. The stereochemistry of 285 follows from its reaction with potassium cyanate in dicyclohexyl-18crown-6 and methylene chloride, which affords the hexacyclic urethane 294. Similarly, the ozonization of tabersonine (78)at 65°C affords a 71% yield of a mixture of 14,15-didehydrovincamine (287) and its 16-epimer (226).

16-Hydroxyvincadifformine indolenine (285)can also be rearranged to a mixture of vincamine (286) and 16-epivincamine by pyrolysis or flow thermolysis at 580°C (295). The same group of workers have also investigated the dye-sensitized photo-oxygenation of vincadifformine. After reduction of the reaction mixture with sodium thiosulfate, the related 16-hydroxyindolenine derivative 285 was obtained, which (without isolation) was rearranged in acetic acid to vincamine in 46% yield. Tabersonine behaved similarly (227). These results are broadly in agreement with those obtained by Levy and his collaborators in an independent study of the photochemical oxidative rearrangement of vincadifformine (228). An independent method (229) involves passing oxygen through a solution of vincadifformine (76)in the presence of metal salts (e.g., copper sulfate, ferric chloride, or cobalt stearate) in aqueous hydrochloric acid at 50°C for 8 days; vincamine (286) is thus obtained in 20% yield and 16-epivincamine in 15% yield, Again, tabersonine gave similar results. In all the preceding reactions the rearrangement of the vincadifformine skeleton to the eburnane skeleton was achieved via a 16-hydroxyindolenine derivative, such as 285; the analogous rearrangement of the 16-chloroderiv-

283 Oxymetavincadiftorrnine

76 Vincadmorrnine R = H

289a

78 Tabemnine R = H 87 I l - M e t h o x y v i f ~ ~ d ~ o nRn i=~ O M viii - x

R

3H m R = H

___

.. ., 290 R = H AI4.l5

28Bb Apovincine

I

286 Vincamine R = H 287 14,15-DMehydrovincamine R = H.

A

14.15

288a Vincine R = OMe -: i, pOzNGH4C03H; ii, PPh3, AcOH; iii, methylation; iv, reductin; v, 12, K103; vi. Cr&; vii, KCNO, dicycbhewyl-18crown-6,CHfl2, r.t.; viii, Ha Pt; ix, KOH, MeOH. Np; x, H3O+, heat; xi, LiALH4.

SCHEME 5

66

J. E. SAXTON

ative had not been studied. In 1984, a new preparation of the 16-chloro derivative was reported which allowed the whole rearrangement sequence to be carried out as a one-pot process (220).Chlorination of vincadifformine (76) by means of N-chlorosuccinimide in formic or trifluoroacetic acid affords 16-chloro-l,2-didehydro-2,16-dihydrovincadifformine (295), which rearranges at 110°C in the same solvent to give apovincamine (296) in 71% yield. Similarly,the ethyl ester analog 2W gives a 73% yield of the clinically useful ethyl apovincaminate (298). One of two possible mechanisms for this conversion is illustrated in Scheme 6. In both mechanisms the conversion of the rearranged intermediate 299 into the apovincamine skeleton is regarded as a 1,5-sigmatropic shift of C-16from carbon to nitrogen. Similarly, the synthetic racemic base 300 has been rearranged to (?)-19-ethoxycarbonyl19-demethylapovincamine (301) (221).

76 vincedmormine, R' =

p =Ma

= Et, R2 =Me 300 R' = Me, R2 = COZEt 297 R'

Reagents; 1, Nchiorosuccinimide in HCOzH or CF3C02H; /I,HCOzH or C F ~ at~iaooc. H

SCHEME 6

1. ALKALOIDS OF THE ASPIDOSPERMINE GROUP

67

Other compounds in this series that have been subjected to the rearrangement reaction include 3-oxovincadifformine (97), oxidation of which with rn-chloroperbenzoic acid gave 3-oxovincamine (302), 3-oxo-16epivincamine, and a dilactam 303, obtained by oxidative fission of the 2,16-bond (228). Under carefully controlled conditions, the intermediate hydroxyindolenine 304 could be isolated. As expected, 304 could be shown to be an intermediate in the formation of 302 and 303 (Scheme 7). In exactly analogous fashion, the oxidative rearrangement of 3oxotabersonine (107) gives 3-oxo-14,15,-didehydrovincamine (305) and the tetracyclic lactam 306 (222,223).A third product, resulting from the enlargement of ring B on solvolysis of 3-oxotabersonine 16-chloroindolenine with silver perchlorate or simply on heating in aqueous tetrahydrofuran, is also reported to be obtained (vide infru). Hydroboration-oxidation of tabersonine (78) gives mainly 14phydroxyvincadifformine (307), together with a small amount of the 14aepimer (224). The regioselectivity of this reaction is presumably the consequence of quaternization of Nb by borane. If this reaction is accompanied by inversion of N b , as occurs in the quaternization of aspidospermine, the 0 0

HO

Me02c ’

H

303

302 305 814.15

306 A’4s15

Reagents: i, 2 eq.m-CIQH4C03H. PhH; ii, 1 eq. m-CIGH4C03H, O°C; iii, allow to stand at r.t. SCHEME I

I

COZMe

68

J. E. SAXTON

a-face will be less accessible to reagent than the @-face,and hydroboration must necessarily give rise preferentially to a 14fl-hydroxy derivative. Further, the inductive effect of the positively charged Nb no doubt results in a transition state of lower energy for the introduction of boron to C-14, rather than C-15. The rearrangement of 307 and its 16epimer, by oxidation with peracid, followed by deoxygenation of the &-oxide with triphenylphosphine and reaction with acid, proceeds well, the products being 14@hydroxyvincamine (308) and its lCepimer, respectively, together with their C-16 epimers. The most recent method of converting the anilinoacrylate alkaloids into derivatives of vincamine has emerged from a fascinating investigation in which the oxidation of vincadifformine (76) and tabersonine (78) by means of Fremy’s salt has been examined (225).Vincadifformine gave a hydroxylamine sulfonate derivative 309, the structure and stereochemistry of which were established by X-ray crystallographic analysis. This is believed to be the first authenticated example of such an intermediate, although analogous intermediates have been widely held to participate in oxidations with Fremy’s salt. Reaction of 309 with hydrochloric acid at 70°C gave a mixture of the isoxazolidine derivative 310 and the azepino[2,3-b]indole derivative 311. Compounds 312-314 were obtained in identical fashion from tabersonh e (78), and the structures of 311 and 313 were confirmed by the X-ray method. Reductive fission of the nitrogen-oxygen bond in 313 gave a hydroxyamino ester, which on diazotization, followed by loss of nitrogen, fission of the 2,16-bond, and cyclization, gave an equimolar mixture of 14,15-didehydrovincamine(287) and its C-16 epimer (225) (Scheme 8). E.3. PARTIAL SYNTHESIS OF MINOVINCINE, VINCOLINE, KITRALINE, AND KITRAMINE

The availability of 194odotabersonine (278) has allowed the partial synthesis of several aspidospermine alkaloids. For example, Kornblum oxidation of 278 under anhydrous conditions gives 19-oxotabersonine, which on hydrogenation of the 14,15-double bond affords (-)-minovincine (316) (226). In the presence of water, Kornblum oxidation gives some fragmentation product 315, together with 19s-hydroxytabersonine (108). Both 108 and 19R-hydroxytabersonine (88) are obtained on reduction of 19oxotabersonine with sodium borohydride. Subsequent correlation of 19shydroxytabersonine (108) with vincoline (128) and kitraline (l29),and of 19R-hydroxytabersonine (88) with kitramine (130), confirmed the stereochemistry of these alkaloids. Hydrogenation of 19R-hydroxytabersonine (88) was further found to give (-)-minovincinine (80), which also confirms its stereochemistry (Scheme 9).

OH

308

i

76 Vincadifformine

-03SHN 309 312 A14*15

Q-vEt 78 Tabersonine A14,15

/ -

ii or iii

iii

iv

H

c02Me

310 313 A14s'5

31 1 314 Al4.l5

I

287 A'4-Vincarnine

Reagents: i: Frernvs salt; ii, 0.1M TFA, Hfl, r.t., 90h; iii, 1M HCI, 7OoC, 90 rnin.; hr, 0.1M TFA I Hfl, 7OoC, 2 h; V, Zn, ACOH; vi, BU'ONO, THF, O°C . SCHEME 8

70

J. E. SAXTON

*.

316 Minovinclne 128 Vimline; R = H, 19s 129 Kitraline; R = Me, 19s 130 Kitramine; R = Me, 19R Reagents: i, AgBF4, DMSO; ii, AgBF4, DMSO, H20; iii, NaBH4; iv, Pb(OAc)4, C H ~ C I ~ , then silica gel, Et20, H20; v, Pb(OAc)s, CH2C12, then NaOMe, MeOH; vi, H2, Pd. SCHEME 9

1. ALKALOIDS

OF THE ASPIDOSPERMINE GROUP

E.4. FUNCTIONALIZATION IN RINGSD

AND

71

E

The photo-oxidation of vincadifformine (76) in the presence of Rose Bengal and potassium cyanide affords the nitriles 317 and 318, presumably by nucleophilic attack by cyanide ion on the appropriate gives C-3 or C-5,Nb-iminium ion; N-acetyl-2,16-dihydrovincadifformine mainly the 3a-cyano derivative (227). Tabersonine (78) and N-acetyl2,16-dihydrotabersonine give exclusively 3a-cyano derivatives, owing to the superior stability of the 3,Nb-iminium ion. Cyanide attack at C-15 in this ion was not observed. Functionalization of vincadifformine can also be achieved via a Polonovski reaction. Thus, vincadifformine 16-chloroindolenine (295) gives the aminonitrile 319 by a Polonovski reaction followed by treatment with cyanide (228). A second Polonovski reaction gives the lactam 320 when the N oxide of 319 is treated with acetic anhydride. However, when trifluoroacetic anhydride is used, 320 is the minor product, the major product being a rearranged aminonitrile, which was originally (228)formulated as 321a,the result of a familiar rearrangement, akin to the rearrangement of vincadifformine chloroindolenine to vincamine. However, in the light of the course of the rearrangement of the 6-bromo derivative of 318 (vide infiu), this product is now (229) formulated as 321b. Longer reaction times, starting with the N-oxide of 319, or separate treatment of 321b with trifluoroacetic anhydride, results in the formation of epimeric tetracyclic chloroesters, which are presumably 322a and 322b (Scheme 10). The alkaloids of the vincadifformine group are extremely difficult to quaternize at Nb. In fact, attempts to form the Nb-methiodide from 2,16dihydrotabersonine 323 result in the formation of the N,-methyl derivative, and the N,-trifluoroacetyl derivative of 323 fails to react with methyl iodide in methanol. Interestingly, when 2,16-dihydrotabersonine is acylated with

317, A' = H.F? = CN 318, R'

= CN, R2 = H

72

J. E. SAXTON

CN

Meos

321 b

'6

it

3228, 16R 322b, 16s

Reagents: I, m-CPBA, CHS12; 11, (CF3CO)zO, CHzC12, N2, O°C; ill, KCN, H20; iv, (MeCO)&, CHzCI2,r.t.; v, MOWH20 b pH 9; vl. 0.5M NaOH/H@; vil, (CF3CO)&10, C H G , r.t., 60 h.

SCHEME 10

1.

13

ALKALOIDS OF THE ASPIDOSPERMINE GROUP

a large excess of trifluoroacetic anhydride N-acylation is accompanied by oxidation and C-acylation, with formation of 324 (230). Similarly, tabersonine itself gives the analogous product 325. These reactions must involve &,c-3 oxidation to give an iminium ion 326a which then gives an enamine 326b by capture of a nucleophile. Enamine acylation, followed by hydrolysis of the C-15 acyloxy group during workup, then gives 324 and 325. Vincadifformine (76), which lacks the 14,15-double bond, gives a product 327 resulting from oxidation to the 5,6-enamine, and acylation (Scheme 11).The Nb,3-or Nb,5-iminium cations can also be generated by the 9,lO-dicyanoanthracene-sensitizedphoto-oxygenation of tabersonine or vincadifformine. These cations can be efficiently trapped by trimethylsilyl cyanide, with formation of the a-aminonitriles 328 and 329, products that may be useful for further interconversions in this alkaloid series (232). Recent experiments on the Polonovski reaction of vincadifformine 16chloroindolenine &,-oxide (330) have resulted in the development of a method for functionalizing C-6. Thus, reaction of 330 with trifluoroacetic anhydride, followed by addition of methanol, gives 331, which, on treatment with cyanogen bromide in dichloromethane, gives the two epimers 332a and 332b,- -presumably via the 5,6-enamine (233). Reaction of this mixture with sodium iodide removes the chlorine and regenerates the

323 2,l SDihydrotabersonine

326a

32%

1 H

I CF3CO 327

Reagent: i, (CF3COhO

SCHEME11

"

O

COCF3

Et

H

74

J. E. SAXTON

anilinoacrylate chromophore, with formation of 333a as the sole stereoisomer; the C-5 epimer is not formed. Reduction of 333a with sodium borohydride gives 6s-bromovincadifformine (33313) (Scheme 12). In an attempt to convert the vincadifformine ring system into a compound containing the meloscine ring system, the epimeric mixture of bromonitriles 332ah was heated with trifluoroacetic acid. The product, however, contained neither the meloscine nor the vincamine ring system. It was shown instead, by X-ray crystallographic analysis, to have the structure 334 (229) and is the result of a quite remarkable rearrangement, in which two 1,5sigmatropic shifts occur. In the first of these, C-6 migrates from C-7 to C2, and in the second C-16 shifts from C-2 to C-7. The overall result is therefore an exchange of positions for carbons 6 and 16 (Scheme 12). As noted previously, this result prompted a reappraisal of the structure of the rearrangement product from the Polonovski-Potier reaction on 5cyanovincadifformine chloroindolenine (319) (Scheme 10).

CN

COZMf? 329

328 X

Et

335a, X = H 2

335b, X = 0

338

"I

334

-

\

' 334

N'

/ Br

Re-: i, TFAA, CHfl2, then MeOH; ii, BCN, CHSIz; iii, Nal, AcOH; iv, NaBH4, MeOH; v, AcOH, TFA, H N q ; vi, NBS, TFA, r.t.; vii, S d l or~ hydrogendysis; viii, O.QMHSO4, THF, heat, 45 min.; ix, NaBH4; x, TFA, Wt.

SCHEME 12

76

J. E. SAXTON

E.5. MISCELLANEOUS REACTIONS OF VINCADIFFORMINE AND TABERSONINE

The electrochemical (anodic) oxidation of tabersonine or 3-oxotabersonine gives dimeric products 335a and 33513, respectively (232).In the oxidation of 3-oxotabersonine the dimer 335b was the sole product, but in the oxidation of tabersonine itself some of the symmetrical 10,lO’-dimer (5%) was also obtained, together with a trimer (2%) and several other, unidentified, products. Reaction of 3-oxotabersonine (107) with nitrosonium tetrafluoroborate in dichloromethane at 0°C gives a mixture of lO-nitr0-3-oxotabersonine, the 16-nitroindolenine derivative 336, and the dimeric species 33513 (234). The configuration at C-16 in 336 has not been proved unequivocally, but is based on the known selectivity of reactions at this position in the parent alkaloid. The nitration of vincadifformine (76) gives a mixture of the 10-nitro derivative and 16-nitrovincadifformine indolenine (337a). Reduction or hydrogenolysis of the latter regenerates vincadifformine, whereas treatment with trifluoroacetic acid at room temperature causes isomerization to 10nitrovincadifformine (235). Reaction of 337a with aqueous sulfuric acid, however, results in hydration of the indolenine double bond, followed by fission of the 2,16-bond, with formation of the oxindole derivative 338a. An exactly similar sequence of reactions can be performed on 10bromovincadifformine, via 10-bromo-16-nitrovincadifformine indolenine (337b). Reduction of 338b by means of sodium borohydride results in fission of the 7,21-bond, with formation of the epimers 339 (Scheme 12).

F. STRUCTURE AND STEREOCHEMISTRY OF VINCATINE The keto-dilactam 303, obtained as a by-product in the oxidative rearrangement of 3-oxotabersonine, was used in an investigation that clarified the behavior of vincatine (340)on reduction (217). Reduction of 303 by potassium borohydride gave the epimeric alcohols 341; the hydroxyl group was then removed by standard methods. Preferential reduction of the 30x0 group in the product 342 was expected to give demethylvincatine or a stereoisomer. However, reduction of 342 with diborane gave a tricyclic oxindole 343, in which fission of the 7,21-bond had also occurred (Scheme 13). This result prompted a reappraisal of the reduction of vincatine (340), which had earlier been reported to give a tetracyclic carbinolamine 344, identical with the product obtained by the reduction of one stereoisomer of synthetic 345. For convenience, the reduction was attempted on the more accessible stereoisomer 346, obtained by total synthesis, and the product was shown conclusively to be the tricyclic oxindole alcohol 347 (Scheme 14). It was therefore concluded that the common reduction product

1.

ALKALOIDS OF THE ASPIDOSPERMINE GROUP

77

iii

(on 342)

I, ii

C

341, R = OH 342, R = H

343

Reagents: i, SOClp, py; ii, Zn. AcOH; iii, diborane, THF.

SCHEME 13

of vincatine (340)and of the synthetic lactam also has the gross structure 347 (217). The stereochemistry of vincatine (340) was finally established by a partial synthesis from (- )-vincadifformine (76), which conclusively proved that its absolute stereochemistry is 7RJ20SJ21R(Scheme 15) (236). Initially assigned the enantiomeric configuration (7S,20R,21S) (237,238), (-)vincatine was synthesized from (- )-vincadifformine &,-oxide by a process that did not affect the stereochemistry at C-20, although the lability of the stereochemistry at C-7 and C-21 resulted in the formation of all four

344

340 Vincatine, R = H2

345 R = O

Me Reagent; i, L~AIH,,

346 SCHEME 14

78

J. E. SAXTON

0-

i, ii

Me (-)-VincaditformineN-oxide

iv, v

c---

340 (-)-VinCatine ~eagents:i, 3 ~ 2BU'OK, , B U ~ H ii, ; ~ ~ 0 iii,4( M; ~ O ) ~ P O C H MH, ~M~ DME; , iv, KO&N=NmzK, MeOH, AcOH; v, W-2 Reney nickel, DME, r.t. SCHEME 15

7,21-stereoisomers. The validity of the conclusions of Pakrashi and his coworkers (237,238) concerning the relative stereochemistry of (-)-vincatine was accepted, and the fact that their synthetic 7S,20R,21S base and (-)vincatine (340),prepared from (-)-vincadifformine, exhibited enantiomeric circular dichroism curves, proves unequivocally that (-)-vincatine has the absolute configuration 7Rl20S,21R (236). It should be added that bases of the vincatine type (cf. the oxindole analogs of the heteroyohimbine alkaloids) can readily isomerize at positions 7 and 21 by a reversible Mannich reaction, even in chloroform solution, and optical rotation values tend to be variable and unreliable. OF VINCADIFFORMINE INTO THE GONIOMITINE RINGSYSTEM G. CONVERSION

One of the more interesting series of transformations performed in this area in recent years has been initiated by Lewin and co-workers, who are attempting to obtain goniomitine (135) from its presumed biosynthetic precursor, vincadifformine (76) (239). The 16-chloro-5-methoxy derivative 331, prepared as described previously, was oxidized by means of mchloroperbenzoic acid, which gave the tetrahydro-oxazine derivative 348. probably via the peroxybenzoic ester 349..Methanolysis, followed by acidcatalyzed rearrangement, then gave a mixture 350a and 350b,of which the

1. ALKALOIDS OF THE ASPIDOSPERMINE

331

GROUP

79

i

350b

350a

351 (+)-16-Hydroxymethy!goniomitine

Reagents: i, m-CPBA,CHS12; ii, 0 . N NaOH in M O H ; iii, TFA, CH2C12; iv, LiAIH.,, THF. heat; v, H2, Pd/C; vi, TiC13, M O H . H B .

SCHEME16

former was later (240) converted by three reduction processes into (+)16-hydroxymethylgoniomitine(351) (Scheme 16). However, it has not yet been found possible to convert either 350a or 351 into goniomitine (135). H. PARTIAL SYNTHESIS OF BALOXINE 19s-Hydroxytabersonine (108), in another series of transformations, has been used in a partial synthesis of baloxine (352), an alkaloid of Melodinus balansae. Protection of the hydroxyl group in 108 as its tetrahydropyranyl ether 353, followed by regiospecific hydroboration-oxidation, gave a mixture of epimeric C-14 alcohols (354) that, on oxidation and removal of the tetrahydropyranyl group, gave baloxine (352), whose structure as 19shydroxy-14-oxovincadifformineis thus confirmed (241) (Scheme 17).

80

J. E. SAXTON

108 R = H

Reagents: i, EtaO’BF;;

Qv 354

1

353 R = Thp

ii, NaBH4, THF; iii, H202, NaOH;

iv, DMSO, AqO; v, HCI, H20, EtOH

‘‘.pA&

H c02Me 352 Baloxine

SCHEME 17

I. PARTIAL SYNTHESIS OF MELOSCINE AND SCANDINE

The conversion of the vincadifformine ring system into the meloscine ring system has long been a desired objective, and the first attempts to achieve this conversion were reported earlier ( I ) . More recently, it has been found that solvolysis of 3-oxotabersonine 16-chloroindolenine (355) by means of aqueous silver perchlorate gives a product, which was proved to be the tetrahydroquinoline derivative 356 by X-ray crystallography (221). Analogous products 357 and 358 have also been obtained by rearrangement of tabersonine chloroindolenine (359)(242) and vincadifformine chloroindolenine (295)(243).These products presumably arise by displacement of the halogen by N,in the carbinolamine analogs 360of the initial indolenines; the intermediates are thus presumably aziridines 361 (Scheme 18). The base 358 is only one of four products obtained when vincadifformine chloroindolenine (295)is allowed to stand with aqueous acetic acid (243). The other products are the corresponding hydroxyindolenine 285;the pentacyclic base (362), identical with that obtained earlier by solvolysis of 295 with hot aqueous tetrahydrofuran (244); and a new tetracyclic base, formulated as 363. When heated in acetic anhydride, the chloroindolenine

1. ALKALOIDS OF THE

81

ASPIDOSPERMINE GROUP R

355 R = 0 359 R = H2 295 R = HP: 14,ltidihydro R

R

b2Me 361

356 R = 0 357 R = H2

358 R = H5 14,lMihydro Reagents: i, AgClO4, H20, MeCOMe; ii, THF, H20, heat.

SCHEME18

295 affords the N-acetyl derivative 364 (243),and in anhydrous acetic acid the product is yet another base, which must have the structure 365 (243), in view of the X-ray crystal structure determination of its N-methyl-1,2dihydro derivative 366 (245,246) (Scheme 19). Two mechanisms have been proposed for the formation of 365; both must satisfy the experimental observation (245) that one hydrogen is transferred from C-3 to C-17. Lewin’s mechanism (Scheme 20) proceeds via 367a and postulates the formation of 3,16- and 5,20-bondswithout disturbance of the original tryptamine residue (245). LCvy’s mechanism (Scheme 21), on the other hand, follows Bernauer’s earlier proposal (247) for the formation of 362 and requires the fission of the 5,6-bond, with loss of C-5, in the formation of both 362 and 363. Formation of 6,21- and 5,7-bonds affords

82

J. E. SAXTON

366 Reagents: i, AcOH, H20; ii, AqO; iii, AcOH; iv, CH20, NaBHsCN, AcOH

SCHEME 19

1.

ALKALOIDS OF THE ASPIDOSPERMINE GROUP

83

SCHEME20

a route to 367b and thence to 365a. This mechanism has the advantage of explaining the genesis of 362 and 363,as well as 365, and suggests that 365 may be obtainable by the reaction of 363 with formaldehyde. In fact, when

84

J. E. SAXTON

"-5

365a

362 SCHEME 21

363 was heated with formaldehyde in acetic acid, the base 365 was obtained in 60%yield (243). Which of these two mechanisms is correct depends on the absolute configuration of the product 365. In Lewin's mechanism C-20 suffers inversion, whereas in Levy's mechanism C-7 becomes inverted. In consequence,

1.

ALKALOIDS OF THE ASPIDOSPERMINE GROUP

85

the two end products, 3651, and 3651,are enantiomers. In view of the X-ray crystal structure analysis of 366 it would appear that 36% represents the absolute configuration, and hence Lewin’s mechanism must be preferred. In 1984 the conversion of vincadifformine (76) into alkaloids of the scandine-meloscine group was finally achieved by two groups of workers. The approach adopted by Hugel and LCvy (248) involved reduction of 16chloro-l,2-didehydro-2,16-dihydrovincadifformine (295) by means of sodium cyanoborohydride, which gave the aziridine ester 368. The stereochemistry depicted for 368 is the only possible one (molecular models), and in any case follows from the known preference for @-attackat C-2 in the vincadifformine series. Flow thermolysis of 368 at 400°C resulted in a modest yield of the dihydroquinoline derivative 369. This apparently constitutes the first case of the migration of a C-C bond rather than a 1,2shift of hydrogen in an aziridine rearrangement. Oxidation of the imine function in 369 then gave tetrahydroscandine (370), and hydrolysis and decarboxylation of the latter gave tetrahydromeloscine (371) (Scheme 22). Subsequently, repetition of this route using 18J9-didehydrotabersonine (279), prepared from 19R-vindolinine (109), resulted in the first partial synthesis of scandine (228) and meloscine (225) (249). The conversion reported by Palmisano et al. (250) was based on the premise that the stereoelectronic requirements for enlargement of the indoline ring to a tetrahydroquinoline system were ideally provided in the aketol 373, which was readily prepared from vincadifformine (76), via the hydroxyacid 372. Unfortunately, rearrangement could not be satisfactorily accomplished if N , was unprotected or if it was temporarily protected by benzyl or urethane groupings; hence, the N-methyl derivative was used. Rearrangement of 373 proved to be surprisingly easily achieved to give a single lactam (374), whose stereochemistry was firmly established by X-ray crystal structure determination of its methiodide. Removal of the 16-hydroxyl group from 374, with complete retention of stereochemistry, proved to be nontrivial and was eventually achieved by use of the Barton procedure, which gave a moderate yield of the related A16-lactam 375. Reduction of this lactam by means of magnesium in methanol then gave the thermodynamically preferred cis-fused lactam 376, which was identified as N-methyl-tetrahydromeloscine (Scheme 23) (250).

J. PARTIAL SYNTHESIS OF VINDOROSINE AND VINDOLINE In view of the importance of vindoline (44) as a constituent of the oncolytic bisindole alkaloid vinblastine, methods for the synthesis of both vindorosine (43) and vindoline from members of the quebrachamine and vincadifformine groups have been extensively investigated. The first results

86

J. E. SAXTON

368

295

@ - - c02Me

iii or iv

ii

E0,Me

I

g

E

‘CO2Met

H

369 370 Tetrahydroscandine

v. vi

I

H 371 Tetrahydromeloscine

279 18,19-Didehydrdabersonine

Reagents: i, NaBH&N, AcOH; ii, flow thermolysisat400°C; iii, KMn04. MeCOMe, HC104; iv. m-CPBA, Fe2+, then Sop; v, saponification; vi, decarboxyiation. SCHEME 22

1 ___)

I

76 Vincadimine

ii, iii

iv

372

H

373 vwwl

vy. viii

Me 374

375

ix

I Me

225 Meloscine 376 N-Methyltetrahydromeloscine

R8aLWntS: i, 03, MeOH, Hfl, at 0%; ii, NaBHaCN, CHzO. AcOH; iii, 1 % KOH, MeOH, N2: iv, Cu(OAch.Hz0.PY, PhH, %. then Pb(OAck; v. KH, DME. dibenzo-18crown-6; Vi. NaH. THF; vii. NaH. CSz. THF. 40°C. then Mel; viii. n-Bu$nH, PhMe; ix, I@. MeOH; X, H2. WIC; xi, Mel, NaH. THF.

e.

SCHEME23

88

J. E. SAXTON

in this area, that is, the synthesis of vindoline from (2)-vincaminoridine, were summarized in Volume 17 of this series (I);details of this work were subsequently published (251). Other workers have concentrated on the introduction of functionality into ring C of tabersonine (78). Danieli et al. (252) introduced the 17hydroxy group by oxidation of tabersonine by means of phenylseleninic anhydride. Presumably, the Na,17-didehydrotabersonineinitially produced suffers nucleophilic attack by water during workup, the stereochemistry of attack being controlled by the adjacent ethyl group. Oxidation of the product, 377, at (2-16 by means of peracid also proceeds preferentially at the P-face to give the N-oxide 378 of the desired diol. Reductive methylation and acetylation then complete the partial synthesis of vindorosine (43) (Scheme 24) (252). The synthesis of vindoline (44)from 11-methoxytabersonine (82)is hampered by the lack of availability of starting material. Hence, Danieli et al. (253) have developed a method for the conversion of the much more abundant tabersonine into 11-methoxytabersonine and thence into vindoline. Since electrophilic substitution in tabersonine and 2,16-dihydrotabersonine could not be effected cleanly and efficiently, N-acetyl2J6-dihydrotabersonine was chosen as substrate. Nitration gave a high yield of the 10-nitro derivative, which was then converted by standard processes into 1l-methoxy-2,16-dihydrotabersonine(379), which was obtained as a mixture of C-16 epimers. Attempted dehydrogenation to 11methoxytabersonine by phenylseleninic anhydride was fortuitously accompanied by introduction of the desired C-17 P-hydroxyl group. The product 380 was converted into vindoline (44)by the method described previously for the synthesis of vindorosine (Scheme 25). K. PARTIAL SYNTHESIS OF PACHYSIPHINE The partial synthesis of pachysiphine (W), the 14,156-epoxide of tabersonine, might seem at first sight to be a simple process. However, owing to the sensitivity of both Nb and the anilinoacrylate system toward oxidation, the direct oxidation of tabersonine (78) is not possible. Instead, the 2J6-double bond was removed by saturation, N , was protected by means of a trichloroethoxycarbonyl group, and Nb by carrying out the oxidation in acid solution (254). Finally, the 2J6-double bond was reintroducted by dehydrogenation of the intermediate 381 with DDQ. Further oxidation of pachysiphine (90)gives the Nb-oxide 382 of the related 16-hydroxyindolenine derivative, which rearranges to the P-epoxide 383 of 14,15-didehydrovincamine when treated with triphenylphosphine in acetic acid. A small yield of 383 is also obtainable by the direct oxidation of pachysiphine with m-chloroperbenzoic acid (Scheme 26).

1.

ALKALOIDS OF THE ASPIDOSPERMINE GROUP

78 (-)-Tabersonine

89

377

Catharosine

378

43 Vindorosine

Reagents: i, PhSe(O)OSe(O)Ph; ii, m-CPBA; iii, C H S , NaBHaCN, pH 4.2; iv, Raney nickel; v, AQO, NaOAc, r.t.

SCHEME 24

L. SYNTHESIS AND ABSOLUTE CONFIGURATION OF STREMPELIOPINE A rearrangement of yet another type in the vincadifformine series has been reported with 18-methylenevincadifformine(384), prepared by total

90

J. E. SAXTON

78 (-)-Tabersonine

Me0

1

Q-V-Bra vi

vii, viii

0

H H

379

Ac

c02Me

602Me

X

380 44 Vindoline Reagents: i, NaBH,CN, AcOH; ii. AcONa, Ac,O; iii, HNO,, TFA, N,, 0°C; iv, Zn, AcOH; v, NBS, DMF; vi, Me,CHCH,CH,ONO,

THF, heat;vii, NaOMe, Cul, collidine, 120°C;

viii, MeOH, HCI; ix. (PhSeO),O or PhSe(O)OH, benzene, 140°C; x, see Scheme 24.

SCHEME 25

synthesis (255) (vide infra). Unexpectedly, when 384 was hydrolyzed by alkali, and the acid thus obtained was heated briefly in 3% aqueous hydrochloric acid, the only product that could be obtained was a diene-imine that was assigned the structure 385 (255). This was the first report of an

1.

ALKALOIDS OF THE ASPIDOSPERMINE GROUP

91

78 Tabersonine iii, iv

1

383

382

Reagents: i, NaBH,CN, AcOH, on the hydrochloride; ii, CICO,CH,CCI,, CH,CI,. then NaOH, H,O; iii, m-CPBA. MeOH; iv, Zn, MeOH; v, DDQ, dioxan; vi, m-CPBA, PhH; vii Ph,!? AcOH.

SCHEME26

intramolecular 477 + 277 cycloaddition reaction involving an indolenine. When heated in benzene in the presence of p-toluenesulfonic acid, 18methylenevincadifformine (384) is smoothly hydrolyzed and decarboxylated, with exclusive formation of the indolenine 386, which can be quantitatively transformed into 385 by heating with 3% aqueous hydrochloric acid.

92

J. E. SAXTON

The indolenine 386 was neatly used in the synthesis of (2)-strempeliopine (387), the levorotatory enantiomer of which occurs in Strempeliopsis strempelioides K. Schum. (256). Reductive rearrangement of 386 by means of zinc and copper sulfate in acetic acid gave the indoline 388, together with 18-methylenequebrachamine. Formylation of 388, followed by ozonolysis, oxidative workup, and removal of the N-formyl group, then gave ( 2 ) strempeliopine (387) (256). Subsequently (253, the synthetic (2)-18methylenevincadifformine (384) was resolved, and the dextrorotatory enantiomer was shown to have the absolute configuration depicted. Its conversion into (-)-strempeliopine (387) then established the absolute configuration of this alkaloid (Scheme 27).

M. ENLARGEMENT OF RINGC The bromination of vincadifformine (76) followed by nitration gives an indolenine base 389, which on reduction and treatment with base affords a bromonitroester 390, as the result of an unusual migration of the ester function from C-16 to N,, presumably via an N, anion (258). The structure of 390 was confirmed by the X-ray method (259). When treated with trifluoroacetic acid, followed by aqueous workup, the ester 390 undergoes an intriguing rearrangement, and the product 391 is a cyclic hydroxamic acid containing the aza-homoaspidospermane skeleton. Another reaction of interest is the behavior of the nitroester 389 with nucleophiles, which affords the unsaturated nitro compound 392, apparently without the intermediacy of the acid corresponding to 389. When 392 is reacted with t-butyl hypochlorite followed by trifluoroacetic acid, the initially formed 16-chloroindolenine rearranges to 10-bromovincamone 393. Similarly, the analog of 392 lacking the bromine atom can be smoothly converted into vincamone (Scheme 28) (258).

IV. Total Synthesis of the Aspidospermine Alkaloids During the past two decades the total synthesis of the aspidospermine group of alkaloids has attracted considerable attention from numerous organic chemists, and virtually all the subgroups of alkaloids have now yielded to synthesis. Several routes of exceptional ingenuity have been developed, as well as notable attempts to mimic the presumed biosynthesis of the alkaloids in the laboratory. Most of the outstanding work of recent years was summarized in Volume 50 (4); hence, the present account will not attempt to be exhaustive, but will nevertheless include all the salient references.

1. ALKALOIDS OF THE ASPIDOSPERMINE GROUP

384 i, ii

I

/

93

386

iv

385 388 v - vii

387 Strernpeliine

Reagents: i, OH-, H20; ii, 3% HCI, H20, heat; iii, TsOH, PhH, heat; iv, Zn, CuSOII, H20, AcOH, heat; v, HCOzH, A c g ; vi, 0 3 ,Hfl, HCI, MeOH; vii, Hflz. 21 SCHEME

94

J. E. SAXTON

390 iii

I

392

I

vi. Vii; or viii

B % r

iii

1

Et 393 10-Bromvincarnone 391

Reagents: I* NaBH&N, AcOH; ii, NaH, DMF; ili, TFA, heat; iv, KOH, H20, MeOH, N2; V, NaOMe, MeOH, Nz; Vi, Bu’OCl, NEk. CH&2; Vii, TFA; Mil, NCS, TFA (+393 dimy).

SCHEME 28

A. SYNTHESIS OF SECODINE AND

ITS RELATIVES

Secodine (394) is a fugitive substance, which readily dimerizes or cyclizes. In consequence, it and its simple derivatives are more often prepared as transient intermediates in the biomimetic synthesis of alkaloids of the

1. ALKALOIDS OF THE ASPIDOSPERMINE

GROUP

95

aspidospermine and ibogamine-catharanthine groups, with no attempt being made to isolate and characterize them. Nevertheless, two syntheses of secodine are on record, as well as syntheses of N,-methylsecodine and N,benzylsecodine. Since secodine is a relatively simple compound with no stereochemical complications, there is little scope for variety in approaches to its synthesis, and most attempts begin with a 3-(2-haloethyl)indole derivative, convert it into an N-pyridinium salt by reaction with 3-ethylpyridine, then partially reduce the pyridine ring, and finally introduce the indole 2-substituent. The scheme adopted by Kutney and his collaborators (260)follows such a route, the starting material being 2-ethoxycarbonyl-3-(2-chloroethyl)indole (395), which was condensed with 3-ethylpyridine and the quaternary salt so obtained reduced to the tetrahydropyridine derivative 396. The ester group was then homologated, and the methylene group introduced by formylation, reduction, and dehydration, as shown in Scheme 29. Secodine was thus obtained as an unstable base, which dimerized within 2 h at room temperature to a mixture of secamine and presecamine. The penultimate compound in this synthesis, 16,17-dihydrosecodin-17-01(397), is itself an alkaloid, and evidence has been obtained for its presence in Rhazya orienrulis (261). It had been synthesized as early as 1970 by Battersby and Bhatnagar by a variant of the preceding route, starting with the homolog of 395, that is, 3-(2-chloroethyl)indole 2-acetic ester. This was condensed with 3-ethylpyridine, the quaternary salt was reduced, and the primary alcohol function introduced by formylation followed by reduction (261). The synthesis of secodine by Raucher et al. (262) follows a different course for the introduction of the acrylic ester substituent at the indole 2position. Here the orthoester derived from the benzylic-type alcohol 398a (constructed as shown in Scheme 30) and P-methoxyorthopropionate suffered simultaneous Claisen rearrangement and elimination of methanol when heated to give the desired intermediate 398b in one step. Removal of the amide carbonyl group and the protecting group on nitrogen then gave secodine (394). The synthesis of Na-methylsecodine (399) by Atta-ur-Rahman el al. (263) follows the familiar course of condensation of 3-(2-bromoethyl)indole with 3-ethylpyridine, then partial reduction of the pyridinium ring. The acrylic ester function was then incorporated into position 2 of the indole ring by a Friedel-Crafts acylation with oxalic ester chloride, followed by a Wittig reaction (Scheme 31). The later synthesis of Na-benzylsecodine (400) by the same group (264) is merely a repetition of this synthesis, with the obvious substitution of an N-benzyl group for the N-methyl group. The Kuehne biomimetic synthesis of alkaloids of the vincadifformine group (vide infra) proceeds via a transient secodine derivative, which is not usually isolated. However, in one of two syntheses of minovincine (265)

96

J. E. SAXTON

+

QEt

-

H

Et

395

I

H

Et

396

viii

1

394 Secodine

Reagents: i, NaBH4; ii, LiAIH4; iii, PhCOCI, py; iv, KCN, DMF; v, MeOH, H20, HCI; vi, PhH, NaH, HC02Me; Vii, NaBH4, MeOH, -3OOC; viii, NaH, PhH.

SCHEME29

reported in 1983, Kuehne and Earley prepared, as penultimate intermediate, a 19-oxosecodine (401),which proved to be stable and isolable, owing to the presence of the C-19 carbonyl group. Other workers (266) have synthesized the methylthio derivative 402, which gave a mixture of dimers when attempts were made to remove the

1.

97

ALKALOIDS OF THE ASPIDOSPERMINE GROUP

398a

vi

1

39Bb

394 secodine

Reegents: i, MeLi; ii, HCI; iii, indole 3glyoxylylchloride, NEt3; iv, CIC02CMe2CCI3.NEb, CH&12; v, NaBH,; vi, MeOCHSH&OMe)3, nmsitoic add,Ar, heat; Mi, (h@ocfjH4)2-P&; viii, &.O+BFi; ix. NaBH4,MeOH, AcOH; x, Zn, MeOH, AcOH.

SCHEME 30

iii

Reagents: i. 3-eltiYlpfldine;

1

ii. NaBH4, NEh; iii, CICO.C02Me,AIC13; iv, Ph3PMe' B i , MeLi, Etfl. -m°C.

SCHEME 31

98

J. E. SAXTON

phenylthio group by oxidative elimination with m-chloroperbenzoic acid. Distillation of the dimers was stated to give the unstable monomer, but attempts to isolate it and characterize it were frustrated. In the case of the N,-phenylsulfonyl derivative 403,synthesized by Sundbergetal. (267),attempts to move the double bond in the tetrahydropyridine ring into the 20,21-position failed; instead, disproportionation of the tetrahydropyridine ring supervened. The didehydrosecodines are, as expected, even less tractable than secodine and have only been prepared when the dihydropyridine ring is stabilized by electron-withdrawing substituents, or as metal carbonyl complexes. Wilson et al. (268) attempted to prepare them by reduction of the pyridinium salt 404, but over-reduction occurred, and the product contained some secodine and its 16,17-dihydro derivative. However, the related oxoderivatives, in which the ethyl group in the partially reduced pyridine ring is replaced by an acetyl group, are more stable and permit isolation. Thus, reduction of the pyridinium salt 405 gave an inseparable mixture of the acyldihydropyridines 406a and M b , which were stable in dichloromethane solution under nitrogen at -10°C. Kutney and his collaborators adopted the device of stabilizing the dehydrosecodines by complexation with chromium tricarbonyl (269). The pyridinium salt (407),prepared by a conventional synthesis, was partially reduced to the dihydropyridine stage, then complexed with trisacetonitriletricarbonylchromium(0). The C-17 methylene group was then introduced by aminomethylation with Eschenmoser’s salt, followed by Hofmann elimination. The product was a mixture of the protected complexed dehydrosecodines 408 and 409. Release of the bases from the complexes gave the labile N-benzyldehydrosecodines 410 and 411, which were not isolated, since they readily cyclized in situ. The isomer 410 gave (412)(even in the a mixture of Na-benzyl-16j3-methoxycarbonylcleavamine absence of reducing agent) and N,-benzyl-didehydro-pseudovincadifformine (413),and 411 gave, after reduction by sodium borohydride, the same cleavamine derivative 412, together with Na-benzylcatharanthine (414) (Scheme 32) (269). The synthesis of the much more stable hydrogenated secodines poses no problems. The synthesis of tetrahydrosecodine (1)by Kalaus et al. (270) begins essentially with the known intermediate (415),which by well-tried methods was converted into the aminoester (416).Formylation and reduc(417),which on dehytion then gave 15,16,17,20-tetrahydrosecodin-17-o1 dration gave 15,20-dihydrosecodine(418a);hydrogenation then gave tetrahydrosecodine (l), the alkaloid of Rhazya orientalis and R. stricta. The major aim of this investigation was the total synthesis of vincadifformine (76)and pseudovincadifformine (q.v.), which were obtained via the tran-

1. ALKALOIDS OF THE ASPIDOSPERMINE GROUP

99

sient secodine 418b, generated in situ from tetrahydrosecodin-17-01 (417) (Scheme 33). (+)-Demethoxycarbonyl-15,16,17,20-tetrahydrosecodine (2) has been obtained by an enantiocontrolled synthesis that unequivocally establishes its absolute configuration (272).The chiral bromocylopentenol419, prepared from the corresponding racemate by preferential transesterification of its enantiomer by means of vinyl acetate in the presence of porcine pancreatic lipase, followed by separation, was converted via a Claisen rearrangement of the acrylate ester 420 into the aldehyde 421 (Scheme 34). Conventional elaboration of 421 led, via the cyclopentene derivative 422, to the dimesylate 423, which was the substrate for condensation with 2-ethyltryptamine. The product 424 was then hydrolyzed, and the hydroxyl group removed by the Grieco method, to give (+)-demethoxycarbonyl-15,16,17,20tetrahydrosecodine (2), which exhibited a specific rotation of +11.8". This compound definitely has the R-configuration, but at the time of writing it is not possible to identify it unequivocally with the alkaloid of this structure isolated from Tubernuemontuna cumminsii, Aspidosperma marcgruviunum,

401

403

402

404 R = E t 405 R = C O M

100

J. E. SAXTON

410

413

412

SCHEME 32

or Huplophyton crooksii (see Table I), since no optical rotation has been quoted, or with the alkaloid of Rhuzya strictu, for which a specific rotation of (+)-90" was recorded.

1. ALKALOIDS OF THE ASPIDOSPERMINE

415

Et'

101

GROUP

416

Q-p) N H

cO2h

vh vii

- &?

OH

cO2k

418a 15,~Dihydrosecodine

417 15,16,17.2&Tetrahydrosecodin-l74

1

ix, viii

1 Tetrahydrosecodine

76 Vincadlfformine

H N

viii

c02Me 418b

Reagents: i. HP,PdIC, MeOH; ii, LiAIH4,THF; iii, PhCOCI, py; iv, KCN, DMSO; v, MeOH, HCI, Hfl (trace); vi HC02Me, NaH; vii, NaBH4, MeOH; viii, Ac20, py; ix, m-CPBA, CHS12.

SCHEME 33

Crooksidine (4), the alkaloid of Huplophyton crooksii, has been synthesized by two groups of workers. The first of these (272) consists of a very straightforward route in which condensation of 2-ethyltryptamine with methyl 4-formylhexanoate gave the dihydropyridone derivative 425. Reduction followed by oxidation then gave crooksidine (4) (Scheme 35). The second route (273) is an enantiospecific one that starts from (+)-Sl-benzyloxycarbonyl-3-piperidein-5-ol(426), obtained from the corresponding racemate by preferential lipase-catalyzed esterification of its enantiomer by means of vinyl acetate, as in the preparation of 419. Reaction of 426 with triethyl orthoacetate, followed by Johnson-Claisen rearrangement, gave the tetrahydropyridine ester 427, which was converted by unexceptional means into the ketoamide 428. Reductive removal of the functional groups then provided another synthesis of (+)-R-demethoxycarbonyl-15,16,17,20-tetrahydrosecodine(2), and Dess-Martin oxidation

102

J. E. SAXTON

o&od,M, OH

I

419

420

OMS vi, vii

..,CH20SiButPhp 423

422

viii

.

\OSiButPh2

ix

H

-

xi

424

H 2 (+)-Dfmethoxycarbonyi-l5,16,17,20-tetrahydrosecodine

Reagents: i, HGCCOzMe, N-methylmorpholine, Et20; ii. Lii, DMF. 140°C; iii, NaBH4; iv, 'BuPhzSiCl, 'Pr2NEt, CH2CIz; v. BuLi, THF. then (C@H)z.H&; vi. 0 3 , MeOH. Me& then NaBH4; vii, MsCI, NEt3. CH2CI2; viii. 24hyltryptamine, W N , Lil. 1 2 c m - 4 ; ix, Bu~NF,THF; x, o-O2N&.H4SeCN, PBu3. THF; xi, NiCI2, NaBH4, MeOH, THF.

SCHEME 34

of the latter finally gave (+)-crooksidine (4), [a],+7.8", which is thus unequivocally shown to have the R-configuration (Scheme 36). Because of the discrepancy in the recorded value, [a],+27.6", for the optical rotation of natural crooksidine, the preceding synthesis was repeated with the enantiomer of 426. which gave (-)-S-crooksidine, [a],-7.4". B.

QUEBRACHAMINE

The most popular route to quebrachamine is that which proceeds via the tetracyclic base 429, first prepared by Kutney et al., whose contributions in this area have been summarized in earlier volumes in this series ( I ) . Takano's first syntheses, details of which have since been published (274), were also described in Volume 17.

1.

ALKALOIDS OF THE ASPIDOSPERMINE GROUP

103

4 Crooksidine

Reag8nts: i, EtCH(CHO)CH2CH&Q&k,

PhH, heat; ii, H2, Pd/C, EtOH; iii, LiAIH4; iv, DDQ, THF, H S .

SCHEME 35

The first enantioselective synthesis of (+)-quebrachamine was also developed by Takano and his collaborators (275), and in principle is an elegant adaptation of the Kutney route, the required aldehyde-acid 430, with the S-configuration at the future C-20, being prepared from the lactone 431, itself obtained from L-glutamic acid. Alkylation of the anion from 431 gave 432, and alkylation of 432 gave 433, both alkylations proceeding preferentially from the less hindered side. Removal of the protecting group from 433, followed by oxidation, gave the aldehydo-acid 430, which was condensed with tryptamine and then converted into the epimers 434 by conventional procedures. These were separated, but it was strictly not essential, since both could be transformed into (+)-quebrachamine, as outlined in Scheme 37. In a subsequent communication, Takano et al. (276) reported an alternative synthesis of (+)-quebrachamine from the lactone 433, together with a synthesis of (-)-quebrachamine (5) from the same lactone, which was achieved by reversing the roles of C-2 and C-4. The new synthesis of (+)quebrachamine essentially involved an alternative route for the conversion of the tetracyclic lactam 436 into the familiar tetracyclic aminoalcohols 434, via the rearrangement of the terminal epoxide derived from 436, and reduction of the aldehyde so produced (reagents xiii-xvi in Scheme 37). For the synthesis of (-)-quebrachamine ( 5 ) , the lactone 433 was

104

J. E. SAXTON COSHzPh

CO&HZPh

i

C06HZPh

AcO

426

0

-

427

iii

-

vi

1

vli

428

viii - x

I

&a0*'xi

'

N

H

I 4 (+)-RCrooksMine

2 (+)-BDeemethoxycaItJorlyi15,16,17,20-tetrahydrosecodine

SCHEME36

detritylated, then ozonized to the aldehyde 437, which was condensed with tryptamine to give the tetracyclic lactam-diol438. Again, two methods were developed for the conversion of 438 into the epoxide 439, which was then rearranged to the aldehyde 440, and the synthesis of (-)-quebrachamine (5) completed as before (Scheme 38). As in the previous syntheses, mixtures of C-3 epimers were produced, but separation of these epimers was not necessary, since the asymmetry at C-3 was destroyed during the final stage. Yet another synthesis of the aldehydo-acid 430 by Takano's group (277) constitutes a further formal synthesis of (+)-quebrachamine. Here, butyronitrile was bisalkylated by ally1 bromide, and the product converted into the iodolactone 441 by reaction with iodine in mild aqueous alkali. Hydrolysis then gave the corresponding alcohol, which on further hydrolysis and

1. ALKALOIDS

105

OF THE ASPIDOSPERMINE GROUP

434 a-Et

P h 3 C O T 0 T 0

p

h

3

C

O

~

I

432

T

N N H 436

y

H

407'-

~

ii

___)

431

o

~ Ph3

CH2CH=CH2

-

iii

Et CH2CH=CH2

433

-v

I

vi

CH&H=CH2 kt

vn- x xyi

Et

435 (+)-Quebrachamine

Reagents: 1, LIN'Pr2, H e C H C H a , THF, -78OC; ii, LiN'Pr2, EtBr, THF, -78OC; iii, HCI, EtOH; iv, NaOH, H20, NaOH, H A , H a ; ix,LiAiH4; x. sepamtbn of diestereo(somrs; xi, MBCI; xii, Na. NH3, EtOH; xiii, 12, H20. THF; xiv, KOH, H20, MeOH; xv, mol.

m;v, M a ; d, byp(amine. ACOH, heat; vii, e;lHd,DMS, THF; viii,

&ms,

PhH, heat; mi. MIH4, THF.

SCHEME 37

oxidation gave the racemic aldehydo-acid 430. This was condensed with tryptamine, and the synthesis of (+)-quebrachamine [(9 - 5 1 completed as before (Scheme 39). Wenkert's ingenious approach (278) to the synthesis of the aminoalcohol 429 involved the addition of diazoacetic ester to 3-ethyldihydropyran,which

vi

- viii H 5 (-)-Quebrachamine

Reagents: i, W H , HCI; ii, 03, NEt3; iii. tryptamine, AcOH; iv, Et02C-N=N-C02Et,PhaP, PhH, heat; v, 5A mol. sleves, silica gal, PhH, heat; vi, LiAIH4, THF; vii, MsCI, py; viii, Na, NH3, EtOH; ix. HC(OMe)2NMe2; x, A c g ; xi, 12, H20, THF; xii, KOH, Hfl, MeOH.

SCHEME 38

iii

SCHEME 39

1

1.

107

ALKALOIDS OF THE ASPIDOSPERMINE GROUP

resulted in the formation of the cyclopropyl ester 442. Acid-catalyzed rearrangement of 442, followed by reduction, then gave the hemiacetal 443, whereas reduction of 442, followed by FCtizon oxidation, gave the enol ether 444. Condensation of either 443 or 444 with tryptamine then gave the pentacyclic carbinolamine ether 445, which, on reduction by means of sodium cyanoborohydride, gave [(9-4291 (Scheme 40). Other syntheses of the tetracyclic intermediates 434 and 436 that merit mention, and thus constitute additional formal syntheses of (+)quebrachamine, have been contributed by Fuji et al. and by Asaoka and Takei. Fuji’s approach (279) starts with the chiral lactone 446, which is readily available from 2-ethyl-Gvalerolactone. Partial reduction to the aldehyde stage, followed by acetal formation, gave 447, which on condensation and reduction (lithium aluminum hydride) gave a mixture of C-3 epimers 434, the late intermediate in the (+)-quebrachamine synthesis (Scheme 41). Asaoka and Takei (280) started from R-( -)-5-trimethylsilyl-cyclohexenone 448, which was converted into the S-ketone 449. Critical stages in Et

442

Reagents: i, N$H,C02Et, Cu, heal; ii, H3O+; iii, ‘Bu2AIH; iv, LiAIH4; v, AgC03, Celite, PhH, N2; vi, lryplamine.HCl, H20, AcOH, NaOAc; vii, NaBH3CN. SCHEME 40

108

J. E. SAXTON

ii, Ill

tEJ&

0

1

TNL

H

434 H

435 (+)-Quebrachamine

Et'

H

OH

Reagents: i, TiCI3. W H , pH 5; ii, tryptamine, AcOH, heat; iii. UAIH4, THF; iv, M e w ,NEb. CW3; v, Na, NH3, EtOH.

SCHEME 41

this synthesis were the 1,Caddition of diethylaluminum cyanide to 449, which gave exclusively the 3R,SS-ketone 450, and the silicon-directed Baeyer-Villiger oxidation of the ketoester 451. Reduction of the product 452 to the related hemiacetal, followed by condensation with tryptamine and elimination, then gave the tetracyclic lactam 436,which is also a late intermediate in Takano's syntheses (Scheme 42). 0

6- 6 vl - Q-qNZ: %

&-Et

w3si

Et

448

449

m3sr

CN

&*Et

M e s i'

450

435 (+)-Quebracharnlne

Et

-

W2M

451

vi, vii

(J;zm

452

ReaaentS: I. EU. then PCC; ii, EtdCN, THF; MI. conc.HCI. heat; iv. HC(OMB)~,MeOH, TsOH (cat); CHzClz, Hz0, Na2HPO4; vi. DIBAL, THF, -1OO'C; vii, ttyptamlne. AcOH. heat. SCHEME 42

V,

MPBA,

1. ALKALOIDS

OF THE ASPIDOSPERMINE GROUP

109

The approaches to quebrachamine adopted by other workers were rather different. Pakrashi and his collaborators (281) developed a synthesis via the known pentacyclic lactam 453 (prepared from 2-hydroxytryptamine and dimethyl 4-ethyl-4-formylpimelate) and 1,2-didehydroaspidospermidine (27), the final stage being simply the reduction of 27 by means of potassium borohydride, as in the last stage of the original synthesis of quebrachamine by Stork and Dolfini (Scheme 43). Ban’s independent approach (282-284) employed the lactam 455, prepared by a novel photoisomerization of the lactam 454, as a common precursor for both the Sfrychnos and Aspidosperma ring systems. The conversion of 455 into (2)-quebrachamine, by a series of conventional steps, is outlined in Scheme 44. In an attempt to convert the tetracyclic lactam 456 into vincadine (7), Ban and his collaborators (285) found that reaction of 456 with t-butyl hypochlorite, followed by potassium cyanide, did not give the expected 16cyano derivative but instead the 7-cyano derivative 457. However, reaction of the 7-chloroindolenine derivative 458 with dimethylamine followed by methyl iodide gave the quaternary salt 459, which then gave the desired 16-cyano derivative 460 on prolonged reaction with potassium cyanide. An unexpected product, obtained in comparable yield, was the pentacyclic lactam 461, whose structure was established by X-ray crystallography (Scheme 45).

453

I

;-9 iii, iv

’

H

27

Quebrachamine Reagents: i, Pfi5; ii, Ac@.

N’

w ;iii, Ni, THF; iv, 6M HCI, N2, heat; vii, SCHEME43

KBH4, H B , MeOH.

110

J . E. SAXTON

-

TNH2 i

0

455

454

Quebrachamine

-:

1. W H . hv; ii, PMx]cI, NEb; iii, dihydropyran,camphorsulfonk acid; iv, LDA, CICH&H2CH21; v, MCHsH2NH2, CH&lp, r.t.; vi, NaH, KI,18crown-6; vii, LDA, THF, HMPA; viii, Etl, -6OOC; ix, LiAIH4, dioxan. heat; x, H+, H B .

SCHEME 44

In contrast, Wenkert and his collaborators (278) successfully applied their strategy to the synthesis of (?)-vincadine (7) and (+)-16-epivincadine (462). Reaction of 3-ethyldihydropyran with diazopyruvic ester gave the dihydrofuran ester 463, via thermal rearrangement of the initially formed cyclopropyl ester adduct. Hydrolysis of the ester with concomitant hydration of the double bond, then re-esterification, gave the a-hydroxyester 464, which on reaction with tryptamine, followed by reduction, gave the tetracyclic esters 465, as a mixture of epimers. Completion of the synthesis by the well-established method ultimately gave (+)-vincadine (7) and ( 5 ) 16-epivincadine (462) (Scheme 46). C. ASPIDOSPERMIDINE AND ITS SIMPLE DERIVATIVES

Almost two decades after the first synthesis of aspidospermine, the Stork route still attracts attention, and a new preparation of Stork's racemic

458

456

/(J--G ’ ii

iii, iv

II

N’

CN I

459 V

I

457

+he3

\ H CN 460

9 E461

Reagents: i, BubCI; ii, KCN; iii, Me2NH; iv, Mel; v, KCN, 18-crown-6, MeCN, heat, 24 hours.

SCHEME 45

112

J. E. SAXTON

1

L

463

11, ill

% Me02c

I

Et

Et

464

1

qpL&

pNQ - Q

Meo2c 465

aw

N H

M e w

OH Et

ix. x, iii

I

Et

H

7 Vincadim R' = H, R2 = C02W 462 Epivincadine R1 = C02Me, R2 = H

SCHEME46

1.

113

ALKALOIDS OF THE ASPIDOSPERMINE GROUP

tricyclic amidoketone 466, by Martin et al. (286), provided a new formal synthesis. The hydrolulolidine system in 466 was neatly constructed by cheletropic expulsion of sulfur dioxide from the amidosulfone 467, followed by an internal Diels-Alder cycloaddition. Subsequent adjustment of the functionality in the cyclohexane ring then gave 466, the substrate for the Fischer indole reaction in Stork’s original synthesis (Scheme 47). The route developed by Fowler and his associates (287) involved an ingenious application of the aza-Cope rearrangement, in which the bridged hydroxamic acid derivative 468, prepared as shown in Scheme 48, was subjected to flash vacuum thermolysis. The product, the enol ether 469, was not isolated but immediately hydrolyzed to the ketone 470, which was then hydrogenated and cyclized to the racemic ketone 466. This appears to be the first application of the aza-Cope rearrangement in synthetic chemistry, since the reaction is normally not thermodynamically favored when C-1 is replaced by nitrogen. However, it is clearly successful when the nitrogen is acylated, as in the present example. Meyer’s route to the tricyclic ketone takes advantage of an original method for the preparation of asymmetric 4-substituted cyclohexenone derivatives (288). The asymmetry was ensured by use of the bicyclic

V

467

ii

-

.i

466

Reagents: i, heat at W 0 C ; ii, SeOz, AcOH, 100°C; iii, KOH, H20, EtOH, r.t.; iv, pyridiniurnchromate on silica gel; v, HP,PdlC, EtOH.

SCHEME47

114

J. E. SAXTON

479 Deoxylimapodine

478

0Ac H

Ac

aocx 4 CI

CI

47Q

Viii, IX

OM0

1

469

ZCI

466 Reagents: i, MeAIC12, CHc13,0%; ii, NHflH.HCI; in, BHa py, HCI; hr. (CICH@)20. NEt& vi, flash vacuum themlysis; vii, oxaiic acid; vlii, H2, Rh, E1oAc; ix, KOBU', PhH.

SCHEME 48

V,

CICqMe, NEt&

1.

115

ALKALOIDS OF THE ASPIDOSPERMINE GROUP

amido-alcohol471, which was the major product obtained from the condensation of the S,S-aminodiol472 with 5-oxohexanoic acid (289).Stereoselective bis-alkylation of 471, first with ethyl iodide, then with ally1 bromide, gave the amido-alcohol473, which on reduction followed by hydrolysis and cyclization gave the chiral cyclohexenone derivative 474. Subsequent stages to the tricyclic ketone 475 are unexceptional, the major point of interest being the cyclization of the amide 476. With toluene-p-sulfonic acid in benzene, a mixture of cis and trans isomers was formed, but when the mixture was heated with toluene-p-sulfonic acid in ethylene glycol, the sole product was the desired cis isomer 477. The final product of this synthesis was the chiral tricyclic ketone 475, which is the intermediate required for the synthesis of (+)-aspidospermine (55), the enantiomer of the familiar (-)-aspidospermine (33) (Scheme 49) (288).

476

x, xi

474

1

Et

0 0 477

475

SCHEME49

116

J. E. SAXTON

Ban’s synthesis of quebrachamine ( 5 ) (282-284) (Scheme 44)was readily modified to afford syntheses of several aspidospermidine derivatives. Thus, angular alkylation of the tetracyclic lactam 478, followed by appropriate reduction and cyclization stages, afforded (+)-N-acetylaspidospermidine (26), whereas acylation at the future C-20 by means of oxalic ester provided a route to (+)-deoxylimapodine (479) and (2)-N-acetylaspidoalbidine (480).( t)-Deoxyaspidodispermine (481)was obtained by C-20 hydroxylation of 478 by means of oxygen and LDA, followed by reduction and cyclization stages (4,282-284). The synthesis of (+)-aspidospermidine [(?)-241 by Magnus et al. (290,291)proceeds by way of an indole-2,3-quinodimethane482a,which is not isolated. It undergoes a spontaneous Diels-Alder cycloaddition to give the tetracyclic intermediate 483, which contains the desired cis C/D ring junction, presumably because the transition state for the reaction is derived from the conformation 482b. Oxidation of 483 by rn-chloroperbenzoic acid followed by reaction with trifluoroacetic anhydride gave 484 by way of a Pummerer reaction, and the synthesis was completed by cyclization, deprotection, and reduction stages (Scheme 50). The enantioselective approach to quebrachamine adopted by Fuji and collaborators (Scheme 41) (279) has also been modified to afford a new synthesis of (-)-aspidospermidine (251).Here, the lactone 446 was converted by titanium trichloride into the lactone hemiacetal485, which, after appropriate reduction and oxidation stages, gave the acetal acid 486. Condensation with tryptamine gave the tetracyclic lactam 487,which was then rearranged by means of trifluoromethanesulfonic acid to the pentacyclic indolenine lactarn 488,reduction of which gave (-)-aspidospermidine (251) (Scheme 51). Wenkert’s first synthesis of (?)-aspidospermidine [( 2)-24](292)involves a modification of the cyclopropyl ester route for the construction of ylactones, which was successfully applied in the synthesis of quebrachamine. In this case the piperidine ring destined to become ring D was present in the starting material, 3-acetyl-N-methoxycarbonyltetrahydropyridine (489)’ which was protected as its thioacetal and converted into the cyclopropyl ester 490 by hydrogenolysis followed by reaction with diazoacetic ester. Hydrolysis at high temperature with potassium hydroxide in diethylene glycol resulted in rearrangement with formation of the lactone 491,which, on condensation with indole, gave the amino acid 492.Thereafter, the stages to (t)-aspidospermidine (24)were the conventional ones of cyclization, reduction, a double alkylation, and a final reduction (Scheme 52). Two further syntheses of aspidospermidine have been contributed by the Wenkert group. Both use as starting material the pentacyclic ketolactam 493,which was readily prepared from indoleacetic anhydride and 3-acetyl-

1. ALKALOIDS

OF THE ASPIDOSPERMINE GROUP

117

mcHo i

TS

Me

&5& Ts

Ts

G$ 0

-

N Ts

482a

-??J- ;c iii, iv

'

483

N

Ts

Ts

404

24 @-Aspldospermidina -: 1, PhSCH&H2NH2; ii, =I. 1@C; iii, M P B A . NaHC03. CH&, 130°C; vi, Raney nickel, EtOH; vii. LiAIH4.

0%; iv, TFAA, CH&,

0%; V, PhCI,

SCHEME 50

1,4,5,6-tetrahydropyridine(293). N,-Protection, alkylation, and reduction stages on 493 completed a brief, new synthesis of aspidospermidine (Scheme 53) (294). In the later synthesis (295), Wenkert and Liu converted the ketolactam 493 into the ring C diene 494, which gave the aspidofractinine

118

J. E. SAXTON

446

486

-

vii

1

viii

&Et

’

N0

488

ix

1

487

251 (-)-AspidospermMine

w,

Re@: I, TK&, DME; ii, M B h ; ill. 5% HCI, heat; hr, m3,Hfio4, MeCOMe; V, DIBAL, E t g ; vi. TsOH. MeOH. heat; vii, tryptamine, AcOH, heat; viii, CFsSOaH, 110°C; ix, LiAIH4, Et20.

SCHEME 51

derivative 495 on Diels-Alder cycloaddition with phenyl vinyl sulfone, followed by removal of the urethane grouping. Base-catalyzed elimination on 495, with fission of the 2,18-bond, gave a pentacyclic indolenine 496, which on reduction gave (t)-aspidospermidine (% together I),with some 16,17-didehydroaspidospermidine(Scheme 53). In a lengthy (22-stage), enantioselective synthesis of (+)-aspidospermidine (24), by Desmaele and d’Angelo (296), chirality is introduced at the outset by tl, alkylation of a chiral enamine from 2-ethylcyclohexanone with acrylic ester. The product, converted into the trimethylsilyl ether 497, was further elaborated to the diketone 498, which was reacted with 2iodoaniline and cyclized to the tetrahydrocarbazole derivative 499. Conventional stages led to the amide 500. Ring D was then closed by treatment with trifluoroacetic acid, the stereochemistry being controlled by the configuration at the future C-20. Oxidation of the product, followed by a

1. ALKALOIDS

119

OF THE ASPIDOSPERMINE GROUP

CO2H H

vii -ix

I

492

H 491

24 Aspidospermidine

Reagents: i, HS(CH2)3SH, HBr, EtB. O°C; ii, W-2 flaney nickel, EtOH, N2. heat, 12 h; iii, N2CH.C02Et,Cu; iv,

HOCHzCklflH. KOH, H20, dlathYi8ne glycol, llO'%;v, indole, AcOH. H20, dioxan, HCI (2 drops). SOOC; vi, PPA, 90%; vll, chromatographicseparation; viii, LiAIH4, dbxan, heat: ix, BrCH$H2Br, K2C03;x, LiAIHd.

SCHEME 52

Pummerer rearrangement and cyclization, completed the construction of the aspidospermidine ring system, and (+)-aspidospermidine was finally obtained by appropriate reduction procedures (Scheme 5 4 ) (296). Two further syntheses in this area have been reported by Gramain and collaborators (297-299). The first of these, a synthesis of 19-oxoaspidospermidine (501) (297), starts essentially from the previously prepared 4-0x0tetrahydrocarbazole derivative 502. Noteworthy stages in this synthesis include the regio- and stereoselective alkylation-cyclization of 502, the preferential hydrogenolysis in acid solution of the N,-benzyl group in the product 503, and the reduction, by means of lithium aluminum hydride, of

120

J. E. SAXTON

0

0

H 493

0

H

H

AspMospermidiW

1

(&$ a

H

0

495

"\

I

BOPPh

496 Reegents: i, n-BuLi, TsCI; ii, KH, Lil, Etl; iii, LiAIH,, THF, heat; iv, H2, Pt; v, BuLi, CK=o2Me,THF; vi. NaBH,, Cd&, k O H ; Mi, BF3,EtpO; viii, PhSO$H=CHp, PhH; ix, EtSLi, HMPA, THF; x, KOBU', HOCHSHflH, 150°C.

SCHEME 53

the enamino-ketone 504a to the epimeric aminoketones 504b. The remaining stages to (+)-19-oxoaspidospermidine (501) are unexceptional (Scheme 55a). The second synthesis was a brief, six-step synthesis of N,-benzylaspidospermidine (JOS), from the amine 506, which was readily prepared from N-benzylaniline and cyclohexan-1,3-dione (298,299). A double alkylation of 506gave the intermediate 507, which was cyclized by photochemical means to a mixture of epimers of the hexahydrocarbazolone 508, which contains a trans B/C ring junction. However, alkylation of the derived anion

1. ALKALOIDS

OF THE ASPIDOSPERMINE GROUP

121

24 (+)-Aspldosperrnidim

Ar = p MeOC&14ReagenEs: i, (R)-(+)-l-phenylethylarnine, TsOH. PhMe; ii, CH&H.W2Me, sS°C. then AcOH, Hfl; iii, MesSiCI, NEk, DMF. l@C; iv, D W . P,blutMIne, PhMe; v. PhSH, NEt3; vi, NCS, CCl4; vii, NaOMe, MeOH. heat; viii, 1 M *I, THF; ix. o-ICaH4NH2.TsOH. PhMe. heat; x, NaH, HMPA. then Cul, 120%; xi, LiBEt3H, THF. N2. -4OOC; xii. Ma.NEt3, DMAP. CHzCI2, THF, 0% xiii. NaN3, DMF, 80%; xiv. p-MeOC&I&OfiI, 50% NaOH-H20, CH2Cle; xv, NaBH4, EtOH, heat; xvi. PPh3, THF; xvii, PhSCH2COCl. 1 M. NaOH, CH2Cl2; wiii. TFA. CH&12.0°C; xix. Na104. THF. MeOH: xx, TFAA. CHfl2, then PhCI, 135OC; xxi, Raney Ni. DMF. EtOH; xxii, LiAIH4,THF.

SCHEME54

by means of nitroethylene gave exclusively the desired product 509 as an inseparable mixture of nitroketones containing a cis B/C ring junction. Reductive cyclization then gave a mixture of tetracyclic imines, 510a and 510b, of which the one with the required stereochemistry, 510b, cyclized spontaneously to give the iminium salt 511. Stereoselective hydrogenation of 511 then gave (2)-N,-benzylaspidospermidine (505) (Scheme 55b) (298,299).

122

J. E. SAXTON

n

cAc

Ac 504b

Ac H 504a

501 1OOxoaspidosprmidine

Reagents: i, ICHzCONHCHZPh,KH; ii, H ,I Pd/C, CHC13, EtOH, HCI; iii, (+)-lO-CSA,mi.s i e w ; iv, LIAIH4,THF; V, MeCOCI, NEts, CHC13; vi. LiAIH4. THF, Ar, -25OC, 1 min.; vii, Hz, Pd. EtOH, CHC13; viii, i(CH2)3CI,DMF, K2C03; ix, Nal, Mecow,heat; x. NaH, PhH, THF, heat; xi, HCI, EtOH, heat.

SCHEME 55a

The most recent synthesis of aspidospermidine has been contributed by Rubiralta and co-workers (300) and involves the construction of a pyridocarbazole derivative, which constitutes rings A-D of aspidospermidine; ring E was then closed in the later stages of the synthesis. The first stage involved a Michael addition of the dianion from 2-(1,3-dithian-2-yl)indole onto N-(2-benzyloxyethyl)-3-methylene-2-piperidone,followed by angular ethylation in a one-pot process. The product was then reduced and cyclized to the tetracyclic dithian derivative 5l2a. Isomerization by means of acetic acid, then debenzylation, gave the desired tetracyclic intermediate 5Ub, which on tosylation and treatment with base gave the dithian derivative of 1,2-didehydro-l6-oxoaspidospermidine.Removal of the dithian function by means of Raney nickel in ethanol then gave some (2)-aspidospermidine

1.

ALKALOIDS OF THE ASPIDOSPERMINE GROUP

123

I

~eaeens:i. LDA.RI,THF, -78% ii, LDA, I(cH~)~u. THF. -*C; iii, k,P ~ H Ar; . iv. LDA. C H ~ H N O ~ . . T H F . -78% v. HCOONb. 10% WC,MeOH, 65% vi, H2, WAI&, EtOH. 3atm. SCHEME 55b

[(2)-24], together with (2)-N,-ethylaspidospermidine, but desulfurization with Raney nickel in dioxane gave 30% of (2)-aspidospermidine and 35% of (2)-1,2-didehydroaspidospermidine[(?)-27], which could subsequently be reduced to (+)-aspidospermidine by lithium aluminum hydride (Scheme 56) (300). Several aspidospermidine derivatives containing additional substituents in the ring system have also been the target of synthesis. Ban and collaborators synthesized (301) (2)-eburcine (513) and (t)-16-epi-eburcine (514) from 1,2-didehydroaspidospermidine (27), which was protected as its

124

J. E. SAXTON

U

N,-Ethylaspidosperrnidine

24 Aspidospermidin9

27 1,2-Dldehydroespidospermidlne

Reaeen$: I,

"BBUli. THF. HMPA, -7a°C, then N - ( 2 - b e n r y l o ~ ~ ) - 3 - ~ t then h ~Eti, 2 -78%; ~ ~ ~ 11,~ DIBAL; , ill. AcOH, H@, heat. 2 h; iv, Me#, EFs.Et20, CH$I2,35'C, 2 h; v, KOBu' (xs), TsCI, THF; vi, W-2 Raney Ni, EtOH; vii, W-2 R a w Ni,man,heat, 30 min; Vlii. LiAIH4.

SCHEME56

N,-urethane (the double bond moving into the 2,16-position) and then formylated by the Vilsmeier-Haack reaction to give the aldehyde 515. Surprisingly, Corey oxidation of 515 gave (5)-eburcine (513) directly, although in poor yield. Equally surprising, the reaction of the aldehyde 515 with sodium cyanide in methanolic acetic acid also gave some (+)-eburcine, together with some (f)-l6-epi-eburcine (514) (Scheme 57). The detailed mechanism of this redox process is not at present clear. Several of the synthetic endeavors have been directed to the aspidospermidine derivatives that contain a functionalized C-18. The first synthesis of cylindrocarine (516a) and cognate alkaloids was described in an earlier volume ( I ) , and details of this work are now available (302). A second

1.

125

ALKALOIDS OF THE ASPIDOSPERMINE GROUP

-

iii (

iv (

* 513 and 514) 513)

513 Eburcine p-CO2Me 514 IbEpi-eburcine a-C02Me

Reagents: i, CIcO2Me, NEb; ii, POC13, DMF; iii, NaCN, MeOH. AcOH: iv, Mn02, NaCN, W H , AcOH

SCHEME 57

synthesis (303),from the same laboratory, involved the construction of the vincadifformine framework by an adaptation of the Kuehne synthesis. In this case, the chloro-aldehydo-ester 517 was reacted with the tetrahydroP-carboline ester 518 to give a spirocyclic ammonium salt, which when heated rearranged to the vincadifformine derivative 519 (Scheme 58). Subsequent stages to (?)-cylindrocarine (516a) were unexceptional. At the same time, the demethoxy derivative 300 was synthesized by the same route and converted into (+)-12-demethoxy-N-acetylcylindrocarine(516b). Pearson and Rees developed iin ingenious synthesis of limaspermine (35) by taking advantage of the fact that iron carbonyl complexes of alkoxycyclohexadienes (e.g., 520) behave as stable equivalents of cyclohexenone ycations. The initial synthesis (304-306) of 35 required some 30 stages. In a subsequent modification (303,limaspermine was obtained in seven fewer stages from p-hydroxyphenylacetic acid, via the complex 520, as shown in Scheme 59. This procedure has the advantage that fewer protection stages are required, and much improved selectivity was achieved in the alkylation stage, that is, from the iron carbonyl complex 520 to the cyclohexadiene derivative 521, by the use of an isopropyl ether, rather than a methyl ether,

126

J. E. SAXTON CHzC02Et

I

CI(CH2)3CHCH=CHz

Cl(CH&3iCHO I

CH2C02Et 517

300 R = H

I

- viii (on519, gives 516N (on300.gives 516b) vi - ix

vi

Reagents: i, MeC(OE1)3, EtCOZH, 130% 3 hours; il, 145OC. 14 hours; iii, 0 3 , WOH; iv, Me#, -1O'C; V, TsOH. PhMe, Nz, heat; Vi, NaCN, HMPA, Nz, 80-90°C, 6dayS; Mi, NaBH4, EtOH; viii, NaOMe, W H ; Ix, py. Ac&

SCHEME58

as in the original synthesis. Conversion of the malonic ester residue in 521 to a cyanoethyl group, followed by reduction, decomposition of the complex, and hydrolysis of the enol ether grouping, gave an unsaturated arninoketone, which cyclized to the bicyclic aminoketone 522. The final stages led, via the Stork-type tricyclic amidoketone 523, to limaspermine (39, by familiar processes. One of the most original and ingenious routes to the synthesis of the aspidospermine alkaloids is the tandem aza-Cope rearrangement-Mannich cyclization route developed by Overman and collaborators. This was originally introduced in a synthesis of 1l-methoxytabersonine (q.v.), and it has also been applied to the synthesis of deoxylimapodine (479) and N acetylaspidoalbidine (480) (308). This work has already been discussed in an earlier volume (4,to which the reader is referred for details. The first total synthesis of (+)-obscurinervidine (50) (309) starts essentially from the benzoxazine 524, which was prepared from pyrogallol. Construction of the pyrrole ring on the N-amino derivative of 524 gave, after

1. ALKALOIDS OF THE ASPIDOSPERMINE

GROUP

127

SCHEME 59

hydrazinolysis, the tryptamine analog (525) in the relatively little known pyrrolobenzoxazine series. Condensation of 525 with ethoxymethylenemalonic ester, followed by Takano cyclization, stereoselective reduction, and separation of epimers, gave the pentacyclic amidoketone 526, which was elaborated by Biichi's method to the enone 527. Stereospecific alkylation at C-20, reduction, and lactonization then gave (2)-obscurinervidine (50) (Scheme 60). The synthesis of an advanced intermediate 528 in a projected synthesis of alalakine (64) has been reported (SIO),but the work has not been pursued beyond this point. D. VINDOROSINE AND VINDOLINE Owing to its importance as one of the two monomeric units required for the synthesis of the oncolytic alkaloid vinblastine, considerable attention

128

J. E. SAXTON

I-k

*

HO OH 524

50 obscurlnervldine

527

526

Raagenm: I, " 8 0 4 , NaOH; 11, HNO3, AQO; Ill, CICHflMe on K salt; k, HP,Pd/C; v, NaN02,HCI. H20; vl, UAIH4; vll. 5-~Mheiimidopentan-2-one, AcOH; vlU. N2H4; in diathyl etho-lonate; w, AcOH, Ayo,heat, 4 days; xi, LI, h O H . NH3; xii, separationof diasteredsomrs; xill. Et30' BFi; xb, NaHC03, Hfl; xv, H@CHCHO, NaOMe; d. MeSOfl, PY; Wll, B r C H m B , K&, Mil, NaBH4.

SCHEME 60

has been paid to the synthesis of vindoline, and also to its demethoxy analog, vindorosine. As was the case with aspidospermine, the first synthesis of vindoline, by BUchi and collaborators (322,322), has been widely studied, and several new syntheses of the critical intermediates 529 and 530 have been reported. Takano's two approaches to these intermediates were discussed in Volume 17 (I).A second preliminary communication on the same theme followed (313), and details were published in 1979 (324). The N-acyliminium ion cyclization method for the synthesis of nitrogen heterocycles, developed by Speckamp and his collaborators, has also been applied to the synthesis of the vindorosine intermediate 529 (325). In this synthesis, the imine 531, derived from 3-(a-aminophenyl)-N-benzylsuccinimide, was cyclized by base and acetylated to give 532, which was partially reduced to give the substrate 533 for N-acyliminium cyclization. Treatment of 533 with acid then gave the tetracyclic enol ester 534,which was converted into the target tetracyclic amino ketone 529a by obvious methods (Scheme 61) (325). Langlois' notable contributions in respect of vindorosine/vindoline synthesis began with a new preparation of the pentacyclic ketones 530a,b (326). Subsequently, Feldman and Rapoport (32 7) developed an independent synthesis of 530b from a chiral precursor, only to find that it was racemic. Hence, in order to avoid racemization, an alternative route was devised (328).The cause of the racemization during this and Langlois' synthesis

528

0

Me 529a R = H

53oa R = H 53Ob R = O h

529bR=OMe

i, ii coflu' Ac 531

532 iii

I

0

(&&

H

533 Ac

534

Me

0

CO#U'

MeH

0

529a Reagents: i, 'BuOLi, 'BuOH. THF. r l . ; ii, Ac20; iii, NaBH4, H'; iv. HCI, MeOH, 30 min; H+; vii, Met, NaHC03; viii, UAIH4; ix, Hz, WIC.H+;x. H30'.

SCHEME61

(1.

HCi, H20; vi, (CHflHk,

130

.I.E. SAXTON

was later clarified by Langlois and co-workers (329).This important work was discussed in some detail in Volume 50 ( 4 ) . Relevant to the preparation of the ketones 530 is another study by Langlois’ group (320).In the original investigation (316),the sulfoxides 535 were rearranged to the pentacyclic ketones 536. Later (320),the behavior of the unmethylated analog 53% was examined. In toluene-p-sulfonic acid 535c gave a mixture of the vindorosine intermediate 536c, its A1!2-isomer 537, and the Eburna intermediate 538. When the indole nitrogen was protected by methoxymethylation, as in 535d, rearrangement to the eburnamine ring system was not possible, and the only product obtained was the pentacyclic base 536$ which on hydrolysis with aqueous hydrochloric acid gave 536c in an overall yield of 69% (Scheme 62). Natsume and Utsunomiya have adopted a different strategy for the synthesis of the vindorosine intermediate 530a (322,322). In this “singlet oxygen” approach, the critical stage is the coupling of an endoperoxide, derived from the sensitized photo-oxygenation of the dihydropyridine derivative 539, with indole in the presence of a Lewis acid catalyst, which affords the intermediate 540. Elaboration of 540 by relatively unexceptional methods gave the tricyclic ketone 541, the mesylate of which was induced to undergo intramolecular alkylation at the &position of the indole ring. Mannich closure of the resulting indolenine ketone then gave a pentacyclic ketone, which was methylated to give Bilchi’s vindorosine intermediate 530a (Scheme 63). The synthesis of vindorosine (43) and vindoline (44) by Kuehne and his collaborators is particularly notable, since it constitutes the first enantioselective synthesis of these alkaloids (323). Essentially, this consists of an extension of the synthesis ( 4 )of tabersonine (78) and ll-methoxytabersonine (82) by the same group of workers, the last stages being in principle very similar to those employed by Danieli et al. (vide supra, Scheme 24, Ref. 252). Since the starting materials for these syntheses are available in R, S, and racemic forms, both enantiomers and the racemates of these alkaloids are accessible by total synthesis. A particularly ingenious new synthesis of the tetracyclic aminoketone 529a by Winkler er al. (324) constitutes yet another formal synthesis of vindorosine. Whereas Bilchi’s Lewis acid-catalyzed cyclization of an enaminoketone 542 presented serious regiochemical problems (much of the isomeric tetrahydrocarboline derivative was formed) the photochemical cyclization of 543, prepared as outlined in Scheme 64, gave, in high yield, the cyclobutane aminoketone 544, which by a retro-Mannich reaction gave the iminoketone 545. A forward Mannich reaction then gave the desired tetracyclic aminoketone 546. The synthesis of 529a was completed by appropriate displacement of substituents on both nitrogen atoms, followed by

1. ALKALOIDS OF THE ASPIDOSPERMINE

131

GROUP

R’

536a OMe Me

OMe Me

53%

iicz 536b

5 3 5 b H M e 535cH 5354 H i

I

R2

H CHflMe

H

Me H

H

CHflMe

(on535c)

%

“Et

MeS

538 0

/

Reagents: i, TsOH, heat, 5 min; ii, H20, tiCL

SCHEME62

hydrolysis of the orthoester function and Barton decarboxylation (Scheme 64). Padwa’s radical new approach to the synthesis of vindorosine (325) involves the formation of rings C and E by an ingenious tandem intramolecular cyclization-cycloaddition of a transient carbenoid intermediate 547, generated from the diazoimide 548 by treatment with rhodium acetate (Scheme 65). The product of this cyclization is the hexacyclic ketoester 549, which was further elaborated to deacetoxy-17-oxo-14,15ihydrovindorosine (550). Relatively few stages are required to complete the synthesis, and indeed the 11-methoxyderivative of 550 has already been converted into vindoline by Kutney and co-workers (252). However, the final stages to vindorosine have not as yet been reported by Padwa’s group.

132

J. E. SAXTON

539 iil

- ix

1

541

XRI

- xv

I

OAc

43 vindomsine

SCHEME 63

E. THEVINCADIFFORMINE GROUP The anilinoacrylate alkaloids have been the subject of intensive study during the past two decades, and numerous syntheses of vincadifformine, tabersonine, and their relatives have been reported. This area has been dominated by the versatile biomirnetic synthesis developed by Kuehne and

1.

133

ALKALOIDS OF THE ASPIDOSPERMINE GROUP

ii, iii

543

544

545

xi-xv

542

SCHEME.64

1

134

J. E. SAXTON

H p J q

i,ii

_____)

I

iii,iv

Et

547

548

I

0

M

H

I

I

-

vi viii

550

Reagents: i, ( I m ) O ; ii, HQSH&O$h, 'PrMgCI; iii, Nifn3thylindde 3-awtyi chlorkle,4A ml.sieves; iv. k N s , NEb; v. RhAOAch (cat.), PhH, 50°C; vl, Lawe9son's reagent, heat; vii, Raney nickel; viii, HP. PtQ, MeOH. HCI.

SCHEME 65

his co-workers, but there have also been important original approaches from Magnus and Overman and their collaborators. The early synthesis of (2)-vincadifformine and (?)-minovine, by Kutney et af., was discussed in Volume 17 ( I ) ; and details of this work have since been published (326). Details of the synthesis of tabersonine by Takano et

1. ALKALOIDS

135

OF THE ASPIDOSPERMINE GROUP

al., which was also discussed in Volume 17, have similarly been published (274). Chronologically, the next synthesis in this subgroup was one of tabersonine (78). 3-Oxovincadifformine (97), available as a racemate by total synthesis (I), or in optically active form from tabersonine itself, was converted into the diphenylselenyl derivative by reaction of the dianion from 97 with phenylselenyl chloride. Reductive removal of one phenylselenyl group gave a mixture of monophenylselenyl derivatives 551, which on oxidation and spontaneous elimination gave 3-oxotabersonine (107). Carefully controlled reduction then gave tabersonine (78) (Scheme 66) (327). Kuehne's prodigious output on the synthesis of the anilinoacrylate alkaloids began with a synthesis of vincadifformine (76) and its 11-methoxy derivative, ervinceine (87) (328,329).The basic strategy involved the construction of a spirocyclic ammonium salt 552 from either the tetrahydro/3-carboline derivative 553 (328) or the isomeric y-carboline derivative 554 (329),presumably via the common intermediates 555 and 556. When treated with base, ring C in the spirocyclic ammonium salt 552 was opened by

0

97 3-Oxovincadiftormine

107

iii

I

b2Me

78 Tabersonine Reagents: i, LiNPS2, HMPA, THF, -78OC; ii, PhSeCI; iii, PhS: iv, m-CPEA; v. LiAIH4,THF, 0% 4 h.

SCHEME 66

136

J. E. SAXTON

Hofmann elimination, and the unstable secodine derivative 418b thus obtained cyclized spontaneously to give (2)-vincadifformine (76)in high yield (Scheme 67) (328). Subsequently (329), the independent hydrolysis and monodecarboxylation of esters of type 556a was found to be unnecessary, and an even more direct approach to vincadifformine was developed using the dimethyl ester 556b,which, on hydrogenolysis,reaction with the appropriate bromoaldehyde, and treatment with base, suffered spiroalkylation, hydrolysis, and decarboxylation in situ, followed by Hofmann elimination and recyclization, to give vincadifformine (76)(Scheme 67) (329).Extension to the synthesis of ervinceine (87)required, as starting material, the tetrahydro-y-carboline derivative 554b, which was more readily accessible by direct synthesisfrom N-benzyl-4-piperidonethan the isomeric/3-carboline derivative (329). Later, a modified version of the synthesis was reported, in which the important secodine precursor is a tetrahydro-@-carbolinederivative, such as 557-559, rather than an indoloazepine ester, as in 560. This led to a simpler synthesis, the tetrahydro-@-carbolinederivatives required for the preparation of 557-559 being obtained directly from the appropriate tryptamine derivative and pyruvic acid ester. By this route, (2)-vincadifformine (76), (-+)-minovine (N,-methylvincadifformine) and ( 2 )ervinceine (87) were synthesized in comparatively high yield, and in essentially two stages from the starting tryptamine (330). Nevertheless, in many subsequent applications of the Kuehne synthesis the indoloazepine ester 560 is the preferred starting material. This ester, for example, can condense with aldehydes at Nb and the &position of the indole ring to give a bridged azepine, and in a further extension of his synthesis Kuehne and his collaborators have applied this reaction in a synthesis of 3-oxovincadifformine (97) (331). Condensation of 560 with methyl 4-formylhexanoate at 110°C gave a mixture of epimeric bridged azepines 561 (not isolated), which spontaneously fragmented and cyclized to give 3-oxovincadifforminedirectly in 85%yield, based on 560.Alternatively, when prepared under milder conditions (40"C), the same epimeric mixture of bridged indoloazepines 561 could be isolated and benzylated. Fragmentation followed by recyclization then gave a tetracyclic aminoester 562a, which on debenzylation and cyclization gave 3-oxovincadifformine (97) (Scheme 68). The next target for synthesis by Kuehne's group was tabersonine (78),and three syntheses were recorded (I34,323,332-334). Following the synthesis of racemic tabersonine (332) from the indoloazepine ester 560 and the lactol chloride 563,the procedure was refined by use of the chiral epoxyaldehyde 564 (333,334),which eventually afforded enantioselective syntheses of both (-)-vincadifformine (76)and (-)-tabersonine (78).Subsequently (323),

2

2

H 554a R = H 554b R = O M

553

i, ii

555

2

556b x = M e

1

iv. vii (on556b)

(-

R

5)

76)R

Et

Et

COMe

552

v 2

Et H 2

418b

76 vincadntormine R = H 87

Ewinceine R=OMe

SCHEME 67

c02-

138

J. E. SAXTON

SCHEME 68

the availability of the chiral lactol chloride 563 allowed the synthesis, by the same route, of (-)-tabersonine and (-)-11-methoxytabersonine (82), en route to vindorosine (43) and vindoline (44).The third approach resulted in a brief synthesis of (+)-tabersonine from the indoloazepine ester 560 and the unsaturated chloroketone 565 (134). All this work was discussed earlier in Volume 50 ( 4 ) . Kuehne's biomimetic approach also lent itself to the synthesis of minovincine (316), for which two routes were developed. In the first of these ( 3 3 3 , the indoloazepine 560 was condensed with the chloroaldehyde acetal566, the end product of the fragmentation-recyclization reaction of the intermediate quaternary ammonium ion 567 being minovincine ketal (568). Since the starting chloroacetal566 is not readily available, and the hydrolysis of 568 did not proceed smoothly, an alternative was sought. Two variants of the new route were eventually developed. The more efficient of these involved the reaction of the indoloazepine 560 with the sodium salt of formylacetone, which gave the vinylogous amide 569. Cyclization was achieved in a separate stage, and benzylation of the product 570, followed

1. ALKALOIDS OF THE ASPIDOSPERMINE GROUP

139

by fragmentation and recyclization, then gave 571, which was converted into minovincine (316) by standard stages (Scheme 69). The immediate biogenetic precursor of minovincine may well be the biological equivalent of 20,21-Jidehydro-19-oxosecodine(401). The synthesis of such a base is therefore of considerable interest, and Kuehne's second

t

ReeQents: I, THF, heat; il, N b , MCN, M t . 24 h; iii, 20% H2S04. H@, MeOH, 18 h, r.t.; iv,

,Ha, W, THF (or HDIxx)Me, W N ) ; v, HCI,THF; vi, CI(CH2)31. THF, 48 h, r.t.; vii, NEQ, PhM, heat, 28 h; Viii, MI, MecoMe; IX, KOBU'. Lt.; X, PhCHZBr,THF; xi, NEQ,MeOH, I&. 2 h; xii, t&, Pd/C, fl. a(W. K@3.

W, heat, 7 h. SCHEME 69

140

J. E. SAXTON

synthesis of minovincine in fact proceeds via 401 (265). Basically, the route follows that illustrated in Scheme 70 and involves the formation of the vinylogous amide 572. Cyclization of 572, followed by quaternization and fragmentation, gave the stable secodine derivative 401, which, on subsequent thermal cyclization, gave minovincine (316).

565

564

mN

.. H

572

(

'a

SCHEME 70

1. ALKALOIDS OF THE ASPIDOSPERMINE GROUP

141

Several other groups of workers have contributed syntheses of vincadifformine, tabersonine, and their 3-0x0 derivatives, either by independent methods or by variants of the Kuehne biomimetic approach. Imanishi er al. reported a synthesis (336,337) of the ketolactam 573, which has already been converted into tabersonine by Ziegler and Bennett (I).This synthesis followed a strictly conventional approach in which N-ethoxycarbonyl-l,6dihydro-3 (2H)-pyridinone (574) was converted into the allylic alcohol 575 by Grignard reaction followed by allylic alcohol rearrangement. Claisen rearrangement of the latter with ethyl vinyl ether then gave the aldehyde 576, and the remaining stages to the ketolactam 573 were unexceptional, as outlined in Scheme 71. The preparation of 18-methylenevincadifformine (384) by Hijicek and Trojinek (255) is a straightforward application of Kuehne's synthesis, in which 2-allyl-5-chloropentanal (577) was reacted with the tetrahydro-pcarboline ester 578, first in boiling toluene, and subsequently in the presence of base. 18-Methylenevincadifformine (384) was thus obtained in essentially a one-pot preparation. The syntheses of vincadifformine by Szhtay and Das, and their collaborators, simply constitute alternative routes to the important secodine intermediate 418b. Szantay's route (270) was outlined previously (Scheme 33), since it also afforded a preparation of 15,20-dihydrosecodine.As expected, the transient secodine obtained cyclized readily to vincadifformine (76), N,-methylation of which gave minovine. The synthesis by Das et al. (338) started from the previously prepared protected indoleacrylic ester derivative 579, which was activated by mesylation and oxidation and condensed with an appropriate aminoacetal to give the indoloazepine derivative 580. Release of the aldehyde function, followed by cyclization to the quaternary ammonium ion, fragmentation to the secodine 418b,and spontaneous cyclization, then gave vincadifformine (76) in 50% overall yield from 579 (Scheme 72) (338). n

574

575

576

573

0

Reaaents: I, EtMgBr. Etfl. 0%; ii, 1% HCI, MecDMe; iil. EtOCH=CHz, Hg(OAc)z,20s°C, 43 h; iv, HOCH2CH@H, H+ v, KOH. H20, EtOH, heat, 72 h; vi, indoie 3-acetyl chloride; vii, 10% HCI. THF, H20, heat, 8 h; viii, Agfl; ix, PPA, S°C.

SCHEME 71

142

J. E. SAXTON

384 18-Methylenevincadflorrnine

I

580

76 Vif!cadiHmine

418b

m

w;

Rsegents: i, M e w , ii, mCPBA; iii,H&J(CH&CHEtCHC€H&Hfl, py, Nal, r.t.; iv. 1 M HCI, Hfl, THF.

SCHEME 72

As noted previously (Scheme 68), 3-oxovincadifformine (97) is a convenient target for synthesis, as is its 14,15-didehydro derivative, 3-oxotabersonine (107), and several syntheses have been recorded. The synthesis of 3-oxotabersonine by Magnus and his co-workers (339) adopts the strategy developed earlier, in which the rings A-D of the aspidospermine framework of 581 are constructed by a Diels-Alder reaction between an indolo-2,3quinodimethane, generated in situ, and an appropriate dienophile (Scheme 73). The tabersonine ring system was then completed by Pummerer reaction on the related sulfoxide, followed by catalytic removal of the phenylthio group. The 14,15-double bond was introduced into the intermediate 582 via the corresponding thiolactam; oxidative removal of the sulfur then gave the unsaturated lactam 583. The C-16 ester group was introduced by Vilsmeier formylation, oxidation, and esterification, and the synthesis of 3-oxotabersonine (107) was completed by removal of the urethane function. Szlntay's synthesis of 3-oxovincadifformine and 3-oxominovine (340342) makes use of the same starting material 416 that was used in the earlier synthesis of vincadifformine. Here the carbon-carbon double bond

1. ALKALOIDS

OF THE ASPIDOSPERMINE GROUP

143

co2W c02Me

\

' N

co2M

CO2Me

503

&,Me

582

CHO

c02Me 107 3-Oxotabersonine

Re-

I, H2C'CEtCH&H&O&O2Et, 'Pr2NEt, PhCI, heat,

11,

m-CPBA,

111,

TFAA, heat, N. Raney nlckel. EtOAc,

v, p-PhOCaH4PS&PC&OPh-p, THF, -3 to-25% vl, p-MeC&SOCI, 'Pr2NEt. PhCI, heat, WI, POCl3, DMF, r t 1 h then W C , 15 mm , Mil, 2M NaOH. ix. NaH, CIC&Me, THF. x, NaCI&, H2NSO3H. H2C=CMeOAc. MeCOMe. NaH2P04. XI, CH2N2, XII, 1M MOM, MeOH

SCHEME73

and the carbonyl group in 416 were preserved while the P-hydroxypropionic ester function was constructed. Generation of the 3-oxosecodine (584) was then followed by spontaneous cyclization to 3-oxovincadifformine (97), methylation of which gave 3-oxominovine (585) (Scheme 74). Szhntay's later synthesis (34.3) of 3-oxovincadifformine consisted essentially of an independent synthesis (Scheme 75) of Kuehne's tetracyclic aminoester 562a, which on debenzylation cyclized to 3-oxovincadifformine (97). The double bond was then introduced at the 14,15-position via the thiolactam, in a procedure reminiscent of that adopted by Magnus in his synthesis of 3-oxotabersonine (107). Desulfurization of the intermediate unsaturated thiolactam 586 gave yet another synthesis of tabersonine, whereas oxidative removal of the sulfur atom gave 3-oxotabersonine (107). Alternatively, condensation of the starting tryptamine derivative 587 with

144

J. E. SAXTON

0

0

416

I

viii

&Q

H

(%&Me

0

' Fl

SCHEME14

a protected hydroxyaldehyde gave a new tetracyclic aminoester 588, obtained as a mixture of C-20 epimers, which on debenzylation and cyclization gave (2)-vincadifformine (76).It is of interest that both epimers of 588 gave (2)-vincadifformine. Presumably, the C-20 epimer of vincadifformine, formed from the undesired C-20 epimer, epimerized at C-21 via a reversible Mannich fission of the 7,21-bond under the conditions of the cyclization (Scheme 75) (343). The aminoester 587 has also been used in a new synthesis of 19-ethoxycarbonyl-19-demethylvincadifformine (300), which thereby constitutes a second formal synthesis of (+)-12-demethoxy-N-acetylcylindrocarine (516b)(see Scheme 58) (344). Condensation of 587 with ethyl methyl 3formyladipate, followed by dehydration and cyclization, gave a mixture of epimers which, following chromatographic separation, gave the diester 562b, exactly in analogy with the formation of 562a. Cyclization of 562b, followed by removal of the lactam oxygen atom via the corresponding thiolactam, then gave the desired ester 300 (Scheme 75). The synthesis of 3-oxovincadifformine ethyl ester (589) by Danieli et al. (345)also proceeds via thermal cyclization of an appropriate 3-oxosecodine derivative, which in this case was generated by oxidation of the lactam 590 by means of phenylseleninic anhydride (Scheme 76). The most recent synthesis of vincadifformine, 3-oxovincadifformine,and tabersonine is described in yet another substantial contribution from

1.

ALKALOIDS OF THE ASPIDOSPERMINE GROUP

5Ma R = Et5621, R = CH2QEt

587 ix

145

I

iiil

OCOPh

0

588

@ /

N

\

-300

(R = CHD2Et)

76 Vincadmormine

586

78 Tabersonine R = H2 107 3-Oxotabersonine R

xiii

=0

ReagantS: i, 4-fOrmylhexanoicester,PhMe. cat. TsOH. Ar; ii, chromatographicseparation; iii, H2, Pd/C, AcOH; iv,

P$5. THF; v, P-M~C~H~SOCI, HN&, CH2C12, heat; vi, Mel; vii, NaBH4, MeOH; viii, m-CPBA, CH&i2, -24OC; ix, OHCCHEt(CH2)30COPh,PhMe, Ar, heat; x, Hz, P W ; xi, DMF, heat; xii, EtO&ZH&H(CHO)CH2CH&02M, TsOH.H20, PhMe. heat, 12 h; xiii, Raney nickel.

SCHEME 75

146

J. E. SAXTON

0

ii

c----. COpEt

589 Reagents: i, Phenylseleninic anhydride, PhH; ii, PhMe, heat.

SCHEME 76

Kuehne and his co-workers (346),who have developed a new strategy that combines features of the biomimetic synthesis with new, intramolecular free-radical-induced cyclizations and Heck cyclizations. The synthesis of vincadifformine starts with the formation of the tetracyclic amine 591 by a familiar, Kuehne-type preparation from the indoloazepine ester 560. This intermediate consisted of an epimeric mixture in which the desired N,Se-cis-isomer, obtained in 49%yield, predominated. Nevertheless, both epimers could be used in the ensuing stages. Alkylation of 591 with 2,3dibromopropene gave 592, and ring D was then closed by a radical cyclization in which the configuration of the C-20 phenylselenyl group had little, if any, effect. In fact, vincadifformine (76) was obtained in 85%yield from 592a, and in 80%yield from 592b (Scheme 77). For the synthesis of 3-oxovincadifformine, the phenylselenyl group in the intermediate 591 was replaced by a propionic ester residue, again by a radical-induced reaction, this time with acrylic ester, to give the epimeric mixture 593. The final cyclization gave mainly 3-oxovincadifformine, epimerization occurring at C-20 during this last stage. The intermediate 591a was also used in a synthesis of tabersonine. Alkylation of 591a by 2-1,3-di-iodopropene followed by elimination of the phenylselenyl group gave a ring C diene 594, which was cyclized by a reductive Heck reaction with palladium acetate, sodium formate, triphenylphosphine, and base, with formation of tabersonine (78) in 43% yield (Scheme 77) (346).

1.

560

H

591a IU,Se cis 591b NSe trans

592a N,Secis 592b N,Setrans

97

CO2Me

I

vii, viii

76 Vincadlffonine

147

ALKALOIDS OF THE ASPIDOSPERMINE GROUP

1

595

594

I

I

H

co2Me

78 Tabemnine

Reagents: i, MeCHpCH(SePh)CHO, PhMe. heat, 18 h; ii, CHFCBrCH2Br. THF, 5 d; iii, Bu~SnH.AIBN, PhH, 85OC.2 h; iv. BuaSnH, AIBN. CH2=CHC02Me; v, TsOH, PhMe, heat, 18 h; vi, (2)-ICH&H=CHI, K2C03, THF, heat, 6 h; vii, m-CPBA, CHzC12, -75%; viii. PPh3, -3O'C; ix, Pd(0Ac)z. PPh3, HC02Na. NEt3, MeCN, heat, 12 h.

Overman's brilliant strategy (347) for the synthesis of 1l-methoxytabersonine was discussed in Volume 50 ( 4 ) ,but may be illustrated again, since it has also been applied to the synthesis of deoxoapodine (modestanine, 94) (308). The tricyclic urethane 595, prepared by carefully controlled coupling of the hydropyrindinone derivative 596 with the dianion derived from the trimethylsilyl cyanohydrin 597, followed by a simple Wittig reaction, was hydrolyzed to the aminoalcohol598 under extremely vigorous conditions. Condensation with paraformaldehyde then gave an oxazoline 599, which on acid treatment suffered an aza-Cope rearrangement, followed by an internal Mannich reaction and cyclization, to give the indolenine derivative 600. Introduction of the methoxycarbonyl group and debenzylation gave 18hydroxytabersonine (601), which, on reaction with mercury trifluoroacetate followed by sodium borohydride, gave (2)-deoxoapodine (94) (Scheme 78) (308).

148

J. E. SAXTON

viii, ix

Irn

SCHEME 78

Of the major approaches to the vincadifformine ring system, there remains that owing to Magnus and co-workers. Following a preliminary investigation (348)in which it was established that their strategy was compatible with the presence of a methoxyl group at position 11, a synthesis of 11methoxytabersonine (82) was completed (349). In this synthesis, rings A-D of the aspidospermine framework were constructed via a Diels- Alder cycloaddition between an indoloquinodimethane and an appropriate

1. ALKALOIDS OF THE ASPIDOSPERMINE

GROUP

149

dienophile. An added advantage here was the incorporation of an asymmetric unit, which ensured that the cycloaddition was stereoselective. Ring E was closed in the adduct 602 via a Pummerer reaction, and the asymmetric unit was then discarded. The synthesis was then completed by use of methods previously devised (Scheme 79). This work was also discussed in Volume 50 (#), to which the reader is referred for further details. Finally in this section, reference may be made to a synthesis of 18,19didehydrotabersonine (279). Following much preliminary work (350),in which numerous derivatives of 3-oxovincadifformine were prepared, the synthesis of 18,19-didehydrotabersoninewas achieved (352) by condensation of the aldehydo-ester 603 with 2-hydroxytryptamine, and cyclization

\ iii

602

Vii-X

I

SCHEME 79

150

J. E. SAXTON

0

H 604

xiii, xiv

"\ H

&Me

279 18,19Dklehydrotaberine

-agents: i, pyrroliine, K 2 m 3 , Et20; ii, H+CHCO2Me. MeOH, N2. O°C, then heat, 48 h, then H B , AcOH, heat. 8 h; iii, M04,H&, W H ; iv, Cecq, heat. 18 h; v, Phydroxytrytamlne, PhH, heat; vi, partial separation of isomers; vii, Me30*BF4-, CH2C12, Nz,3 d; viii, DMSO, dimsylsodiurn; ix, separation of isomers; x. 'Pr2NH,BuLi, THF, HMPA. Nz, -7@C xi, PhSeCi, THF; di, mCf'BA, CH&. N2, -78%; xiii, t&O+BFi, CHfl2. N2. 18 h; xiv, NaBH4. EtOH.

m,

SCHEME 80

of the product 604. Introduction of the 14,15-doublebond into 605 via the 14-phenylselenyl derivative, and removal of the 3-OX0 group, completed the synthesis (Scheme 80). The intermediate 605 has also been prepared by LCvy and collaborators (352), by essentially the same route; only the very early stages and the order of intermediate steps differed from that shown in Scheme 80.

F. THEVINDOLININE GROUP Two partial syntheses of tuboxenine and one of vindolinine and epivindolinine have been reported by LCvy and collaborators (352-354). Reaction of the indolenine 606, obtained by the hydrolysis and decarboxylation of

1. ALKALOIDS

151

OF THE ASPIDOSPERMINE GROUP

18,19-didehydrotabersonine(279),with sodium in dry tetrahydrofuran, gave tuboxenine (144) directly, together with the by-products, 607 and 608. Presumably, electron addition to 606 gives a radical ion 609,which either can cyclize and pick up a hydrogen atom and a proton to give tuboxenine (144),or can suffer fission of the 6,7-bond, and by obvious processes give 607and 608 (Scheme 81) (353).Subsequently (352), a more efficient process was developed, in which fission of the tryptamine bridge was discouraged by use of the lactam 610,prepared by hydrolysis and decarboxylation of 605. Reaction of 610 with sodium in tetrahydrofuran then gave 3-oxotuboxenine (611) in 55% yield, from which tuboxenine [(?)-la] could readily be obtained by reduction. In their synthesis (354)of vindolinine (109)and its 16- and 19-diastereoisomers, LCvy and collaborators formed the 2,19-bond by sonochemical cyclization of the radical produced by treatment of 19-iodotabersonine (278) with sodium. The yields and proportions of the four 16- and 19stereoisomers varied according to the experimental conditions. At lower ultrasonic intensities, vindolinine (109)and 16-epivindolinine (612)were obtained in a 1:2 ratio; at higher intensities all four stereoisomers were produced (Scheme 82).

606 R = H 2 610 R = 0

A

R

H 607 R = Et

608 R = H Magants: i,

Na,THF, Ar, heat; ii, LiAIH4

SCHEME81

H

Me

144 Tuboxenine R = H2 iic 611 R = 0

152

J. E. SAXTON

+ 278

109 Vindolinine 612 16-Epivinddinine

Reagent: i, ultrasound (500W, 20 KHz), THF, Na,Ar, O°C.

SCHEME 82

G. VALLESAMIDINE

Vallesamidine (6W), the alkaloid of Vullesiu glubru, belongs to a very rare group whose ring system can be generated by migration of C-21 in an aspidospermidine ring system from C-7 to C-2. As a 2,2,3-trisubstituted indole derivative, vallesamidine poses synthetic issues that have not frequently been addressed; its synthesis by Dickman and Heathcock (355,356) is therefore of particular interest. The racemic precursor 614 of the vallesamidine ring system was constructed in high yield in an elegant, four-stage process from 2-ethylcyclopentanone (Scheme 83). Reaction of 614 with N bromosuccinimide, followed by silver nitrate in aqueous methanol, gave a mixture of predominantly the hydroxyamide 615 and the related methoxyamide, by a mechanism that is still obscure. However, the structure and relative stereochemistry of 615 are not in doubt, since they were established by X-ray crystallography. Reductive methylation, followed by another reduction, then gave (?)-vallesamidine (613). Subsequently (353,the bicyclic imine [R-(+)-6161 was prepared by an asymmetric synthesis from 2ethylcyclopentanone, via the ketoester 617 (Scheme 83), which clearly opens the way for an asymmetric synthesis of vallesamidine itself. GROUP H. THEASPIDOFRACTININE Several syntheses of aspidofractinine and its simple derivatives are now available, most of which were discussed in Volume 50 (4). These include LCvy’s remarkably short, direct synthesis, which gave aspidofractinine (146) and 19-hydroxyaspidofractinine (358,359).Ban’s synthesis reported in 1986 (360) was essentially an improvement on his earlier synthesis (362),which was outlined in Volume 17 ( I ) . Here, the Michael addition at the severely hindered position in the anion from the intermediate 618 was achieved by

1.

153

ALKALOIDS OF THE ASPIDOSPERMINE GROUP

i, ii

viii, i x l

% MQ

614

Et

613 Vallesamidine

fbagenb: i, CHFCHCN. NaOEt, THF; ii, Hg, Haney Nickel,KOH, MeOH; iii. 0'02-H4C!-i=CHCO2H,

diown,

heat; iv. Hg, R02, W H ; v. NBS, CHS12; vi, AgNO3, HgO, MeOH; vii, AcOH, H f l ; viii, C H S , NaBH3CN, AcOH: ix. LiAIb; x, (R)-(+)-lphenylethytamine, PhMe, TsOH, heat; xi, H&=CHC02Me; xii, HOCH&H20H, TsOH. heat; xiii. NH40H, H S ; xiv, HCI, H S .

SCHEME83

phenyl chloromethoxyvinyl sulfoxide, which gave the unsaturated sulfoxide 619. Removal of the sulfoxide function gave an enol ether, which, on hydrolysis, gave the ketone 620. Removal of the hydroxyl group in 620 proved not to be straightforward and was eventually achieved via the serendipitous formation of the 2-hydroxyisomer 621 when 620 was treated with thionyl chloride followed by aqueous sodium bicarbonate. Hydrogenation, followed by detosylation with concomitant dehydration, gave the indolenine 622, which, on cyclization and reduction, afforded (+)-aspidofractinine (146) (Scheme 84) (360). Several of the synthetic approaches to the aspidofractinine skeleton involve Diels-Alder addition to a ring C diene system in an aspidospermidine derivative. This is the situation in Magnus and co-workers' first enantioselective approach in this area (4,362),which resulted in the first syntheses of (-)-kopsinine (149) and (--)-kopsinilam (5-oxokopsinine). The same

154

J . E. SAXTON

0

n

SCHEME 84

applies to the synthesis of several aspidofractinine derivatives by Kuehne and his collaborators (4,363).Here, the crucial diene &-oxides 623 were built up via the desethylvincadifformine derivatives 624, which were themselves constructed by the conventional Kuehne synthesis. These diene N oxides did not need to be reduced to the corresponding tertiary amines because the reaction of all three dienes 623a-c with phenyl vinyl sulfone gave the hexacyclic products 625a-c with concomitant reduction of the N oxide function. Further elaboration of 625a-c by unexceptional means then afforded syntheses of pleiocarpinine (626), kopsinine (149), aspidofractine (627), pleiocarpine (157), kopsanone (235), and N,-methylkopsanone (628), as illustrated in Scheme 85. An independent synthesis of the dienes 629 and 630, by Natsume and co-workers (364),constitutes another formal synthesis of these hexacyclic alkaloids. The tricyclic intermediate 631, previously prepared, was converted by a conventional sequence of reactions via the ketoester 632 into the pentacyclic ester 633, which was oxidized to the unsaturated ester 634. Elimination of the C-17 ether substituent then gave 629, and methylation, followed by elimination, gave 630 (Scheme 86). Wenkert's synthesis (365)of the diene 629 made use of the hydroxyester 635, previously prepared (366) as shown in Scheme 87. Straightforward

624 R = H, Me, or CHzPh

62% R = M e 623b R = CH2Ph 62% R = H

iii (-

62%)

co2Me SOzPh

629

62% R = M e 625b R = CHzPh 625c R = H

626 Plebcafpinine R = Me 149 Kopsinine R = H

\

628 N-Methylkopsanone R = Me 235 Kopsanone R = H

(on 626)

CHO

cO2Me 157 Pleiocaipine

627 Aspkbfradine

m n t s : i, mGPBA; ii, PPh3; iii. PhSOZCH=CH2, 100°C, 12 h; iv, Raney nickel, H20, EtOH, heat; V, M O H , mwhrbe,2oooc;Vi, PhNEkj' ho4'; vii, CICO#e. N a D 3 , CHfl2, Nz, r.t.

SCHEME 85

156

J. E. SAXTON

Q-;? N

I

- iii

-

Ho-N+

H 631

Reegem: i, (TMSI)2NLi,HMPA, THF, -70% then NC.CqMe; Ii, H2. WC;iii, ethybna o m ; iv, ~ S q c l , v, B U M , HMPA, THF, -75 to 20°C; vi. NaBH4; vil, MeoCHfi, 'PrNEt2, 40°C; viii, AcOH, W H r.t.; h, p-leninic an-, NB3.85%; x, (TMSi)zNK,THF, -70%; xi, Me9O4; xil, 2% TsOH, W H .

K 0 3 ,CHfl2;

SCHEME86

dehydration of 635, via the mesylate, gave an unsaturated ester, which on oxidation by means of lead tetra-acetate gave 629. Somewhat later, Wenkert and his collaborators reported (367) a synthesis of 17-oxoaspidofractinine (636), via a different diene 637, prepared from Wenkert's pentacyclic unsaturated ketone 638 (293), as outlined in Scheme 88. Attachment of a methoxycarbonyl group to N, in 636then gave dihydrokopsinone (639), identical with the hydrogenation product of kopsinone (165). In an even more recent communication, Wenkert and Liu (295) have reported another preparation of (2)-aspidofractinine (146) by the twostage reduction of the sulfone 495, a late intermediate in a synthesis of (?)-aspidospermidine (Scheme 89). Similarly, 19-oxoaspidospermidine (501), synthesized by Gramain, Husson, and their collaborators, was oxidized by Swern's method to the related indolenine 622, which cyclized to 19-oxoaspidofractinine(640)when

1. ALKALOIDS

OF THE ASPIDOSPERMINE GROUP

157

iv, v

vi I

629

COZMe

Reagents; i, PPA; ii, BzH,;

iii,

treated with acid (297-299,368).The synthesis of 19-oxoaspidospermidine (501) has been described previously (Scheme 55) (297-299). This route superseded an earlier synthesis, which consisted, in its early stages, of the synthesis of the intermediate 641 (368), two variants of which were developed (Scheme 90). Carefully controlled reduction of the enamine

638

637

SCHEME 88

158

J. E. SAXTON

495

146 Aspidofmtlnine

SGPh

k a W n b ; 1, Ni, kb&HOH, Ar; ii, LiAIH,, THF.

SCHEME 89

I 502

H

kPh

\11,

622

v ix

501

640 IsOxaaspidotractinine KH, THF; ii, 4A mol. sieves, CHSI2, heat; iii
SCHEME 90

1.

ALKALOIDS OF THE ASPIDOSPERMINE GROUP

159

double bond in 641, release of the primary hydroxyl group from the ally1 ether, cyclization, and hydrogenolysis of the N-benzyl group then gave 19-oxoaspidoaspermidine,which was oxidized and cyclized to 19oxoaspidofractinine (640)as described previously. The synthesis of kopsijasmine (183), by Magnus et al. (369), broadly follows the theme of their earlier synthesis of kopsinine (149),except that provision was made for the introduction of the 16,17-double bond in the later stages. The pentacyclic diem 642,prepared earlier as an intermediate in the synthesis of kopsan-22-one (235) (370), was alkylated by means of 2-chloroallyl iodide. Internal Diels-Alder cycloaddition then gave the heptacyclic chlorolactam 643. The synthesis was then pursued as in the synthesis of kopsinine as far as the chloroketone 644,which in a two-stage treatment with base suffered methanolysis of the P-dicarbonyl system and elimination of the elements of hydrogen chloride to give the unsaturated ester 645. Removal of the lactam carbonyl group then gave kopsijasmine (183)(Scheme 91). GROUP I. THEMELOSCINE

The only total synthesis reported so far in this small group is that due to Overman and co-workers (308,372). In its early stages this synthesis shared common intermediates with the synthesis of deoxoapodine (Scheme 78). However, in the case of the meloscine approach the tricyclic urethane 595 was subjected only to relatively mild hydrolysis, so that the aromatic amide function remained intact. Condensation of the product of hydrolysis with formaldehyde, followed by the aza-Cope rearrangement and Mannich cyclization,then gave the amidoketone 646.The opportunity was now taken to contract ring C via the photochemical rearrangement of the a-diazo derivative. Removal of the aromatic amide group and cyclization then gave the quinolone 647 as a mixture of C-16 epimers. Introduction of the double bond into the separated epimers 647a and 64% then gave (2)-meloscine (225)and (+)-16-epimeloscine (226),respectively (Scheme 92). J. THE:KOPSINE GROUP

Synthetic work in this most complex group is so far entirely due to Magnus and collaborators. Their very first essay in the area of aspidospermine alkaloid synthesis culminated in a brilliant synthesis of kopsan-5,22dione (236)and kopsan-22-one (235)(370). Although performed without enantioselective control, this synthesis nevertheless established the Magnus strategy and laid the foundation for later, more refined syntheses. The synthesis involved the construcdon of a tetracycle 648 by the Diels-Alder

160

J. E. SAXTON

AcO

/

Reagents; I, KH; II, CHTCHCH~I; ill, PhMe. heat; Iv. TsNHNHz, NaOAc,THF, EtOH, H B ; v, m-CPBA, NaHG03; vi, AgOAc..AcOH,mS°C; vii, UOH. HzO. THF; vili, Jones' reagent; ix, W H , NaOH; x, DBN, DME. h W XI, Ne,anthracene, DME. -30%; Xll, ClCQMe, KZCO3. EbNBUCI; Xlii, CHzNz, THF, EtzO; xiv, BH3.THF; xv, 6M HCI.

SCHEME 91

cycloaddition of an indole-2,3-diquinomethaneand an appropriate dienophile. Replacement of the Nb-substituent by a phenylthioacetyl group, oxidation, Pummerer rearrangement, and cyclization gave the aspidospermine ring system, the presence in ring C of a chlorine atom then allowing the generation of a diene system, as in 649. Allylation at C-6, followed by

1.

ALKALOIDS OF THE ASPIDOSPERMINE GROUP

161

vi-x

H

o

H

225 Meloscine pHatC-16

647s p-H at C-16 647b a-HatC-16

226 Epimelascine a-Hat C-16

Reaeents: i, KOH, Hfl, EtOH, 130°C; ii, (CH20)". CSA, PhH, heat; iii, (Me&H)&Hfi02N3, "BudNBr, 18-crown-6. PhH, Hfl. KOH; iV. W H , Et20. hv; v, KOH, EtOH, Hfl. 150°C; vi. Na, NH3; vii, TsCI, py, CHC13; viii. O ~ N C E H ~ S ~ NaBH4. C N . EtOH; ix. m-CPBA, CH2C12. -7OOC;x, Me& NEt3, r.t.

SCHEME 92

an internal cycloaddition, gave the kopsane framework 650. The structures of both 650 and its predecessor were established by X-ray crystallography. Elimination of phenylsulfenic acid from the sulfoxide derived from 650,

162

J. E. SAXTON

649

vii

I

Ar = pM&X&l&O2

652 Kopsine ReaaentS: i, Zn,AcOH, THF, H@; ii. PhSCHdXXl. rn-CPBA; iii, TFAA, CH 2& ;l hr, PhCI. 130%; v, KN(SiMe& THF; vi, CH2=CHCH& vii, lWC; viii. TsNHNH~.NaOAc, EtOH; h, mCPBA; X, &C; XI,TFM, PhCI, 13oOc; Xii, Li, NH3, THF; xiii, Motf~HOXbUOfl; dv, W , NaOH, W,THF, then HCI, rvi, Ne,C1&, DME, then CICO2Me, Hfl, K-3, PhCH2NEW; Mi, MeflHCH&CCI, NEh, NaBH4, THF; wiii, o-NCS&~H~NO~, PBu, THF; XiX, H& m,.0 8 0 4 , NMO.’BuOH, THF, H S ; mi, (COa)2. DMSO. N&, CHfl2; mii. I D A , THF, - 7 W , a, BH3, THF, then 5M HCI.

w;

SCHEME 93

followed by re-addition, gave an isomeric sulfoxide, which on Pummerer rearrangement gave a protected 5,22-dioxokopsane 651. Obvious methods then gave kopsan-5,22-dione (236) and kopsan-22-one (235) (370), whereas

1.

ALKALOIDS OF THE ASPIDOSPERMINE GROUP

163

the application of a sequence of (mainly) conventional reactions converted the late intermediate 651 into k.opsine (652) (Scheme 93) (4,372).

V. Alkaloids of the Pseudoaspidospermidine-Pandoline Group

A. OCCURKENCE AND STRUCTURE The alkaloids of the pseudoaspidospermidine-pandoline group can readily be imagined to arise, like the aspidospermine group, by the cyclization of a dehydrosecodine derivative, derived from the fragmentation of stemmadenine (653). Whereas iabersonine (78) can arise by cyclization of the biological equivalent of an intermediate such as 654, a simple series of proton exchanges following the fragmentation of stemmadenine can give rise to the isomer 655, which by an exactly analogous process can cyclize to give the precursor 656 of pandoline (657) and the other alkaloids of this group (Scheme 94). The recent reports of the occurrences of these alkaloids are given in Table 11. Pandoline (657) has been isolated from the leaves and stems of Melodinus polyudenus (Baill.) Eloiteau (99, 373), from Ervutumiu obtusiusculu Mgf. (373),and from the leaves of E. lifuunu Boiteau (374),Tubernuemontunu citrifoliu L. (32),Stenosolen heterophyllus (Vahl) Mgf. (29, 375), and E. orientalis (R. Brown) Domin (374). 20-Epipandoline (658) occurs in the first four of these species, and pandine (659) in the last four, and also in the stems and leaves of Tubernuemontuna punducuqui Poir (376). New alkaloids include (+)-19-hydroxy-20-epipandoline(660), which has been found in the stem bark of French Guyanan Tubernuemontunu ulbifloru (Miq.) Pull. (377).The UV and IR spectra of this alkaloid clearly indicate that it belongs to the anilinoacrylate group, and the mass spectrum indicates that it contains two hydroxyl groups in the piperidine part of the molecule (peak at d z 156).A detailed analysis of its 'H NMR spectrum and comparison with those of pandoline (657) and 20-epipandoline (658) reveal the structure 660, the high positive optical rotation indicating that it has the absolute configuration shown; the stereochemistry at C-19 is unknown. The parent alkaloids of this group, (+)-2OR-pseudoaspidospermidine (661) and (-)-2OS-pseudoaspidospermidine (662), are also among the new alkaloids, having been found in the leaves, stem bark, and root bark of the Madagascan shrub Pundtzcu boiteuui (378).( +)-2OS-1,2-Didehydropseudoaspidospermidine (664) occurs in the same species, whereas its 20R epimer (663), already known, has been found in the leaves of Tubernuemontuna eglundulosu Stapf (28), together with its hydroxyl derivative, 20shydroxy-1,2-didehydro-pseudoaspidospermidine(665). Of the analogs of

164

J . E. SAXTON

653 Stemmadenine

78 Tabfmonine

SCHEME 94

vincadifformine in this series, (+)-2OR-pseudovincadifformine (666) was already known and has been isolated more recently from the leaves and stems of Melodinus polyadenus (99) and from the leaves of T. eglundulosa, where it occurs with its 20s-epimer 667, which was previously unknown as a natural product. A dihydroxy derivative, identified as (+)-2OR-18,19dihydroxy-pseudovincadifformine (668), has been found in T. ulbiflora (377); again, the configuration at C-19 is unknown. The remaining new alkaloid in this group is dichomine, which occurs in the leaves and twigs of T. eglandulosa (28), and in rather greater amount in the leaves of T. dichotorna Roxb. (379). A complete analysis of its proton and 13CNMR spectra revealed that it has the structure 669. This structure, together with the relative stereochemistry depicted, was confirmed by the coupling constants of all the signals in the 300 MHz proton NMR spectrum, and by comparison with expected values, deduced with the aid of Dreiding models. The absolute configuration was assumed to be 14S, since all

TABLE I1 PSEUDOASPIDOSPERMIDINE A N D PANDOLINE GROUP

Alkaloid Pandoline

Pandine

20-Epipandoline

( +)-19-Hydroxy-20-epi-pandoline ( + )-2OR-1,2-Didehydro-pseudoaspidospermidine

(+)-2OS-1,2-Didehydro-pseudoaspidospermidine ( + )-2OR-Pseudoaspidospermidine ( - )-2OS-Pseudoaspidospermidine 20S-Hydroxy-l,2-didehydro-pseudoaspidospennidine ( + )-2OR-Pseudovincadifformine 20s-Pseudovincadifformine

+

( )-20R-18,19-dihydroxyy-pseudovincadiffonnine

Dichomine

Plant Source Ervatamia lifuana Ervatamia obtusiuscula Ervatamia orientalis Melodinus polyadenus Stenosolen heterophyllus Tabernaemontana citrifolia Ervatamia lifuana Ervatamia orientalis Stenosolen heterophyllus T a b ~ i i t i ~ i i i ~ i iiiirifuiiu ia~~i Tabernaemontana pandacaqui Ervatamia lifuana Ervatamia obtusiuscula Melodinus polyadenus Tabernaemontana citrifolia Tabemaemontana albiflora Tabernaemontana eglandulosa Pandaca boiteaui Pandaca boiteaui Pandaca boiteaui Tabemaemontana eglandulosa Melodinus polyadenus Tabernaemontana eglandulosa Tabernaemontana eglandulosa Tabernaemontana albiflora Tabernaemontana dichotoma Tabernaemontana eglandulosa

Plant Part" L L L, s L L L L L i L, s L L L, s L

Structure 657

659

L, s L L

65%

663 664

661 662 665 666 667 668

L L

374 373 374 99,373 29,375 32 374 374 29,375 32

660

L L,SB,IU3 L,SB,RB L,SB,RB L

Ref.

669

376 374 373,374 99,373 32 377 28 378 378 378 28 99 28 28 377 379 28 (continues)

TABLE I1 (continued) ~~

Alkaloid (+)-Ibophyllidine Ibophyllidine N-oxide 20-Epi-ibophyllidine Desethylibophyllidine 19-Hydroxyibophyllidine 19R-Hydroxy-20-epi-ibophyllidme 19s-Hydroxy-20-epi-ibophyllidine 18-Hydroxy-20-epi-ibophyllidine

Plant Source Ibophyllidine and iboxyphynine group Anartia meyeri Tabernaemontanaalbijlora Tabemaemontana flavicans Tabernaemontanaf2avicans Tabernaemontana albiflora Amcampta disticha Tabernaemontana albiflora Tabemaemontana albiflora Tabernaemontana albiflora Tabernaemontana albiflora Tabernaemontana albiflora

~~~~

Plant Part" SB TrB S S TrB TrB SB SB

Structure 672

673 674

SB

675 676 671

SB

678

Ref. 382 380 381 381 380 383 380 384 384 384 384

L. leaves; SB, stem bark RB.root bark R. roots: S, stems: WP,whole plant: C, cell cultures; F. flowers; P, pericarp; E, endocarp; Sd. seeds; AP, aerial parts; TB, trunk bark T, twigs; Df. double flowers: Fr, h i t s ; Sdl, seedlings; BB, branch bark Tr. trunk; B. bark Br, branches.

1.

167

ALKALOIDS OF THE ASPIDOSPERMINE CROUP

known Tubernuernontuna alkaloids have this configuration. Proof was obtained by reduction of dichomine (669) with lithium aluminum hydride, which gave 14S,20R-velbanamine (670), presumably by the mechanism shown in Scheme 95. The rather strained ring system in dichomine may well originate from an alkaloid such as 20R-hydroxy-1,Zdidehydropseudoaspidospermidine (671)by a series of simple Mannich processes and prototropic shifts, as illustrated in Scheme 95.

OH

'OH

c02Me

c02Me

660 (+)-1SHydroxy-20-epipandoli

659 Pandine

661 2

m

-

Vidine R' = H, $ = Et

682 20S-Pseudoespklospemidirte R' = Et, R~= ti

663 20R1,2-Didehydropseudoaspidospermidine

H

Et

664 X ) S - 1 , 2 - D i d e h y d r o p s e u s p i ~ ~ ~ i n eEt 665 20sHydroxy-1,2-didehydro-

H

pseudoaspidospennidine

666 20R-PseudovincadMormine a-Et 667 20SPseudovincedi(formine p-Et

OH

668 (+)-20R-18,19-Dihydroxypseudovincadifforrnine

Et

168

J. E. SAXTON

669 Dichomine

H

H 670 14S,20RVelbanamine

SCHEME95

B. IBOPHYLLIDINE AND IBOXYPHYLLINE GROUP Ibophyllidine (672) has been shown to occur in the trunk bark of Tubernuemontuna ulbiflora (380),in the stems of Peruvian T. flavicans (381),and in the stem bark of Anarfia meyeri (G. Don) Miers (382),and its &-oxide occurs in T. flavicans (381). New alkaloids include 20-epi-ibophyllidine (673), a constituent of the trunk bark of T. ulbifloru (380),and desethylibophyllidine (674), which occurs in the trunk bark of T. ulbifloru (380) and in Anucumpta disticha (A.DC) Mgf. (383). The structures of 20-epiibophyllidine (673) and desethyl-ibophyllidine (674) were determined largely by a complete analysis of their 400 MHz proton NMR spectra, and comparison with that of ibophyllidine (380).The remaining four new alkaloids have been isolated from the stem bark of T. albiflora; these are 19-hydroxyibophyllidine (675), 19R-hydroxy-20-epi-ibophyllidine(676), and its 19s-epimer 677, and 18-hydroxy-20-epi-ibophyllidine (678) (384). There are no recent reports of the occurrence of iboxyphylline (679).

1.

ALKALOIDS OF THE ASPIDOSPERMINE GROUP

169

C. CHEMISTRY OF THE PSEUDOASPIDOSPERMIDINE-IBOPHYLLIDINE GROUP

There is relatively little chemistry to report on this small group of alkaloids. (-)-2OS-Pseudovincadifformine (680), prepared from catharanthine by reduction (sodium borohydride, then hydrogen-platinum oxide) followed by oxidation (mercuric acetate), undergoes the same rearrangement as vincadifformine (76) when oxidized, then treated with triphenylphosphine and acetic acid. The products are pseudovincamine (681) and its C-16 epimer 682 (Scheme 96), and it is of interest that these compounds were prepared by this transformation well before this ring system was found in Nature (385). The alkaloids of this group appear to behave differently from those of the vincadifformine (vide supra) group on photochemical oxidation. Iboxyphylline (679) is rapidly oxidized at C-16 to give a hydroxyindolenine 683,but only in the presence of oxygen and in the absence of cyanide (227). D. SYNTHESIS OF THE PSEUDOVINCADIFFORMINE-PANDOLINE GROUP Several syntheses of these alkaloids are on record, the great stability of the anilinoacrylate function arid the preference for the desired relative stereochemistry at positions 7, 3, and 14 rendering them a relatively easy target. The first synthesis in this area was that of Levy and collaborators (386),who modified their synthesis of 3-oxovincadifformineby condensing 3-aminoethyloxindole with the aldehydoester 684. The tetracyclic lactam nitrile so produced was methanolyzed and cyclized, via the iminoether 685, to 3-oxo-desethylvincadifformine (686),by a similar procedure to that used in the synthesis of 3-oxovincadi€formine.Alkylation of 686 adjacent to the lactam carbonyl group then gave 3-oxo-pseudovincadifformine (687), of unspecified stereochemistry at 42-20 (Scheme 97). Kuehne’s biomimetic approach has also been applied to syntheses in this group, and inevitably several variations on this theme have been published, which have allowed almost all the alkaloids of this group to be synthesized. The first synthesis (387) involved the condensation of the ubiquitous indoloazepine ester (560) with 5-bromo-4-ethylpentana1,which gave a mixture of the crystalline C-20 epimeric pseudovincadifformines 666 and 667, presumably via the intermediate secodine 688 (Scheme 98). The availability of the pure, crystalline epimers 666 and 667 allowed the stereochemistry at C-20 to be firmly established. Thus, according to X-ray crystal structure analysis, pseudovincadifformine (666),which can also be obtained by hydrogenation of pseudotabersonine, has a /3-hydrogen at C20, and is the major constituent of natural pseudovincadifformine, which

Ma

\

0 H

602Me

H

672 (+)-lbophyllidine R = a-Et 673 20-Epi-ibophyllidine R =

c02Me

675 19-Hydroxyibophyllidine

& Et

674 Desethylibophyllidine R = H

676 19RHydroxy-20-epi-ibophyIlidine 19R 677 19SHydroxy-209pi-ibhyllldine 19s

678 18-Hydroxy-20-epi-lbophyllidine

679 lboxyphylline

883 lboxyphylline hydroxyindolenine

680 (-)-20S-Pseudovincadmormine 681 20SPseudovincarnine &OH 682 20S16Epipseudovincamine a-OH

Reagents: i, o-O2NCaH&O$i;

ii, PPh3, AcOH, H@.

SCHEME 96

H

o

V

iw H

CN 684R

iv

CN

+ /

N

H

/

' c02Me

N' 685

OM c02Me

686 20-Desethyl-3-oxovincadifforrnine 3-0xopseudovincadifformine

V C687

Reagents: I, PhH, heat; ii, MeOH, HCI, -2OOC; iii, Me30+BFd;iv, NaH, DMSO, heat; v. LDA. Etl.

SCHEME 97

i, ii

-

c02Me

560

,I

c02Me

H

666 Pseudovincadifforrnine a-Et

667 20Epipseudovincadifformine p-Et Reagents: i, BrCH2CHEtCHfiH2CH0, MeOH; ii. NEt3, 4OoC.

SCHEME 98

172

J. E. SAXTON

also appears to be a mixture of the C-20 epimers 666 and 667. In turn, this would appear also to suggest the intermediacy of an achiral secodine derivative related to 688 in the biosynthesis of these alkaloids. 20-Epipseudovincadifformine is thus 667. This work neatly explains the discrepancy in earlier proposals for the stereochemistry at C-20 in pseudovincadifformine (387). The same approach has also been modified to encompass the synthesis of the C-20 epimeric pandolines. Condensation of the indoloazepine ester 560 with the epoxyaldehyde 689 gave an intermediate quaternary salt 690, which on fragmentation and recyclization gave, via an intermediate secodine, a mixture of pandoline (657) and 20-epipandoline (658) (Scheme 99) (387).In a later, improved synthesis of the pandolines (332),the quaternary ammonium ion 690 was prepared by condensation of 560 with the chlorolacto1 691in the presence of toluene p-sulfonic acid at room temperature. The conversion was then completed by adding triethylamine and heating the mixture under reflux for 48 h. Pandoline (657) was thus obtained in 46% yield and 20-epipandoline (658) in 27% yield. The synthesis of (t)-20-epi-pseudoaspidospermidine (20s-pseudoaspidospermidine, 662) and (?)-2O-epi-pseudovincadifformine (20spseudovincadifformine, 667) by Wenkert et al. (388) consists of a remarkably brief sequence from 3-acetyl-5-ethylpyridine, which was

Q-CH i, or ii,iii

N

560

H

0 co2Me

H2C/--\CEtCH2CH&HO

691

Et

Reagents: i, 689, MeOH, Nz, heat; ii, TsOH, MeOH, Nz,r.t.; iii, NEts, heat, 48 h.

&2hk

657 Pandoline p-Et 658 Epipandollne a-Et

SCHEME 99

1.

ALKALOIDS OF THE ASPIDOSPERMINE GROUP

173

reduced to the tetrahydro stage and coupled with indole-3-acetic acid. The crucial stage in the synthesis is a Lewis acid-catalyzed double cyclization of the product 692, which gave three stereoisomers, 693-695, one of which, 693, on reductive removal of both oxygen atoms, afforded 20-epipseudoaspidospermidine (662). N-Methoxycarbonylation, followed by photolytic rearrangement, then gave 20-epi-pseudovincadifformine (667) (Scheme 100). The synthesis of (2)-pseudovincadifformine (666) by Szhtay and collaborators (270) accompanied the same workers' synthesis of vincadifformine, discussed previously (Scheme 33). Thus, application of the Polonovski reaction to the N-oxide of tetrahydrosecodinol (417) gave the precursor 418b of vincadifformine, and also an isomeric secodine 696, which spontaneously cyclized to pseudovincadifformine (666) (Scheme 101). Kuehne's second synthesis of (2)-pseudovincadifformine (666) (389) is distinctly longer than the first one and was achieved in the course of a

SCHEME 100

174

J. E. SAXTON

666 Pseudovincadifforrnine

, Reagents: i, m-CPBA; ii, A c ~ Opyridine.

SCHEME101

program aimed at developing a total synthesis of vinblastine and related oncolytic alkaloids. In this new synthesis the required tetracyclic framework 697 was obtained by condensation of the indoloazepine ester (560)with the aldehydoester 698,and benzylation of the product 699. Fragmentation to the fugitive secodine, followed by cyclization, then gave a mixture of epimers, 697a and 697b. These compounds were converted into the corresponding primary tosylates 700a and 700b,which were separated by chromatography, The epimer 700b, when heated at llO"C, epimerized and cyclized to an intermediate 701, which, following debenzylation, afforded 20-epi-pseudovincadifformine (667) (Scheme 102) (389). For steric reasons, the epimer 700a did not cyclize as readily, but did so after debenzylation (and partial epimerization), via 702a and 702b. Chromatographic separation of the product then gave pseudovincadifformine (666)and C/D trans-pseudovincadifformine (703)(Scheme 103) (389). A third synthesis from Kuehne's group proved to be even more versatile and led to syntheses of pseudovincadifformine,pseudotabersonine, ibophyllidine, and iboxyphylline, as well as ibogamine and coronaridine (390).The extremely versatile intermediate, appropriately named versatiline (704), was prepared by the route outlined in Scheme 104. Debenzylation of 704, followed by hydrolysis and cyclization, gave a regio- and stereoisomer 705 of pseudotabersonine that, on oxidation to the dienamine 706,then partial reduction, gave pseudotabersonine (707); further reduction then gave pseudovincadifformine (666)(Scheme 104) (390). An ingenious new approach to the synthesis of pseudotabersonine (707) has been developed by Carroll and Grieco (391). Here the intermediate oxindole 708 was constructed by a remarkable process in which the anion from the precursor oxindole 709 was alkylated by Grieco's spiroaziridinium triflate 710.N-Benzylation of the product 711,followed by a reverse DielsAlder fragmentation, then an intramolecular aza-Diels- Alder cyclization, gave the tetracyclic oxindole 708.Introduction of the three-carbon unit into position 2 in 708 was achieved by condensation with 2-lithio-lJ-diethoxy-2-

1. ALKALOIDS OF THE

ASPIDOSPERMINE GROUP

175

701 €67 20-Epipseudovincadiine Reagents: i, MOH, Ar; ii, PhCHnBr, Ar; iii, MeOH, NEt3, Ar, heat; iv, LiAIH4, THF; v. TsCI, DMAP. py, Ar; vi, separation of isomers; vii, PhMe, 110°C; viii, H2 PdE. AcOH.

SCHEME 102

propene, which gave the unsaturated acetal 712. Hydrolysis of the acetal function, and dehydration with concomitant fission of the 3,7-bond then gave the required secodine derivative in situ, which promptly cyclized to the pentacyclic aldehyde 713. The remaining stages, which appear to be trivial, proved to be far from straightforward, but were eventually achieved via the pentacyclic base 714, as shown in Scheme 105, to give (2)-pseudotabersonine 707. Following their recent synthesis of (2)-vincadifformine (Scheme 75) (343,344,Szdntay and his collaborators have contributed another synthesis of pseudovincadifformine and its epimers (392). Condensation of the tryptamine derivative 587 with the aldehydoester 698 gave, via an unstable secodine derivative, the epimeric tetracyclic esters 715, which, without separation, were subjected to debenzylation, with partial epimerization and cyclization. The product, a mixture of the two cis C/D-fused pentacyclic

176

7028

668 pseudovlncad~onnlne

J. E. SAXTON

.

"L"

703 C/D trans-Pseudovlncadmormlne

Reagmis: I, MI%,THF; 11, TsCI, DMAP, py, Ar; Ill, separation of Isomers; hr, H2. P*,

AcOH; v, PhMe, 110%.

SCHEME 103

esters 716 and 717, together with the two tetracyclic esters 718 and 719, was cyclized by more vigorous treatment to give a mixture of 716, 717, and the trans CID-fused pentacyclic ester (720). Separation, and removal of the 21-0x0 group from these three compounds, then gave (&)pseudovincadifformine (666),(~)-2O-epi-pseudovincadifformine(667), and (~)-14-epi-pseudovincadifformine (721). Reaction of the mixture of 716 and 717 with phosphorus pentasuwde gave a mixture of the 21-thio compounds 722 which, when treated with toluene-p-sulfinyl chloride, gave a single product, formulated as 723. Oxidation by means of rn-chloroperben-

1.

ALKALOIDS OF THE ASPIDOSPERMINE GROUP

177

iii &2Me

704 iv - vi

I vii

m

602Me 705

viii

I

707 Pseudotakersonine Reagents: i. W H , m0C, 2 h; ii, PhCH$r, THF, heat: iii, NEt3, MeOH, heat; iv, H2, Pd/C; V, HCI, ~

~M, 0 H+, ;

llO°C; vii, (PhC00)z; viii, NaBH4.

SCHEME 104

zoic acid resulted in elimination, and replacement of sulfur by oxygen, with the formation of (+)-2l-oxotabersonine (724) (Scheme 106) (392). The most recent synthesis of pseudovincadifformine consists of yet another distinguished contribution from Kuehne's laboratory (346)and offers

178

I. E. SAXTON

I CHZPh

CHZPh 708

'

N

-

-

712

PhH&

CHO

713

xii

714

707 Pseudotabemnine

Reagents: i, PhMe, NEh, heat; 11, sepratbn of cis and trans isomers; iii,KN'Pr2,THF, -76°C; iv, 710, -78°C to r.t.; KOBU', THF. PhCHS, BUNI; Vi, BF3.EtzO. PhMe, l@C; Vii, (EtOkCHCLiSH2; Mil. TsOH, MeCOMe, H a , r.t.. then F N , NEh, 80°C; ix, 2M HCI, 120°C; x. neutral A1203; xi, lithium 4,4'di-t-butylbiphenylkle,THF. -5°C; xii. UNPr'2, THF, -7!3OCto O°C; then CICOzMe, -78°C to r.t.

V.

SCHEME 105

another example of the closure of ring D by a free-radical-inducedcyclization. Alkylation of Nbin the indoloazepine ester 560 by means of 2-ethylallyl bromide gave the tertiary base 725, which reacted with phenylselenylacet-

1.

179

ALKALOIDS OF 'THEASPIDOSPERMINE GROUP

aEt 0

'

\

(on 717)

c O2Me 710 a-Et 719 PEt

iv

I

720

716 a-E3

667 20-Epipseudovincadflorrnine

c02m

c02Me

722

.

723

vil/

721 14-Epipseudovincadflorrnine

724 21-Omcopseudotabersonine

Reagents: i, PhMe, TsOH, Ar. heat, 48 h; ii, I$,Pd/C; iii, PhMe, TsOH, heat, 16 h; iv, P4S10. then Raney nickel; v, P4s10; vi, pMeCaH4SOC1,'PrzNH; vii, rn-CPBA.

SCHEME106

aldehyde to give, in 16%yield, the tetracyclic intermediate 726, as always via an unstable secodine derivative. Free-radical-induced cyclization of 726, by means of tributyltin hydride and aza-bis-isobutyronitrile, then gave a

180

J. E. SAXTON

mixture of pseudovincadifformine (666) and 20-epi-pseudovincadifformine (667) in a combined yield of 85% (Scheme 107). E. SYNTHESIS OF THE IBOPHYLLIDINE-IBOXYPHYLLINE GROUP

Ibophyllidine, iboxyphylline,and their close relatives have also lent themselves to synthesis by the Kuehne biomimetic approach. The first essay in this area involved the synthesis of desethyl-ibophyllidine (674), which had recently been isolated from Tubernaemontunaalbiflora (380). With 4chlorobutanal, the indoloazepine ester 560 condensed to give an epimeric mixture of intermediate quaternary salts, formulated as 727a, either of which, on reaction with triethylamine, gave desethyl-ibophyllidine (674) via a reactive secodine derivative (Scheme 108) (331). For the synthesis of the ibophyllidines themselves, Kuehne and his coworkers condensed the indoloazepine ester with 4-bromohexanal, but this procedure ultimately gave 20-epi-ibophyllidine (673) as the sole product, via 7271, (Scheme 108) (393). This difficulty was circumvented by the adoption of a modified strategy, which involved the preparation of the tetracyclic intermediate 728 (Scheme 108) by the standard Kuehne method. The fivemembered ring D was then added in the final stages of the synthesis. It is of interest that the epimeric mixture of quaternary bromides 729 fragmented

667 PEpipseudovincedHformine

Reaaents: i, CH&EtCHflr,

K$%,

666 Pseudovincadflormne

WCOMe; ii. PhSeCH@O, P h M , heat, 8 h; iii, BuaSnH. AIBN, PhH.

SCHEME 107

1.

ALKALOIDS OF THE ASPIDOSPERMINE GROUP

181

727a R = H 727b R = Et Et0 zCHrI

674 Desethylibophyllidine R = H 673 2O-Epi-ibophyliidi~R = Et

I

vi. vi

672 lbaphyllidine

THF. 20%, 3 h; it, NEb, MeOH; iii. 4-bromhexanal, THF. W C ; hr. OH, W C , : h; V. PhCHa; vi, MeOH, 10% Ha, Hfl; vii, H2. WC,AcOH.

Reagents: i, CCH$H$H$HO,

SCHEME 108

and cyclized to give a single product containing the stereochemistry shown in 728. The vital reversal of the configuration at C-3 and at C-7 presumably occurred during the final hydrogenolysis-hydrolysishydrogenation stage, since protonation at C-16 affords an indoleninium ion that can equilibrate with the 3,7-epimeric series by reversible Mannich

182 fission of the 3,7-bond. The final hydrogenation, following cyclization of the intermediate aminoketone, results in the desired configuration at C-20 by delivery of hydrogen to the less hindered face of the molecule (Scheme 108) (393). Other workers have also used variations of the Kuehne biomimetic approach in the synthesis of ibophyllidine. Das and collaborators (338) prepared the secodine precursor 730 by an obvious modification of the route used in the synthesis of vincadifformine. Acid hydrolysis of 730, followed by quaternization, fragmentation, and cyclization, then gave the ibophyllidine ring system. Use of the racemic aminoacetal (RS-731)in the first essential stage in Scheme 109 was reported ultimately to give ibophyllidine (672) and 20-epi-ibophyllidine (673),whereas the simpler aminoacetal 732 gave desethyl-ibophyllidine (674).Subsequent repetition of this synthesis (394), using the chiral S-aminoacetal (S-731)resulted in an enantioselective synthesis of (+)-2O-epi-ibophyllidine [(+)-6731.Similarly, the enantiomeric Racetal (R-731)was converted into (-)-2O-epi-ibophyllidine [(-)-6731.Contrary to the earlier report, it now appears that no ibophyllidine is produced in these syntheses.

672 lbophyllidine a-Et

674 Desethylibophyilkline

673 (+)-2O-Epl-ibophyilidine p-Et

Reagent: i, 1M HCI, Hfl, THF

SCHEME 109

1. ALKALOIDS OF THE ASPIDOSPERMINE GROUP

728

183

733a

+

/ ii - iv

7331,

734 734b 3,7-bis-epimer

735a.b

736a R' = H. R2 = Me 736b R' = Me, R'= H

v (on736b)

p

Y

Y

O

H

679 lboxyphylline

Reagents: i, H2, Pd(OH)z/C, &OH; ii, CHfl (gas), MeOH, O°C; iii, HCI, Et20, heat; iv, separation of isomers; v, LIBffdIH. THF. -78OC.

SCHEME 110

184

J. E. SAXTON

Kuehne's first synthesis (395) of iboxyphylline started essentially from the tetracyclic base 728 and was neither regiospecific nor stereospecific. Debenzylation of 728 gave an epimeric mixture of bases 733a,b which, when reacted with formaldehyde and hydrolyzed by acid, underwent a Mannich cyclization, with formation of no fewer than six aminoketones, 734-736 (Scheme 110), one of which, following separation by chromatography, gave iboxyphylline (679) on reduction. Since the structure and stereochemistry of iboxyphylline were established by X-ray crystallography, the iboxyphylline precursor must have the stereochemistry shown in 736b. This synthesis was soon superseded by a second synthesis of iboxyphylline, which also afforded a second synthesis of ibophyllidine (390). For the preparation of these alkaloids it was obviously vital to ensure the cis stereochemistry of the CID ring junction, whereas in the intermediate base 705, obtained from (racemic) versatiline base, as described previously (Scheme 104), this ring junction is trans. The change of stereochemistry was achieved by photochemical oxidation to the amidoketone 737, followed by ketone protection and hydrolysis, which gave the amine 738. A Mannich reaction on the derived aminoketone completed the closure of ring D, and equilibration with acid followed by reduction then gave iboxyphylline (679), with the desired stereochemistry (Scheme 111). Alternatively, acid-

679 lboxyphylllne

H &Me 672 ibophyllidine

738

ReaaentS: 1. 0 2 , C m 3 , hv; ii. (CHBH)g, BFa.Etz0,PhH; iii, NaOMe; iv, CH20, H;' v, H30'; vi, Selectride; vll. HCI, &OH; viii. Hg, W/C.

SCHEME 111

1. ALKALOIDS OF THE ASPIDOSPERMINE GROUP

185

catalyzed equilibration of 737, with concomitant hydrolysis of the amide function and cyclization, completed the formation of the ibophyllidine ring system and hydrogenation then gave ibophyllidine (672). The epimerization at positions 3 and 7 in these intermediates appears not to be possible in compounds containing a preformed six-membered ring D, as in the enamine 705 (390). Finally, two syntheses of desethyl-ibophyllidine (674), by Bosch and collaborators, may be described. In the first of these (396,397),the tetracyclic tetrahydrocarbazole derivative 739 was constructed, as outlined in Scheme 112. The 6,7-bond was then formed by a tandem Pummerer rearrangement-cyclization reaction, the phenylthio group was removed from the product 740 by hydrogenolysis, and the synthesis was completed by photochemical rearrangement of the methoxycarbonyl group. The second synthesis (398) is an extraordinarily simple and direct one, in which the protected tetracyclic indoloquinolizidine aldehyde 741, obtained as two C-14 epimers and prepared as shown in Scheme 113, was subjected to cleavage of the 3,Nb-bondby reaction with benzyl chloroformate in aqueous tetrahydrofuran. The resulting C-3 alcohol was converted into the corresponding nitrile 742, which was again obtained as a mixture of C-14 epimers, regardless of whether the starting material 741 was either

0

0

Ha.

Aeegents: I. U. NHa -78% Ii, phsocn=CH2, BOH; Ui, 2M 90%; hr. NaOH. H&; V, F'hNHNH.r. BOH, heat; vi. W H . S0C: Mi. NCCqMe. UIA. THF, HMPA, -78%; vlH, TFAA, TFA, 80% ix, Raney nickel w2) EtoH; , x, k.

SCHEME 112

186

J. E. SAXTON

iv - vi

H

74 1

H

742

vii

I

0

0

U

COZMe

COzMe

I

I

674 Desethylibophyilidine

Reagents: i, NaEH4, &OH; ii, AcOH, Hfl; iii, (CHZOH)~, CaCI2, Amberlyst-15; iv, CICGCHZPh, Hfl, THF, N a m 3 , 50°C; V, Ac~O.DMAP; Vi, NaCN, DMSO, 95’C; vii, HCI (g), MeOH, 4OC. 16 h, then Hz0,W min.

SCHEME113

of the two pure epimers or the epimeric mixture. When the nitrile 742 was treated with hydrogen chloride in methanol, and then water, no fewer than six chemical processes ensued, and the product was desethylibophyllidine (674).

References 1. G. A. Cordell, in “The Alkaloids” (R. H. F. Manske and R. Rodrigo, eds.), Vol. 17, p. 199. Academic Press, New York, 1979. 2. G . W. Gribble, in “The Alkaloids” (A. Brossi, ed.), Vol. 39, p. 239. Academic Press, New York, 1990. 3. G. A. Cordell and J. E. Saxton, in “The Alkaloids” (R. Rodrigo, ed.), Vol. 20, p. 3. Academic Press, New York, 1981. 4. J. E. Saxton, in “The Alkaloids” (G. A. Cordell, ed.), Vol. 50, p. 343. Academic Press, New York, 1997. 5 . G. M. T. Robert, A. Ahond, C. Poupat, P. Potier, C. JollBs, A. Jousselin, and H. Jacquemin, J. Nat. Prod. 46, 694 (1983). 6. K.-H. Pawelka and J. StBckigt, Z. Naturforsch. Ted C 41, 385 (1986). 7. M. A. Mroue, M. A. Ghuman, and M. Alam, fhyrochembrry 33,217 (1993). 8. M. A. Mroue, K. L. Euler, M. A. Ghuman, and M. Alam, J. Nu?. Prod. 59,890 (1996).

1.

ALKALOIDS OF THE ASPIDOSPERMINE GROUP

187

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369. P. Magnus, I. R. Matthews, J. Schultz, R. Waditschatka, and J. C. Huffman. J. Org. Chem. 53,5772 (1988). 370. T. Gallagher and P. Magnus, J. Am. Chem. SOC. 105,2086 (1983). 371. L. E. Overman, G . M. Robertson, and A. J. Robichaud, J. Org. Chem. 54,1236 (1989). 372. P. Magnus, T. Katoh, I. R. Matthews, and J. C. Huffman, J. Am. Chem. SOC. 111, 6707 (1989). 373. J. Bruneton, A. CavB, E. W. Hagaman, N. Kunesch, and E. Wenkert, Tetrahedron Lett. 3567 (1976). 374. L. Allorge, P. Boiteau, J. Bruneton, T. SCvenet, and A. Cav6,J. Nar. Prod. 43,514 (1980). 375. A. Henriques, C. Kan, H.-P. Husson, S. K. Kan, and M. Lounasmaa, Acta Chem. Scand., Sect. B 34,509 (1980). 376. F. Abe, T. Yamauchi, and B. Q. Guevara, Biochem. Syst. Ecol. 21,847 (1993). 377. C. Kan, H.-P. Husson, S. K. Karl, and M. Lounasmaa, Planta Med. 41, 195 (1981). 378. M. Andriantsiferana, F. Picot, F’. Boiteau, and H.-P. Husson, Phytochemistry 18, 911 (1979). 379. P. Perera, T. A. van Beek, and R. Verpoorte, Planta Med. 49,232 (1983). 380. C. Kan, H.-P. Husson, H. Jacquemin, S. K. Kan, and M. Lounasmaa, Tetrahedron Lett. 21, 55 (1980). 381. H. Achenbach and B. Raffelsberger, 2.Naturforsch, Teil B 35, 1465 (1980). 382. F. Ladhar, M. Damak. A. Ahond, C. Poupat, P. Potier, and C. Moretti, J . Nat. Prod. 44,459 (1981). 383. C. Miet, N. Kunesch, J. Poisson, and C. Moretti, Communication au Colloque “Substances Naturelles d’lntbrtt Biologique du Pacijique, ” NoumCa (New Caledonia), August, 1979; quoted in Ref. 380. 384. C. Kan, H.-P. Husson, S . K. Kan, and M. Lounasmaa, Tetrahedron Lett. 21,3363 (1980). 385. J. Le Men, C. Caron-Sigaut, G . Hugel, L. Le Men-Olivier, and J. LCvy, Helv. Chim. Acta 61,566 (1978). 386. J. Y. Laronze, D. Cartier, J. Laronze, and J. Levy, Tetrahedron Lett. 21,4441 (1980). 387. M. E. Kuehne, C. L. Kirkemo, 1’. H. Matsko, and J. C. Bohnert, J. Org. Chem. 45, 3259 (1980). 388. E. Wenkert, 8. Porter, D. P. Simmons, J. Ardisson, N. Kunesch, and J. Poisson, J. Org. Chem. 49,3733 (1984). 389. M. E. Kuehne and W. G. Bornmann. J. Org. Chem. 54,3407 (1989). 390. W. G. Bornmann and M. E. Kuehne, J. Org. Chem. 57, 1752 (1992). 391. W. A. Carroll and P. A. Grieco, J Am. Chem. SOC.115, 1164 (1993). 392. G. Kalaus, 1. Greiner, M. Kajtlr-Peredy, J. Brlik, L. Szabo, and Cs. Szlntay, J . Org. Chem. 58,6076 (1993). 393. M. E. Kuehne and J. C. Bohnert,.I. Org. Chem. 46,3443 (1981). 394. S. Jegham, J.-L. Fourrey, and B. C . Das, Tetrahedron Lett. 30, 1959 (1989). 395. M. E. Kuehne and J. B. Pitner, J. Org. Chem. 54,4553 (1989). 396. J. Catena, N. Valls, J. Bosch, and J. Bonjoch, Tetrahedron Lett. 35,4433 (1994). 397. J. Bonjoch, J. Catena, and N. Valls, J. Org. Chem. 61, 7106 (1996). 398. J.-C. Fernindez, N. Valls, J. Bosch, and J. Bonjoch, J. Chem. Soc., Chem. Commun. 2317 (1995).

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-CHAPTER &

CEPHALOTAXUS ALKALOIDS M. A. JALILMIAH,*TOMAS HUDLICKY, AND JOSEPHINE W. REED Department of Chemistry, University of Florida Gainesville. Florida 3261 1-7200

.................................................................................. 199 ...................... 200 111. Synthesis of Cephalotaxus Alkaloids ................................................... 208 IV. Synthesis of Cephalotaxiiie Esters ...................................................... 224 A. Harringtonine .......... ............ 224 B. Homoharringtonine .. ................................................. 228 C. Deoxyharringtonine .. ............................ D. Isoharringtonine ...... ................................................. 233 I. Introduction

11. Isolation and Structural Studies of Cephalotaxus Alkaloids

V. VI. VII. VIII.

E. Neoharringtonine and Anhydroha Model Studies toward the Synthesis of the Cephalotaxine Ring System ...... 236 Unnatural Cephalotaxus Esters and Their Antitumor Activity .................. 254 Analytical and Spectroscopic Studies ................................ Pharmacological and Clinical Studies ............................... Note Added in Proof ....................................................................... 264 .................................. ........... 264

I. Introduction This chapter updates the literature published on the Cephalotaxus alkaloids since the last comprehensive review in this series (I). Another review (2) in 1987 concentrated on the synthesis of these compounds, and several reviews are available that focus on the biological and clinical properties of these alkaloids (3-5). The early synthetic accomplishments were summarized in a 1975 article (6),and another review, published in 1991 in China, covers new developments in the total synthesis of cephalotaxine (7). Cephalotaxine (1) is the parent member of the group of Cephalotaxus alkaloids (Z), belonging to the structurally unique homoerythrina class. It occurs in about eight known species of evergreen shrubs in the genus Cephalotaxus, including C. harringtonia and C. manii. Activity on the synthesis of these compounds was no doubt spurred by the discovery of the

* Present address: Department

of Chemistry, Rajshahi University, Rajshahi, Bangladesh.

199 THE ALKALOIDS. VOL. 51 0099-9598/98 $25.W

Copyright 0 1998 by Academic Press. All rights of reproduction in any form reserved.

200

’

MIAH, HUDLICKY, A N D REED

antitumor activity of several naturally occurring cephalotaxine esters, as well as by their novel structure. Even though synthetic activity has waned somewhat since the 1980s, this chapter still covers the earlier syntheses of the parent alkaloid, its esters, and the model studies directed toward total synthesis. The readership will be better served by having all published activity in this area placed in context with new developments; therefore, the syntheses already discussed in the 1987 review are included in this chapter as well, along with the appropriate updates in the three major areas: synthesis of the title alkaloid, preparation of its esters, and new approaches to the skeleton and unnatural derivatives of cephalotaxine that may have been designed from the point of view of medicinal chemists. The synopsesof total syntheses are given in chronological order in Section 111. The syntheses of cephalotaxine esters are discussed in Section IV; approaches to the ring system and model studies follow in Section V. The syntheses are presented as described in the original literature with a minimum of analysis of either the strategies employed or the methods used, although some editorial comments and comparisons of various synthetic strategies have been made. At the end of Section 111, a brief analysis is provided of the types of connectivities actually used to attain the various syntheses of cephalotaxine, with the hope that its inclusion may stimulate further ideas for innovative construction of these exciting and challenging molecules. Section VI deals with some of the unnatural ester derivatives of cephalotaxine, and Section VII reports analytical or spectroscopic studies. The last part of this chapter, Section VII, summarizes the clinical and pharmacological studies of harringtonine and homoharringtonine and provides a guide to the literature in this area. The literature is reviewed through May 1997.

11, Isolation and Structural Studies of Cephalotaxus Alkaloids

Table I lists the Cephalotaxus alkaloids that have been isolated from natural sources to date. The new compounds isolated since the last report include the following compounds. Homoharringtonamide (32)was isolated from the bark of C. harringroniu. Its structure was determined by tandem mass spectrometric analysis (8). Two new alkaloids, neoharringtonine (11)and anhydroharringtonine (12),were isolated from C. fortunei (9). Their structures were determined by spectral analysis and semisynthesis. In addition, a number of known

&PHALOZAXUS

TABLE I ALKALOIDS ISOLATED

FROM

NATURAL SOURCES

OMe Cephalotaxine (1)

(R = H) Esters of cephalotaxine

R=

C02Me

Ha-

rcs

COzMe

Homoharringtonine (3)

Deoxyharringtonine

Nordeoxyhamngtonine

Isoharringtonine

(4)

cog Deoxyharringtonic acid (5)

(6)

(7) (continues)

TABLE I (Continued)

\ CO2Me

H&CO$l

H

Isoharringtonic acid (8)

Homodeoxyharringtonie (9)

Bishomodeoxyharringtonine (10)

cycoN

w

Neoharringtonine

C4Me Anhydroharringtonine

(a)

(a)

(-)-Acetylcephalotaxine

(W

CO2Me

Homoneoharringtonine (14)

3 ’S-Hydroxyneoharringtonine

(W

l i bcod

H 3’S-Hydroxy-S-des-Omethylhamngtonine (17)

5’-Des-0methylhomoharringtonine (18)

5 ’-Des-0-methylharringtonine (16)

Variations on cephalotaxine

<XI$ HO

I

HO OMe

0

0

Epicephalotaxine

Demethylcephalotaxine

Demethylcephalotaxinone

(19)

(W

(21)

OMe Cephalotaxinone (22)

QMe

0 Isocephalotaxinofie

Cephalotaxinamide

(23)

(24)

HO

1

HO OMe

HQ

“f

HO

5

HO

0 4-Hydroxycephalotaxine (U)

11 -Hydroxycephalotaxine (26)

1 1-Hydroxycephalotaxinamide (27) (continues)

TABLE I (Continued)

OMe Drupacine

!2

OH Demethylneodrupacine

(a)

(29)

Hainanensine (30)

Other esters

bMe

+

( )-Acetylcephalotaxine

(31)

Homoharringtonamide (32)

I

C02Me

co2m

Drupangtonine (33)

1 lru-Hydroxyhomodeoxyharringtonine

(34) HO

1

nuY

\

co* 1 lp-Hydroxydeoxyhamngtonine (36)

11p-Hydroxyhomodeoxyharringtonine (35)

1,1811

Cephalotaxidine (37)

0

206

MIAH, HUDLICKY, AND REED

alkaloids were also isolated: deoxyharringtonine (4), isoharringtonine (7), isocephalotaxinone (23), acetylcephalotaxine (13), cephalotaxine (l), harringtonine (2), and homoharringtonine (3). Also isolated from C. fortunei by another group were cephalotaxine (1) (which accounted for 50-54% of the total alkaloid content), cephalotaxinone (22), acetylcephalotaxine (13), demethylcephalotaxine (20), epicephalotaxine (19), harringtonine (2), and homoharringtonine (3) (10). Most recently, Japanese researchers have isolated and characterized a number of new compounds from C. harringtoniu var. drupuceu; these are listed in Table I1 along with their activities against P-388leukemia cells. For comparison, the activities of the established active compounds harringtonine (2), homoharringtonine (3), deoxyharringtonine (4), and isoharringtonine (7) are also shown. The compounds were identified by spectroscopic methods. Of four esters having a free carboxylic acid isolated ( I I ) , two are new compounds: 5’des-0-methylharringtonine(16) and 3’S-hydroxy-5‘-des-O-methylharringtonine (17). Another, 5’-des-0-methylhomoharringtonine (la), was previously identified as a metabolite of homoharringtonine in liver microsomes TABLE I1 BIOLOGICAL ACTIVITIES OF ALKALOIDS ISOLATEDFROM CEPHALOTAXUS HARRINGTONIA VAR. DRUPACEA

Compound 5 ‘-Des-0-methylisoharringtonine (isoharringtonic acid) (8) 5’-Des-O-methylharringtonine(16)

3‘S-Hydroxy-5’-des-O-methylharringtonine (17) 5’-Des-O-methylhomoharringtonine (18) Drupangtonine (33) Nordeoxyharringtonine (6) Homodeoxyharringtonine (9) Bishomodeoxyharringtonine (10)

11a-Hydroxyhomodeoxyharringtonine(34) 1 lp-Hydroxyhomodeoxyharringtonine(35) 1lp-Hydroxydeoxyharringtonine(36) Cephalotaxidine (37) Neoharringtonine (11) Homoneoharringtonine (14)

3’s-Hydroxyneoharringtonine(15) Harringtonine (2) Homohamngtonine (3) Deoxyharringtonine (4) Isoharringtonine (7)

Biological Activity in P-388 Leukemia Cells: ICSO(pglml)

Ref.

0.41

11

1.0 65.0

4.6 0.0070 0.027 0.056 0.024 0.38 0.33

0.17 1.8 0.012 0.28 0.19 0.032 0.017

0.0075 0.018

11

11 11 14 15 I F

15 17 17 17 18

19 19 19 11,14 14 I4J 5,I 7 11

2.

CEPHALOTAXUS ALKALOIDS

207

from rats and rabbits (12);this is the first isolation from a natural source. was previously reported in The fourth, 5'-des-O-methylisoharringtonine7 C. hainensis as isoharringtonic acid (8) (13).The methyl esters were prepared and were found to be identical to authentic samples of the known alkaloids. The same species also yielded an ester of drupacine, drupangtonine (33) ( I d ) , which shows antileukemic activity comparable to that of deoxyharringtonine. Nordeoxyharringtonine (a), homodeoxyharringtonine (9), and bishomodeoxyharringtonine (10) (15) were also isolated. Homodeoxyharringtonine had previously been detected in cell cultures of the same species (16). Three oxygenated cephalotaxine esters were isolated (17): lla-hydroxyhomodeoxyharringtonine (34), 116-hydroxyhomodeoxyharringtonine (35), and 116-hydroxydeoxyharringtonine(36).Also isolated was the first example of a dimeric Cephalotaxus alkaloid, cephalotaxidine (37),which consists of a homoharringtonine unit and a homoharringtonamide unit connected by a C-C linkage (18). Two new aromatic esters, homoneoharringtonine (14) and 3's-hydroxy-neoharringtonine (15),were isolated (19),as well as neoharringtonine (11). A Chinese group has studied the variation of the content of harringtonine in C.oliveri (20). The concenkation of harr>artine in the lower stem was found to increase from spring to summer to fall to winter. The roots of the tree were found to have a higher concentration, followed by the lower stem and upper stem, with the least concentration found in the branches. When the content of harringtonine was compared in 18-year-old, 29-year old, and 46-year old trees, it was found to increase with the age of the tree. Another group has investigated the relative content of harringtonine and homoharringtonine in various parts of C. fortunei and C. sinensis (21), as shown in Table 111. Both species show the highest concentration of the alkaloids in their seeds. TABLE 111 RELATIVE CONTENT OF ALKALOIDS IN Two CEPHALOTAXUS SPECIES Content (%) of Harringtonine and Homoharringtonine in

Twigs Bark Stems Roots Seeds

Cephalotaxus fortunei

Cephalotaxus sinensis

0.0167 0.014 0.008

0.0136 0.0134 0.0113 0.0174 0.030

0.0251 0.0296

208

MIAH, HUDLICKY, AND REED

III. Synthesis of Cephalotuxus Alkaloids The first total synthesis of cephalotaxine was reported by Auerbach and Weinreb (22,23) in 1972,as illustrated in Scheme 1.Condensation of prolinol (40) with 3,4-methylenedioxyphenacetyl chloride (39) gave an alcohol, which on oxidation with N,N-dicyclohexylcarbodiimide/dimethylsulfoxide (DMSOIDCC) yielded aldehyde 41 (Scheme 1).The acid-catalyzed closure of 41 to enamide 42, followed by the reduction of 42 with lithium aluminum hydride, provided the key intermediate, enamine 43, featured in many subsequent approaches to the title alkaloid. The vinylogous amide 44 was prepared by the reaction of 43 with a mixed anhydride derived from pyruvic

-

-Q

LAH

BF3*Et20

0

0

87%

0

42

41

Q

100%

-Q 2.2-DMP

0

0

P-TsOH 45%

0

21

22

1

(f)-cephalotaxine SCHEME 1

2.

209

CEPHALOTAXUS ALKALOIDS

acid and ethyl chloroformate. The cyclization of 44 to demethylcephalotaxinone (21),followed by 0-methylation and stereospecific borohydride reduction of cephalotaxinone (22),yielded cephalotaxine (1).This first synthesis incorporated an interesting Mg(OMe)*-catalyzed closure in the formation of the spirocyclic ring system. The reaction could be rationalized as a Nazarov-type cyclization of a magnesium enolate anion. Racemic cephalotaxine was thus prepared in nine steps with approximately 7%overall yield. The second synthesis of cephalotaxine was reported by Semmelhack and co-workers (24), also in 1972. Their convergent strategy involved the alkylation of spirocycle 49, prepared in several steps from pyrrolidone 45, with p-nitrobenzenesulfonate ester 50, prepared from piperonal in 45-55% overall yield as shown in Scheme 2. The resulting key intermediate, 51a (X = Cl), was converted to (+)-cephalotaxinone (22),initially through an aryne intermediate, Route I, Scheme 3, in 15%yield. Cephalotaxinone was then converted to (t)-cephalotaxine (1) upon reduction with diisobutylaluminum hydride. The Semmelhack group expended considerable effort studying the conditions of the nucleophilic aromatic substitution (i.e., 51s-c 1. EtO’BFd2. CH2=CHCH2MgBr

H

1. rerr-butoxycarbonyl azide

2. 03,MeOH: H2S

COzMe - K HC O Z M e

61%

45

47

46 5541%

Na/K alloy, TMSCI, PhH

H

ROTMS

1. Br2. -78 lo -30 “C

“OTMS

2.

CH2N2

H

49

48

50 R=p-nimbenzenesulfonyl X=CI, Br, I (‘Pr),NEt, CH3CN 6547%

<=3 51b X=CI 51a X=Br

/ OMe -ph3CK+

51c X=I

‘%,I

/

(*)-22 0

I

OMe

(*)-I SCHEME 2

210

MIAH, HUDLICKY, AND REED Route I (via benzyne): Ph3C-K+ (15%) Route 11: (1) Ph3CLif; (2) Ni(C0D)Z (30%) Route III: (1) KNH2; (2) Nan< (45%) Route IV: (1) KOBu; (2) hv (94%)

(*I-22

OMe

SCHEME 3

to 22). The yield of the cyclization was greatly improved (25,26) either by employing a marylnickel complex (Route 11, Scheme 3) or by setting up the conditions for an SRNlreaction in which added metal (Na/K reduction, Route 111) or irradiation (Route IV) is used to close the ring. The Semmelhack synthesis provided racemic cephalotaxine in 12-13% yield from pyrrolidone 45 in 11 steps (25,26).The SRNlreaction employed in the second-generation approach to the key aryl bond formation added novelty as well as efficiency to the overall design. The overall sequence is longer than Weinreb's most likely because of the effort expended in the construction of spirocycle 49. These two milestone syntheses were soon followed by others, and activity in this field continued to be driven by interest in the biologically active esters of cephalotaxine. In 1986, Hanaoka et al. (27) reported the stereoselective synthesis of (2)-cephalotaxine and its analog, as shown in Scheme 4. The amide acid 52, prepared by condensation of ethyl prolinate with 3,4dimethoxyphenylacetyl chloride, followed by hydrolysis of the ethyl ester, was cyclized to the pyrrolobenzazepine 53 by treatment with polyphosphoric acid, followedby selective O-alkylation with 2,3-dichloropropene (54) in the presence of sodium hydride. The resulting enol ether 55 underwent Claisen rearrangement on heating to provide C-allylated compound 56, whose reduction with sodium borohydride yielded the alcohol, which on treatment with 90%sulfuric acid underwent cationic cyclization to give the tetracyclic ketone 57. Presumably, this sequence represents the intramolecular version of the Wichterle reaction. On treatment with boron tribromide, ketone 57 afforded the free catechol, which was reacted with dibromomethane and potassium fluoride to give methylenedioxy derivative 58, suited for the final transformations to cephalotaxine. Oxidation of ketone 58

2.

CEPHALOTAXUS ALKALOIDS

211

-

PPA __L_

Me0

Me0

52

NaH, DMF 91%

HOpC

53

0

"q> Roxg PhIO, KOH, MeOH

RO

~

RO

HO 0 57, R=Me

Me0

1

(1) BBr3 (79%) (2) CH2Br2, KF (33%)

58, R+R=CH2

59, R=CHj (80%) 60,R+R=CHz (79%)

Roqj, Roq p-TsOH, THF*

Lid&

___t

OMe

RO

/

RO

HO

HO

Me0

OMe

OMe

(*)-61, R=CH3 (85%)

(*)-62,R+R=CH2 (86%)

(f)-63,R=CH3 (78%) (*)-I, R+R=CHz (91%)

SCHEME 4

with iodosobenzene in the presence of potassium hydroxide afforded the hydroxy ketal60 as a sole product, which on reduction and treatment with p-toluenesulfonic acid gave cephalotaxine, (+)-1.In addition, ketone 57 was oxidized as discussed previously and converted to the dimethoxy cephalotaxine analog (?)-63 by an identical sequence. The total synthesis was accomplished in 10 steps with approximately 4.5% overall yield.

212

MIAH, HUDLICKY, AND REED

In 1988, Kuehne et al. (28) reported another synthesis of (t)-cephalotaxine and (2)-8-oxocephalotaxine (69), as illustrated in Scheme 5. The synthesis began with the preparation of ene lactam 64 by the condensation of 2-(2-carbomethoxyethyl)cyclopentanone and 3,4-(methylenedioxy)-Pphenethylamine. The spiro ketoamide 65, resulting from an interesting

(1) Pb(OAc)r, PhH (2) NaOMe (78-94%)

65

64

(1) NM0,OsOd (99%)

(2) Me& NCS. CH2Clz (89%) "#

67

68

\

0

(f)-24 SCHEME5

I

OMe

2.

CEPHALOTAXUS ALKALOIDS

213

oxidative rearrangement of 64 mediated by lead tetraacetate, was treated with bis(benzonitri1e)palladium dichloride to form the enone, which was reduced with aluminum isopropoxide to afford allylic alcohol 66.Treatment of this material with stannic chloride and nitromethane afforded lactam 67, which was converted to the corresponding cis-diol on treatment with N-methylmorpholine N-oxide and osmium tetroxide. Oxidation of the diol with dimethyl sulfide and N-chlorosuccinimide produced the lactam diketone 68,which was selectively alkylated with trimethylsilyl methyl ether and triflic acid to enol ether 69. Reduction of 69 with sodium borohydride whereas the reduction with lithium alugave (2)-cephalotaxinamide (a), minum hydride completed the synthesis of (2)-cephalotaxine (1) in nine steps and 38% overall yield (from amide 64). Conceptually, this synthesis employed the reversal of Semmelhack’s strategy, namely, the alkylation of a nucleophilic aromatic ring with a spirocyclic electrophile. Hanaoka et al. (29) reported in 1988 a second synthesis of cephalotaxinamide (U), Scheme 6, based on a strategy similar to that used in their earlier preparation of cephalotaxine (27).The amide ester 70 (the methylenedioxy analog of the previously reported starting material 52) was reduced with sodium borohydride to give the alcohol, which was subjected to hydrogenolysis over Pd-C in acetic and perchloric acids then saponified, yielding the amide acid 71. Cyclization of 71 by means of trifluoroacetic anhydride and boron trifluoride etherate yielded pyrrolobenzazepine 72, whose treatment with ally1 bromide in the presence of sodium hydride yielded 73 as a major product along with the C-alkylated derivative as a minor product. Claisen rearrangement of 73, followed by Wacker oxidation, produced acetonyl derivative 74. Base-catalyzed aldol cyclization of this compound and hydrogenation of the resulting enone (or the aldol product itself) over Pd-C yielded stereoselectively the cis-fused cyclopentanone 75. Oxidation with iodosobenzene gave the hydroxy ketal 76. Swern oxidation of 76, elimination of methanol induced by heating with dimethyl sulfoxide, and finally sodium borohydride reduction furnished (2)-cephalotaxinamide (24). In addition, compound 76 was reduced with aluminum hydride to give amine 62, the penultimate compound in Hanaoka’s earlier cephalotaxine synthesis (27). The attainment of this material constituted a formal synthesis of (2)-cephalotaxine (1) in a 2% overall yield, but without improvement of the earlier strategy. In 1988 and 1990, Fuchs reported a new approach to the synthesis of the Cephalotaxus alkaloids (2)-cephalotaxine (1)(30,31),(2)-11-hydroxycephalotaxine (26) (31),and (?)-drupacine (28) (31),which was based on the exploitation of vinyl sulfones as convenient multifunctional synthons (Schemes 7 and 8). The synthesis of cephalotaxine (Scheme 7) began with the ortho ester 77, obtained from piperonyl alcohol in five steps, which was

214

MIAH, HUDLICKY, AND REED

(1)

(98%)

(2) H ,PdjC, HOAC,HClOi (82%) (3) KbH, EtOH (82%)

70

TFAA,BFyOEt* (75%)

(a

eBr 0

-

'0

NaH, DMF

72

PhIO,KOH, MeOHw

71

0

(73%)

<%yo

(1) TFAA,DMSO (43%)*

(f)-24

(2) DMS0.A (51%) (3) NABH4 (83%)

(58%

76 HO

Me0

OMe

SCHEME 6

treated with tert-butyllithium, followed by vinyl sulfone 78 as the acceptor for the conjugate addition. Trapping of the intermediate anion with ally1 bromide provided the homoallyl sulfone 79. Further treatment with tertbutyllithium yielded exocyclicdiene 80, the precursor for the 4+2 cycloaddition with an a-nitroso carbonyl moiety. Hydroxamic acid 81 was obtained from 80 by treatment with p-toluenesulfonic acid in aqueous THF followed by hydroxylamine in methanolic potassium hydroxide. The reaction of 81

2.

215

CEPHALOfAXUS ALKALOIDS

with tetrabutylammonium periodate, followed by quenching with sodium bisulfite, provided the intermediate 4+2 adduct 82, which was exposed to sodium amalgam to cleave the N -- 0 bond and liberate an allylic alcohol

'BuLi; then

* then ally1 bromide, THFMMPA (7684%)

77

79

'BuLi (2) NH20H, MeOH

81

(1) Na(Hg), EtOH

"Bu~NIO~

~

(2) MsCI, Et3N, CHzClz (3) NaH.THF

D

(66-74%,2 steps)

(46% cis-fused;23% trans-fused)

k6

(1) 1N HCI. THF (1) Hz. Pd/c. EtOH

(2) DMSO,TFAA (75-89%)

(2) BF3-THF.THF (81% cis)

(87% rrans)

84-cis 84-lrans

HO

0

216

MIAH, HUDLICKY, AND REED

LDA, THF

-

then PhSS02Ph, THF-HMPA

LiHMDS, toluene

+

then@ (81%)

(2) (1) BF3-THF (3) -4c2O.p~ 1N HCI. THF (8 (96%) 1%) (90%)

86


Hob'**'

~

6H

(1) DMSO, TFAA (88%)

(2) 2,2-DMP, P-TSOH. (43%) (3) NaBH4 (88%)

(f)-26

(83%)

-

(f)-28

SCHEME 8

functionality. The allylic alcohol was converted to its mesylate and alkylated with the sodium salt of the amide to complete the pentacyclic skeleton in 83. Because the cycloaddition did not proceed with complete selectivity, a mixture of isomeric compounds 85 was obtained (46% cis, 23% rruns) and was subjected to the preceding sequence without separation to yield intermediates 83-cis and 8 3 - t ~ n s ,at which stage the isolation and separation took place. The remainder of the synthesis was carried out on each isomer separately. Hydrogenation of the double bond and lactam reduction provided compounds 8 4 4 s and 84-truns, which were deprotected and subjected to Swern oxidation yielding intermediate 21. This material was converted to (+)-cephalotaxine (1)according to Weinreb and Auerbach's protocol (22,23),the entire synthesis consuming in excess of 21 steps. Fuchs also prepared (5)-11-hydroxycephalotaxine (26), Scheme 8, starting from tetracyclic lactam U-cis, which was treated with lithium diisopropylamide followed by S-phenyl benzenethiosulfonate to give monosulfenylated lactam 85 (31). Treatment of 85 with lithiated hexamethyldisilazane (LiHMDS), followed by molecular oxygen, afforded cY-keto lactam 86. Reduction with BH-, acylation, and deprotection of the diol yielded 87, which was oxidized under Swern conditions. Treatment with 2,2-dimethoxy-

2.

217

CEPHALOTAXUS ALKALOIDS

propane and p-toluenesulfonic: acid, and finally borohydride reduction, yielded (2)-11-hydroxycephalotaxine (26). Following the literature conditions of Powell (32),26 was converted to (2)-drupacine (a), lending some generality to the overall approach. In 1990, Danishefsky and co-workers (33) reported a new methodology for the synthesis of cephalotaxine based on the transformation of substituted dihydroisoquinolines of type 88 to functionalized benzazepines, as illustrated in Scheme 9. The mixture of acylated compounds 90 and 91, obtained from the reaction of norhydrastinine (88) with 3-carbomethoxypropionyl

+

(86%)

CI Me$

88

89

CHO

91

SCHEME 9

_J

218

MIAH, HUDLICKY, AND REED

chloride (89), was treated with 1,2-ethanedithiol and boron trifluoride etherate to give a single dithiolane product 92, which cyclized on treatment with sodium hydride to imide dithiolane 93. Treatment of 93 with Lawesson's reagent gave monothioimide 94, which afforded enamide 95 through tungsten-hexacarbonyl-mediated cyclization. Lithium aluminum hydride reduction of 95 produced enamine 43, the key intermediate in Weinreb's synthesis of cephalotaxine. The key cyclization in this formal synthesis of cephalotaxine, namely the tungsten-mediated process, is interesting: Presumably the reaction involves the generation of a tungsten carbenoid at the benzylic site, its insertion into the carbon-sulfur bond, and the extrusion of elemental sulfur. This supposition was tested on the cyclization of diazo-

NO?

(1) CH~=C(CHzTMS)CH~OAc (99).

Pd(0AC)z. ('RO)sP, THF (90%) (2) CHz=CHC02Me. Triton B (100%)

98

(1) Raney Ni

TFAA ~ P - T s O H . t

(3) (93% (2) Swemfrom 104) KzC03

1

cq; 0

OAc

(*I-1 SCHEME10

2 3 steps

2.

219

CEPHALOTAXUS ALKALOIDS

esters derived from 96 (R = COz Me) via their rhodium carbenoids, affording benzazepines of type 97. (See also Scheme 39, Section V,for details of the model studies.) Ikeda and co-workers (34,35) reported in 1990 a methodology for the total synthesis of cephalotaxine as shown in Scheme 10. A methylenecyclopentane derivative, obtained as a diastereomeric mixture from the reaction of nitrostyrene 98 with 2-(trimethylsilylmethyl)-2-propenylacetate (99) in the presence of palladium( 11) acetate and triisopropyl phosphite, was treated with methyl acrylate to give nitro ester 100 as a single stereoisomer that was reduced and cyclized to lactam 101. Oxidative cleavage of the exocyclic methylene with osmium tetroxide-sodium periodate, followed by protection of the resulting ketone, provided ketallO2, which was reduced and acylated to afford 103. Deprotection, reduction with sodium borohydride, acetylation, and oxidation with sodium periodate afforded the sulfoxide 104, which was treated with either trifluoroacetic anhydride or p-toluenesulfonic acid to give benzazepinone derivative 105, presumably via a Pummerer-type process. Removal of the thiomethoxy group with Raney nickel followed by treatment with potassium carbonate and Swern oxidation afforded the keto lactam 58, identical to the intermediate in Hanaoka's synthesis (27).The formal synthesis of (+)-cephalotaxine 1 was completed by relying on Hanaoka's procedure. The overall yield of this synthesis, as reported, is around 30%,which is remarkable considering that it is some 19 steps in length. Zhong and co-workers (36) reported the synthesis of (-)-cephalotaxine in 1994 (Scheme 11). Racemic cephalotaxine (22) was synthesized from

Q 0

<"

OMe

0

(-)-22 acid

OMe (*I-22

Lg OMe (+)-22 SCHEME11

(-1- 1

220

MIAH, HUDLICKY, A N D REED

+)-glutamic acid and piperonal by Weinreb's method (22,23) and then resolved into its enantiomers by means of L-( +)-tartaric acid. Treatment of (-)-cephalotaxine with sodium borohydride yielded (-)-cephalotaxine (1) of the same absolute configuration as natural cephalotaxine. Mariano et al. (37,37u) described another approach to the synthesis of cephalotaxine, as represented in Scheme 12. The synthesis began with L-(

(1) 12-bis(TMSO)cyclobutene, BFyEt20, THF

(1) BrMgCHZCHzR (82%) 4

0)MsCI. Et3N, CHzC12 (100%)

(2) TFA. MeOH (90%) (3) Deprotectionkyclization

(3) HCI, acetone (92%)

108

(1) BnNH3+CI-. NaCNBH3 NAOAc, T?IF

109

(2) DIEA.MeCN (64%)

110

bH

SCHEME12

2.

CEPHALOTAXUS ALKALOIDS

221

the iodo arene 106. Hydroxyl group protection with tert-butyldimethylsilyl chloride followed by transmetallation and formylation gave the aldehyde 107,which was transformed to 108 through sequential aldol condensation with 1,2-bis(trimethylsiloxy)cyclobutene,acid-catalyzed pinacol rearrangement, deprotection of the TBDMS group, and cyclization. Treatment of 108 with the Grignard reagent derived from the ethylene glycol acetal of P-bromopropanal, followed by acetal hydrolysis, yielded aldehyde 109, which was subjected to reductive amination and cyclization to amino enone 110. Compound 110 was deprotected by hydrogenation, and the resulting secondary amine was converted to its t-Boc derivative 111.Treatment with lithium diiospropylamide, followed by oxygenation with [( -)-camphor-10ylsulfonyl]oxaziridine, afforded the a-hydroxy enone 112. This material was subjected to Swern oxidation and treated with trimethylsilyl triflate; the free secondary amine underwent a Michael addition to the enone to give desmethylcephalotaxinone (21),which was converted to (+)-cephalotaxine by means of Weinreb’s procedure (22). This particular synthesis proceeded in 13 operations (some combining individual steps) from arene 106 with 8% overall yield (12% reported). In 1995, Isono and Mori (38) reported the asymmetric total synthesis of (-)-cephalotaxine as portrayed in Scheme 13. Bicyclic lactone 113 was prepared from D-( +)-proline, following the method of Seebach et af. (39,40), and alkylated to give 114, which was converted into vinyl iodide 115 by treatment with IC1 and KF-induced desilylation with concomitant elimination of chloride. Hydrolysis of 115 with 10% sulfuric acid followed by treatment with BoczO and diazomethane afforded 116. Removal of the Boc group with trifluoroacetic acid followed by alkylation with nosylate 117 provided 118, which was reduced with lithium aluminum hydride to the corresponding primary alcohol and then oxidized with the sulfur trioxide-pyridine complex and dimethylsulfoxide to aldehyde 119. Treatment of 119 with Me3SiSnBu3and cesium fluoride provided the allylic alcohol 120, which was cyclized with polyphosphoric acid to the benzazepine derivative 121, in direct analogy to the strategy employed by Kuehne (28) in his synthesis of racemic 1 [120 differs from Kuehne’s intermediate 66 (see Scheme 5) only in the methylenedioxy and amide functionalities that are present in the latter compound]. The exchange of o-dimethoxy groups in 121 for the appropriate methyleiiedioxy functionality present in 122 was accomplished by a known procedure [see Section 4,Hanaoka’s synthesis (291, and 122 was treated with osmium tetroxide to give the cis-diol 123, which on oxidation with dimethyl sulfoxide and trifluoroacetic anhydride gave demethylcephalotaxinone (21).When this compound was treated with methyl orthoformate in the presence of p-toluenesulfonic acid, cephalotaxinone (22)was obtained, found to be identical with natural cephalotaxinone,

222

MIAH, HUDLICKY, A N D REED

113

114

115

d -

Me0

2. i-RZNEt 117

BOC "COOMe

116

Me0

88%

117 = M

e

o

p

s

Me0 Ns= pNOzG,H4SOr

Me3SiSnBu3

'SF 85%

-

Me0

1. LAH 2. S03-Py

118 R = C02Me

l.BBr3

) 2.CHzBrz NaOH __c

Me0

(5 1%)

120

122

123

21

SCHEME 13

and was transformed to (-)-1, completing this asymmetric synthesis in 19 steps with approximately 1%overall yield. The approaches to cephalotaxine discussed in this section differ in the fundamentals of strategies used to construct the rather unusual homo-

2.

223

CEPHA1,OTAXUS ALKALOIDS

erythrina ring system. Scheme 14 illustrates all of the disconnective strategies to accentuate the major features of each. The key step of every synthesis is portrayed as a connection o€ the key reactive intermediate with the aromatic fragment. The key carbon fragment is outlined in solid bold lines, and the incipient bond-forming sequence (in broken lines) is annotated

CS@ 124

v

Weinreb Hanaoka Danishefsky (formal)

126 Kuehne

Mon

125 Semmelhack

127

v

Danishefsky

128

129

Fuchs

lkeda

Mariano SCHEME 14. Types of connectivity used in the synthesis of cephalotaxine, 1972-1995. Broken lines indicate the connectivity parameters of the approach. Solid lines outline the constitution of reactive intermediates. Letters indicate the order of bond construction.

224

MIAH, HUDLICKY, AND REED

with letters to indicate the order of bond formation. For example, in 124 the key sequence used by Weinreb consisted of acylation of the “Weinreb enamine” (bond a) followed by the intramolecular addition of an enolate to an iminium species (bond b). Hanaoka used a [3,3] sigmatropic rearrangement to accomplish the attachment of ring E in his synthesis, but the connectivity remains identical, that is, a three-carbon fragment attached to the tetracyclic ring system. Danishefsky’s synthesis listed with 124 is a formal one, repeating the sequence of Weinreb. The key strategy of Danishefsky’ synthesis is shown with 127. It is interesting to note and compare, for example, the strategies that have relied on the attachment of a spirocyclic amine to the arene portion. The Semmelhack connection in 125 is made from a “nucleophilic” radical intermediate to the “electrophilic” arene radical in the improved SRNl process, following the earlier strategy in which an enolate anion was added to benzyne. However, Kuehne and Mori attached their spirocycle as an electrophile in 126, taking advantage of the nucleophilic disposition of the methylenedioxy arene unit. The nitroso Diels-Alder approach of Fuchs reduces to the connectivity shown in 128 (the original oxygen of the nitrosyl unit is “extruded” following its conversion to a leaving group). Ikeda’s synthesis is interesting in its unique use of the Pummerer rearrangement to form bond b in 129, whereas Mariano’s synthesis involves the addition of a secondary amine to an enone (bond c) in 130. Those readers interested in general connectivity analysis for complex molecules are referred to the excellent discussions of these subjects by Wender (41) and Bertz (42).

IV. Synthesis of Cephalotaxine Esters

The synthesis of cephalotaxine esters has been motivated by the recognition of the antitumor properties associated with some of these compounds, most notably homoharringtonine. Most, if not all, of their syntheses focus on the efficient preparation of the side chains and methods of esterification of the intact cephalotaxine nucleus, usually obtained from natural sources, where it is far more abundant than any of the corresponding esters. Because of the hindered nature of the cephalotaxyl alcohol, many approaches rely on partial esterification and further functionalization of the side chains. A. HARRINGTONINE

Kelly and co-workers (43) reported the first synthesis of the acid side chain of harringtonine in 1973 as portrayed in Scheme 15. The lithium

2.

CEPHALOTAYUS ALKALOIDS

225

132

131

1. LiCH2C02Me

Pd(C)I Hz *

,h p

<

2.CF3CQH

133

134

135 SCHEME 15

acetylide, obtained from the treatment of the protected propargylic alcohol 131 with n-butyllithium, was reacted with rert-butyl ethyl oxalate to give ester 132. Addition of methyl lithioacetate to 132, followed by treatment of the intermediate diester with trifluoroacetic acid, provided the ester acid 133. Hydrogenation of 133 afforded 134, the side-chain acid of harringtonine, which lactonized spontaneously to 135. The first synthesis of harringtonine was reported by Huang et al. (44) in 1979 (Scheme 16). Butyrolactone 136 was condensed with ethyl oxalate, and the resulting compound was treated with acid to give hemiketal 137, which was converted to the cephalotaxine ester 140 through the intermediacy of either 138 or 139. Hemiketal 137 was dehydrated and the resulting acid was treated with oxalyl chloride to give acid chloride 139, which, on esterification with cephalotaxine followed by hydration, yielded 140. In another approach, 137 was converted to the a-methoxy acid, which, in turn, underwent DCC-catalyzed esterification with cephalotaxine to give the cephalotaxyl derivative 138 whose hydration afforded hemiketal 140. The Reformatsky reaction of 140 with methyl bromoacetate gave a mixture of harringtonine (2) and its epimer in a ratio of about 1 : 1.This type of partial esterification strategy has been shown to work well in many approaches to the esters of cephalotaxine, whose direct formation is impeded by both the

226

S

MIAH, HUDLICKY, AND REED

O

(1) (COZEth. NaOEt

(1) MeOH

(2) NaOH

(3) cephalotaxine,DMAP

(3) HC

136

137 (1) Benzene (2) NaC03 (3) (COC02

D

138

1

HOAc, HCI

(1) Cephalotaxine

= cephalotaxyl

~o'coc'

w

(2) HOAc,HCI

139

(1) ZnClz, K, THF

(2) BrCHzC02Me (3) H2O.THF

'OCp

2

I 140

+

Epihamngtonine

ICOZMe

SCHEME 16

steric hindrance of the cephalotaxyl alcohol and the bulky environment of the side-chain carboxylate. Mikolajczak and Smith (45) reported the synthesis of harringtonine following a methodology identical to that of Huang, with the exception that the acid chloride 139 was obtained from ethyl 4-methylpent-3-enoate (141) via ester 142, as illustrated in Scheme 17. At about the same time Kelly etal. (46) reported a synthesis of harringtonine, as shown in Scheme 18. The synthesis began from cyclohexene 143, which was doubly protected as the benzyl ether-benzyl ester 144. Oxidation of 144 with osmium tetroxide/periodate resulted in the cleavage of the cyclohexene ring to the corresponding ketone and aldehyde. The aldehyde was further oxidized with Jones reagent to provide acid 145. Addition of methylmagnesium bromide, followed by lactonization and partial hydrogenation, provided the lactone carboxylic acid 146, which was transformed V

E

t

(1) NaOH

(1) (COzEt)2, NaH

(2) aq HCI. reflux (3) HCI,MeOH

141

142 SCHEME 17

139

2.

144

143

COzBz f i I O z H

1. CH,MgBr 2.(coci), 3. Pd(C)/H,

1-

0 146

145

1. (COCl),

227

CEPHALOTAXUS ALKALOIDS

*

2. cephalotaxine

qrcp

1. MeO-/MeOH

2. W(C)IH2

2

+

Epihaningtonine

0 147 SCHEME 18

to its acid chloride and treated with cephalotaxine to give 147. Finally, compound 147 underwent methanolysis and hydrogenation to yield harringtonine (2) and its epimer as a 1 : 1 mixture. In 1975, the Tumor Research Group of the Chinese Academy of Medical Science (47) reported a short synthesis of harringtonine (2) as shown in Scheme 19. Treatment of the olefinic pyruvate 148, obtained from the reaction of cephalotaxine and the corresponding acid, with mercuric trifluoroactate, followed by reduction with sodium borohydride yielded the known herniketal140. Reformatsky reaction of 140 with methyl bromoacetate yielded harringtonine (2).

I c p = cephalotaxyl I SCHEME

19

228

MIAH, HUDLICKY,

AND REED

B. HOMOHARRINCTONINE

Zhao and co-workers (48) reported the first synthesis of homoharringtonine (3) in 1980 (Scheme 20). Unsaturated keto acid 151,prepared either from 5,5-dimethyl-Svalerolactone 150, or by chain extension from the commercially available bromide 149,was esterified with cephalotaxine to give the cephalotaxyl derivative 152,which reacted with methyl bromoacetate under Reformatsky conditions to yield a mixture of epimers of dehydrohomoharringtonine 153.This mixture was converted to homoharringtonine and its epimer by means of oxymercuration, as well as by acid catalysis. As in the aforementioned syntheses of harringtonine, the Reformatsky reaction proceeded with no stereoselectivity, and diastereomeric mixtures resulted from all of these approaches. Another synthesis of homoharringtonine was reported by Wang et al. (49-51) in 1980 (Scheme 21). Treatment of the sodium salt 154 of the protected keto acid with oxalyl chloride, followed by cephalotaxine, gave the cephalotaxyl ester 155,which, under Reformatsky conditions, reacted with methyl bromoacetate to furnish the expected diastereomeric mixture of ketals 156. Hydrolysis of 156 yielded an equilibrium mixture of ketone 157 and its cyclic hemiketal 158. Treatment of this mixture with methylmagnesium iodide yielded homoharringtonine (3) and its epimer. Hudlicky and Hiranuma (52) reported a synthesis of homoharringtonine in 1982, as shown in Scheme 22. Ozonolysis of the cyclopentenyl acid 160

(1) HCI.EtOH

m

c

o

z

H

(1) (COClk

(2) cephaletaxine

150

151

SCHEME 20

1sZ

2.

n

229

CEPHA1,OTAXUS ALKALOIDS

o

BrCH2C02Me * Zn

154

155

MeMgI

1

3 + epimer

Cp = cephaloraxyl

0

-1. M@20 2. (C02E~)2

n

0 h

B

r

154

3. NaOH

159 SCHEME 21

162

158

Cp = cephalotaxyl

3, Homoharringtonine ( single isomer )

SCHEME 22

230

MIAH, HUDLICKY, AND REED

gave the diketo acid 161, which, on treatment with cephalotaxine yielded cephalotaxyl ester 162,the free ketone of the known protected intermediate used by Wang (49-51). The Reformatsky reaction of 162 with methyl bromoacetate produced the equilibrium mixture of 157 and 158,as observed in Wang’s synthesis, but in this preparation a single isomer was obtained. The difference in stereoselectivity can be rationalized by the preferred chelation of the organozinc reagent to both the pyruvate carbonyl and the terminal ketone in 162 (Scheme 22); the resulting cyclic chelate offers only one face of the pyruvate to the addition of the Reformatsky reagent. This situation is not possible in Wang’s synthesis because the terminal ketone in 155 (Scheme 21) is protected as a ketal, therefore significantly altering the donor capabilities of the terminal oxygen functionality. The detailed rationale for this selectivity is reported in the full paper published in 1983 (53).The addition of methylmagnesium bromide to the mixture of 157 and 158 completed the stereocontrolled synthesis of homoharringtonine. The cephalotaxine portion in this synthesis was obtained by repetition of Weinreb’s preparation on a medium scale and with some improvements in yields. In the follow-up detailed report, Hudlicky’s group (53)also described the synthesis of homoharringtonine from the unsaturated keto acid 151 (Scheme 23). Acid 151 was treated with formic acid in the presence of perchloric acid to provide the intermediate formylated derivative 163, which, on treatment with aqueous sodium hydroxide, produced hydroxy acid 164. Esterification of 164 with cephalotaxine yielded the cephalotaxyl ester 165, which underwent the Reformatsky reaction with methyl bror

n

C

O

151

164

Z

H HC02H/HC104c

[

~

C

O

163

165

Z

H

w }

2.

231

CEPHALOTAXUS ALKALOIDS

moacetate to give homoharringtonine 3, along with its epimer. Noteworthy in this approach are two items: first, the conversion of the hydroxy acid 164 to its acid chloride without the necessity of protecting the hydroxyl, and, second, the lack of stereoselectivity in the Reformatsky reaction. This latter observation lends credence to the argument that the selectivity of this transformation observed for 157 was the function of the chelation with the distal carbonyl group, as discussed previously. Cheng et al. (54) reported an asymmetric synthesis of homoharringtonine developed by Huang's group in 1984, as illustrated in Scheme 24. Condensation of chiral sulfinyl ester 166 (obtained by resolution of menthyl sulfinate followed by displacement of the chiral auxillary group with the anion derived from t-butyl acetate) with the pyruvate 152 produced cephalotaxyl ester derivative 167,which was hydrated to the tertiary alcohol 168. Desulfurization of 168 with aluminum-mercury amalgam, followed by ester hydrolysis with trifluoroacetic acid and subsequent methylation of the resulting acid with diazomethane, yielded homoharringtonine (3) as a single isomer. The level of asymmetric induction was greater with the (R)-isomer of sulfoxide 166. C. DEOXYHARRINGTONINE

Mikolajczak et al. (55) reported the first synthesis of deoxyharringtonine (4) in 1974, as shown in Scheme 25. Lithium 3-methylbutyne acetylide (169)

9'

..

\-COz'Bu

+

166

Y-p

2. NH,CI

fl 167

152

1 c p = cephalotaxyl I 1. AI-Hg c

2. F A A 3. CHzNz

168 SCHEME 24

3 Homoharringtonine

232

MIAH, HUDLICKY, AND REED

169

170

171

1. (COc1)2

2. TFAA

CO2H

2. ccphslourxinc

172

-

LiCHp202Me

173

d

4 + epimer Deoxyhamingtonine

SCHEME 25

was allowed to react with ethyl tert-butyl oxalate (170)to give unsaturated keto ester 171,which on hydrogenation, followed by hydrolysis with trifluoroacetic acid, provided the saturated keto acid 172. Treatment of 172 with oxalyl chloride and subsequent reaction of the acid chloride with cephalotaxine produced cephalotaxyl pyruvate 173, the saturated analog of 148 (Scheme 19). Reaction of 173 with methyl lithioacetate yielded deoxyharringtonine (4) as a mixture of epimers. Huang (56) and Li (57) also reported the synthesis of deoxyharringtonine (4) starting from saturated keto acid 172. The only difference in their procedure was the use of the Reformatsky reaction, rather than the lithio acetate, to introduce the acetate portion of the final product (Scheme 25). Auerbach et al. (58) described the synthesis of the acid side chain of deoxyharringtonine as shown in Scheme 26, in their attempt to prepare deoxyharringtonine. The unsaturated diester 174 was treated with trifluo-

174 1. ('Bu)zCuLi

2. H,. Adam's catalyst

175

Ho2cv %-

MeO&

176 SCHEME 26

2.

CEPHAL.0TAXUS ALKALOIDS

233

0

D

(1) 'BuMgBr

Q-CO;B" +

+OCP

0

(2) NHlCl

173

166

177 (1) AI-Hg e

4 Deoxyharringtonine

(2) "FAA (3) CHzNz

ICp = cephalotaxyl I

SCHEME 21

roperacetic acid to give the epoxy compound 175. Addition of the isobutyl moiety to compound 175 with isobutyl copper reagent followed by hydrogenation over Adam's catalyst furnished the acid side chain 176 of deoxyharringtonine. The same acid was also prepared by Mikolajczak et al. (59). However, attempted esterification of the acid 176 with cephalotaxine to furnish deoxyharringtonine (4) was unsuccessful. Cheng et al. (54) also reported the synthesis of deoxyharringtonine in 1984 by the use of an identical strategy employed for the stereoselective preparation of homoharringtonine (Scheme 27). Condensation of the chiral resolved sulfoxide ester 166 with cephalotaxyl keto ester 173 gave sulfoxide ester 177. Desulfurization and ester hydrolysis of 177, followed by methylation of the resulting acid, yielded deoxyharringtonine (4), also stereospecifically. The descriptions of the two syntheses were published together in one report (54). D. ISOHARRINGTONINE Pan and co-workers (60) reported a synthesis of isoharringtonine (7) in 1982 (Scheme 28). The mixed ketall78 was treated with lithium diisopropyl-

1Cp = cephalotaxyl] SCHEME 28

isoharringtonine

+ stereoisomers

234

MIAH, HUDLICKY, AND REED

amide and the resulting anion was allowed to react with the cephalotaxyl keto ester 173 to give the condensation product 179, which, on acidcatalyzed hydrolysis, yielded isoharringtonine (7), along with its stereoisomers. Another synthesis of isoharringtonine starting from keto ester 173 was reported by Li et al. (61) (Scheme 29). Reformatsky reaction of benzyloxybromoacetate 180 with 173,followed by hydrogenation, gave a mixture of isoharringtonine (7) and its isomers, which were laboriously separated by radial chromatography. An alternative synthesis of isoharringtonine was reported in 1984 (62). The cephalotaxyl keto ester 173 was condensed with ethyl glyoxalate 181 by titanium-induced pinacol coupling to yield isoharringtonine (7)as a mixture of isomers (Scheme 29). This approach, although completely nonstereoselective, reflects a very clever and effective strategy for the formation of the diol unit in isoharringtonine. A stereocontrolled synthesis of the side-chain acid 186 of isoharringtonine from (R,R)-(+)-tartaric acid was reported by Zhang et al. (63) (Scheme 30). Dimethyl ( 2 4 3R)-tartrate acetonide (182)was allylated in the presence of lithium diisopropylamide to give 183, which underwent basecatalyzed epimerization to 184. Catalytic hydrogenation, followed by hydrolysis and by treatment with methanol in the presence of sulfuric acid, yielded the half ester 185,which was treated with aqueous trifluoroacetic acid to provide the side-chain acid of isoharringtonine (186)with the appropriate stereochemistry.

Br

~

C

0

HOAC02Me

180

7 [Cp = cephalotaxyl

0

isoharringtonine and stereoisomers

I

173. (cyclopentadienyl)TiC13 L

HKCO2Me

LiAIHd, THF

181 SCHEME 29

7 and stereoisomers

.

p

2.

235

CEPHACOTAXUS ALKALOIDS

6e. MeOH

182

183

(1) Hz, Ni (100%)

t

(2) KOH,MeOH (95%) (3) MeOH. H2S04 (72%)

184

qx TFA9H20, (100%)

H

C02Me

i 0 C02Me

185

186

SCHEME 30

E. NEOHARRINGTONINE AND ANHYDROHARRINGTONINE Two new cephalotaxine esters having significant antileukemic activity, were isolated in 1992 neoharringtonine (11)and anhydroharringtonine (n), by Wang and co-workers (9) from C. fortunei Hook f. These authors also reported their semisynthesis from cephalotaxine and harringtonine, respectively (Scheme 31). On treatment with phenyl pyruvyl chloride in the presence of pyridine, cephalotaxine (1)produced an intermediate a-keto ester. Reformatsky reaction of this cephalotaxyl phenyl pyruvate with methyl bromoacetate yielded a mixture of neoharringtonine (11) and its epimer. (1) PhCH2COCOCl. CH2C12, Py

Cephalotaxine

1

(2) BrCH&O2kte, Zn

11neoharringtonineand epimer

vocp -

P-TsOH

C02Me

2 harringtonine

12 anhydrohamngtonine SCHEME 31

236

MIAH, HUDLICKY, A N D REED

Anhydroharringtonine (12) was prepared by treating harringtonine (2) with p-toluenesulfonic acid. The synthetic strategies for the esters of cephalotaxine follow, for the most part, the partial esterification method. The ideas that are exploited in the access to the fragments vary, but most use as the last step the anionic attachment of the acetate portion. The one method that remains to be exploited here is the enzymatic esterification of the natural enantiomer of cephalotaxine either with a racemate of the complete side chain (kinetic resolution) or with the appropriate enantiomer of the ester side chain. It is hoped that the solution to this particular problem in either enzymatic catalysis or plant tissue culture preparation will materialize in the near future.

V. Model Studies toward the Synthesis of the Cephalotaxine Ring System An early approach to the synthesis of cephalotaxine (Scheme 32) was reported by Dolby et al. (64) in 1972, shortly before Auerbach's and Weinreb's report (22). The Vilsmeier-Haack condensation of piperonylamide 187 with pyrrole yielded ketone 188, which was successively reduced with sodium borohydride, hydrogenated, and acylated to give the precursory chloro amide 189.The photocyclization of 189 produced lactam 190,which, after reduction of the carbonyl with lithium aluminum hydride and subsequent oxidation with mercuric acetate, yielded the enamine 43. This mate-

187

188 CI

(2) Hg(OAc)z

189

190 SCHEME 32

'0

43

2.

CEPHALOTAXUS ALKALOIDS

237

rial has been referred to in the literature as the “Weinreb enamine” or the “Dolby enamine.” Another approach to cephalotaxine intermediate 43 was reported by Weinstein and Craig (65) in 1976 (Scheme 33). The reaction of 3,4-(methy1enedioxy)-/3-phenethyltosylate (l91),a derivative of the previously used nosylate 117,and sodium 2-carboethoxypyrrole (192),followed by hydrolysis, produced the carboxylic acid 193. Intramolecular Friedel-Crafts acylation of 193 with stannic chloride and trifluoroacetic anhydride yielded the benzazepine 194, which was reduced, hydrogenated, and finally oxidized to produce the tricyclic “Dolby-Weinreb” enamine 43. An approach to the saturated amine 200 was reported by Tse and Snieckus (66)in 1976 (Scheme 34). An intermediate imide, prepared from 3,4-(methylenedioxy)-/3-phenethylamine(195)and maleic anhydride 196, was iodinated to furnish 197.Grignard addition of methyl magnesium iodide followed by dehydration afforded 198, which underwent photocyclization to afford the tricyclic system 199.Successive hydrogenation and reduction of 199 provided the fully saturated amine 200,from which the Dolby-Weinreb enamine 43 is easily obtained on oxidation with mercuric acetate. A model cyclization of an iminium salt 201 to the spirocyclic amine 202 was reported by Mariano et al. (67) in 1982 (Scheme 35). Similar photocyclization of iminium ion 203 gave tricyclic amine 204 (68), which would be suited for the electrophilic closure to the complete skeleton of cephalotaxine (for details of this synthesis, see Scheme 41). In an approach to cephalotaxine, Greene, in 1984 (69), reported a ring expansion of an isoquinoline aziridinium ion of the type 206 to benzazepine 207 (Scheme 36).

191

193

SCHEME 33

238

MIAH, HUDLICKY, AND REED

195

197

hv, (4690) Et3N

c"w 0

/

/

199

198

(2) LiAIH4

c"Q 0

200 SCHEME 34

I

N'C104

R

O

g

&

hv. MeCN

201

RO

202

C02Et I

Bub,C'

203

204 SCHEME 35

2.

239

CEPHALOTAXUS ALKALOIDS

Me0

+ BF4’Me0

Me0

Me0

\ L

205

206

207

SCHEME 36

An attempt to prepare cephalotaxine and 11-hydroxycephalotaxine from chiral precursors by means of a ring expansion of isoquinoline derivatives prepared by the Pictet-Spengler condensation was made by Hudlicky in 1981 (70,71)as shown in Scheme 37. Acid 210 was prepared by condensation of biogenic amines 208 (X = €I or OH) with the pyruvate 209. Borane reduction to the corresponding alcohols 211, followed by acid-catalyzed solvolysis, led to the tricyclic enamines 212 and 213 (71). This approach was modeled on the biogenetic condensation of amines with pyruvates to generate 1,l-disubstituted tetrahydroisoquinolines, ubiquitous in alkaloid biogenesis (70). Several other biomimetic approaches to the synthesis of cephalotaxine have also been reported. In 1977, Kupchan et al. (72,73) prepared tetrahydroisoquinoline 214, which underwent intramolecular oxidative coupling to 215 by means of vanadium( V) oxytrifluoride and trifluoroacetic acid/ trifluoroacetic anhydride (Scheme 38). Treatment of 215 with 1 N sodium hydroxide in methanol yielded the ring-expanded product, imine 216,which was converted in five steps to amine 217. Transannular cyclization of 217

MeodNH

Me0

208

i-HO2C4

2

0

2

H

0

Me0

209

210 H02C

X=H,OH

-

-

[dl

H+

Me0

211

/

Meo*~ Me0

/

/

212 X = H 213 X = O H

OH

SCHEME 31

240

MIAH, HUDLICKY, AND REED

Me0

VOF3. CHzClz

NaOH, MeOH

t

TFA-TFAA

\ I 215

214

BnO

OMe

H

5 steps

216

I OBn

217

218

I OH

//

0

OMe

SCHEME 38

with potassium ferricyanide gave the cephalotaxine-like skeleton 218, a structure resembling some postulated biogenetic precursors to cephalotaxine (2). Danishefsky er al. (33)reported a method of one-carbon chain incorporation necessary for the elaboration to the five-membered D-ring of cephalotaxine (Scheme 39). (See also Scheme 9, Section 111, for the formal total synthesis of cephalotaxine by this method.) Reaction of dihydroisoquinoline 219 with acid chlorides 220 or 221 followed by the addition of aqueous sodium bicarbonate gave carbinolamides 222 or 223, respectively, which, on treatment with 1,3-propanedithiol and boron trifluoride etherate, yielded the ring-opened dithiane 224 or 225. These dithianes were converted by treatment with sodium hydride or potassium ten-butoxide to 226 or 227, respectively. Removal of the dithiane moiety in 226 or 227 by N-bromosuccinimide gave the a-keto esters 228 or 229, which on treatment with Lawes-

2.

CEPHALOTAXUS ALKALOIDS

+

l.CH2C12 I0"C b

0

CozMe

219

241

2.NaHC03

220 K=C02Me 221 K=CH2CI 0

e

0

1. HS(CH2)jSH

224 R=COZMe, 37% 225 R=CHzCI, 55%

222 R=COZMe,74% 223 R=CHZCl, 78% X NaH

1

KO'Bu

[231 x=H;,Y=s

97 x=o 232 X=H2 SCHEME 39

son's reagent yielded the mono thioimides 230 or 231. The thioimides 230 or 231 were converted in two steps to the corresponding diazo esters, which were cyclized upon treatment with rhodium(I1) acetate dimer to yield carbomethoxy-substituted benzazepines 97 or 232. This study was performed as a complement to the investigation of the cyclization of thioketals of type 96 (Scheme 9, Section 111) by means of tungsten carbenoids. Mariano et al. (74) reported in 1984 several approaches to the synthesis of the ring system of cephalotaxine or its derivatives that represented on advanced integration of the experience gained from his earlier model studies (67,68).The tricyclic intermediates 236 and 237 (Scheme 40)and the derivative 204 lacking the complete B-ring (Schemes 35 and 41) were prepared

242

MIAH, HUDLICKY, A N D REED

by adaptation of the chemistry reported earlier (67,68)for the cyclization of iminium salts (Scheme 35). These compounds were subjected to further cyclization reactions in attempts to obtain tetracyclic ring systems. The tricyclic p-aminocyclohexenone 234 was obtained via intramolecular photoarylation of the bromo arene derivative 233 (Scheme 40). Enamide 234 was treated with sodium hydride, followed by the mesylate derivative of [(trimethylsilyl)methyl]allyl alcohol, to give the allylated compound 235, which was converted to two allyliminium salts 236 and 237. However, attempts to photocyclize these compounds to tetracyclic derivatives were not successful, in contrast to the results of the earlier studies (Scheme 35) in which the spirocyclic system was easily generated in intermediates not rigidly tethered to the aromatic ring. As a consequence of the preceding failures, the closure of the benzazepine ring B was left for later stages of the synthesis. The key intermediate 203, suited for the closure of the B-ring, was prepared from a-aryl-pchlorocyclopentenone 242 (Scheme 41) (68). Reaction of piperonal with the Wittig reagent derived from ethyl y-chlorobutyrate gave styryl ester 240, from which the epoxide was prepared and then isomerized by means of boron trifluoride etherate to the y-keto ester 241. Claisen cyclization

ZCH3CN (

0

O

5

NaH.THF. CH2=C(CH2ThlS)CH2OSO2Me

234

"

MeI, AgCIO,

236 R = Me 237 R = CO'Bu

239 R = CO'Bu SCHEME 40

c

2.

243

CEPHALOTAXWS ALKALOIDS

(1) mCPBA, K2HPO4

<&CH(CHz)2C02Et

D

(2) BFyEt20

(2) aq.NaOH (3) ClCOCOCl

240

'0

241

Q

(1) Et02CCH2NH&I

q- F

0

(2) NaH then CH~=C(CH~TMS)CH~OMS

243

<%)F-

0

TMS

EtOzC

'BuCOCI, AgC104 MeCN *

!-BuCO~

hv, thenMeCN; NaHC03*

o

TMS

203

204 SCHEME 41

gave the cyclopentanedione, which was converted to its sodium salt, then treated with oxalyl chloride to afford 242. The chloro enone was reacted with ethyl glycinate and then N-allylated with the mesylate derivative of 2-[trimethylsilyl)methyl]allyl alcohol. The p-enaminone 243 was converted to its O-pivaloyl allyliminium perchlorate 203 by a silver-ion-promoted reaction with pivaloyl chloride. The irradiation of 203 produced the tricyclic compound 204 in which the B-ring has not been closed, although the necessary functionality to do so was in place. In 1987, Hill and co-workers (75) reported a clever synthesis of the pentacyclic cephalotaxine analog 246 starting from the nitrostyrene derivative 98 (Scheme 42). The Diels-Alder adduct 244, obtained by the reaction of butadiene sulfone with 98, was treated with methyl acrylate to give a single stereoisomer of the nitro ester, which was reduced with zinc in ethanolic HCl to yield the lactam 245 and further reduced by Red-A1 to the corresponding pyrrolidine. Pictet-Spengler cyclization with formaldehyde gave the pentacyclic amine 246. Alternatively, the reduced pyrrolidine obtained from 245 could be formylated, cyclized to the iminium salt by a Bischler-Napieralski protocol, and finally reduced with sodium borohydride to 246. Nearly identical sequences have also been reported by Bryce

244

MIAH, HUDLICKY, AND REED

<%

(1) CHZ=CHCOzEt, Triton B

butadiene sulfone hydroquinone. toluene *

244

98

c

(2) Zn,HCI.EtOH

w

0 (1) Red-A1 or

A c ~ OHCOzH: , POC13;

then NaBH4

246

u

SCHEME 42

and Gardiner in 1986 (76) to yield 245, and in 1988 (77) to prepare the pentacyclic amine 246. In 1989, Mariano and Kavash (78,37u) reported the preparation of the complete cephalotaxine ring system 254 (Scheme 43), by means of a singleelectron-transfer-induced photospirocyclization methodology, combining all of the experience gained in the previous studies. Iodopiperonyl ethanol 106 was sequentially submitted to 0-benzylation, lithiation, and formylation to yield aldehyde 247, which was reacted with l,2-bis-[trimethylsilyloxy]cyclobutene 248 in the presence of boron trifluoride etherate, followed by a pinacol rearrangement induced by trifluoroacetic acid, to yield 2-aryl-1,3cyclopentandione. This was converted to the /3-chloroenone 249, which was treated with silylmethylamine250, followed by benzyl bromide, to give the p-enaminone 251. Silver-perchlorate-facilitated 0-acylation of 251 with pivaloyl chloride gave the intermediate 0-pivaloyl iminium perchlorate, similar to the previously reported compounds from the model cyclizations. Irradiation of the perchlorate salt, followed by sodium bicarbonate work-up, yielded the spirocyclic amine 252, whose ozonolysis, followed by ethylene dithioketal formation and Raney nickel desulfurization, gave 253. Catalytic hydrogenation of 253, followed by treatment with triphenyl phosphine in carbon tetrachloride, yielded the complete pentacyclic cephalotaxine derivative 254. This accomplishment concluded the long-term study, the goal of which was the synthesis of the entire ring system of the title alkaloid. It became evident that the spirocyclization cannot succeed with the rigid benzazepine ring system in place. The synthesis of 254 was completed in 17 steps from the piperonyl derivative 106. In 1990,Bryce and co-workers (79)reported syntheses of several cephalotaxine analogs (Schemes 44 and 45). The synthesis of 257 commenced with the known spirolactam 245, used previously by Hill (75) and these authors

2.

cdoH

1.BnBr KOH

~

2.n-BuLI N-fonnylpipendine

0 106

245

CEPHALOTAXUS ALKALOIDS

79%

3.NaOW (COC1)2

247

Q

tOBn

0

1. AgClO,/tBuCOCI. 95%

2. hv 3. NaHCO,, 73%

249

55% (two steps)

foBn

2. DMS

252

JoBn 1. Pd(0H)Z

1.03

3.HS(CH$2SH 4.Raney Ni 30%

(%

HZ

2. Ph3P

t BuCOO

253

254 SCHEME 43

SCHEME 44

TEA 65%

246

MIAH, HUDLICKY, A N D REED

M e o W ~ o z(1) ~ MaH ec l Z

Jw

Me0

(1) butadienesulfone w

(2) CHFCHCO~M~

(2) MeNO2

CH=CHNOz

Me0

259

258

(1) Zn.HC1

(2) DIBAL-H

MeO

26 1

(1) Zn,HCI L

(2) HCHO

SCHEME 45

(76,77), as indicated in Scheme 42.This material was converted to the spirocyclic amine-aldehyde derivative 255 by N-alkylation with tert-butyl bromoacetate followed by transesterification and diisobutylaluminum hydride reduction (Scheme 44). Treatment of aldehyde 255 with 6 M HCl gave a single isomeric benzazepinol derivative 256, which, on exposure to boron trifluoride etherate, afforded the enamine 257. Several other derivatives containing variations on the cephalotaxine ring system were prepared by a similar strategy. The synthesis of 261 began with 258, the methyl ester of 3,4-dimethoxyphenylaceticacid (Scheme 45). Formylation with dichloromethyl methyl ether in the presence of aluminum chloride gave the aldehyde ester, which was transformed to the nitrostyrene derivative 259 on reaction with nitromethane anion. Diels-Alder reaction with butadiene sulfone yielded the cyclohexene adduct, which, in turn, underwent Michael addition with methyl acrylate to afford the nitro diester 260. Clemmensen reduction of the nitro group gave a single lactam ester, which was treated with diisobutyl aluminum hydride to give the single stereoisomeric product 261. A similar strategy was employed in the synthesis of the azacephalotaxine derivative 263. Dinitro ester 262, prepared in an analogous fashion from nitropiperonal, was reduced to the lactam amine, then cyclized with formaldehyde to produce benzodiazepine 263. Sha and co-workers (80) reported a synthesis of a complete cephalotaxine ring system 273 in 1991, as shown in Scheme 46.The protected lactam 265

2.

&

247

CEPHALOTAXUS ALKALOIDS

&

-('Bu0zC)zO DMAPET3N

CH3Li (2.2 equiv)

97%

264

265 R= C02Bu

96%

14%.

266

(two steps)

267

273 SCHEME 46

was reacted with methyllithium to afford carbinol266, which was converted to the spiro compound 267 by treatment with p-toluenesulfonic acid, then ozonolyzed to give 268. Removal of the tert-butoxycarbonyl group of 268 by trifluoroacetic acid yielded 269, which, on treatment with p-(nitropheny1)sulfonyl ester 270, yielded the spirocyclic amide 271, containing all of the carbons for the cephalotaxine skeleton. Similarly, compound 272 was obtained from the reaction of 269 and the known nosylate 139. Attempted Friedel-Crafts cyclization of 271 under various acid catalytic conditions to close the seven-membered ring failed, presumably because of the rigidity of the intermediate cationic species. However, compound 272 cyclized smoothly in polyphosphoric acid to yield the complete ring system of the title alkaloid, tetracyclic amine 273. In 1993, Ikeda et al. (81) described the results of their efforts toward the synthesis of 11-hydroxycephalotaxine (Scheme 47) from the key

248

105

MIAH, HUDLICKY, AND REED

274

275 OAC

I OAc

1

p-TsoH

276

275 (27%) 277 (72%)

OAc

OAc

278(86%) 279(73%)

PhI(OAc)z, KOH

1 MOMo

281 (18%) Me0

OMe

intermediate 105, whose preparation the group had previously reported (see Scheme 10, Section 111) (3435). The sulfoxide 274, prepared by the oxidation of sulfide 105 with m-chloroperbenzoic acid, was treated with trifluoroacetic acid to give the intermediate trifluoroacetate,which on silica

2.

CEPHALOTAXUS ALKALOIDS

249

gel chromatography, produced the 11P-alcohol275,along with the diketone 276 as a minor product. The diketone 276, also obtained from 274 via the Pummerer rearrangement by treatment with anhydrous p-toluenesulfonic acid, was reduced with sodium borohydride to a mixture of alcohols 275 and 277. Protection of the hydroxyl groups in these isomers with dimethoxymethane, followed by deacylation and Swern oxidation yielded the diastereomeric ketolactams 278 and 279. Subsequent oxidation of the a-isomer 279 with iodobenzene diacetate yielded the hydroxy acetal 280 and its regioisomer 281. However, the compound of interest, namely the &isomer 278, failed to undergo the same reaction. The following year, 1994, Ikeda’s group also reported (82) the synthesis of the optically active aza-spiro heterocycle 285 as a part of their effort toward the synthesis of optically active cephalotaxine analogs (Scheme 48). Their synthesis, similar in concept, as well as execution, to the approach reported by Mori (38) (see Scheme 13, Section 111),began with the chiral azabicyclic compound 282, prepared from L-proline according to Seebach’s procedure (39,40).Treatment of 282 with 3,4-methylenedioxyphenyllithium was followed by protection as the N-Boc derivative 283. Wacker oxidation of 283 gave diketone 284, which underwent base-catalyzed aldol condensation to afford the aza-spiro heterocyclic enone. Catalytic hydrogenation of this enone produced the saturated ketone 285 as a single isomer. Schinzer and Langkopf (83) reported in 1994 their synthesis of various seven- and eight-membered N-heterocyclic systems resembling the benzazepine framework of cephalotaxine (Scheme 49) by means of tandem Beckmann rearrangement-allylsilane cyclization. Treatment of compounds 286 and 287 with diisobutylaluminum hydride yielded the heterocycles 288 and 289, respectively. [See Note Added in Proof, p. 264.1

SCHEME 48

250

MIAH, HUDLICKY, A N D REED

'm

RC

A

I!

DIBAL

L

R o /m N H I ,

288, R=R=Me

286, R=R=Me 287, R+R=CH2

(41%)

289, R+R=CHz (36%) SCHEME 49

Toke and co-workers (84,85) have reported the stereoselective preparation of the azacephalotaxine analog 293, containing an isoquinoline ring instead of a benzazepine, by means of a 1,3-dipolar cycloaddition methodology (Scheme 50). Silver-acetate-catalyzed cycloaddition reaction of nitrostyrene 98 with imine 290 produced cycloadduct 291, which was acylated, then reacted with methyl acrylate to give pyrrolidine 292. Reductive spirocyclization with zinc and hydrochloric acid, lithium aluminum hydride reduction of the lactam, and finally cyclization under Pictet-Spengler conditions with formaldehyde yielded the isoquinoline analog 293. Laronze and co-workers (86) reported in 1993an approach to the synthesis of indolic analogs of cephalotaxine via a spiro-cyclohexene intermediate 295 (Scheme 51). Bromoaldehyde 294, obtained by the Diels-Alder cyclization of 3-methyl-2-phenylthiobutadienewith 1-bromoacrolein, was treated

<s:h 291

290

(1) Zn, HCI, EiOH

"%'J C02Me

EtO&

(2) (CH,O),, (3) LiAIH, HCI. PhH

El

Ac

292

293 SCHEME 50

2.

-

CEPHALOTAXUS ALKALOIDS

/=-= I

lryptamine ..

L.&f

\

(1) Raney Ni (R=H. 15%)

___)

(2) Os04.py; NaHS03 (R=H, 19%)

I 294

251

295

I

with tryptamine to give the spiro compound 295. Raney nickel desulfurization (15% yield) followed by osmylation (19% yield) afforded the diol296, whose further oxidation with sodium periodate gave, via cyclization and further oxidation, the keto lactam 297. Desulfurization of the trifluoroacetamide derivative of 295 (R = COCF3) resulted in higher yield (71%); however, further manipulation of this product proved unsatisfactory. In 1996, the same group (87) reported further work on the synthesis of indole analogues of the cephalotaxine ring system (Scheme 52). The key intermediate in this ring-expansion approach, bromoiminium ion 300, was prepared in three steps from tryptamine and the chloro diester 298 via enamine 299. On treatment with several bases, the iminium ion 300 underwent rearrangement, presumably via the intermediate alkoxide 301,to give the azepinone derivative 302, which was reduced with sodium borohydride to a mixture of isomeric alcohols 303. The alcohols 303 underwent rapid intramolecular cyclization when treated with a 95% solution of sulfuric acid to yield pentacyclic ketone 304. In 1996, Fuchs and Jin (88), continuing to exploit the chemistry of vinyl sulfones, reported a stereospecific synthesis of the azabicyclic ring system of the cephalotaxine ring by means of palladium(0)-mediated aminospirocyclization of tertiary allylic sulfones, as shown in Scheme 53. Treatment of compounds 305 and 306 with either triethylamine or tetramethylguanidine (TMG) in the presence of Pd(Ph3P), produced the spiro azabicycles307 and 308, respectively. The tertiary allylic sulfone 309, under identical reaction conditions, yielded 310, which contains the A/C/D ring system of cephalotaxine.

c

252

MIAH, HUDLICKY, AND REED

301

NaFM&leOH

95% H2S04 c

L

98%

80%

302

303

0 304 SCHEME 52

In early 1997, de Oliveira and his group (89) reported an approach to the tetracyclic core of cephalotaxine that essentially mimicked the earlier chemistry reported by Danishefsky (33) (see Scheme 9,Section 111).The thio amides 311 and 312 (Scheme 54) were prepared by alkylation of succinimide with the corresponding P-piperonyl bromide prepared in two steps from safrole, then functionaliied further to the nitrile or ester by chloromethylation,followed by displacement and/or hydrolysis and esterification. The base-catalyzed closure produced the tetracyclic ring systems 313 and 97 in 75 and 22% yield, respectively. These compounds were thus

2.

CEPHALOTAXUS ALKALOIDS

253

51 - 91%

30s R=Ts 306 R=Bn

Base = Et3N 01

TMG

307 R = TS 308 R = Bn

Pd(PPh,),, 10% MeCN, Base Reflux

R = p-methoxybenzyl-

OM

0 SAS

L/ 310

309

Yield, 9%

Reaction

Base

1

Et3N

64

2 3

AgZC03

50

TMG

98

SCHEME 53

obtained in 7- to 12-step sequences, with overall yields of 12 and 1%, respectively. The multitude of approaches to the core of cephalotaxine that are presented in this section attest to the continuous interest in the development of a more practical route to the alkaloid. All model studies follow the

K.H (10 eq.) THF/24 hDO0 C R

R

311 R = CN 312 R = C a M e

313 R = CN. 75% 97 R = C02Me. 22% SCHEME 54

254

MIAH, HUDLICKY, AND REED

strategic disconnections illustrated for the total syntheses in Scheme 14, Section 111. Although some of the approaches are quite creative and some offer a synthesis of the appropriate enantiomer or an unnatural derivative, few compete with the very first and simplest route to the alkaloid-that of Weinreb. Future improvements in this area should address the asymmetric version of the Weinreb synthesis, or else offer a completely new strategy (hopefully an asymmetric one), which would deliver the title alkaloid in fewer than six steps and in an enantiodivergent manner. The evolution of synthetic organic chemistry, since the first preparation of cephalotaxine 25 years ago, places more specific demands on the practitioner today. A sequence of 15 or more steps to assemble a relatively simple molecule is not acceptable as the discipline enters the 21st century. The reader is referred to a recent review that summarizes the requirements for “proper” synthetic strategies for the present and certainly for the future (90). In conclusion, the synthesis of cephalotaxine and, more important, its esters remains a wide-open field that awaits the next good idea.

VI. Unnatural Cephalotuxus Esters and Their Antitumor Activity

The unnatural ester derivatives of cephalotaxine reported since 1983 are shown in Table IV. Virtually all of the work during this period has been performed in China. Researchers at the Lanzhou University (91) have prepared isoharringtonine analogs, (2’R,3’R) and (2’S,3’S) cephalotaxinyl methyl tartrates (314),by a monoester exchange reaction of cephalotaxine with dimethyl (2R,3R)-tartrate or dimethyl (2S,3S)-tartrate acetonide followed by hydrolysis. An ester exchange reaction was also used to prepare ethyl cephalotaxine oxalate (315),which was treated with appropriate Grignard reagents to produce the a-keto acyl cephalotaxines 316 and 317 (92). An attempt to achieve a Reformatsky reaction on 2’-oxo-6’-methylheptanoyl cephalotaxine with zinc, tributyl phosphite, and methyl bromoacetate resulted in the isolation of phosphonyl derivative 318 as a mixture of epimers (93). The Lanzhou group (94)has prepared a mixture of homoisoharringtonine (319) and its stereoisomers by treatment of 2’-0~0-6’-methylheptanoyl cephalotaxine with lithium diisopropylamide and methyl O-(l-methyoxyisopropy1)glycolate. The four stereoisomers were separated by thin-layer chromatography (TLC) and characterized by ‘H NMR spectroscopy. A series of isoharringtonine analogs (320-324),as mixtures of stereoisomers, has also been prepared (95). The isoharringtonine analog and homoisoharringtonine mixtures all exhibited activity against L-7712 leukemia cells.

TABLE IV UNNATURAL CEPHALOTAXINE ESTERS

OMe Cephalotaxine (1)(R = OH)

R =

R =

Kef. 91

314

315

Ref.

EtYc-

91

4-

92

0

Me06

OH

316

mc* u 92

0

0

317

0

(continues)

TABLE IV (Continued)

R= 319

321

E m

R=

Ref.

ekz

%z...-

94

320

95

H

O

V

d

0 95

95

322

* C * H O Y -

0

0 95

323

Ref.

95

324

HO

325

nC" %

326

%

%

328

%

CqEt

327

OH -

329

97

330

97

( 2 ' 9 and (2's) d

97

331

332

-

(2'R j and (2's)

(2'R) and (2's) 333 4

&*

97

334

97

97

336

97

97

338

97

CQMe

335

337

)y."ycQr 0

(continues)

TABLE IV (Continued) R = 339

R=

Ref.

97

340

EtNYCOr

Ref. 97

97

343

98

345

98

347

98

348

98

98

350

98

NHCbz 349

98

351 NH2

352

98

260

MIAH, HUDLICKY, AND REED

TABLE V EFFECTS OF CEPHALOTAXINE ESTERSON HL-60 LEUKEMIA CELLDIFFERENTIATION AND INHIBITIONOF L-1210 IN V m d Induction of Differentiation of HL-60 Cells (6 Days after Administration) Dosage

Ratio Differentiation

NBT (+)

Inhibition of L-1210 in vitro

(%)

IC ( P g / A )

80 0.5 1.5 2.0 73

5.75 10.5 24.0 1.74 0.00688

(CLglml)

325 324 327 328 3

1.5 2.0

78

2.0 1.5 0.03

4 1.5 78

5

Wei and co-workers (96) have reported the preparation and cytotoxic activities of the unsaturated cephalotaxine esters 325-328. Ester 325 showed significant cytotoxic activity, as shown in Table V. The activity of homoharringtonine (3) is shown for comparison. Wang et al. (97) have synthesized the cephalotaxine esters 329-342. Their cytotoxic activities against P-388 leukemia cells are shown in Table VI. Note that the antileukemic activities of compounds 329,2'R-330,2'R-330 2'S-330,2'R-332,and 333 are comparable to that of homoharringtonine (3), and four others (2'R-331,2'S-331,340,and 341) show moderate activity. The activity of homoharringtonine (3) is shown for comparison.

+

TABLE VI GROWTH INHIBITION(YO)OF CEPHALOTAXINE ESTERS AGAINST P-388 LEUKEMIA CELLSIN VITEO

329 2'R-330 2'R-330 + 2's-330 2'R-331 2's-331 2'R-331+ 2's-331 2'R-332 2'R-332 2'R-332+ 2's-332 333

100pg/ml

10pg/ml

lpg/ml

98.6 99.3 98.6

100 100 99.3

100

91.9 99.7 100 98.7 0 100 100

100pg/ml

lOpg/ml

1 pg/ml

95.1 97.2

334 335 336

99.3 100 0

64.8 95.1 0

0 0 0

97.2 96.8 95.7

18.3 81.0 68.1

337 338 339

0 0 0

0 0 0

0

99.7 0 86.2

90.5 0 15.7

340 341 342

96.0 95.3 90.7

78.7 76.7 42.0

19.3 8.6 0

97.9

3

99.3

99.3

100

100

0

2. GROWTH INHIBITION (%)

343 344 345 347 348

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CEPHALOTAXUS ALKALOIDS

OF

TABLE VII CEPHALOTAXINE ESTERS AGAINST HL-60 LEUKEMIA CELLSIN VITRO

100 p g / d

10 pg/ml

1 pg/ml

0 0 0

5.43 25.91 14.76 62.53

1'1.62 57.72 61.62 51.46 75.20

349 350 351 2

lOOpg/ml

lOpg/ml

lpg/ml

0 0 0 94.06

17.22 22.44 99.04

35.24 28.47 39.06 100

Researchers in Beijing have prepared cephalotaxyl amino acid esters

343-352,which have a wide variety of structural features (98). The activities of several of them against leukemia HL-60 cells are summarized in Table VII, with the activity of harringtonine (2)shown for comparison. Compound 348 is the most active, yet not as potent as harringtonine.

VII. Analytical and Spectroscopic Studies

There have been several reports on chromatographic separations of Cephafotaxus alkaloids. High-performance liquid chromatographic methods have been developed for separating the epimers of partially synthesized harringtonine (2)(99-101) and deoxyharringtonine (101). Epimers of partially synthesized homoharringtonine have been separated by thin-layer chromatography (102). Cai and co-workers were successful in separating harringtonine, homoharringtonine, and isoharringtonine by high-speed countercurrent chromatography (103,104). Wang et ai. separated the principal alkaloids from Cephafotuus bark by high-performance liquid chromatography (HPLC) (105). Cephalotaxine, harringtonine, and homoharringtonine have been separated from C. harringtonia callus and root cultures by HPLC (106). A sensitive, reliable, and rapid technique for quantification of homoharringtonine in plasma or serum by HPLC with amperometric detection has been developed by Chan and co-workers (107). Previous determinations of homoharringtonine in plasma entailed the use of radiolabeled alkaloids (108,109).Tang et af. have used HPLC for the determination of harringtonine in human plasma (110). The crystal structures of harringtonine (2)and homoharringtonine (3) have been determined by X-ray diffraction using the RANTAN and

262

MIAH, HUDLICKY, A N D REED

MULTAN programs (111). The structure and unit cell packing of each are shown in Fig. 1. Circular dichroism spectra of 10 Cephaloraxus alkaloids have been reported (112). Cephalotaxine was studied by two-dimensional nuclear Overhauser effect correlated spectroscopy (NOESY) (113).

VIII. Pharmacological and Clinical Studies Clinical research on homoharringtonine and other cephalotaxine esters has been extensive, as clinical trials in the treatment of myeloid and lymphoblastic leukemia continue in both China and the United States. This re-

hwringtonine

FIG.1. Molecular models and unit cell packing of harringtonine and homohamngtonine.

2.

CEPHALOTAXLJSALKALOIDS

263

search has been reviewed (3,224-217). Most of the studies in the United States have focused on homoharringtonine, whereas investigators in China have performed studies on unpurified homoharringtonine, which contains 30% harringtonine (227). The study of the mechanism of action of the Cephulotuxus alkaloids, especially harringtonine and homoharringtonine, has been under way for more than 20 years. These alkaloids act primarily as inhibitors of protein synthesis. It has been shown that harringtonine and homoharringtonine are not significantly different in their activities or mechanisms of action (118, 229). In the seminal research in this area, Huang (218) showed that harringtonine and homoharringtonine inhibit the initiation of protein synthesis. More recently, researchers have further investigated inhibition of protein synthesis by harringtonine (220,222) and homoharringtonine (222224). Studies of the action of h.arringtonine against L-1210 leukemia in vitro and in vivo show that its cytotoxicity is in direct proportion to its protein synthesis inhibition (220). Russian researchers have shown that homoharringtonine inhibits polypeptide chain elongation at the step of peptide bond formation (222,123). Ling and co-workers have observed inhibition of glycoprotein synthesis during exposure to homoharringtonine (224). Harringtonine and homoharringtonine have been shown to induce apoptosis (125-228), an active process of programmed cell suicide. Reports of clinical investigations of harringtonine and homoharringtonine in the treatment of leukemia abound in the literature (229-247). Phase I studies (148-154) have been completed, and Phase II/III (255-259) clinical trials are currently underway. These trials indicate that homoharringtonine is a safe and effective antileukemia drug. Negative results, however, have been obtained from studies in solid tumors in ovarian, breast, colorectal, head, and neck cancers, as well as sarcoma and melanoma, although the patients tested in most of these studies had been heavily pretreated (160-164). Future studies are warranted in patients not having received prior therapy. Because of the lack until recently of sensitive methods for detecting harringtonine or homoharringtonine in plasma (see Section VII), pharmacokinetic studies have been limited. Tritiated homoharringtonine has been used to study its pharmacokinetics in human patients (107) and in dogs (108). More recently, a report has appeared on the pharmacokinetics of harringtonine and harringtonine liposomes in rabbits (265). Homoharringtonine has been investigated in the treatment of malaria (166). It was found to cause 50% growth inhibition in two strains of chloroquine-resistant Plasmodium falciparum malaria in vitro. In mice infected with P. yoelii, homoharringtonine also inhibited parasite growth. In a similar study, in vitro antimalarial activity of cephalotaxine, homoharringtonine,

264

MIAH, HUDLICKY, AND REED

and several other protein synthesis inhibitors was assessed in chloroquineresistant and chloroquine-sensitive strains of P. fulcipurum (167). There were no differences in the sensitivities of the two strains to these compounds. In addition, ester-containing compounds (e.g., homoharringtonine) were more active than non-ester-containing compounds, (e.g., cephalotaxine). In fact, homoharringtonine is nearly 10,OOO times more active than cephalotaxine. Harringtonine and homoharringtonine were both found to be inactive as inhibitors of HIV-1(268) and HIV-2 (169) reverse transcriptase. Applications of homoharringtonine in ophthalmology have also been investigated (170-274).

Note Added in Proof In 1997,Schinzer and coworkers [D. Schinzer, U. Abel, and P. G. Jones, Synleft 632 (1997)l reported as asymmetric synthesis of the cephalotaxine subunit (S,R)-288 from (S)-286 (see Scheme 49). The stereochemistry of the 2-(dimethylphenylsilylmethyl)propenyl group in 286 was established through a planar chiral $-chromium arene complex.

Acknowledgments

The authors thank the University of Florida for financial assistance; M. A. J. Miah is grateful to the University of Rajshahi, Bangladesh, for a sabbatical leave of absence.

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145. D. Russo, A. Michelutti, C. Melli, D. Damiani, M. G. Michieli, A. Candoni, D. C. Zhou, J. P. Marie. R. Zittoun. and M. Elaccarani. Leukemia 9.513 (1995). 146. S . O’Brien, H. Kantarjian, M. Keating, M. Beran, C. Koller, L. E. Robertson, J. Hester, M. B. Rios, M. Andreeff, and M. Talpaz, Blood 86,3322 (1995). 147. E. J. Feldman, K. P. Seiter,T. Ahmed, P. Baskind, and Z. A. Arlin, Leukemia 10,40 (1996). 148. C. J. Coonley, R. P. Warrell, Jr., and C. W. Young, Cancer Treat. Rep. 67,693 (1983). 149. J. A. Neidhart, D. C. Young, D. Derocher, and E. N. Metz, Cancer Treat. Rep. 67, 801 (1983). 150. S . S . Legha, M. Keating, S. Picket, J. A. Anjani, M. Ewer, and G. P. Bodey, Cancer Treat. Rep. 68, 1085 (1984). 151. S. C. Malamud, T. Ohnuma, V. Coffey, P. A. Paciucci, L. P. Wasserman, and J. F. Holland, Proc. A m . Assoc. Cancer Res. 25, 179 (1984). 152. N. Savaraj, K. Lu, L. G. Fuen, D. Wang, and T. L. Loo, Proc. Am. Assoc. Cancer Res. 26,359 (1984). 153. J. A. Stewart and I. H. Krakoff, invest. New Drugs 3, 279 (1985). 154. J. A. Neidhart, D. C. Young, E. Kraut, B. Howingstein, and E. N. Metz, Cancer Res. 46,967 (1986). 155. Z. Arlin, E. Feldman, and S. Biguzzi, Proc. Am. SOC. Clin. Oncol. 6, 160 (1987). 156. E. J. Feldman, Z. A. Arlin, T. Ahmed, A. Mittelman, J. L. Ascensao, C. A. Puccio, N. Coombe, and P. Baskind, Acta Haematol. 82, 117 (1989). 157. H. M. Kantajian, M. J. Keating, R. S. Walters, C. A. Koller, K. B. McCredie, and E. J. Friereich, Cancer 63, 813 (1989). 158. E. Feldman, Z. Arlin, and T. Ahmed, Leukemia 6, 1189 (1992). 159. S. O’Brien, H. Kantjarian, E. Feldman, M. Beran, M. Andreeff, M. Keating, C. Koller, and M. Talpaz, Blood 80 (Suppl I), 358, (1992). 160. J. A. Anjani, I. Dirnery, S. P. Chawla, K. Pinnamaneri, R. Benjamin, S. S. Legha, and I. H. Krakoff, Cancer Treat. Rep. 70,375 (1986). 161. T. Zhao, G. Ding, G. Haoyong, 2.. Shen, and L. Yeuyun, Tumori 72,395 (1986). 162. J. J. Kavanagh, D. M. Gershenson, L. J. Copeland, J. T. Wharton, F. N. Rutledge, and I. H. Krakoff, Cancer Treat. Rep. 68, 1503 (1984). 163. M. A. Runge-Morris, M. S . Kies, E. Vokes, R. Blough, L. Weidner, R. Knop, and U. Rowland, Invest. New Drugs 7, 269 (1989). 164. L. G. Fuen, N. Savaraj, H. Landy, H. Levin, and T. Lampidis, J. Neuro-Oncol. 9, 159 (1990). 165. H. Wu, G. Weng, Z. Wu, and Y. Lu, Zhongguo Yaoli Xuebao 15, 84 (1994); Chem. Abstr. UO,9471511. 166. J. M. Whaun and N. D. Brown, Ann. Trop. Med. Parasit. 84,229 (1990). 167. R. M. Ekong, G. C. Kirby, G. Patel, J. D. Phillipson, and D. C. Warhurst, Biochem. Pharmacol. 40,297 (1990). 168. G. T. Tan, J. M. Pezzuto, A. D. Kinghorn, and S. H. Hughes,J. Nut. Prod. 54,143 (1991). 169. G. T. Tan, J. F. Miller, A. D. Kinghorn, S. H. Hughes, and J. M. Pezzuto, Biochem. Biophys. Res. Commun. 185,370 (1992). 170. X. Su, S. Li, and J. Zheng, Yen KO Hsueh Pa0 11,32 (1995). 171. H. Guo, S . Li, and X. Cao, Chung Hua Yen KO Tsa Chih 31, 102 (1995). 172. F. Shi, H. Shi, and Z. Li, Cheung Hua Yen KO Tsa Chih 31,345 (1995). 173. K. Yu, D. Peng, and X. Liu, Yen KO Hsueh Pa0 10,108 (1994). 174. S. Q. Zeng, C. Z. Hu, J. P. Li, and H. R. Wei, Ann. Ophrhalmol. 23,337 (1991).

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--CHAPTER

3-

THE IPECAC ALKALOIDS AND RELATED BASES Tozo FUJIIAND MASASHIOHBA Faculty of Pharmaceutical Sciences Kanazawa University Takara-machi, Kanazawa 920, Japan I. Introduction 11. Occurrence

.........................

..........................................

271

...........................................

111. Chemistry and Synthesis .. A. Protoemetine, Protoemetinol, 9-Demethylprotoemetinol, 10-Dernethylprotoemetinol, Ankorine, and Alancine ........... B. Emetine, 0-Methylpsychotrine, and Emetamine ............... C. Psychotrine, 9-Demethylpsychotrine, and Alangicine .......... D. Cephaeline, Isocephael E. Tubulosine, Isotubulosine, 9-Dernethyltubulosine, 10-Demethyltubulosine, and 0-Methyltubulosine ............................... 289 F. Deoxytubulosine, 10-Demethyldeoxytubulosiqe,and Alangimarckine ..... 290 G. Ipecoside, Alangiside, and Related Tetrahydroisoquinoline-Monoterpene Alkaloid Glucosides ..................................................................... 291 H. Related Alkaloids of Alangii ......................... ............................................. 296 IV. Related Compounds .............. V. Analytical Methods ..............................

........................ ................ 305 ......................................................... 307 References ................................ .................. 308

VII. Biological Activity

I. Introduction The previous chapter on the ipecac alkloids in this series appeared in Volume XXII in 1983 ( I ) , with coverage of the analogs and P-carboline congeners isolated from the Alangium plants. Since that time, certain aspects of the subject have been reviewed in several forms (2-11). The aim of the present chapter is to supplement the previous one ( I ) by surveying the work performed on new or already known alkaloids of this group during the past 14 years. Although the synthetic routes to the main groups of the ipecac alkaloids and their P-carboline congeners had been well established by 1971, THE ALKALOIDS, VOL. 51 0099-9598/98 $25.00

27 1

Copyright 0 1998 by Academic Press. All rights of reproduction in any form reserved.

272

FUJI1 AND OHBA

many studies were still directed toward synthesis during this last period, featuring the use of new approaches and synthetic strategies as in the period 1972-1982. In addition, isolation studies have resulted in the structural elucidation of three new benzo[u]quinolizidine-type alkaloids, 28 new tetrahydroisoquinoline-monoterpeneglucosides, and a new tetrahydroP-carboline-monoterpene glucoside. These achievements may afford a better understanding of the main biosynthetic pathway to the group of alkaloids under review. This chapter is organized in much the same manner as its predecessor, with some subsections expanded whenever warranted. Unless otherwise noted, the structural formulas of optically active compounds in this chapter represent their absolute configurations, and the numbering system employed for the benzo[u]quinolizidine alkaloids is identical with that used previously (1,12). It is known that the 22 species of the genus Alungium constitute a monogeneric plant family, the Alangiaceae (13-15). Several of these species have been investigated chemically, and the Indian medicinal plant Alungium lumurckii Thwaites, a deciduous shrub or small tree widely distributed throughout India, Sri Lanka, Myanmar, Southern China, Malaysia, and the Philippines (13-15), has been found to be a particularly rich source of alkaloids, especially those structurally related to ipecac alkaloids (1,4,5,7,10,12). The chemical structures of all of the 20 ipecac alkaloids [six benzo[u]quinolizidine-type (1-6) and 14 tetrahydroisoquinolinemonoterpene glucoside-type (7-20) alkaloids], the 57 Alungium alkaloids [21 benzo[u]quinolizidine-type (1-3 and 21-38), 20 tetrahydroisoquinolineor tetrahydro-P-carboline-monoterpene glucoside-type (18-20 and 39-55), and 16 other alkaloids (56-71)] reported so far are shown in formulas 1-71,' where the ipecac alkaloids are marked with an asterisk the A. lumurckii alkaloids, with a dagger; and the alkaloids from other species of Alungiurn, with a double dagger. In addition, the new structures, the revised or established structures, and the already known, newly isolated, structures encountered since the last review (1) are marked with a section, parallel, and paragraph, respectively. As regards the 21 benzo[u]quinolizidine-typeAlungium alkaloids, they can be structurally classified into four types according to their substitution patterns in the aromatic ring A (i) 9,lO-dimethoxy type (72), (ii) 8-hydroxy9,lO-dimethoxy type (73), (iii) 9-hydroxy-10-methoxytype (74), and (iv) 10hydroxy-9-methoxy type (75) (7,10,16). Thus, type 72 includes 10 alkaloids

*

For formulas 1-71: * Ipecac alkaloids, 'f A. lamarckii alkaloids, alkaloids from other species of Alangium, B new structure, 11 revised or established structure, Iknown but newly isolated structure.

*

1' Emtine**+R = Me 2 Cepha&ne*gtBR = H

3 Psychotrine**+*R = H 4 0-Methylpsychotrine* R = Me

*

Nm OMe

CHO

6 Protoemetine*

5 Emetamine*

HO

H02C

7 Ipecoside* R ' = R Z = H 8 6-0-Methylipecoside** R' = Me, Rz = H 9 7-0-Methylipecoside** R' = H. Rz = Me

1 0 Ipecosidic acid**

OH

11 trans-Cephaeloside** R = H 1 2 6-0-Methyl-~~s-cephaelosi&*,R -- Me

'

13 cis-Cephaeloside** R = H 14 6-0-Methyl-cis-cephaelosi&** R = Me

274

FUJI1 AND OHBA

RO

HO

15 Neoipccoside**DR = H 1 6 7-O-Mcthylneoipecosidel' R = Me

'

17 3,4-Dch droneoipecoside** (possigly an artifact)

*

19 Deme&ylalangiside** *, t* R' = Rz = H 20 3-O-Demcthyl-2-O-~th~m~side*~ R' = H, R~ = MC

21 Isoccphaalinet R = H (l'a-H instead of 1'BH) 22 Almgamidct R=MeNH-CO(possibly m artifact)

23 Demethylccphaehet R' or R2= Me, RZorR' = H

3.

275

THE IPECAC ALKALOIDS AND RELATED BASES

OR

*

% N

OH

24 9-Demethylpsychotrinet R' = R2 = H 26 Alangicinet R' =Me, R2 = OH R'O F?O

26 Tubulosinet* R = H 27 Isotubulosinet R = H (l'a-H mtead of 1'p-H) 28 O-MethyltubulosinetSq R = Me

9; +''

OH 29 9-DemethyltUbulosine*~'R' = H, Rz = Me 90 10-Dcmethyltubulosinet9 R' = Me, R2 = H

*

*

31 Deoxy&bulosinet* R' = H, Rz = Me 32 10-Demethyldeoxytubulosinet* R' = R Z = H 33 Alangimarckinet R' = OH, Rz = Me

Meo Me0

H.."

CH2

I

R

CH2OH

34 Rotoemetinolt R' = Rz= Me 35 9-~emethylprotoemetino1~ R' = H, Rz = Me 36 10-Demethylprotoemetinolt R' =Me, Rz = H

*

37 Ankorine'* R = CH~OH 38 Alancinet*O R=COzH

276

FUJI1 AND OHBA

R'O R20

Me0

HOQNTo

46 6 - 0 4 s -and jrmrs-Feruloylde~~~~thylalmgisidCS** R =H (Isolated as a mixlu~~) 47 6-o-cis- and -troneSinapoyldCI R = OMe m~thylhgisidCS*~ (Isolated as a mixture)

'

M

e

O

q0

;O ((H' i

HO 48 Ncoalangisidet*

OH

HO

OH

'

49 Demcthylntoalangisidet*

3.

THE IPECAC ALKALOIDS AND RELATED BASES

51 MethyIisoalangisidet7 R1= Rz = Me 52 3-O-Demetbyl-2-O-methylisoalangisidet. R' = H. Rz= Me

50 Isoalangiside'.

63 10-Hydmxyvincosidelactamt'

277

*

'

54 [(9R)-isom~r]~*(possibly an artifact) 5b [(9S)-isomrlt9 (possibly an artifact)

278

FUJI1 AND OHBA

Me0

Me ~lamaridine+*D(relative

62 Dihydroalamariaet*' R' = MC, R~= H

61 Ahgimaridimt

configuration shown)

t19 Dihydroisoalaaarinct' R' = H, R~= MC MeO

Me0 Me

FH2OH

&"

3

PhCONH-C-H

I

CH2Ph

68 N-Benzoyl-Lphenylalaninolt

69 (*)-habashe* 70 Alangiobussinet* 71 Alangiobussinine** (3,4didehydro)

*

[emetine (l),cephaeline (2), psychotrine (3), isocephaeline (21), alangamide (22) (possibly an artifact), tubulosine (26), isotubulosine (27), O-methyltubulosine (28), deoxytubulosine (31), and protoemetinol (34)]; type 73, four alkaloids [alangicine (25), alangimarckine (33), ankorine (37), and alancine (38)]; type 74, four or three alkaloids [9-demethylpsychotrine (24), 9-demethyltubulosine (29), and 9-demethylprotoemetinol (35), with or without demethylcephaeline (23)]; and type 75, three or four alkaloids [lo-demethyltubulosine (30), 10-demethyldeoxytubulosine (32), and 10demethylprotoemetinol (36), without or with demethylcephaeline (23)]. However, all of the six benzo[a]quinolizidine-type ipecac alkaloids [emetine (l),cephaeline (2), psychotrine (3), 0-methylpsychotrine (4), emetamine (9,and protoemetine (6)] are of the 72-type.

3.

THE IPECAC ALKALOIDS AND RELATED BASES

279

R = CHpOH, CHO, COzH, or a heterocyclic ring

11. Occurrence

The number of new alkaloids isolated from ipecacuanha and Alangium plants during the period of this review amounts to 39. From the dried roots of Cephaelis ipecacuanha (the crude drug "ipecac"), Nagakura's group (17,18) has isolated 6-O-methylipecoside (8) [mp 154-155°C; [agz-184" (MeOH)], ipecosidic acid (10) [mp 248-250°C; [ag2-166" (MeOH)], neoipecoside (15) [mp 184-185°C; lag8 -161" (MeOH)], 7-O-methylneoipecoside (16)[[aBo- 150" (EtOH)], 3,4-dehydroneoipecoside (17)(possibly an artifact) [mp 154-156°C; tag3 -206" (MeOH)], and demethylalangiside (19) [mp 180-182°C; [ag4-73" (MeOH)], along with the known alkaloids alangiside (18) (as an Alangiurn alkaloid) and ipecoside (7).Further investigations of the same source have resulted in the isolation (19) of crans-cephaeloside (11) [mp 170-172°C; [a%' -193" (MeOH)], 6-0methyl-trans-cephaeloside (12) [mp 162-164°C; [ag2 -189" (MeOH)], cis-cephaeloside (13) [mp 164-165°C; [ag8 -183" (MeOH)], and 6-0methyl-cis-cephaeloside(14)[mp 154-155°C; tag8 -157" (MeOH)], as well as that (20) of 7-O-methylipecoside (9) [mp 149-151°C; [agl -194"

280

FUJI1 AND OHBA

(MeOH)], 3-0-demethyl-2-0-methylalangiside (20) [mp 275-277°C; [ag6 -48" (MeOH)], and alangiside (18) [[ag5-95" (MeOH)]. The occurrence of demethylalangiside (19) (21) and 3-0-demethyl-2-0methylalangiside (20) (20) has been duplicated in the dried fruits of A . lurnurckii, from which 14 other new tetrahydroisoquinoline-monoterpene glucosides and a tetrahydro-P-carboline-monoterpeneglucoside have been isolated. They are 2'-0-zruns-feruloyldemethylalangiside(39) [mp 175-177OC; [a%' - 162" (MeOH)] (22), 2'-0-truns-feruloylalangiside (40) [[ag4- 153" (MeOH)] (22), 2'-0-~runs-feruloyl-3-0-demethyl-2-0methylalangiside (41) [[a%' - 115" (MeOH)] (22), 2'-0-truns-sinapoyldemethylalangiside (42) [mp 183.5-186°C; [ag6-155" (MeOH)] (22), 2'0-trans-sinapoylalangiside(43) [mp 179-181°C; [a%, - 157" (MeOH)] (22), 2'-0-truns-sinapoyl-3-0-demethyl-2-0-methylalangiside (44)[[a%*- 126" (MeOH)] (22), 2'-0-fruns-[C(2-hydroxy-l-hydroxymethylethoxy)-3-methoxycinnamoyl]alangiside (45) [mp 166-169°C; [ag7- 153" (MeOH)] (22), neoalangiside (48) [[a$,+7.7" (MeOH)] (21),demethylneoalangiside (49) [mp 193-195°C; [a%' -9.8" (MeOH)] (21), isoalangiside (50) [[a%' -118" (MeOH)] (21,23),methylisoalangiside (51) [[a$ -141" (MeOH)] (21,23), 3-0-demethyl-2-0-methylisoalangiside (52) [[a%' - 169" (MeOH)] (21,23), 10-hydroxyvincoside lactam (53) [[a]D4- 120" (MeOH)] (21), 54 (possibly an artifact) (24),and 55 (possibly an artifact) (24).Other parts of A. lurnarckii have been found to contain 12 other either new or known alkaloids, among which alancine (38) [hemihydrate, mp 216-220.5"C; [ago -29" (MeOH)] (25-27) has been isolated from the stem bark (25);deoxytubulosine (31), from the flowers (28); alangimarine (56) (mp 247°C) (29,30), isoalangimarine (57) (mp 249°C) (30),alamarine (58) [mp 288°C; [a]D 20" (CHCl,)] (29,30),isoalamarine (59) (mp 301-303°C) (29,30), alangimarinone (60) (mp 282°C) (30), alangimaridine (61) [mp 278°C; [a],, +429" (CHCl,)] (29,30),dihydroalamarine (62) [mp 252-253°C; [a]D +347" (pyridine)] (30), dihydroisoalamarine (63) [mp 268-270°C; [a]D + 140" (pyridine)] (30), bharatamine (65) [mp 182-183°C; [a]D 20" (CHCl,)] (30,31), and alamaridine (64) (mp 196°C) (32-34), from the seeds. Of these 12 alkaloids,preliminary studies concerning 56,58,59,61, and 65 were summarized in the last review (I). Some other species of Alungiurn have been found to contain similar alkaloids. From the leaves of Alungium plutunifoliurn var. triloburn were isolated two new tetrahydroisoquinoline-monoterpeneglucosides, namely, 6'-0-feruloyldemethylalangiside(46)and 6'-0-sinapoyldemethylalangiside (47), along with demethylalangiside (19) (35). The antitumor alkaloid C Z ~ H ~ ~[mp N@ 200°C; ~ [ago-40" (pyridine)], found together with tubulosine (26) in the bark of Alungiurn vitiense (1,36-38), was determined to be 9demethyltubulosine (29) (38-40). From the leaves of Alungium bussyunurn

3.

THE IPECAC ALKALOIDS AND RELATED BASES

281

were isolated tubulosine (26), 10-demethyltubulosine (30),deoxytubulosine (31), 9- or 10-demethylprotoemetinol (35 or 36) (41,42), O-methyltubulosine (a), 10-demethyldeoxytubulosine (32), alangiobussine (70), and alangiobussinine (71)(43). Of these eight bases, the first four were already known as A. lamarckii alkaloids; the last three are new alkaloids; and 0methyltubulosine (28) [mp 183°C; [a%' +15.4 2 0.5" (MeOH)] was known semisynthetically (5,44,45), but not encountered before in Nature. However, a review on alkaloids from the medicinal plants of New Caledonia (46) appears not to have accurately reflected the results (43) of this isolation study. Anabasine (69)was found in Alangium salviifolium, Alangium chinense, and Alangium chinense pancijlorum in their fine roots and in the bark of thick roots and twigs (47). The distribution and contents of total alkaloids and (2)-anabasine (69)in thick root, rootlet, fibrous root, leaf, and twigs of A . chinense (Lour.) Harms have been studied (48). In the meantime, the formation of the main alkaloids in C. ipecacuanha under a variety of conditions has been extensively investigated: emetine (1)in callus cultures (49) and under the effects of L-tyrosine supplementation (50); emetine (1) and cephaeline (2) in Panamanian ipecac (5I), in Nicaraguan ipecac (52), in regenerates obtained by clonal propagation (53,54),in tissue cultures (55) and under the effects of exogenous feeding of shikimic acid and L-phenylalanine (56), in cell suspension and excised root cultures (53,in adventitious root cultures (58), and in callus cultures (56,59) and the effects of age and electrokinetic potential (60); ipecoside (7)in the roots (61); and the effect of Atotobacter, leaf mold, and farmyard manure on alkaloid content (62). In addition, micropropagation systems for C. ipecacuanha have been developed (63-65). Interestingly, psychotrine (3)and tubulosine (26)have been isolated from the freeze-dried sap of Pogonopus speciosus (Jacq.) K.Schum. (Rubiaceae) (66).These two alkaloids (3 and 26) and cephaeline (2)were also isolated from the bark of the Bolivian medicinal plant Pogonopus tubulosus (D. C.) Schumann (Rubiaceae) (67).

III. Chemistry and Synthesis A. PROTOEMETINE, PROTOEMETINOL, 9-DEMETHYLPROTOEMETINOL, 10-DEMETHYLPROTOEMErINOL, ANKORINE, AND ALANCINE For the same reason as described previously in Section III,A of the last review (I),new syntheses of the (2)-and (-)-tricyclic esters 76 or 77 as the key intermediates in later new syntheses of (2)-and (-)-emetines (1)

282

FUJI1 AND OHBA

and related alkaloids of type 72 are tantamount to new formal syntheses of protoemetine (6) and protoemetinol (M), both in their racemic and chiral forms, and they are summarized in Subsections B-F and Section IV. Me0

CHZ

I

C02R

79

78

76 R = E t 77 R = M e

MeO ' O

w

p

."

H

%

MeOZC H,,a* " ~ t Me@C

C02Me

80

81

' Br O T 0 t'EH t

CH2

COzMe

I

CHzOCHzPh

COzMe

MeO&

d

CHZ

I

:::Tl CH20H

83

84

82

Mamy .-" ::a+ Me0

,*"

H

$8'

OCH2Ph 86

OCHZPh

OCHzPh

88

87

A new synthetic approach to (%)-protoemetine [ ( + ) - 6 ]was reported by Brown and Jones (68), who prepared the tricyclic ester (-)- 77 from the cyclopentenolone (2)-78 through the lactol(2)-79 and the tetrahydronico+

3.

THE IPECAC ALKALOIDS AND RELATED BASES

283

tinate derivative (&)-so, with or without passing through the tricyclic base (2)-81 beyond (2)-80. Reduction of (?)-77 with diisobutylaluminum hydride then produced ( 2 ) - 6 . In a chiral synthetic approach to (-)protoemetine (6) and ( -)-protoemetino1 (34),Fukumoto’s group (69-72) obtained the (+)-lactone 82 from the (-)-(Z)-ester 83 or the ethyl ester of its (E)-isomer by radical cyclization using tributyltin hydride, followed by reduction with diisobutylaluminum hydride, benzylation of the resulting alcohol (84), hydrolysis of the cyclic hemiacetal with aqueous AcOH, and oxidation with Fetizon’s reagent (Ag2C03on Celite). The (+)-lactone 82 was then converted into (-)-protoemetino1 (34)through the (+)-amide 85, the iminium salt 86, and the (-)-tricyclic base 87. Finally, oxidation of synthetic 34 with Me2S0- (CF,CO),O -Et3N gave (-)-protoemetine (6) (71). The preceding cyclization of (-)-83 was alternatively effected in a highly stereoselective manner by means of [Ni(cyclam)](ClO&-catalyzed indirect electroreduction (72,73). (?)-Protoemetino1 [(+)-MI was stereoselectively prepared by Hirai et al. from the ketoamide (+)-88 by intramolecular Michael reaction to give the tricycle (?)-89 and two-step reduction of (+)-89 through the lactam ester ( 9 - 9 0 (74,75).

C02R 88

89

90 R = E t 91 R = M e 92 R = H

(-)-Ankorine (37) and its unnatural (+)-antipode (97) have been synthesized by Fujii’s group through a “lactim ether route” (76).Treatment of the ( + )-trans-lactim ether 93 (77,78)with 2-benzyloxy-3,4-dimethoxyphenacyl bromide yielded the (+)-lactam ketone 94. Reduction of (+)-94 with NaBH4, followed by catalytic hydrogenolysis, gave the (+)-lactam phenol 95, a known synthetic precursor (1,79) of (-)-ankorine (37). A parallel sequence of conversions starting .from the (-)-trans-lactim ether 96 (77) produced the (+)-enantiomer 97 [mp 176-177°C; [aE7+58.2”(CHCl,)] of natural ankorine (76). For an alternative chiral synthesis of 37, the (-)cis-lactim ether 98 was converted into the (-)&-lactam phenol 100, another known precursor (2,76,79)for the synthesis of 37, by a similar “lactim ether route,” which proceeded through the (+)-&lactam ketone 99 (76).

284

FUJI1 AND OHBA

b02Et

90

99

84 R=CH2Ph,Z=O 9b R=H.ZmHz

EtO

Me0

MeO

CH2

CH2

I

CH20H

97

CO2Et 86

I

CO2Et

k R=C€IzF%,Z=O 100 R = H . Z = H z

Fujii et al. (42) reported, together with the syntheses of (?)-9demethylprotoemetinol [(+)-351 and its diacetate [(+)-loll, a full account of their preliminary work (41) on the syntheses and structure determination of (-)-9-demethylprotoemetinol(35),( 5 ) -and (-)-10-demethylprotoemetinols [(+)-36and 361, and their diacetates [101, (2)-102,and 1021, which has been summarized (I). In the case of synthetic 35, a direct comparison with the Alangium alkaloid inferred to be 9-demethylprotoemetinol (80) at the diacetate or the original level has still remained impossible on account of paucity of the natural base, thus leaving its chemistry incomplete. Diallo et al. (43) reported on the isolation of 9- or 10-demethylprotoemetinol (35 or 36) from the leaves of A. bussyanurn. However, their description of the structure assignment also seems incomplete.

CH2

CH2

CH2

CH20Ac

CH20Ac

COzH

I

I

101

102

I

103

3.

285

THE IPECAC ALKALOIDS AND RELATED BASES

(-)-Alancine (38)is a newcomer of type 73 isolated from the stem bark of A. lamarckii by Schiff’s group (25). Its tricyclic amino acid structure, unique among the known benzo[a]quinolizidine alkaloids, was elucidated (25) on the basis of spectral evidence and chemical correlation with (-)ankorine (37). Fujii’s group (26,27) synthesized (2)- and (-)-alancines [(t)-38 and (-)-381 from the (2)-and (-)- forms of the tricyclic amino acid 103, a key intermediate in the previous racemic and chiral syntheses of alangicine (25) ( 1 , 8 1 4 3 )and alangimarckine (33) (2,84-86), by catalytic hydrogenolysis. Separate treatment of (2)-38 and (-)-38 with aqueous HCl afforded the hydrochloride salts (+)-38*HC1and (-)-38*HCl, respectively. The synthetic hydrochloride salt (-)-38*HCl was found to be identical with a sample isolated from A. lamarckii, indicating that the natural sample, previously considered to be in the free base form (25),was actually in the hydrochloride form (26,27). B. EMETINE, 0-METHYLPSYCHOTRINE, AND EMETAMINE At the time when the previous chapter (I) on the ipecac alkaloids was prepared, the chemistry of emetine (1) was essentially complete, including a significant number of successful syntheses of this alkaloid. Because of its rather complicated structure, but well-established stereochemistry, the emetine molecule 1and its key synthetic precursors continue to be favorite targets of synthetic organic chemists for evaluating their own methodology of transformation of organic materials and for checking the stereochemical outcome of new synthetic routes adaptable to analogous alkaloids (with unestablished or established stereochemistry). Me0

Me0

4

5

Me0

11

104

1a7

105 R - H 106 R-Et

Meo% Me0

/

R

108

111 112 113 114

R=.OH R=OCH20Me R=OLi

R=H

286

FUJI1 AND OHBA

Several formal syntheses of (2)-emetine [(k)-l] were achieved in the form of the syntheses of the tricyclic ester (2)-76or (+)-77or its derivatives. These included the synthesis of (+)-77 by Brown and Jones (68) and that of ( 9 - 9 0 by Hirai et al. (74,75),as summarized in Section II1,A. Ninomiya’s group (87,88) prepared the tricyclic lactam ester ( 9 - 9 1 , a synthetic precursor for conversion into emetine (1)and related alkaloids, from the enamide 104 by reductive photocyclization to form the furanoquinolizine (+-)-105, followed by ethylation to give the 8a-ethyl derivative (+)-106, hydration with 15%sulfuric acid and subsequent oxidation of the resulting hemiacetal with pyridinium chlorochromate to produce the lactone (+)-lo> reductive cleavage of (?)-lo7 with Ca in liquid NH3 at -70°C to afford the lactam carboxylic acid (2)-92; and esterification of ( q - 9 2 with diazomethane. The same research group (89) also obtained the tetrahydrofuran (2)-110 from the isomeric enamide 108 by reductive photocyclization followed by catalytic hydrogenation of the resulting dihydrofuran (+)-109. The tetrahydrofuran (+)-110was then treated with lithium diisopropylamide in tetrahydrofuran at -78°C to give the a,p-unsaturated lactam (?)-ll$and the Michael acceptors (5)-112, (9-113, and (9-114 obtained from (+)-111were separately led to key synthetic precursors of (?)-emetine [(+)-l](89). Hirai et al. (74,75) synthesized the tricyclic ester (+)-76 from (+)-9O by treatment with triethyloxonium fluoroborate followed by NaBH4 reduction. In an alternative approach, they also prepared (+)-76 from the ketonic a,punsaturated ester (9-115 by intramolecular Michael reaction to give the tricyclic keto ester (9-116and subsequent desulfurization of its dithioketal derivative with Raney Ni (747.5).

CHp

‘h02Et

I

r n N y -.a$ :ID$ C02Et

11s

Me0

“‘H

Me

\ 0

tBuO

0

OMe 117

118

1lQ

3.

THE IPECAC ALKALOIDS A N D RELATED BASES

120

287

121

A formal chiral synthesis of (--)-emetine (1)was accomplished by Fukumoto's group (71) in the form of the synthesis of (-)-protoemetine (6),as summarized in Section III,A. Guiles and Meyers (90)adopted their favorite chiral formamidine methodology for the synthesis of the (-)-enone 119 from the formamidine 117 through the (-)-benzylisoquinoline 118. The racemic enone (5)-119 is a known precursor (1,91) for the synthesis of (5)-emetine [( 5)-11.They further synthesized the (-)-tricyclic ketone 121, a well-known emetine precursor ( I ) , from 117 via the quinolizidine precursor 120 (90). Hirai et al. (92,93) obtained the (-)-keto ester 123 from the a,P-unsaturated ester 122 by an asymmetric intramolecular Michael reaction using (R)-1-phenylethylamine in tetrahydrofuran in the presence of molecular sieves 5 A. The (-)-keto ester 123 was then led to the emetine precursor (+)-124 (77,78) by a five-step conversion (94) involving Nmethoxycarbonylation/debenzylation (92,93), NaBH4 reduction (92,93), 0-imidazole-1-thiocarbonylation, tributyltin hydride reduction, and Ru04 oxidation.

122

123

124

Regarding the chemical behavior of (-)-emetine (l), the stereochemistry of asymmetric electroreductions of bromocyclopropanes at a mercury cathode in the presence of adsorbed 1 has been studied (95,96). Bertz et al. (97) have reported asymmetric induction (with 70:30 R/S ratio, but in only 6% chemical yield) that occurred in the conjugate addition of an ( - )-emetine-incorporating pheriylamidocuprate to 2-cyclohexenone. Fraser-Reid's group (98,99) has reported that the NH group of 1 is readily protected as the N-pent-4-enoyl derivative, which can be rapidly

288

FUJI1 AND OHBA

and efficiently deprotected (in 92% yield) by treatment with 3 eq iodine in aqueous tetrahydrofuran for 6 h. Emetine (1) is known to decompose photochemically or thermally to various fragmentation and/or oxidation products, among which are 0methylpsychotrine (4) and emetamine (5) (1,100). Teshima et ul. (101) have studied the stabilizing effects of p-, y-, and 2,6-dimethyl-p-cyclodextrins against the photodegradation and thermal degradation of 1 in aqueous solution.

c. PSYCHOTRINE, 9-DEMETHYLPSYCHOTRINE,AND ALANCICINE On the basis of ‘H and 13CNMR spectral data, McLaughlin’s group (66) has confirmed that (+)-psychotrine (3), newly isolated from the sap of P. speciosus ( Jacq.) K. Schum. (Rubiaceae), has the genuine 3,4-dihydroisoquinoline structure (the endocyclic double bond structure) as in the case (1,102) of 0-methylpsychotrine (4). The same conclusion had already been reached by Fujii’s group (83) as a result of their I3C NMR study of 3. Fuji and co-workers disclosed full accounts (103,104) of their preliminary studies (105,106) on the syntheses of (2)-9-demethylpsychotrine [( 2)-241 and (+)-10-demethylpsychotrine [(9-1251, and of (+)-9-demethylpsychotrine (24), as reviewed previously (1).

.se OH

125

OMe 126

A full account was also given (83) of their preliminary work (1,81, 82) on the racemic and chiral syntheses and structure establishment of alangicine (25). The I3C NMR spectra of (2)-24 (103) and (2)-25 (83) confirmed the correctness of the endocyclic double bond structure in the dihydroisoquinoline moiety of the two Alungiurn alkaloids, (+)-9-demethylpsychotrine (24) and (+)-alangicine (25).

3.

THE IPECAC ALKALOIDS A N D RELATED BASES

289

D. CEPHAELINE, ISOCEPHAELINE, AND DEMETHYLCEPHAELINE The previous syntheses of cephaeline (2) and isocephaeline (21) in both their racemic and chiral forms included Pictet-Spengler condensation of ( 2 ) -and (-)-protoemetines [( 2)-6 and (-)-61 with 3-hydroxy4-methoxyphenethylamine as the final step (1). Thus, the syntheses of (+)-a and (-)-6 mentioned in Section I I I , A constitute formal racemic and chiral syntheses of 2 and 21. Cephaeline (2),psychotrine (3), O-methylpsychotrine (4), emetamine (5), and rubremetine (126)(1) were found as decomposition products from emetine hydrochloride injection solutions stored in a light stability cabinet at room temperature, 8"C, and 37°C(107).Teshima et ul. (101) investigated the stabilizing effects of p-, y-, and 2,6-dimethyl-~-cyclodextrinsagainst the photodegradation and thermal degradation of cephaeline (2)in aqueous solution.

127

128

The alternative structure 23 (i.e., 127 or 128) has still to be assigned to the Alungium alkaloid (-)-demethylcephaeline ( 1 ) . Fujii and Ohba (108) revealed a detailed account of their preliminary work (1,109) on the syntheses of (-)-9-demethylcephaeline (127) and (-)-lO-demethylcephaeline (128).Unfortunately, however, a sample of natural (-)-demethylcephaeline for a direct comparison remains unavailable, precluding identification of either 127 or 128 with this Alungium alkaloid. E. TUBULOSINE, ISOTUBULOSINE, 9-DEMETHYLTUBULOSINE, 10-DEMETHYLTUBULOSIVE, AND O-METHYLTUBULOSINE In view of the previous racemic and chiral syntheses (1) of tubulosine (26)and isotubulosine (27)from ( 2 ) -and (-)-protoemetine [(5)-6 and (-)-61, the syntheses of ( 5 ) - 6 and (-)-6 described in Section III,A are tantamount to the racemic and chiral syntheses of 26 and 27, respectively.

290

FUJI1 AND OHBA

McLaughlin's group (66) reported the complete 'H and 13CNMR assignments and X-ray crystallographic results for (-)-tubulosine (26),which was isolated from the sap of P. speciosus. Fuji and co-workers (39,220) presented full accounts of their preliminary work (2,211,112) on the syntheses of (+)-9-demethyltubulosine [(9-29] and (2)-10-demethyltubulosine [(?)-MI. They also prepared (-)-9demethyltubulosine (29)via a parallel synthetic route (40,223). As a result, the structures of the A. lamarckii alkaloid (-)-10-demethyltubulosine (30) (210,122) and the A. vitiense alkaloid (-)-9-demethyltubulosine (29)(Section 11) (2,36-40J113) were unequivocally established. Although known semisynthetically for a long time (5,44,45), O-methyltubulosine (28) was not encountered in Nature until, in 1995, Diallo et al. (43) reported the isolation of 28 from the leaves of A. bussyanum. However, their description of the identification of the natural sample appears to be incomplete. 10-DEMETHYLDEOXYTUBULOSINE, F. DEOXYTUBULOSINE, AND ALANGIMARCKINE

Since the previous racemic and chiral syntheses of deoxytubulosine (31) were reviewed ( Z ) , Brown and Jones (68) have reported the synthesis of (2)-deoxytubulosine [(?)-31] and its 1'-epimer (129)by Pictet-Spengler reaction of (?)-protoemetine [(9-61(Section II1,A) with tryptamine. For a study on the biosynthesis of tubulosine (26),Bhakuni etal. (214) prepared didemethyl-deoxytubulosine (131) from deoxytubulosine (31) by demethylation with HBr in AcOH. Both 131 and 31 were then tritiated in an acidcatalyzed exchange reaction to furnish [aryl-3H]didemethyl-deoxytubulosine and [aryl-3H]de~xytubulo~ine, respectively. R

129 R = H 130 R = O H

131

132 Secologauin

3.

THE IPECAC ALKALOIDS AND RELATED BASES

29 1

Diallo et al. (43) claimed, without presenting its characteristics, that 10demethyldeoxytubulosine (deoxydesmethyltubulosine) (32), reportedly a known alkaloid, was among eight alkaloids isolated from the leaves of A. bussyanum. To our knowledge, however, the compound corresponding to structure 32 is so far unknown, thus leaving their claim questionable. Fujii et al. (86) disclosed a full account of their preliminary work (1,84,85) on the racemic and chiral syntheses and structure determination of alangimarckine (33). Their assignments of the configuration at C(1’) of 33 and of its 1’-epimer 130 were based on five criteria (86), which included TLC mobility and ‘H and 13C NMR and CD spectroscopic features. G. IPECOSIDE, ALANGISIDE, A N D RELATED TETRAHYDROISOQUINOLINEMONOTERPENE ALKALOID GLUCOSIDES

When the last review on the ipecac alkaloids and p-carboline congeners ( I ) was prepared, the chemistries of (-)-ipecoside (7) and (-)-alangiside (18), the progenitors of the alkaloid glucosides in the ipecac and Alungium series, were essentially complete. Noteworthy are the significant recent advances in the isolation and structure establishment of new monoterpene alkaloid glucosides in the two series, which have resulted in the addition of 28 tetrahydroisoquinoline-monoterpene glucosides and a tetrahydro-pcarboline-monoterpene glucoside to the preceding lineage. From the dried roots of C. ipecacuunha, Nagakura and co-workers (17,18) isolated six new tetrahydroisoquinoline-monoterpene glucosides, that is, 6-O-methylipecoside (8), ipecosidic acid (lo), neoipecoside (15),7 - 0 methylneoipecoside (16), 3,4-dehydroneoipecoside (17) (conceivably an artifact formed from 15 in the extraction process), and demethylalangiside (19), along with alangiside (18) (previously known only as an Alungium alkaloid) (20) and ipecoside (7). The structures of the new glucosides were determined by spectroscopic and chemical means (17,28). Their further investigations of the same plant material resulted in the isolation and structure establishment (19)of four new tetrahydroisoquinoline-monoterpene glucosides, namely, truns-cephaeloside (ll), 6-O-methyl-trans-cephaeloside ( U ) ,cis-cephaeloside (13), and 6-O-methyl-cis-cephaeloside (14), as well as those (20) of two other new glucosides, namely, 7-O-methylipecoside (9) and 3-O-demethyl-2-O-methylalangiside (20). Regarding the alkaloid glucosides of Alangium origin, Nagakura’s group reported the isolation and structure determination (on the basis of spectroscopic and chemical methods) of demethylalangiside (19) and 3-O-demethyl-2-O-methylalangiside (20), both of which were also isolated from the roots of C. ipecucuanha (18,20), and of the glucosides 39-55, as summarized in Section 11. Interestingly, 10-hydroxyvincosidelactam (53)

292

FUJI1 AND OHBA

(21) is the only tetrahydro-P-carboline-monoterpene glucoside isolated so far from A . lamarckii. It should be emphasized that an unusually substituted isoquinoline nucleus is found for the chemical structures of neoipecoside (15) (17,18), 7-0-methylneoipecoside (16) (17,18), 3,4dehydroneoipecoside (17) (17,18), neoalangiside (48) (21), and demethylneoalangiside (49) (21).Also noteworthy are the structures of isoalangiside (50)(21,23),methylisoalangiside(51) (21,23),and 3-0-demethyl-2-0-methylisoalangiside (52) (21,23), which have an a-H at C(13a), since all of the other monoterpene alkaloids isolated so far from C. ipecacuanha and Alangium plants have a P-H at the corresponding position. The A . lamarckii glucosides 39-45 (22) carry an 0-acyl group at C(2’), whereas the A . platanifolium alkaloids 46 and 47 (35) bear it at C(6‘). Nagakura’s group (24) reported on the isolation of 54 and 55 from the methanolic extracts of the dried fruits of A . lamarckii. Since both compounds were obtainable (albeit in a low yield) from alangiside (18) by treatment with MeOH at room temperature for 9 months, they have been considered (24) to be artifacts arising from 18, the co-occurring alkaloid. Beke et al. (115) have reported the preparation of the 19-type alkaloids from secologanin (132) by Pictet-Spengler reaction with phenethylamine derivatives. They have also reviewed the regio- and stereoselectivity in the formation of the ipecosane alkaloids (11).

H. RELATED ALKALOIDS OF Alangium PLANTS The versatility of A. lamarckii in producing alkaloids has further been demonstrated by Pakrashi’s group, who isolated nine benzo[a]pyrido[3,4g]quinolizine alkaloids, namely, alangimarine (56) (29,30),isoalangimarine (57) (30),alamarine [( 9 - 5 8 ] (29,30),isoalamarine (59) (29,30),alangimarinone (60) (30),(+)-alangimaridine (61) (29,30),(+)-dihydroalamarine (62) (30),(+)-dihydroisoalamarine (63) (30),and alamaridine (64)(32-34), from its seeds; and bharatamine [(‘.)-65], the first naturally occurring tetrahydroprotoberberine alkaloid nonoxygenated in ring D (30,31),from the same source. The chemical structures of 56-63 were established on the basis of spectroscopic data and chemical correlation with the congeners, and the absolute configuration of (+)-alangimaridine (61) at C(12b) was deduced from a comparison of its specific rotation with those of the closely related tetrahydroprotoberberines, such as (+)-tetrahydropalmatine (133) (29,30). The structure of alamarine [(?)-58], a typical member of this benzopyridoquinolizine family, was confirmed by its synthesis featuring thermal or photochemical cyclization of the enamide 134 (1,116). Chowdhury (117) synthesized isoalamarine (59) from the isomeric enamide 135 via a parallel route. For the syntheses of (+)-alangimaridine [(?)-61] and alangimarine

3. M Me0 eO%

THE IPECAC ALKALOIDS A N D RELATED BASES

293

, OMe

'

OMe Me

133

1 3 4 R' = Me,RZ= CH2Ph 135 R' = CHZPh, RZ= Me

136

137

138

(56), MacLean and co-workers (118,119) used the activated imine 136 as a carbon electrophile. Thus, condensation of 136 with the lithio derivative 137 produced the amidine 138 in 83% yield. Alkaline hydrolysis of 138 and subsequent debenzylation with hydrochloric acid afforded (+)-61 in good overall yield. Then, dehydrogenation of (+)-61 with iodine in EtOH, as in the case of (+)-61 (29,30),gave 56 in good yield. Nagakura and co-workers (24) reported the formation of alangimarine (56) from the newly isolated glucoside 55 [possibly an artifact derived from alangiside (18) and MeOH] by treating the latter successively with hydrochloric acid and ammonia. They further converted alangiside (18) into (+)-alangimaridine (61) by a route involving hydrolysis with pglucosidase and subsequent treatment with concentrated ammonia followed by trifluoroacetic acid (121).This confirmed the correctness of the absolute configuration of 61 at C(12b). A parallel route starting from 3-0-demethyl2-0-methylalangiside (20) gave (+)-isoalangimaridine (139), unknown as a natural product, but a plausible precursor of isoalangimarine (57). Oxidation of 139 with iodine furnished 57 (121). The gross structure, envisaged on the basis of spectral data and biogenetic considerations (32-34), and the relative stereochemistry of alamaridine have been established by synthesis as shown in formula 64. Pakrashi's group (33,34) obtained the tetracycle 141 from the isoquinolinium salt 140 by

294 MHO

FUJI1 AND OHBA

e

0

9

,

P h Me0 C H 2 0 q F e 2 c10;

Me \ N 139

, \

Nk 141

140

PhCH20

142

145

143 R=CHzPh 144 R = H

treatment with Et,N and pivaloyl chloride, followed by spontaneous oxidation. Reduction of 141 with sodium cyanoborohydride in AcOH gave ( 2 ) 0-benzylalamaridine (142) and its diastereoisomer (143) in 20 and 50% yields, respectively. Finally, separate debenzylations of 142 and 143 with boiling ethanolic HCl provided (*)-alamaridine [(+)-a] and its diastereoisomer (2)-144,respectively. Me0 PhCHpO

146

PhCH20 M e o W PhCH2O N & H2C

150

,

0

\

\

151 x = o 162 X = H z

3.

295

THE IPECAC ALKALOIDS AND RELATED BASES

In an alternative synthesis of (2)-64by MacLean’s group (120)’ the pyridone 145 was treated with MeLi in tetrahydrofuran at -78°C to afford, after reduction with NaBH4, a mixture of (?)-142 and (5)-143.Debenzylation of the mixture by catalytic hydrogenolysis furnished (?)-64 and (+)144 in 20 and 40% yields, respectively. In yet another synthesis of (+)-64, Reimann and Renz (222) obtained the 8-methylisoquino[2,1-b][2,7]naphthyridinium salt 149 by alkylation of the Reissert compound 146 with the 4-chloromethylpyridine derivative 147 in N,N-dimethylformamide in the presence of NaH and subsequent treatment of the resulting 1-substituted isoquinoline (148)with hydrochloric acid in EtOH. Reduction of 149 with NaBH4 in MeOH gave (9-142and (9-143in 9 and 34% yields, respectively. Separate debenzylations of (?)-142 and (9-143with hydrochloric acid in EtOH furnished (+)-64and (?)-144,respectively, in good yields.

PhCH2O

\

153 X = O 1J4 x = s

157

x=n2

155

1 59

156

160 Cantleyine

158 X = O

(2)-Bharatamine [(+)-651 has so far been synthesized by four independent research groups. Pakrashi’s group (31) utilized photochemical cyclization of the enamide 150 to give a mixture of the saturated lactam 151 and the unsaturated lactam 153. The mixture was treated successively with P0Cl3and NaBH4 or reduced first by LiAlH4 and subsequently by NaBH4, yielding (2)-0-benzylbharatamine [(2)-l521.Finally, debenzylation of (9-152with hydrochloric acid produced (2)-65.The tetracycle (q-152 was alternatively obtainable from 153 by treatment with P2S5in pyridine followed by reduction of the resulting thiolactam (154)with NaBH4 (123). The synthesis of (+)-65by Patil and Mali (224) started with condensation of 4-benzyloxy-3-methoxyphenethylamine with isochroman-3-one (155)to

296

FUJI1 A N D OHBA

give the amide 156. On Bischler-Napieralski cyclization with PC15followed by NaBH4 reduction, 156 yielded (2)-0-benzylbharatamine [(t)-l52]. Debenzylation of (2)-152 with concentrated hydrochloric acid in EtOH provided (t-)-65. Takano’s group (125) synthesized (2)-65 via a route involving aryl-radical-initiated 1,6-cyclization of the enamine 157 or the enamide 158 as the key step. Reimann et al. (126) prepared (+)-65 via a route involving alkylation of the Reissert compound 146 with methyl 2bromomethylbenzoate, spontaneous intramolecular cyclization, and reduction of the cyclized product with LiAlH4, followed by NaBH4, as the key steps. Debenzylation of the resulting (+)-152 with boiling ethanolic HCl gave (+)-65 (126). Alangiobussine (70) and alangiobussinine (71) were among the eight alkaloids isolated by Diallo et al. (43) from the leaves of A . bussyanurn. Their structures were established on the basis of spectroscopic analyses and chemical synthesis (43). As regards the absolute stereochemistry of the monoterpene alkaloid (+)-venoterpine, the previously assigned formula (159) (1) has now been revised to the complete expression 66 by Ravao et al. (127) on the basis of chemical correlation with (-)-cantleyine (160). The chemical correlation consisted of hydrolysis of 160 with Ba(OH)* and vacuum flash pyrolysis of the resulting carboxylic acid at 460°C to give a compound [[a]D +38” (CHCl3)], which was identical with natural venoterpine [[.ID +32” (CHCh)].

IV. Related Compounds Alternative racemic syntheses of the ipecac and Alangiurn alkaloids of types 72-75 have now become possible in the form of the syntheses of 161a-d via the generally applicable “3-acetylpyridine route” developed by Fujii’s group (128,129). The route includes the mercuric acetate-edetic acid oxidation of the 3-acetylpyridine derivatives 162a-d or the alkaline ferricyanide oxidation of the quaternary salts (165a-d or 166a-c) of 3acetylpyridine equivalents, Wolff-Kishner reduction of the acetyl group or reductive desulfurization of the thioketal group, sulfenylation-dehydrosulfenylation of the lactams 163a-d, Michael reaction of the a,& unsaturated lactams 164a-d, and de-ethoxycarbonylation (or hydrolysis, decarboxylation, and esterification) of the Michael adducts 167a-d to give 161s-d. (+)-Cincholoipon ethyl ester (168), available from the commercial Cinchona alkaloid (+)-cinchonine in 50% overall yield according to the classical

3.

297

THE IPECAC ALKALOIDS A N D RELATED BASES

1670-d

1 M b d z=o 16Z=S

degradation procedure (130-133), has been shown to be a very useful starting material for the chiral syntheses of alkaloids of types 72-75 (1,4,TlO,26,78).Its racemic or chiral congeners, such as (9-169 (134),( 2 ) 171 (135), 169 (134), 170.HC1 (semisynthetic) (136), and 171 (1 3 3 , as well as the trans-isomers (2)-172 (:75,138,139)and (5)-173 (138),have been prepared by total synthesis. The ( 2 ) -and (-)-amhoketones 121and the tricyclic lactam (9-174 were the key intermediates used in earlier emetine syntheses ( I ) , and several new synthetic routes to (?)-121 (140-143) and to the (-)-lactam 174 (144) and (2)-174 (145) have been reported. C02CH2Ph

(A:

H :

CH2

I

COpR

168 R = E t 169 R = M e im R = H

Hb: Hp: CHp COpEt I 171

H

CHZ

COpR I 172 R=Et 173 R=Me

298

FUJI1 AND OHBA

(-)-8-Hydroxyprotoemetine (73,R = CHO), an aldehyde of biogenetic interest, has been synthesized for the first time by Fujii and Ohba (246) from the (-)-ethyl ester of 103 through the debenzylated ester 73 (R = C02Et). Wolff-Kishner reduction of 73 (R = CHO) produced the (-)-2ethyl congener 73 (R = Me) (246).

175 R = M e 176 R = H

174

OCHpPh

177

178

Formula 175 represents the incorrect planar structure proposed by Brindley and Pyman (247) in 1927 for emetine (1). In this connection, Harada et ul. (248) synthesized the four stereoisomers possible for ( 5 ) - C noremetine Pyman [(2)-176]and isolated them in the form of hydrobromide salts. Takacs and Boito (249) synthesized the (-)-tricyclic alcohol 177, a one-carbon homolog of the Alungium alkaloid (-)-protoemetino1 (34),from the chiral formamidine 117 in 36% overall yield via a five-step route proceeding through the stereoselective iron-catalyzed cyclization of the key intermediate 178.

Me0

Me0 Me0

/

\ N 179

180

181

Compounds (3179 and 180, bearing the same 8H-isoquino[2,1-b][2,7]naphthyridin-8-one systems as those of the A . lumurckii alkaloids

3.

299

THE IPECAC ALKALOIDS AND RELATED BASES

61-63 and 56-60, were obtained (150) by condensation of 3,4-dihydro-6,7dimethoxyisoquinoline (181) with 4-methylnicotinoyl chloride in refluxing pyridine and by autooxidation of the resulting (2)-179, respectively. Many other synthetic benzola]quinolizidine derivatives, structurally more or less related to the alkaloids of types 72-75, have been available; a number of indole alkaloids carrying the indolo[2',3':3,4]pyrido[1,2-b][2,7]naphthyridine ring system, structurally analogous to the A. lamarckii alkaloids 56-64, have been isolated from other plants and/or synthesized. However, this section is not intended to cover them because of the limited space.

V. Analytical Methods As in the period 1967-1982 covered by the previous review ( I ) , the longstanding clinical usefulness of emetine (1) and its various biological activities (1,12) (Section VII) are responsible for the development of many methods suitable for both rapid and accurate analysis of this alkaloid and related bases. Table I lists these methods and the literature contained in Chemical Abstracts, Volumes 97 (1982)-125 (1996), with the exception of a few references. TABLE I ANALYTICAL METHODS FOR IDENTIFICATION AND DETERMINATION OF IPECAC ALKALOIDS AND RELATED BASES Method Extraction

Adsorptionb Paper chromatography Thin-layer chromatography

Sample' Emetine (1) Emetine (1)in A Emetine (1)in E Cephaeline (2) in A Ipecac alkaloids in A Emetine (1)in B Emetine (1) Afangiuni chinense alkaloids and (+)-anabasine (69) in C Emetine (1) Emetine (1)in C Cephaeline (2) Cephaeline (2) in C Ipecac alkaloids in A Ipecac alkaloids in D A. chinense alkaloids and ( 2 ) anabasine (69) in C

Reference 151, 152 153-15.5 156-159 153-155 160 161 162 48

162-169 53 165 53 I 70 171 48

(continues)

300

FUJI1 AND OHBA

TABLE I (continued) Method

Sample"

High-performance liquid chromatography

Emetine (1) Emetine (1)' Emetine (1) in A Emetine (1) in B Emetine (1) in C Emetine (1) in D Cephaeline (2) in A Cephaeline (2) in B Cephaeline (2) in C Cephaeline (2) in D Protoemetine (6) in C Emetine (1) in B Emetine-HC1in D Deoxytubulosine (31)d Emetine (1) Emetine (1) in B Emetine (1) Emetine (1) in B Emetine (1) in D Emetine (1) Emetine (1) in A Emetine (1) in B Cephaeline (2) in A Cephaeline (2) in B Emetine (1)

52,153,154,176-178 101,I79-183 53,55,56,58-60,186,I87 I01 187 188,189 190 28 191,192 191 193,194 195,196 196 191,192,197 198,199 191,198, I99 198,199 198,199 200

Cephaeline (2) Emetine (1) in B Emetine (1) in D

201 202 202

Capillary electrophoresis Titrimetry Spectroscopy Spectrophotometry Colorimetry Spectrofluorimetry

Indirect radiometric X-ray fluorescence analysis Voltammetry Periodate oxidatione

Reference 172-174 175 52,153,154,176-178 I01,179-183 50,53,55,56,58-60,184-187 101

Key: A, Ipecac roots; B, pharmaceutical preparations; C. biological fluids and/or tissues; D, solution: E, buffered aqueous solution. Onto activated charcoal. As an amine modifier of the mobile phase in reversed-phase HPLC. DNA binding. In a flow injection system.

VI. Biosynthesis

In 1982, the hitherto known biosythetic pathways for the ipecac, Alungium,and indole alkaloids, consisting of that for their G-Clo unit portion

3.

THE IPECAC ALKALOIDS AND RELATED BASES

301

[melvalonic acid (182)+ loganin (183)+ secologanin (132)] and those for their nitrogenous portions, were covered in the previous review ( I ) .

7T2H

HO

182 Mevalonic acid

185 Loganin

Tracer experiments by Bhakuni et al. (114) supported the following sequence for the biosynthesis of tubulosine (26)in young A . lamarckii plants: tyrosine + dopamine; dopamine + secologanin (132)+ deacetylisoipecoside (186)+ deoxytubulosine (31)-+ tubulosine (26). A radioimmunoassay technique has been developed for the quantitative measurement of loganin (183)in crude extracts from both fresh and dried material of whole plants and cultivated plant cells, and by labeled precursor feeding experiments members of the genera Weigelia, Lonicera, Hydrangea, and Symphoricarpus have been found to open the cyclopentane ring of 183 (203). This ringopening of 183 to form secologanin (132)(Scheme 1) has been suggested to proceed directly through a radical or ionic process (204). Nagakura and co-workers isolated 7-dehydrologanin (185) and sweroside (189), related to loganin (183)and secologanin (132),respectively, from the roots of C. ipecacuanha (18),and sweroside (189)from the fruits of A . lamarckii (21). These were the first isolations of iridoid glucosides from such plant sources. The previously known biosynthetic pathways (1,205,206) for the ipecac and Alangium alkaloids involve the condensation of secologanin (132)with dopamine in a Pictet-Spengler manner to give both the la-H isomer deacetylisoipecoside (186)and the 1P-H isomer deacetylipecoside (188)(Scheme 1). The la-H isomer 186 is converted, most likely through protoemetine (6)or its equivalent (la), into cephaeline (2)and emetine (1)with retention of configuration in both C. ipecacuanha (205,206) and A . lamarckii (205). By contrast, the 1P-H isomer 188 is exclusively and specifically metabolized to give ipecoside (7) by acetylation in Cephaelis (205,206) and alangiside (18) by lactamization in Alangium (205), both with retention of configuration. Nagakura and co-workers ( I # ) isolated ipecoside (7),alangiside (18), 6-0-methylipecoside (S), ipecosidic acid (lo), demethylalangiside (19), neoipecoside (W), 7-0-methylneoipecoside (16), and 3,4-dehydroneoipecoside (17) (possibly an artifact) from the roots of C. ipecacuanha.

au

()'

w'

*

w' -

o0

a4

_ . . -TI aLo

Ho-n

H=n

apo(aqql

3.

THE IPECAC ALKALOIDS AND RELATED BASES

303

The co-occurrence of 7,8,19, and 18 indicates the presence of two branched pathways from the common intermediate deacetylipecoside (188) in this plant (18). The two new glucosides 15 and 16 with an unusually substituted isoquinoline moiety are most likely biosynthesized from 132 and dopamine through the putative glucoside deacetylneoipecoside (190) (18). The same authors (21,23) also isolated methylisoalangiside (51), isoalan(52), demethylneoalangiside (50), 3-O-demethyl-2-O-methylisoalangiside giside (49), neoalangiside (48), and 10-hydroxyvincoside lactam (53) from the fruits of A . lumurckii. It is of great interest that the new glucosides 50-52 have an a - H at C(13a), the same absolute stereochemistry as that of the type 72-75 alkaloids at Cjllb), since all of the tetrahydroisoquinoline monoterpene alkaloid glucosides isolated so far have had a P-H (wrong stereochemistry) at the corresponding chiral center. The glucosides 50-52 are most likely to be biosynthesized from deacetylisoipecoside (186) via demethylisoalangiside (187). The Alungium alkaloid 10-hydroxyvincoside lactam (53) could be biosynthesized from secologanin (132) by condensation with tryptamine (or serotonin) instead of with dopamine (22). Thus, the biosynthetic pathways for the ipecac and Alungium alkaloids of the benzo [a]quinolizidine-and monoterpene glucoside-types (28,21) may be depicted as shown in Scheme 1. However, the possibility that the methylation of a phenolic hydroxy group in deacetylisoipecoside (186) takes place prior to lactamization in A . lurnarckii cannot be ruled out. This leads to the proposal (21) of alternative plausible pathways to 50-52, protoemetinol(34), and demethylprotoemetinols (35 and 36), as outlined in Scheme 2. The structure determined for the benzo[a]pyrido[3,4-g]quinolizine-type Alungium alkaloid (+)-alangimaridine (61) suggests (29,30)that it is biogenetically derivable from alangiside (18) by glycosidic hydrolysis followed by amination and that 61 could lead to alangimarine (56), alamarine (58), alangimarinone (60),and dihydroalamarine (62) by unexceptional biochemical transformations. Isoalangimarine (57), isoalamarine (59), and dihydroisoalamarine (63) could be derived from the isomeric glucoside 3-Odemethyl-2-O-methylalangiside(20) in a similar manner (30). Such a biogenetic possibility has been enhanced by the realization of the in vitro conversion of 55, obtained from alangiside (18) by treatment with MeOH (24) (see Section III,G), into alangimarine (56), which involved hydrolysis with hydrochloric acid and subsequent amination with ammonia (24). There is also the realization of the in vitro biogenetic conversion of alangiside (18) into (+)-alangimaridine (61) (221), as well as that of 3-Odemethyl-2-O-methylalangiside(20) into isoalangimarine (57) through (+)isoalangimaridine (139) (121) (see Section 111,H). As regards the biogenesis of bharatamine (65), Pakrashi and co-workers (30,31) have suggested the formation of the dialdehyde 192 from the

304

FUJI1 AND OHBA

60

¶4 Rotosmwiaol

61

SCHEME2. Alternative biosynthetic pathways for the glucosides 50-52, protoemetinol (M), and demethylprotoemetinols (35 and 36).

3.

192

305

THE IPECAC ALKALOIDS AND RELATED BASES

199

194

glucoside 191 (Scheme 2) or its 1P-H epimer through hydrolytic cleavage of both the glycosidic bond and the dihydropyran ring followed by loss of the methoxycarbonyl group. Cyclization of 192 to form the tricycle 193 and nucleophilic attack of the vinyl group on the remaining aldehyde group in 193 could lead to the tetracycle 194. Dehydration and aromatization of 194 could then give bharatamine (65). It is not clear whether the occurrence of 65 in the optically inactive form is due to racemization or because of its origin from both 191 and its 1P-H epimer (31).

VII. Biological Activity Much of the earlier work on the pharmacological and biological properties of emetine (1)and both its natural and synthetic congeners, the latter of TABLE I1 PHARMACOLOGICAL AND l3IOLOGICAL PROPERTIES OF EMETINE (1) Pharmacological and Biological Action

Reference

In general Emesis Amebicidal activity Other antiparasitic activities Antiviral activity Antitumor activity No carcinogenicity Cardiotoxicity Formation of ernetine-resistantmutants Neuromuscular effects Inhibition of RNA, DNA, and protein synthesis Toxicity Immunosuppressiveeffect Effects on other biochemical processes

2,207 208,209 2 10-223 224-231 232, 233 234-239 240 241-249 250-276 277,278 279-301 302-306 307 280,308-365

306

FUJI1 AND OHBA

which includes 2,3-dehydroemetine (195),has already been reviewed ( l J 2 ) . Tables I1 and I11 supplement these reviews by summarizing the recent data from ChemiculAbstructs, Volumes 97 (1982)-125 (1996), with the exception of some references. Harada et ul. (148) reported that no significant pharmacological activities were observed for the four synthetic stereoisomers possible for (2)-Cnoremetine Pyman [( 9-1761. An aqueous (boiled) extract of A . chinense (Lour.) Harms, containing (2)-anabasine (69) as the single active component, was tested for its muscle relaxation effects on laboratory animals and clinical cases (405).A fraction of the CHC13extract of A. chinense was found TABLE I11 PHARMACOLOGICAL AND BIOLOGICAL PROPERTIES OF IPECAC AND EMETINE CONGENERS ~~~

Substance Ipecac

Ipecac alkaloids 0-Methylpsychotrine (4) Emetamine (5) Psychotrine (3)

Cephaeline (2)

Tubulosine (26)

Deoxytubulosine (31) 2,3-Dehydroemetine (195)

Pharmacological and Biological Action

Reference

In general Emesis Expectorant effect Effects on other biochemical processes RNA, DNA, and protein synthesis Emesis Antiviral activity Emesis Emesis Antimalarial activity Antiviral activity Antitumor activity Emesis Antimalarial activity Antitumor activity RNA, DNA, and protein synthesis Effects on other biochemical processes Amebicidal activity Antimalarial activity Antiviral activity Antitumor activity RNA, DNA, and protein synthesis Effects on other biochemical processes DNA binding Amebicidal activity Other antiparasitic activities Antiviral activity Cardiotoxicity Neuromuscular effect Mutagenicity Genotoxicit y

2,3 181,304,366-379 9,380 381,382 383 208 232,233,384 208 208 67 232,233 66 208 67 232,233,385 301 350 215,220 67,386 233,384 66 387-389 390 28 213,215,216,391,392 393-395 233 245 2 78 3%-402 403,404

3.

THE IPECAC ALKALOIDS A N D RELATED BASES

307

Me0

Et

1% 2,3-Dchydroemetine

to have a prominent sedative effect with least toxicity in rats. However, the sedative compound in this fraction was suggested to be a triterpenoid (406).

Addendum Ibrahim (407) has reported a microbial transformation of emetine (1) into O-methylpsychotrine (4), which used Cunninghamella blakesleeana MR-198. The first synthesis of the alkaloid glucoside neoalangiside (48) has been achieved with the Aimi et al. (408).It started with the condensation of the brominated phenethylamine 196 with the tetra-O-acetyl derivative of secologanin (132)and proceeded through the intermediates 197 and 198. Nagakura’s group (409) isolated five new tetrahydroisoquinolinemonoterpene glucosides 199-203 from the methanolic extracts of the dried fruits of A. lamarckii, and their chemical structures were determined by spectroscopic and chemical means. This permits the number of new alkaloids isolated from ipecac and Alangium plants during the period of this review to increase from 39 (see Section 11) to 44.Tanahashi et al. (410) found that the methanolic extracts of the dried leaves of Alangium kurzii contained alangiside (18), demethylalangiside (19), and 6-O-methyl-Ndeacetylipecosidic acid (199)as nitrogenous components. As for the biosynthetic pathway (b) in Scheme 1, two novel enzyme activities involved in the condensation between dopamine and secologanin (132) have been discovered by De-Eknamkul et al. (4IZ) in the cellfree extracts prepared from the leaves of A . lamarckii. These extracts allowed dopamine to condense rapidly with 132 at pH 7.5, giving both (1R)deacetylipecoside (188)and (1s)-deacetylisoipecoside (186), which could immediately undergo lactamization to form demethylalangiside (19) and demethylisoalangiside (187),respectively.

308

FUJI1 AND OHBA

i w R’ = MC, R~ = H, i & ~ 200 R’5Me, Rz=H, la-H 201 R’ P H.Rz 5 Mc,la-H 202 R’ = Rz = Me, la-H

209

References 1. T. Fujii and M. Ohba, in “The Alkaloids” (A. Brossi, ed.), Vol. XXII,p. 1. Academic Press, New York, 1983. 2. J. C. Gaignault, C. Marchandeau, and D. Koertge, Actual. Chim. ( 5 ) , 7 (1982); C A W, 44181 (1982). 3. W . Jaroniewski, Farm. Pol. 38,381 (1982); CA 98, 149475 (1983). 4. T. Fujii, Yukuguku Zusshi 103,257 (1983). 5. W.Wiegrebe, W. J. Kramer, and M. Shamma, J. Nat. Prod. 47,397 (1984). 6. M. Ihara, Yukugaku Kenkyu no Shinpo 3,134 (1987); C A 109,93399 (1988). 7. T. Fujii, M. Ohba, and S . Yoshif‘uji, Heterocycles 27, 1009 (1988). 8. S. I. Zav’yalov, A. G. Zavozin, 0. V. Dorofeeva, and G . I. Ezhova, Khim.-Farm. Zh. 19, 190 (1985); C A 103, 123761 (1985). 9. A. Sharma, A. Kumar, R. Tewari, and 0. P. Virmani, Curr. Res. Med. Aroma. Plants 8,182 (1986); C A 107,28241 (1987). 10. T. Fujii. Yukuguku Zasshi 116,335 (1996). 11. G.Beke, K. Szabo-Pusztay, L. F. Szab6, and B. Podtinyi, Gyogyszereszet SO, 483 (1996); CA US,276239 (19%). 12. A. Brossi, S. Teitel, and G. V. Parry, in “The Alkaloids” (R. H. F. Manske, ed.), Vol. XIII, p. 189. Academic Press, New York, 1971.

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,

3.

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THE IPECAC ALKALOIDS A N D RELATED BASES

32 1

390. N. Fajaudon, P. Guilloteau, M. J. Lasselain, and C. Pareyre, Cyrobios 53, 17 (1988); C A 109,70566 (1988). 391. J. R. Cedeno and D. J. Krogstad, J. Infect. Dis. 148,1090 (1983); CA 100,99731 (1984). 392. T. Chintana, P. Sucharit, V. Mahakittikun, C. Siripanth, and W. Suphadtanaphongs, Southemi Asian J. Trop. Med. Public Health 17,591 (1986); CA 107, 112468 (1987). 393. G . D. P. Dutta, Indian J. Parasitol. 7, 165 (1983); C A 102, 146002 (1985). 394. P. D. Walzer, C. K. Kim, J. Foy, M. J. Linke, and M. T. Cushion, Antimicrob. Agents Chemother. 32,896 (1988); C A 109,47851 (1988). 395. N. V. Sopar S . A., Belg., Fr. Demande FR 2,604,903 (1988); C A 110, 128636 (1989). 396. C. Cortinas de Nava, J. Espinosa, L. Garcia, A. M. Zapata, and E. Martinez, Mutat. Rex 117,79 (1983); C A 98,191356 (1983). 397. K. P. Rao, G . S. Reddy, P. S. Chowdary, and M. S. Rao, IRCS Med. Sci. 13,946 (1985); C A 104,14555 (1986). 398. E. K. Shubber, D. Kram, and J. Williams, Jpn. J. Med. Sci. Biol. 38,207 (1985); C A 104, 202059 (1986). 399. M. Arriaga Alba, J. Espinosa-Aguirre, and C. Cortinas de Nava, Tecnol. Aliment. (Mexico City) 22, 11 (1987); C A 107,76273 (1987). 400. E. K. Shubber, D. Jacobson-Kram, and J. R. Williams, Cell Biol. Toxicol. 2,379 (1986); C A 108,124095 (1988). 401. M. Arriaga Alba, J. Espinosa, and C'. Cortinas de Nava, Environ. Mol. Mutagen. l2,65 (1988); C A 109,85754 (1988). 402. M. Arriaga Alba, J. Espinosa-Aguirre, J. Ramirez, and C. Cortinas de Nava, Environ. Mol. Mutagen. 14, 13 (1989); CA 111, 108565 (1989). 403. P. Ostrosky-Wegman, G . Garcia, L. Arellano, J. J. Espinosa, R. Montero, and C. Cortinas de Nava, Basic Life Sci. 29B, 915 (1984); C A 103, 189234 (1985). 404. J. J. Espinosa-Aguirre, C. Aroumir, M. T. Meza, E. Cienfuegos, and C. Cortinas de Nava, Murat. Res. 188, 111 (1987); C'A 107,51463 (1987). 405. Z . Chang, Zhongyao Tongbao 6,34 (1981); C A 96,97527 (1982). 406. M. T. Hsieh, F. Y. Chueh, H. Y. Tsai, W. H. Peng, and C. C. Hsieh, Zhonghua Yaoxue Zuzhi 45,447 (1993); CA UO,69448 (1994). 407. A.-R. S . Ibrahim, Saudi Pharm. J. 5. 52 (1997); C A 126,248687 (1997). 408. N. Aimi, 0. Ohmori, M. Kitajima, arid H. Takayama, Abstracts of Papers, Part 2,117th Annual Meeting of Pharmaceutical Society of Japan (Tokyo, March 1997), p. 21, Abstract 26[A7]-10-2. 409. A. Itoh, T. Tanahashi, M. Shikata, M. Tabata, M. Kakite, M. Nagai, and N. Nagakura, Abstracts of Papers, Part 2, 117th Annual Meeting of Pharmaceutical Society of Japan (Tokyo, March 1997), p. 126, Abstract 26[A4]-15-2. 410. T. Tanahashi, C. Kobayashi, K. Sonobe, N. Takemura, N. Nagakura, K. Inoue, H. Kuwajima, and H. Q. Wu, Abstracts of Papers, 43rd Annual Meeting of the Japanese Society of Pharmacognosy (Tokyo, September 1996), p. 193, Abstract 2B-21. 411. W. De-Eknamkul, A. Ounaroon, T. Tanahashi, T. M. Kutchan, and M. H. Zenk, Phytochemistry 45,477 (1997).

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THE AMARYLLIDACEAE ALKALOIDS OSAMU HOSHINO Faculty of Pharmaceutical Sciences Science University of Tokyo Shinjuku-ku, Tokyo 162, Japan

.............................. I. Introduction and Botanical Sources 11. Lycorine-Type Alkaloids ..........................................

...................................

324 342

................................. ral Elucidation ............

............................................................

365

A. Isolation and Structural Elucidation B. Synthetic Studies ......................... C. Biological Activity V. Galanthamine-Type A ....................... A. Isolation and Struc

......................

387

.....................

393

ral Elucidation

B. Synthetic Studies

X. Miscellaneous ............................

............... 410

A. Pallidiforine B. Obesine ................

F. Joubertiamine-Type Alkaloids References .................... THE ALKALOIDS. VOL. 51 00YY-YSYR/Y8 $25.00

................ 323

Copyright 0 1998 by Academic Press. All rights of reproduction in any form reserved.

324

OSAMU HOSHINO

I. Introduction and Botanical Sources The Amaryllidaceae alkaloids have been isolated from the plants of almost all of the genera of the family Amaryllidaceae and are members of the large group of isoquinoline alkaloids. Although their structures appear to be very different, they are known to be formed biogenetically by intramolecular oxidative coupling of norbelladines. At present, almost 200 Amaryllidaceae alkaloids have been isolated from plants, and many of their structures have been determined. Structures of the alkaloids are classified mainly into seven types, for which the representative alkaloids are lycorine (1)(lH-pyrrolo[3,2,1-d,e]phenanthridinetype), crinine (135) (5,lOb-ethanophenanthridinetype), narciclasine (lycoricidine) (204) (isocarbostyril type), galanthamine (261) (6H-benzofuro[3a,3,2-e,f]-2-benzazepine type), tazettine (298)(2-benzopyrano[3,4-c]indoletype), lycorenine (316)(2-benzopyrano-[3,4-g]indoletype), and montanine (338)($1 l-methanomorphanthridine type). Besides these seven structure types, there are mesembrine (387)and cherylline (440)(4-aryltetrahydroisoquinolinetype). The former structure belongs to the Sceletiurn alkaloids (Aizoaceae), but not the Amaryllidaceae (Fig. 1). Among these alkaloids, narciclasine (1ycoricidine)-type alkaloids are highly oxygenated compounds, the significant antitumor activity of which attracts the attention of biologists and pharmacologists. Recent developments in analytical techniques, as well as isolation procedures, have resulted in the rapid characterization of many structures. In the sections on the alkaloids that have been isolated for the first time from the Amaryllidaceae plants, not only the novel, but also the known, structures have been included. This chapter is a review of the Amaryllidaceae alkaloids that have appeared in the literature (1-7) since a previously published review in this series (8). Noteworthy results in the phytochemical studies, the N-oxides of several Amaryllidaceae alkaloids have been found for the first time in Amaryllidaceae plants, accompanied by the corresponding free bases (52): ungiminorine N-oxide (10)(from Puncrutium muritimurn), and 0-methyllycorenine N-oxide (329)and homolycorine N-oxide (330)(from Lupiedru muritinezii). The stereochemistry of their nitrogen atoms was deduced based on 2 D NOESY experiments. Furthermore, it has been established that these Noxide derivatives are genuine natural products, and not artifacts, by the demonstration that the free bases are not converted into N-oxides when subjected to the same extraction procedure. It is noteworthy that the N oxides have been isolated accompanied by the corresponding free bases.

4.

Lycorine (1)

Crinine (135) OMe

w

M

e

O

a

o N,

325

THE AMARYLLIDACEAE ALKALOIDS

Narciclasine (204)

n

H

Me

Galanthamine (261)

Tazettine (298)

&H Lycorenine (316)

OH

,OMe

<

a

G O M e

HO&. '0

'NH

Montanine (338)

0

Me

Mesembrine (387)

MHO e o a N M e

Cherylline (440)

FIG.1

Following the first examples of the isolation of naturally occurring N oxides from Amaryllidaceae family, extensive investigation of extracts of the bulbs of Lycoris sanguineu has revealed, for the first time, the presence of galanthamine N-oxide (281),sanguinine N-oxide (283),and lycoramine N-oxide (284), together with the corresponding free bases (62). The structures of the N-oxides were characterized by spectroscopic evidence ('H and I3C NMR). Also, hippeastrine N-oxide (332)has been isolated newly from the flowers of Lycoris rudiuta, accompanied by galanthamine N-oxide (281),lycoramine N-oxide (284),0-methyllycorenine N-oxide (329),and homolycorine N-oxide (330) and their corresponding free bases (60).

326

OSAMU HOSHINO

Furthermore,examination of the extracts of the flowers of Lycoris incarnata (58) has shown the presence of ungiminorine N-oxide (10) and galanthamine N-oxide (281),together with the corresponding free bases. The interesting N-oxide oxoassoianine N-oxide (49) has been found in the bulbs of Narcissus bicolor (64). The structures of these metabolites are shown in Fig. 2.

3-O- Acetyl-

Ungiminorine N-oxide (10)

narcissidine N-oxide (22)

Oxoassoanine N-oxide (49)

Me0

Lycoramine N-oxide (284)

Galanthamine N-oxide (281) R=Me Sanguinine N-oxide (283) R=H

Me0

Me0

OMe

O-Methyllycorenine N-oxide (329)

'OH

0

Homolycorine N-oxide (330) R=Me 8-0-Demethylhomo1ycorine N-oxide (331) R=H FIG.2

0

Hippeastrine N-oxide (332)

4.

THE AMARYLLIDACEAE ALKALOIDS

327

Numerous alkaloids have been isolated from Narcissus species as a result of the continuing exploration for novel alkaloids with pharmacological activity in the Amaryllidaceae family. Among them, the alkaloids isolated for the first time are included: norpluviine (25),l-O-acetyl-lO-0demethylpluviine (26), 1,10-0-diacetyl-10-0-demethylpluviine(27), and 0-acetylgalanthamine (262)(from N. pseudonarcissus) (83),oxoassoanine (46) (from N. assoanus) (63),vasconine (55) and 8-0-acetylhomolycorine (320)(from N. vasconicus) (93),roserine (57)and mesemberenone (371) (from N. pallidufus) (78), haemanthamine (155), 8-0-demethylmaritidine (174),homolycorine (318), and 8-0-demethylhomolycorine (319) (from N. primigenius) (82), cantabricine (176) (from N. canraricus) (65), 9-0demethylmaritidine (175)(from N. radinganorum) (86),O-methylmaritidine (179)and 0-methylpapyramine (182)(from N. papyraceus) (81),narcisine (268) (from N. tazetta) (89),0-methyllycorenine (317) (from N . munozii-garnendiae) (73), 9-0-demethylhomolycorine (321) (from N. confusus) (66),5a-hydroxy-9-0-demethylhomolycorine (322)(from N. forriflolius) (91), dubiusine (324)(from N. dubius) (69),and 5,6-dihydrobicolorine (432)and bicolorine (433)(from N . bicolor) (64), accompanied by other known Amaryllidaceae alkaloids. A complete structural analysis of 0-methyllycorenine (317)has now established that the methoxy substituent at C-6 is a rather than the previously reported fl (found in Lapiedra rnartinezii) (52). A reexamination of the polar alkaloid components of the bulbs of Hyrnenocalfis caymanensis (47) has disclosed a glucoalkaloid l-fl-~-glycosyl-2-flD-glycosylpseudolycorine (15). Also, a new glucosyloxy derivative 206 of narciclasine is found in the polar alkaloid components of P. marititimum (96), and both the parent alkaloid and this new derivative were shown to possess strong mitotoxic activity Further examination of the polar alkaloids from a methanolic extract of L. martinezii has revealed the new quaternary alkaloids, N-methylassoaninium chloride (53) and N-chloromethylnarcissidinium chloride (23), together with the lycorine-type alkaloids ungiminorine (8), narcissidine (20),and hippadine (44)(51).However, the latter quaternary alkaloid (23)is thought to have been produced by the isolation procedure (51). A similar observation regarding extraction has been reported; galanthamine (261)forms a quaternary salt N-chloromethylgalanthanium chloride (266),when extracted with methylene chloride or crystallized from the same solvent. The structure and absolute configuration of the quaternary alkaloid were determined by X-ray crystallography (109).This study emphasizes the care that needs to be taken when choosing a solvent to extract plant materials. As a method for the determination of the alkaloids, a microchemical which provides for the differentiation of identification procedure (4,210),

328

OSAMU HOSHINO

MeO& Me0

10-0-Norpulviine (24) R=R~=H 1-0-Acetyl- 100-norpluviine (25) R=Ac, R ' = H 1,lO-0-Diacetyl-100-norpluviine (26) R=R'=AC

Me0

Vasconine (50)

8-0-Demethylmaritidine (174) R = H, R' = Me 9-0-DemethyL maritidine (175) R =Me, R' = H

Me0

Me0

Roserine (52)

R

0-Me thylmaritidine (178) R=H O-Methylpapyramine (182) R = OMe

n

Cantabricine (176)

&

R20

R'O OMe

O-Methyllycorenine (317)

O-Acetylgalanthamine (262) R=Ac,R'=Me N-Formylgalanthamine (264) R = H,R' = CHO Narcisine 268) R = H, = Ac

5.6-Dih ydrobicolorine (432)

0

Bicolorine (433)

FIG.3

'R I 0io

8-0-Demethylhomolycorine (319) R=R'=H,R2=Me 8-O- Acetylhomolycorine (320) R = H , R' = Ac, R2 =Me S~t-Hydroxy9-0-demethylhomolycorine (322) R = OH, R' =Me, R2 = H 9-0-Demethylhomolycorine (321) R = H , R' =Me. R2 = H Dubiusine (324) R = Ac, R' =Me, R2 = COCH2CH(OH)Me

4.

329

THE AMARYLLIDACEAE ALKALOIDS

OH

(0 flZ-D-Gb~osyl

OH 0 4-0-pD-Gl~~0~ylnarciclasine (204)

1-0-p-D-GlUcOSylpseudolycorine (15) OMe

N-Chloromethylnarcissidinium chloride (23)

N-Methylassoaninium chloride (53)

N-Chloromethylgalanthaminiurn chloride (266)

FIG.4

the Amaryllidaceae alkaloids, has been applied to, among others, 3-0acetylcrinine (136), 6c~-ethoxycrinine,6a-ethoxybuphanisine, bulbisine, flexinine (142),augustisine, 3-0-acetylpowelline (163),trisphaeridine (426), and cherylline (440).This procedure ( 4 ) involves microcrystalline techniques and color reactions. Also, a zone refining partition coefficient technique has been developed to separate the alkaloids present in a crude extract of Crinum moorei (32). The crystal structures of haemanthamine (155) (from N. confusus) and eugenine (325)(from N. eugeniae) have been determined by X-ray crystallography. The structure of the former as 155 was confirmed to be the anti position C (11)-OH with respect to the aromatic ring and the half-chair conformation of ring C (111).Also, the structure of the latter alkaloid, 325, was shown to be far from planar, only the benzene ring being so configured (70). Interestingly, although the occurrence of the Schiff 's base craugsodine (28)in Crinum augustum has been reported (23),a new Schiff 's base named isocraugsodine (29)was isolated from the fruits of C. asiaticum (20) (Fig. 5 ) . Its structure was assigned by chemical transformation and comprehensive spectroscopic evidence. Also, the temperature-gradient distribution of the

330

OSAMU HOSHINO

Meo<3 Ho69 HO

Me0

H/

Craugsodine (28)

H O & 9

Me0

-

Isocraugsdne (29)

-

A /

H

E-Isomeric form

H/

Me0

Quinont methide

Me0 H

Z-Isomeric form

FIG.5

three isomeric forms (E-isomer quinone methide 2-isomer) of the Schiff's base was determined by high-resolution 'H NMR analysis. Thus, this compound is considered as a direct precursor to the Amaryllidaceae alkaloids. Isolation and botanical sources of the Amaryllidaceae alkaloids that have been reported in the literature since 1987 are summarized in Table I. Extensive exploration of the pharmacological utility of the Amaryllidaceae alkaloids has been carried out. For example, studies (112) on the effects of Amaryllidaceae alkaloids and their derivatives (prepared by biosynthesis and chemical transformation) upon Herpes simplex virus (type l), the relationship between their structure and antiviral activity, and the mechanism of this activity have been performed, suggesting that the alkaloids that may eventually prove to be antiviral agents had a hexahydroindole ring with two functional hydroxyl groups. Furthermore, the antiviral activity of the alkaloids was found to be due to the inhibition of multiplication, and not to the direct inactivation of extracellular viruses, and the mechanism of the antiviral effect was partially explained as a blocking of viral DNA polymerase activity. Also, the extract of the bulbs of Haemanthus albiflos was found to inhibit viral DNA synthesis (113). It is reported that the total alkaloidal extract of this plant possesses antiviral activity (113). Reviews that include these biological data have appeared (114,215).

4.

331

THE AMARVLLIDACEAE ALKALOIDS

TABLE I THEISOLATION OF AMARYLLIDACEAE ALKALOIDS Species Boophane frava

Brunsvigia josephinae

Clivia nobilis Crinum amabile

Crinum americanum

Alkaloids (sources) 0-Ace1 ylhamayne (bulbs) Augustine (bulbs) Buflavine (bulbs) Buphanisine (bulbs) Crinamine (bulbs) Crinine (bulbs) 8-0-Demethylbuflavine (bulbs) 5,6-Dihydrobicolorine (bulbs) Epi-buphanine (bulbs) Epi-vittatine (bulbs) Hamayne (bulbs) Lycorine (bulbs) Montabuphine (bulbs) Undulatine (bulbs) 11-0-Acetylambelline (bulbs) 3-0-Acetylhamayne (bulbs) Ambelline (bulbs) Brunsbelline (bulbs) Buphariidine (bulbs) Buphariisine (bulbs) Crinamine (bulbs) Crinine (bulbs) Hamayne (bulbs) Hippadine (bulbs) Josephinine (bulbs) Sternbergine (bulbs) Undulatine (bulbs) Clivatine (whole plants) Lycoririe (whole plants) Nobilisine (whole plants) Amabiline (bulbs) Augustine (bulbs) Crinamine (bulbs) Buphanisine (bulbs) Lycorine (bulbs) 0-Acetylcrinine (rhizomes) Augustine (bulbs) Buphanisine (leaves) Crinamine (leaves) Crinan type (rhizomes) Crinine (Crinidine) (leaves) Crinine (bulbs) Dihydrocrinidine (rhizomes) Flexinine (bulbs) Haemanthamine (leaves)

Reference 9 9 9 9 9 9 9 9 9 9 9 9 9 9 10 11 II 9 10

10 II 10

11 11 11 II 12 12 12 12 13 13 13 13 13 14 15 16

16 17 16 14 15 14 16

(continues)

TABLE I (continued) Soecies

Crinum asiaticum

Alkaloids (sources)

Reference

Hamayne (rhizomes) Hippadine (bulbs) Lycorine (bulbs) Lycorine (leaves) Oxocrinine (bulbs) Pratorimine (bulbs) Pratorinine (bulbs) Pratosine (bulbs) Tazettine (leaves) Trisphaeridine (bulbs) Ungeremine (bulbs) Criasbetaine

1,2-O-P-o-Diglucosyllycorine (fruits) Isocraugsodine (fruits) 2-Oxolycorine N-oxide (fruits) 1-O-Palmitoyl-2-0-(1‘-O-palmitoyl-2’-Oo1eoyl)glycerophosphoryllycorine (fruits) l-O-Palmitoyl-2-O-(l’-O-palmitoyl-2‘-0oleoy1)glycerophosphorylpseudolycorine (fruits) l-O-Palmitoyl-2-0-(1 ’-O-palmitoyl-2’-0stearoy1)glycerophosphoryllycorine (fruits) l-O-Palmitoyl-2-0-( l’-O-palmitoyl-2’-0stearoy1)glycerophosphorylpseudolycorine (fruits) Ungeremine Crinum asiaticum var. sinicum Crinine (bulbs) Crinsin (bulbs) Lycorine (bulbs) Powelline (bulbs) Augustamine (whole plant) Crinum augustum Craugsodine Hippadine (bulbs) 6a-Hydroxybuphanisine (whole plant) 6a-Hydroxycrinine (whole plant) Pratorimine (bulbs) Pratorinine (bulbs) Telastaside (phathenocarpic fruits) Crinum bulbispermurn Powelline (whole plant) Pratorinine (whole plant) Crinum firmifoliurn var. Crinamine (whole plants) hygrophilum Criwelline (whole plants) Hamayne (whole plants) 6-Hydroxycrinamine(whole plants) 3-Hydroxy-8,9-methylenedioxyphenanthridine (whole plants) Ismine (whole plants) Lycorine (whole plants) Trisphaeridine (whole plants) 332

15 14 14 16 14 14 14 14 16 14 16 18 19 20 19 19 19

19 19

18 21 21 21 21 22 23 24 22 22 24 24 25 22 22 26 26 26 26 26 26 26 26

TABLE I (continued) Species Crinum giganteum

Crinum jagus

Crinum kirkii

Crinum latifolium

Crinum moorei Crinaum zeylanicum

Galanthus elwesii

Haemanthus albiflos

Alkaloids (sources) Crinine (crinidine) Gal anthamine Hippeastrine Lycorine Tazettine Crinamine (whole plants) Hainayne (whole plants) 6-Hydroxycrinamine (whole plants) Lycorine (whole plants) 3-0-Acetylhamayne (bulbs) Crinine (bulbs) 8-0-Demethylvasconine (bulbs) Hamayne (bulbs) Kirkine (bulbs) Crinafolidine Crinafoline 4,5-Dehydroanhydrolycorine(flower stem fluid) Epi-lycorine (flower stem fluid) Epr-pancrassidine (flower stem fluid) Hippadine (flower stem fluid) Latifine (bulbs) Lycorine (flower stem fluid) Pancrassidine (flower stem fluid) Crinamidine Crinine Powelline Crinine (crinidine) (bulbs) Flexinine (bulbs) 6-Hydroxypowelline (bulbs) Zeylarnine (air-dried rhizomes) N-Demethylgalanthamine (whole plants) 9-0-Demethylgalwesie (whole plants) 9-0-Demethylhomolycorine(whole plants) Galanthamine (whole plants) Galanthine (whole plants) Galasine (whole plants) 16-Hydroxy-9-0-demethylgalwesine(whole plants) 11-Hydroxyvittatine (whole plants) 16-Hydroxygalwesine (whole plants) Galwesine (whole plants) Leucotamine (whole plants) Lycorine (whole plants) 5-Methoxy-9-0-demethylhomolycorine (whole plants) Narwedine (whole plants) Sanguinine (whole plants) Albiflomanthine (bulbs) 333

Reference 27 27 27 27 27 28 28 28 28 29 29 29 29 29 30 30 31 31 31 31 197 31 31 32 32 32 33 33 33 34 35 35 35 35 35 35 35 35 35 35 35 35 35 35 35 36

(continues)

TABLE I (continued) Species

Haemanthus kalbreyeri

Haemanthus multiflorus

Hippeastrum equestre

Hippeastrum hybrids

Hippeastrum puniceum

Hippeastrum solandriflorum

Hymenocallis caribaea Hymenocallis caymanensis Hymenocallis expansa

Alkaloids (sources)

Reference

Albomaculine (bulbs) Galanthamine (bulbs) Haemanthamine (bulbs) Haemanthidine' (bulbs) Lycoramine (bulbs) 7-Deoxypancratistatin (rhizomes) 7-Deoxynarciclasine (rhizomes) Haemanthamine (rhizomes) Haemanthidine (rhizomes) Hippadine (rhizomes) Kalbretorine (rhizomes) Lycorine (rhizomes) Narciclasine (rhizomes) Pancratistatin (rhizomes) Pancratiside (2-~-P-~-Gh1cosylpancratistatin) (rhizomes) 2-0-Acetylchlidanthine (bulbs) Galanthamine (bulbs) Galanthamine Haemultine (bulbs) Hippadine (bulbs) Lycorine Lycorine (bulbs) Sanguinine Hippeastrine (bulbs) Lycorine (bulbs) Phamine (bulbs) Phamine (bulbs) Tazettine (bulbs) Haemanthamine (bulbs) Hippeastrine (bulbs) 11-Hydroxyvittatine (bulbs) Lycorine (bulbs) Montanine (bulbs) Pancracine (bulbs) Tazettine (bulbs) Vittatine (bulbs) 0-Acetylnarcissidine (bulbs) 11-Hydroxyvittatine (bulbs) Vittatine (bulbs) Hamayne (aerial parts and bulbs) Ismine (aerial parts and bulbs) Lycorine (aerial parts and bulbs) Vittatine (aerial parts and bulbs) Ungeremine (aerial parts and bulbs) 7-Deoxy-frans-dihydronarciclasine(bulbs) 4-Hydroxyanhydrolycorine (leaves) Glucoalkaloid (bulbs) Haemanthidine (bulbs/leaves) 334

36 .36 36 36 36 37 37 37 37 37 37 37 37 37 -37 38 38 39 38 38 39 38 40 40 40 40 41 40 42 42 42 42 42 42 42 42 43 43 43 44 44 44 44 44 45 46 47 48

TABLE I (conrinued) Species

Hyrnenocallis latifolia Hyrnenocallis littoralis

Hyrnenocallis rotata

Lapiedra martinezii

Alkaloids (sources)

Reference

Hippeastrine (bulbs/leaves) Tazettine (bulbs/leaves) 7-Deoxy-trans-dihydronarciclasine (bulbs) 5,6-Dihydrobicolorine (bulbs) 8-0-Demethylmaritidine (bulbs) 7-Deoxynarciclasine (bulbs) 7-Deoxy-trans-dihydronarciclasine (bulbs) Haemanthamine (bulbs) Hippeastrine (bulbs) Homolycorine (bulbs) Littoraline (bulbs) Lycoramine (bulbs) Lycorenine (bulbs) Lycorine (bulbs) Marconine (bulbs) 0-Methyllycorenine (bulbs) Narciclasine (bulbs) Pancratistatin (bulbs) Pretazettine (bulbs) Tazettine (bulbs) Vitlatine (bulbs) Alkaloid 13 (bulbs) N-Demethylgalanthamine (bulbs) N-Demethyllycoramine (bulbs) 8-0-Demethylmaritidine (bulbs) 3-Epi-marconine (bulbs) Galanthamine (bulbs) Haemanthamine (bulbs) Ismine (bulbs) Lycoramine (bulbs) Lycorine (bulbs) Pretazettine (bulbs) Tazettine (bulbs) Vitratine (bulbs) N-Chloromethylnarcissidinium chloride Hippadine Homolycorine (aerial parts) Hornolycorine N-oxide (aerial parts) Ismine (bulbs/leaves) N-hlethylassoaninium chloride N-hlethylcrinasiadine (N-methyl-8,9-

48 48 45 49 49 45 45 49 49 49 49 49 49 49 49 49 45 45 49 49 49 50 50 50 50 50 50 50 50 50 50 50 50 50 51 51 52 52 53 51 53

methylenedioxyphenanthridin-6-one) (bulbs/leaves)

8,9-Methylenedioxyphenanthridine(bulbs/

53

leaves)

N-hlethyl-8,9-methylenedioxyp henanthridinium chloride (bulbs/leaves) 0-Methyllycorenine N-oxide (aerial parts) Narcissidine

53

52 51

(continues) 335

TABLE I (continued) Species

Leucojum aestivum sub. pulchellum Leucojum autummale Lycoris ichinensis

Lycoris guangxiensis

Lycoris incarnata

Lycoris radiata

Alkaloids (sources) Ungiminorine Ungiminorine N-oxide (aerial parts) Elwesine Galanthamine Lycorine Sanguinine 3-0-acetylnarcissidine 3-0-acetylnarcissidine N-oxide Crinine (bulbs) Epi-lycoramine (bulbs) Galanthamine (bulbs) Haemanthidine (bulbs) Hippeastrine (bulbs) Homolycorine (bulbs) Lycoramine (bulbs) Lycorenine (bulbs) Lycorine (bulbs) Narciclasine (bulbs) Pulviine (bulbs) N-Allylnorgalanthamine (bulbs) Crinine (bulbs) Galanthamine (bulbs) Lycoramine (bulbs) Lycorine (bulbs) Narwedine (bulbs) Norgalanthamine (bulbs) Pseudolycorine (bulbs) 0-Demethyllycoramine (flowers) Galanthamine (flowers) Galanthamine N-oxide (flowers) Galanthine (flowers) lncartine (flowers) Lycoramine (flowers) Lycorine (flowers) Narcissidine (flowers) Sanguinine (flowers) Unigiminorine (flowers) Unigiminorine N-oxide (flowers) 0-Demethylhomolycorine (flowers) 0-Demethyllycoramine (flowers) Galanthamine (flowtrs) Galanthamine N-oxide (flowers) Hippeastrine (flowers) Hippeastrine N-oxide (flowers) Homolycorine (flowers) Homolycorine N-oxide (flowers) Lycoramine (flowers) Lycoramine N-oxide (flowers)

336

Reference 51 52 54 54 54 54 55 55 56 56 56 56 56 56 56 56 56 56 56 57 57 57 57 57 57 57 57 58 58 58 58,59 58,59 58 58 58 58 58 58 60 60 60 60 60 60 60 60 60 60

TABLE I (confinued) Species

Lycoris sanguinea

Narcissus assoanus Narcissus bicolor

Narcissus cantaricus

Narcissus confusus

Narcissus dubius Narcissus eugeniae Narcissus jacetanus

Narcissus leonensis

Alkaloids (sources) Lycorine (flowers) 0-Methyllycorenine (flowers) 0-Methyllycorenine N-oxide (flowers) Tazettine (flowers) Vittatine (flowers) Galanthamine (bulbs) Galanthamine N-oxide (bulbs) Galanthine (bulbs) Lycoramine (bulbs) Lycoramine N-oxide (bulbs) Lycorine (bulbs) Norbutsanguinine (bulbs) Norsanguinine (bulbs) Pseudolycorine (bulbs) Sanguinine (bulbs) Sanguinine N-oxide (bulbs) Assoanine (fresh plants) Oxoassoanine (fresh plants) Bicolorine (bulbs) 5,6-IXhydrobicolorine (bulbs) 3-Epi-macronine (bulbs) Oxoassoanine N-oxide (bulbs) Pretazettine (bulbs) Cantabricine (whole plant) Crinamine (whole plant) 6a-/b&Hydroxybuphanisine (whole plant) Tazettine (whole plant) Vittatine (whole plant) 1-0-Acetylpseudolycorine 2-O- Acetylpseudolycorine 9-0-Demethylhomolycorine (fresh plants) 9-0-Demethylhomolycorine (aerial parts/ bulbs) N-Formylgalanthamine (fresh plants) Galanthamine (fresh plants) Haemanthamine (fresh plants) Homolycorine (aerial partshulbs) Pretazettine (fresh plants) Pseudolycorine Duhiusine (aerial parts) 5a-Hydroxy-10-0-demethylhomolycorine (aerial part) Eugenine (whole plant) Assoanine (whole plant) Lycorine (whole plant) Oxoassoanine (whole plant) Pseudolycorine (whole plant) Epi-norgalanthamine (whole plant) Epi-norlycoramine (whole plant) 337

Reference 60 60 60 60 60 61,62 61 62 61 61 62 62 62 62 61,62 61 63 63 64 64 64 64 64 65 65 65 65 65 66 66 67 68 67 67 67 68 67 66 69 69 70 71 71 71 71 72 72

(continues)

TABLE I (continued) Species Narcissus rnunoziigarmendiae Narcissus nivalis

Narciassusobesus

Narcissus pallidiflorus

Narcissus pallidulus Narcissus panizzianus

Narcissus papyraceus

Narcissus primigenius

Narcissus pseudonarcissus

Alkaloids (sources) Lycorine (whole plant) Homolycorine (whole plant) Lycorenine (whole plant) 0-Methyllycorenine (whole plant) N-Demethylgalanthamine (fresh aerial parts and bulbs) Galanthamine (fresh aerial parts and bulbs) 9-0-Methylpseudolycorine (fresh aerial parts and bulbs) Bicolorine (whole plants) 5.6-Dihydrobicolorine (whole plants) Epi-macronine (whole plants) Galanthamine (whole plants) Haemanthamine (whole plants) Obesine (whole plants) Pretazettine (whole plants) 8-0-Demethylhomolycorine (whole plants) 5,6-Dihydrobicolorine (whole plants) Haemanthamine (whole plants) Homolycorine (whole plants) Pallidiflorine (whole plants) Pretazettine (whole plants) Mesembrenone (aerial parts) Mesembrenone (whole plants) Roserine (whole plants) 6-Epi-papyramine (whole plants) Galanthine (whole plants) Galanthine (aerial parts and bulbs) Homolycorine (aerial parts and bulbs) Homolycorine (whole plants) Papyramine (whole plants) Pretazettine (whole plants) Pretazettine (aerial parts and bulbs) 0-Demethylhomolycorine (aerial parts) 0-Demethylhomolycorine N-oxide (aerial parts) Homolycorine (aerial parts) Lycorine (aerial parts) 0-Methylmaritidine (aerial parts) 0-Methylpapyramine (aerial parts) Papyramine" (aerial parts) Pseudolycorine (aerial parts) 9-0-Demethylhomolycorine (whole plants) 0-Demethylmaritidine (whole plants) Haemanthamine (whole plants) Homolycorine (whole plants) 0-Acetylgalanthamine (bulbs) 1-0-Acetyl-10-0-demethylpluviine (bulbs) 1-0-Acetyl-10-0-demethylpluviine(bulbs) 338

Reference 72 73 73 73 74 74 74 75 75 75 75 75 75 75 76 76 76 76 76 76 77 78 78 79 79 80 80 79 79 80 80 81 81

81 81 81 81 81 81

82 82 82 82 83 83 84

TABLE I (continued) Species

Alkaloids (sources)

Reference

N-Demethylgalanthamine (bulbs) N-Demethylmasconine (bulbs) 10-0-Demethylpluviine (bulbs)

Narcissus radinganorum

Narcissus var. “Fortune” Narcissus tazetta

Narcissus tortifolius

Narcissus tortuosus Narcissus vasconicus

1,10-Diacetyl-10-0-demethylpluviine (bulbs) Epi-norlycoramine (bulbs) Galanthamine (bulbs) Galanthamine (bulbs) Haemanthamine (bulbs) Hippeastrine (bulbs) Homolycorine (bulbs) Homolycorine (bulbs) Lycoramine (bulbs) Lycorenine (bulbs) Masconine (bulbs) 8-0-Methylhomolycorine (bulbs) 0-Methyloduline (bulbs) Narcidine (bulbs) Narcissidine (bulbs) Nanvedine (bulbs) 10-horpluviine Oduline (bulbs) Vittatine (bulbs) 9-0-Demethylmaritidine (fresh plants) 8-0-Demethylhomolycorine (fresh plants) Homolycorine (fresh plants) Fortucine (leaves) 10-0-Demethylhomolycorine (whole plants) Galanthamine (bulbs) Haemanthine (bulbs) Honiolycorine Lycorine Lycorine (bulbs) Narcishe (bulbs) Pretazettine (bulbs) Pseudolycorine (bulbs) Tazettine Tazettine (bulbs) 8-ODemethylhomolycorine (whole plants) 9-0. Demethyl-2a-h ydroxyhomolycorine (whole plants) Dubiusine (whole plants) Galanthamine (whole plants) Honiolycorine (whole plants) Lycorine (whole plants) Tortuosine (whole plants) 8-0-Acetylhomolycorine (whole plants) Homolycorine (whole plants) Lycorine (whole plants) Vasconine (whole plants)

84 84 84 83 84 85 84 85 85 85 84 84 84 84 85 84 85 85 84 83 84 84 86 86 86 87 88 89 89 90 90 89 89 89 89 90 89 Y1

91 91 91 91

92 92 93 93 93 93

(continues) 339

TABLE I (continued) ~~

Species Pancratium biflorum Pancratium maritimum

Alkaloids (sources) Telastaside (parthenocarpic fruits) Crinine (bulbs) 9-0-Demethylhomolycorine(bulbs) 6-0-Methylhaemanthidine (bulbs)

3P,lla-Dihydroxy-l,2-dehydrocrinane(bulbs)

Reference 25 94 95-97 97 98

(bulbs)

0,N-Dimethylnorbelladine (bulbs)

Sceletium subvelutinum

Sternbergia clusiani

Galanthamine (bulbs) 4-~-P-~-G~ucopyranosyharciclasine (bulbs) Haemanthamine (bulbs) Haemanthidine (bulbs) Habranthine (bulbs) Hippadine (bulbs) Hippeastrine (bulbs) Homolycorine (bulbs) 11-Hydroxygalanthamine(habranthine) (bulbs) 8-Hydroxy-9-methoxycrinine(bulbs) 11-Hydroxyvittatine(bulbs) Lycorenine (bulbs) Lycorine (bulbs) 6-0-Methylhaemanthidine (bulbs) Pancracine (bulbs) Pseudolycorine (bulbs) Sickernbergine (bulbs) Tazettine (bulbs) Trisphaeridine (aerial parts) Trisphaeridine (bulbs) Ungeremine (bulbs) Ungiminorine (bulbs) Ungiminorine N-oxide (bulbs) Vittatine (bulbs) Zefbetaine (bulbs) Dehydrojouvertiamine (whole plants) Dihydrojoubertiamine (whole plants) N,N-Dimethyltyramine (whole plants) Ouvertiamine (whole plants) 0-Methyldehydrojoubertiamine(whole plants) 0-Methyldihydrojoubertiamine(whole plants) 0-Methyljoubertiamine (whole plants) Crinine (bulbs) Galanthamine (bulbs) Haemanthamine (bulbs) Haemanthidine (bulbs) 11-Hydroxyvittatine(bulbs) Lycorine (bulbs) Pretazettine (bulbs)

97 96,97 96 96,97 96,97 97 96 97 96 97 98 96,97 96 94-97 97 96 96 96 96 99 %

96,100 97 52,97 97 96,100 101 101 101 101 101 101 101 102 102 102 102 102 102 102

TABLE I (continued) Species Sternbergia lutea

Sternbergia sicula

Ungernia minor Zephyranthes Java

Alkaloids (sources) Deniethylmaritidine (whole plants) Epi-maritinamine (whole plants) Haemanthamine (whole plants) Haemanthidine (whole plants) Hippadine (bulbs) 11-Hydroxyvittatine (whole plants) Lycorine (bulbs) Maritinamine (whole plants) Tazettine (whole plants) Vittatine (whole plants) Ungiminorine (bulbs) Buphanisineb (whole plants) Deniethylmaritidine (whole plants) 11-Epi-haemanthamine (whole plants) Haemanthamine (whole plants) Haemanthidine (whole plants) 11-Hydroxyvittatine (whole plants) Siculine (whole plants) Siculinine (whole plants) Tazettine (whole plants) Ungiminorine (deacetyllutessine) (whole plants) Vittatine (whole plants) 1,3-O-Diacetyldihydroungerenine 2-0-Glycerophosphoryllycorine (flowers) 2-041‘-0-Palmitoyl-2’-0-oleoyl) glycerophosphoryllycorine (flowers) 2-0-(1’-0-Palmitoyl-2’-0-oleoyl) glycerophosphorylpseudolycorine(flowers) 2-041 ’-0-Palmitoyl-2’-0-stearoyl) glycerophosphoryllycorine (flowers) 2-0-(1’-0-Palmitoyl-2’-0-stearyl/oleoyl) glycerophosphorylpseudolycorine(flowers) 2-0-(1 ’-0-Palmitoyl-2’-0-stearyl) glycerophosphory llycorinium methocationsc (flowers) Criasbetaine (fresh mature seeds) Crinamine (fresh mature seeds) Haemanthamine (fresh mature seeds) Haemanthidine (fresh mature seeds) Kalhreclassine (fresh mature seeds) Lycorine (fresh mature seeds) l-0-B-D-Glucopyranosyllycorine(fresh mature seeds) Maritidine (fresh mature seeds) Melhylpseudolycorine (fresh mature seeds) Narciclasine (fresh mature seeds) Pratorinine (fresh mature seeds) Prerazettine (fresh mature seeds) 341

Reference 103 103 103 103 104 103 104 103 103 103 104 103 103 103 103 103 103 103 104 103 103 103 105 106 106 106 106 106 106

107 107 107 107 107 107 107 107 107 107 107 107

(continues)

342

OSAMU HOSHINO

TABLE I (continued) Alkaloids (sources)

Species

Pseudolycorine (fresh mature seeds) 1-0-P-D-Glucopyranosylpseudolycorine (fresh mature seeds) Ungeremine (fresh mature seeds) Zefbetaine (fresh mature seeds) Zeflabetaine (fresh mature seeds) a

Reference 107 107

107 107 I07

As a mixture of 6a- and 6p-epimers. Enantiomer of (-)-byhankhe. As a mixture of a-and fl-N-methyl epimers.

II. Lycorine-Type Alkaloids A. ISOLATION AND STRUCTURAL ELUCIDATION

The structures of the representative alkaloids isolated since 1987 are listed in Fig. 6. Investigation of the components of the flowers of Amaryllidaceae plants has not been carried out extensively, compared with that of the bulbs and the whole plants, because of the limitation for the collection of these plants. The flower stem fluid of Crinum lutifolium (31) has been examined, from which numerous Amaryllidaceae alkaloids have been isolated. Among them, two lycorine-type alkaloids, 2-epi-lycorine (4) and 2-epi-pancrassidine (7), are included, structures of which were determined by spectroscopy. In addition, a study of the metabolism of lycorine (1) and 2-epi-lycorine (4) has been performed using the flower stem fluid in a phosphate buffer, revealing that lycorine (1) produces, in succession, 2-oxolycorine (5) and 2-0x0-pyrrolophenanthridiniumbetaine (ungeremine) (a), and that 2-epilycorine (4) forms 2-epi-pancrassidine (7), 4,5-dehydroanhydrolycorine (43), and hippadine (44) (31) (Scheme 1). As a result of these in vitro studies, a reexamination of the flower stem fluid has shown that trace amounts of 2-epi-pancrassidine (15) are indeed present. Further investigations of the flowers of Amaryllidaceae species has revealed several new alkaloidal phospholipids, 2-0-glycerophosphoryllycorine (30), phosphatidyllycorine (31-34), phosphatidyllycorinium methocations (39, and phosphatidylpseudolycorine (36-39), respectively, in an extract of the flowers of Zephyranthesflava (107) (Fig. 7). The structures of the alkaloids were established by comprehensive spectroscopic analyses

Lycorine (1)

Lycorine N-oxide (3)

R=H 1-0-Acetyllycorine (2) R=Ac

OMe HO.&ORU

Pancrassidhe (6) R = P-OH 2-Epi-pancrassidine (7)

2-Oxolycorine (5)

& <& Q '0

0 0

2-Epi-lycorine (4)

0

Ungiminorine (8) R=H 3-0-Acetylungiminorine (9) R=Ac

Ungiminorine N-oxide (10)

Siculinine (11)

9-0-Methylpseudolycorine (17)

Incartine (19)

R = a-OH

HO

R=H

Stembergine (16)

Galanthine (18) R=Me

Me0

Pseudo1 corine (12) R = RY = H 1-0-Acetylpseudolycorine (13) R = AC. R' = H 2-O- AcetvlMe0

OMe HO.&.ofl

I!

CHzCl

3-O- Acetylnarcissidine N-oxide (22)

N-Chloromethylnarcissidinium chlorode (23)

RIO&

Rlo&9 Me0

RO

MeO&

/

H

HO

Formcine (Kirkine) (27)

hugsodine (28) R =H, R' = M e Isocraugsodine (29) R = Me, R' =H FIG.6

10-0-Norpulviine (24) R=R'=H l-O-Acetyl-100-norpluviine (25) R-AC. R ' = H lJ0-O-Diacetyl- 100-norpluviine (26) R = R ' =AC

344

OSAMU HOSHINO

OH

0

-Q& 0

Lycorine (1)

2-Oxolycorine (5).

2-Epl-lycorine (4)

{)& 0

Ungerenine (48)

2-Epi-pancrassidine (7) SCHEME 1

and chemical transformation. For example, the location of the acylglycerophosphoryl substituent at the allylic position of the pseudolycorine moiety was determined by the demonstration that diacetylphosphorylpseudolycorine when treated with sodium methoxide (NaOMe) in tetrahydrofuran (THF) containing palladium(0) catalyst (116), produced 1,lO-di-Oacetylpseudolycorine. As for the presence of both the free and conjugated alkaloids in the plants, their biochemical role has been examined using the fruits of Crinum usiuticum during stress (incisional injury and attack by an insect) (19). Wounding of C. usiuticum fruits caused almost complete hydrolysis of the alkaloidal conjugates and also produced oxidized metabolites of lycorine: Its analogs, e.g., 1-0-palmitoyl-2-0-(1'-O-palmitoyl-2'-O-stearoyl)glycerophosphoryllycorine (33), gave lycorine (1) and the N-oxide 3. Prior treatment of the fruits with anesthetic agents, e.g., ether or lidocaine, not only protected the alkaloidal conjugates from enzymatic hydrolysis, but also prevented their oxidation. These observations reveal that even "fresh" plant extracts can be modified by enzymatic activity. Further exploration on components of the Amaryllidaceae flowers revealed a new lycorine-type alkaloid, incartine (19), from the flowers of Lycoris incurnatu (58),together with lycorine (l),ungiminorine (8), ungiminorine N-oxide (lo), galanthine (18), and galanthamine-type alkaloids (58,59).Their structures were established by spectroscopic methods. Moreover, this epoxide 19 is regarded as a significant intermediate in the biosynthesis of narcissidine (20) from galanthine (18) (59) (Scheme 2).

2-O-Glycerophosphoryllycorine (30) H.R2 ~poCH2CH(OH)CH2OH

R'

2-0-(l'-O-Palmitoyl-2'-0-stearoy1)glycerophosphoryllycorine(31) R' = H,Rz = O#OCH$HCH2O-palrnitoyl 0-stearoyl 2-04 l'-O-Palmitoyl-2'-0-oleoyl)glycerophosphayllycorine (32) R' = H,Rz= O#OCH2

2-0-( l'-O-Palmitoy1-2'-0-stearoyl)glycerophosphorylpseudolycorine(36) R' = H, R2 = &POCH2

2-041'-0-Palmitoyl-2'-0-oleoyl)glycemphosphorylpseudolycorine(37) R' = H, R2 = QPoCH2CHCH2O-palmitoyl b-oleoy1 1-0-Palmitoyl-2-0-( l'-O-palmitoyl-2'-O-steamyl)glycerophosphorylpseudolycorine(38) R' = palmitoyl, R~= O~POCH~

l-O-Palmitoyl-2-0-( l'-O-palmitoyl-2'-O-stearoyl)glycerophosphoryllycorine(33) l-O-Palmitoyl-2-0-( l'-O-palmitoyl-2'-O-oleoyl)R'= palmitoyl. R2 = 02~~2CHCH20-pa1mitoY1 glycerophosphorylpseudolycorine(39) b-stearoyl R' = palmitoyl, R2 = QPoCH2 l-O-Palmitoyl-2-0-( l'-O-palmitoyl-2'-O-oleoyl)glycerophosphoryllycorine(34) R'= palmitoyl. R2 = O~KKFI~CHCH20-palmitoyl 6-oleoy 1

Me

2-( l'-O-Palmitoy1-2'-0-stearoyl)glycerophosphoryllycoriniummethocations (35) (a mixture of a-and P-N-methyl isomers) R=

02POCH2j'HsHa~~palmitoyl FIG.7

-

-

Me0

Me0

Me0

Me0

Me0

Galanthine (18)

Me0

hicartine (19) SCHEME 2

Narcissidine (20)

346

OSAMU HOSHINO

The extract of Sternbergiu siculu gave a new lycorine-type alkaloid, siculinine (11)(104, accompanied by lycorine (l),ungiminorine (8), and hippadine (44),structural elucidation of which was performed by spectroscopic evidence. In this study, deacetyllutessine (41), which was reported previously (117), was found to be identical to ungiminorine (8). Therefore, it is likely that lutessine (40) corresponds to acetylungimimorine (9), although final confirmation of the structure of lutessine remains to be achieved (Fig. 8). A new lycorine-type alkaloid named fortucine has been found in the leaves of Narcissus variety “Fortune” and its structure reported as 27 (87). From the bulbs of Crinum kirkii, two new alkaloids, kirkine (27) and 8-0demethylvasconine (56), have been isolated and their structures established by physical and spectroscopic methods (29). In this study, the structure of kirkine was determined to be the same structure as that proposed for fortucine (87). Therefore, confirmation by direct comparison of each alkaloid remains to be conducted. C-Aromatic lycorine-type alkaloids have been discovered in the plants of the Amaryllidaceae family. Two new 2-0x0-pyrrolophenanthridinium alkaloids, zefbetaine (59)and zeflabetaine (60), together with several known Amaryllidaceae alkaloids, have been isolated from fresh mature seeds of Zephrunthesfluvuby gradient solvent extraction, chromatography, and derivatization (108). Their structures were characterized by comprehensive spectroscopic methods, chemical transformations, and synthesis. They are listed in Fig. 9.

& OMe

Q

.OMe

0

0

Siculinine (11)

Lutessine (40) R=Ac Deacetyllutessine (41)

R=H FIG.8

347

4. THE AMARYLLIDACEAE ALKALOIDS

Me0 "eO&

R

4Hydroxyanhydrolycorine (42)

4,s-Dehydroanhydrolycorine (43) RzHz Hippadine (44) R=O

Assoanine (45) R=H2 Oxoassoanine (46) R=O

.-& Me0

0

c1Anhydrolycorinium chloride (47)

0 0Oxoassoanine N-oxide (49)

Ungeremine (48)

Me0

0 Ratorinine 50) R'=H.R =Me

1

Ratorimine (51) R' =Me, Rz = H Ratosine (52) R' =R2 =Me

N-Methylassoaninium chloride (53)

0

0'

Tormesine (54) R' = R2 = OMe Vasconine (55) R' = H. RZ= OMe 8-O-Demeth ylvasconine (56) R' = H, R~ = OH

MeO&

Me0 OMe

Roserine (57)

Criasbetaine (58) ~1~ ~2 = M~ Zefbetaine (59) R'=Me. R 2 = H

FIG.9

Zeflabetaine (60)

Kalbretorine (61) R=H O-Methylkalbntorine (62) R=Me

348

OSAMU HOSHINO

B. SYNTHETIC STUDIES The synthesis of lycorine-type alkaloids has received the attention of chemists as a target for exploration of new synthetic methods, because the stereoselective construction of the contiguous asymmetric centers reported until now is not always efficient. Since the previously published review (8),two investigations of the total synthesis of (2)-lycorine (1) (128), and the first total syntheses of optically active (+)-lycorine (1)and (+)-1deoxylcorine (84) (119), the unnatural enantiomer of lycorine (l), were reported. Both of the synthetic strategies involve the construction of highly functionalized hexahydroindoline derivatives, followed by cyclization to form ring B. A key step in the one case (128)involves an intramolecular Diels-Alder reaction to form a Slactone 64and its conversion to functionalized hexahydroindoline derivatives (Scheme 3). Specifically, intramolecular DielsAlder reaction (in a sealed tube) of (3E)-hexa-3,5-dienyl-(E)-(3,4-methy1enedioxy)cinnamate(63)in o-dichlorobenzene at 235°C afforded in 86% yield the Slactone 64, along with its stereoisomer. Oxidation of 64 with silver carbonate-Celite in boiling benzene produced a regioisomer 65 of Slactone 64 in 98% yield. Iodolactonization of 65 in the usual manner, and protection as a tetrahydropyranyl ether, afforded tetrahydropyranyloxyiodo-y-lactone, dehydroiodation of which provided tetrahydropyranyloxyy-dehydrolactone 66,Deprotection of 66,followed by Jones oxidation, led to dehydro-y-lactonecarboxylic acid 67. The acid 67 was converted into hexahydroindoline 68, possessing stereochemistry similar to that of the ring juncture in the rings B-C-D of lyconine through Curtius rearrangement of the acid. Epoxidation of the acetate afforded a 5,6-cr-epoxy acetate 69, the Payne rearrangement of which, under mild basic conditions, produced, on acetylation, the 4J-&epoxy acetate 70 in a moderate yield. Phenylselenylation of 70,followed by acetylation, afforded, in 98% yield (two steps), 5~,6a-diacetoxy-4a-phenylselenylhexahydroindolin-2-one (71),possessing the necessary functional groups and a masked double bond. Finally, 71 was converted into (2)-lycorine (1) (86% yield) in two steps (228). On the other hand, 71 gave, in 57% yield, 0-diacetyllycorin-5-one (74),which was previously (220) transformed to (2)-lycorine (l), by way of 5P,6a-Odiacetyl-4a-phenylselenyllycorin-5-one (73). In the other synthetic route (129),Birch reduction-alkylation and transformation of functionalized hexahydroindoline derivatives constitute key reactions (Schemes 4 and 5). Birch reduction of N-(2-methoxybenzoyl)(2s)-methoxymethylpyrrolidine,followed by alkylation with 2-acetoxyethyl bromide, produced a key compound 76, azidation of which, followed by hydrolysis with acid, gave the azide 77in 69% yield (two steps). Iodolactoni-

4.

349

THE AMARYLLIDACEAE ALKALOIDS

66

67

68

69

70

(f)-Lycorine (1) R=H (&)- 1,2-O-Diacetyllycorine (75) R=Ac Reagents and Condirionr : a) o-dichlorobenzene (a sealed tube), 235OC, 86% and 5% (stereoisomer);

b) LiAl&, THF, rt ,97% ;c) Ag&Og-Celite,benzene, reflux, 98% ;d) aq. KzCO3, rt, then 12, aq. KI, rt, 92% ; e) dihydropyran, p-TsOH, CH&, rt, 87% ; f ) 1,8-diazabicyclo[5.4.0]undec-7-ene, benzene, reflux, 98% ; g) p-TsOH, CH2Clz-MeOH (1: l), rt, 92% ;h) Jones oxidation,OOC, 63% ; i) (PhO),P(O)N3, r-BuOH, reflux, 79% ;j) CF$QH, CHzClz, rt, 98% ; k) NaOMe, MeOH. rt, 98% ; I) r-BuMQSiCl, imidazole, DMF,rt, 98% ;m) m-C1@-L&O3H, CHzC12,rt, 85% ;n) Bu4N?-, THF, rt, 38% ;0 ) AczO, pyridine, rt ; p) 5964. KzC03,THF, rt, 61%, 5% (regioisomer); q) (PhSe)z, NaB&, EtOH, reflux. 99%; r) 35% formalin, saturated aq.NazC03,THF, rt ;s) NaI04, THF, MeOH. rt. 57% ;t) NaA1(OCHzCHzOMehHz, toluene, reflux, then CH~=N%QI-, THF, rt, 44% ; u) Ref.

120. SCHEME 3

350

OSAMU HOSHINO

zation of 77 afforded iodo-y-lactone 78 in 82% yield, reductive cyclization of which, followed by treatment with (6-iodo-3,4-methylenedioxy)benzoyl chloride, produced the N-aroylenamido-y-lactone 79. The enamido-ylactone 79 was treated with benzyl alcohol and then butyllithium to produce, spontaneously, the benzyl p-epoxy enamido-carboxylate 80 in 93% yield. Radical-mediated cyclization of 80 with tributyltin hydride (Bu3SnH) in boiling benzene containing azobis(isobutyronitri1e)(AIBN) produced in 53% yield a key intermediate, the 2,3-p-epoxy-a-lycoran-7-one ester 81, having the lycorine ring system. Benzyl 2,3-p-epoxy-a-lycoran-7-one-3a~carboxylate (81) was converted into the thiazoline-2-thion-3-yl carboxylate 82. Oxirane ring opening, followed by elimination of a carboxyl group under chemically mediated radical reaction conditions gave successfully (+)-2-epi-l-deoxylycorin-7-one (83). Finally, 83 produced (+)-l-deoxylycorine (84)by the Mitsunobu reaction and successive reduction with lithium aluminum hydride (LiA1H4) in 56 (from benzoate) or 37% (from acetate) yield (two steps) (Scheme 4). On the other hand, phenylselenylation and dephenylselenylation of 81 provided the allylic alcohol 85, allylic rearrangement of which, with a mixture of acetic anhydride, acetic acid, and concentrated sulfuric acid, afforded a rearranged allylic acetate 86 in 28% yield (three steps). Epoxidation of 86 with dimethyldioxirane gave the corresponding epoxide 87. Catalytic hydrogenolysis of 87 followed by protolysis through a Pyrex filter in benzene containing acridine and t-butyl thioalcohol proceeded effectively to give 1O-acetyllycorin-7-one (88) in 45% yield (two steps). Acetylation of 88 gave 1,2-O-diacetyllycorine (89), the spectral data of which were identical to those reported for the racemate (221).Finally, (+)-lycorine (1)was obtained in 70% yield by reduction of 88 (Scheme 5). The syntheses of (+)-a-lycorane (92) and (+)-trianthine (97) using the retro-Cope elimination step (222), and of (+)-y-lycorane (100) using the palladium-mediated reaction (223), have been reported. When optically active 2-(cyclohex-2-enyl)ethylhydroxylamine (90) [derived from methyl 3-(3,4-methylenedioxy)phenylcyclohex-2-enylacetate] was heated at 140°C, the N-hydroxyhexahydroindoline 91 was obtained in 83% yield. Reductive cyclization of 91 then gave (+)-a-lycorane (92) (Scheme 6). This reaction has been applied to the optically active 5,6-O-isopropylidene-2-(cyclohex-2-enyl)ethylhydroxylamine (95) for the synthesis of (+)-trianthine (97). l-Acetoxy-l-[(3,4-methylenedioxy)phenyl]-5,6-Oisopropylidenecyclohex-2-ene (93) reacted with vinylmagnesium bromide in the presence of copper(1) bromide to give a vinyl compound, which was converted into cyclohexeneacetaldehyde 94. A starting ma-

4.

76

77

79

82

351

THE AMARKLLIDACEAE ALKALOIDS

78

81

(+)-1-Deoxylycorine (84)

83

Reugenrs and Conditions: a) (PhO)2PON3, DEAD, THF, O°C tort, 73%;b) 6M HCl, MeOH, rf, 95%;c) Iz, THF, H20, rt, 82%;d) PPh3,THF, reflux, W% ; e) 6-I-3,4-(CH20&HzCOCI, Et3n, CH2C12, 0 ° C to rt, 98% ;f) PhCH20H, THF, then normal BuLi, -78 to 25"C,93% ; g) Bu3SnH, AIBN, benzene, reflux, 5 3 8 ;h) 10%Pd-C, H2, EtOH, rt, 84% ; i) DCC, Nhydroxy-4-methylthiazolin-2-thione, 4pyrrolidinopyridine,CH2C12,86% ;j) DEAD, PPh3, PhC02H (73%)or AcOH (50%), THF ;k) LiAlH.,, THF, reflux, 76% (from benzoate), 73% (tiom acetate). SCHEME 4

terial95 was obtained by reductive hydroxyamination of 94. The cyclization reaction of 95 proceeded smoothly in degassed benzene at 80°C to afford Nhydroxyhexahydroindoline 96 in 96%yield, reduction of which with Raney nickel, followed by the modified F'ictet-Spengler reaction with Eschenmoser's salt (CH2=N+Me21-),gave (+)-trianthine (97) in 50% yield (two steps) by deprotection (Scheme 7).

352

OSAMU HOSHINO

&

a,b

( 0

0

0

0

89 Reagenrs and Condiriom : a) (PhSe)2,NaBh, EtOH, rt, 93%; b) NaI04, THF, H20, rt, 87% ; c) Ac20, AcOH, H2SO4, 50°C, 35% ;d) dimethyldioxirane,acetone, OOC, 46% ; e) 10%Pd-C, H2,

EtOH, R, 90% ;f) hu, Pyrex filter, acridine, f-BuSH, benzene, rt, 50% ; g) LiAlH4, THF, reflux, 70% ;h) Ac20, 4-dimethylaminopyridine,CHzC12, rt, quantitative ; i) Ref. 121. SCHEME 5

91

(+)-a-Lycorane (92)

Reagents and Conditions :a) degassed mesitylene, 140°C, 83% ;b) Raney Ni, wet Et20, then

CH2=NtMe21-,THF, 40 OC, 74-80%. SCHEME 6

4.

93

353

THE AMARYLLIDACEAE ALKALOIDS

95

94

%

(+)-Trimthine (97)

Reagents and Conditions : a) CHz=CHMgBr, CuBr, Me#, 95% ; b) 9-BBN, H202, then Swern

oxidation ;c) NHzOH, then NaBCNH3, aq. MeOH, pH 3.0,82% ; d) degassed benzene, reflux, 93% ;e) Raney Ni, then CHz=N+MeI-, 'IFIF. 89% ;f) AcCI, MeOH, 56%.

SCHEME7

Intramolecular cyclization of optically active N-[(6-bromo-3,4-methylenedioxy)phenylmethyl]cyclohex-2-enylacetamide (98) (prepared from 1S,4R-dibenzoyloxycyclohex-2-ene)under palladium-mediated reaction (99) conditions afforded 4-methoxycarbonyl-l,2-dehydro-y-lycoran-5-one in 58% yield, carboxylation of which, followed by stepwise reduction, afforded (+)-y-lycorane (100) (Scheme 8). The synthesis of (+)-y-lycorane (loo), or (5)-a-lycorane (92) and ( 2 ) y-lycorane (loo), has been achieved through arylation using the modified Suzuki reaction (124) (Scheme 9) or the cross Grignard coupling reaction (125) (Scheme 10). In the former case (124),methyl dibromo-bicyclo[3.1.0]2-(hexy1)ethylcarbamate (101) (prepared from 3-acetoxycyclopentene) underwent cation-n-cyclization with silver acetate in 2,2,2-trifluoroethanoI (CF3CH20H)containing potassium carbonate to afford a starting material 7-bromo-N-methoxycarbonyl-A6~7-tetrahydroindoline (102) in 87% yield. The cross coupling reaction of 102 with (3,4-methylenedioxy)benzeneboronic acid under the modified Suzuki reaction conditions produced 7-(3,4-methylenedioxy)phenyl-Af'~7-tetrahydroindoline (103) in 87% yield.

354

OSAMU HOSHINO

98

99

Reagents and Condirions : a) Pd(OAc)z, dppb, NaH,

(+)-y-Lycorane (100)

DMF,50°C then i-Pr2EtN,100"C,58% ;

b) NaCl, DMSO-H20, 160°C; c) Pd-C, H2, MeOH ; d) LiAIH,, THF, reflux, 23% (3 steps). SCHEME 8

Reduction of 103, followed by cyclization, produced (+)-y-lycoran-7-one (104), which was reduced in the usual manner to lead to (2)-y-lycorane (100)(Scheme 9). In the latter case (125), palladium-catalyzed intramolecular 1,4-chloroamidation of N-benzyloxycarbonyl-2-(cyclohexa-2,4-dienyl)ethylamine (105) (derived from methyl cyclohexa-2,4-dienylacetate)proceeded regioand stereoselectively to produce N-benzyloxycarbonyl-5-chloro-A6~7tetrahydroindoline (106) in 95% yield. The cross Grignard coupling reaction of 106 with (3,4-methylenedioxy)phenylmagnesiumbromide in the presence of lithium copper( 11) chloride (Li2CuC14)in THF afforded 7-

101

I;~Hco~M~

102

103

(f)-y-Lycorane (100)

104

Reagenrs and Conditions : a) AgOAc, CF~CH2OH,K2CO3,18OC, 87% ;b) 3,4-(CH2O,)W3B(OH),, Pd(PPh&, aq. Na2C03, benzene, EtOH. 8OoC, 87%; c) 10%Pd-C, H2, 18°C. 95% ; d) NC13,

8OoC, 79% ;e) LMW,

THF,65°C. 84%. SCHEME 9

4.

THE AMARYLLIDACEAE ALKALOIDS

355

[(3,4-methylenedioxy)phenyl]-A~6-tetrahydroindoline(107) in 77% yield, which was converted into (2)-a-lycorane (92) or (+)-y-lycorane (loo), respectively, through 108 or 109 by changing the order of the procedure for reduction and cyclization (Scheme 10). Synthesis of (?)-a-lycorane (92) using radical-mediated cyclization of N-bromoaryl-3-hydroxy-3,4,S,6-tetrahydro-lH-indol-2-one has been carried out (226). 1-[(6-Bromo-3,4-methylenedioxy)phen ylmethyl]-3cyclohexylamino-A3~3a~~7~7a~-dihydroindolin-2-one (111) (derived from 3-cyclohexylaminodihydroindolin-~2-one (110) was transformed to 1-[(6bromo-3,4-methylenedioxy)phenylmethyl]-3-hydroxy-A7 (7a)-tetrahydroindolin-Zone (112)by hydrolysis and reduction. Radical-mediated cyclization of 112 with Bu3SnH in boiling benzene containing AIBN gave ( 2 ) hydroxy-a-lycoran-5-one (113)in 79% yield. Dehydroxylation of 113 under radical reaction conditions gave (+)-a-lycoran-5-one, which was reduced with LiAlH4 in boiling THF to afford (+)-a-lycorane (92)(Scheme 11). Cobalt-mediated [2+2+2] cycloaddition of an alkyne to the double bond of an enamide has been found to give spontaneously the lycorane ring system (227). Thus, a formal total synthesis of (+)-y-lycorane (100) has been achieved by this methodology. Also, (+)-y-lycorane (100)has been synthesized starting with pyrrole (228) or homophthalimide (229).

(*)-yLycorane (100)

109

(*)-a-Lycorane (92)

Reugenrs and Conditions : a) Pd(0Ach (5 mo1%), benzoquinone, LEI. acetone-AcOH( 4 1 ) . 95%; b) 3,4-(CHz01)C&MgBr, Li2cUCl4. THF, 77% ;c) P Q . H2. EtOH, rt, 95% ;d) POCI3 (neat), 7OOC, 72% ;e) L A W , THF,7OOC. 92%;9 POC13 (neat), 75OC. 71% ; g) POz,Hz (6.5 kg/cm2), EtOH, rt, 95%;h) LiAM4, THF, 65'C. 85%. SCHEME10

356

OSAMU HOSHINO

113

(It)-a-Lycorane(92)

Reagents and Conditions : a)

6-Br-3,4-(CH2O2)C,+I2CH2Br, NaH,DMF, rt, 74%;b) (C02H)2, THF-HzO, reflux, 70%; f) N a B h , MeOH, rt, 46% ; d) BqSnH, AIBN, benzene, reflux ;e) PhOCSCl, DMAP, pyridine, rt, 85% ; f) LiAW, THF, reflux, 51% (3 steps). SCHEME 11

The C-aromatic pyrrolophenanthridine-type alkaloids are members of the Amaryllidaceae alkaloid group. They have attracted the attention of chemists and pharmacologists because of their significant pharmacological properties (130). Hence, numerous studies directed toward the synthesis of these alkaloids have been conducted. During the past decade, several reports involving mainly two methodologies have appeared; one is based on the construction of ring B, whereas the other concerns the construction of ring C. The cyclization of 1-(6-iodo-3,4-methylenedioxy)phenylmethyl-4,5,6trihydro-1H-indol-2-one (114) (prepared from 110) under palladiummediated reaction conditions afforded pyrrolophenanthridone 115 in 71% yield. Hydrolysis of 115 gave the C-aromatic product anhydrolycorine-4,5dione (116),reduction of which, followed by elimination of the hydroxyl group, produced 4,5-dehydro-anhydrolycorine(43)(126b) (Scheme 12). The reaction of an o-methoxyaryloxazoline with an arylmagnesium halide has been known to cause replacement of a methoxy group with an aryl

4.

THE AMARYLLIDACEAE ALKALOIDS

357

a

110

114

115

0'

0

.

116

3,4-Dehydroanhydrolycorine(43)

Reagents and Conditions :a) 6-I-3.4-(CHz~)C&CHzCl, NaH. DMF, rt, 76%; b) Pd(OAc)z, Bu4N+ CI'*H@, KOAc, DMF,loOOC, 71% ;C) (C02H)2, THF-H20, reflux. 80% ;d) DDQ. benzene, reflux. 21%;e) LiAU& THF,reflux,42%;9 MeS@Cl, Et3N, CH2C12,rt, 9%. SCHEME 12

group, leading to a biaryl. This methodology has been developed for the synthesis of pyrrolophenanthridone-type alkaloids (131) (Scheme 13). The reaction of 2-[(6-methoxy-3,4-methylenedioxy)phenyl]oxazoline123 with the magnesium derivative of N-benzyl-7-bromoindoline (117)in tetrabromodifluoroethane gave the corresponding 7-arylindoline 118 in 68% yield. Hydrolysis and successive cyclization of 118 produced anhydrolycorin-7one (119), which was previously (232) transformed to hippadine (44) by oxidation with 2,3-dichloro-4,5-dicyanobenzoquinone(DDQ). Similarly, the intermediate 7-arylindoline 120 (prepared from 2-aryloxazoline 124) gave kalbretorine (61)through 4,5dihydrokalbretorine (121).The intermediate 7-arylindoline 122, which was synthesized in 73% yield by the reaction of 2-[(2,4,5-trimethoxy)phenyl]oxazoline125 with the magnesium derivative of 117, led to oxoassoanine (46) in a manner similar to that noted previously. Reduction of 46 produced pratosine (52) in 55% yield. Coupling of N-[(2-iodo-4,5;-dimethoxy)benzylidene]cyclohexylamine (126)with 7-[(N-t-butoxycarbonyl (Boc)]indolinyl)copper in ether at -45 to 20°C gave, on treatment with '1 M hydrochloric acid (HCl), N-Boc-7-[(6-

358

OSAMU HOSHINO

Me

(2 steps)

122

0

Oxoassoanine (46)

73% O

0

Ratosine (52)

Reagents and Codifions : a) Mg, BrF2CCF2Br, nflux, then 123.68% ;b) lO%aq. H2S04, EtOH, heat ; c) Pd-C,H2, MeOH, z t ;d) DDQ ;e) Mg, BrFzCCFzBr, nflux, then 124.78% ;f ) Mg. BrF2CCF2Br, reflux, then 125.73%;g) Ref. 132. SCHEME 13

formyl-3,4-dimethoxy)phenyl]indoline(127) in 65% yield. N-Deprotection and concomitant cyclization of the 7-(6-formylaryl)indoline(127) with anhydrous hydrogen chloride in chloroform gave vasconine (50) in quantita-

4. THE AMARYLLIDACEAE

359

ALKALOIDS

tive yield, reduction of which with sodium borohydride (NaBH4) afforded assoanine (45) in 93% yield. On the other hand, oxidation of 50 with alkaline aqueous potassium perrnanganate gave oxoassoanine (46) (133) (Scheme 14). ) ungeremine (48) was performed by The synthesis of hippadine (4and a combination of the directed ortho metallation and the modified Suzuki cross coupling reactions (134) (Scheme 15). (7-Bromo-5-mesy1oxy)indoline reacted with (6-formyl-3,4-methylenedioxy)benzeneboronic acid under the modified Suzuki reaction conditions to give the pyrrolophenanthridone ring system 128, which was reduced with sodium bis(2-methoxyethoxy)aluminum hydride (SMEAH) in boiling toluene to produce ungeremine (48) in 54% yield. Also, starting with 7-iodoindoline, a similar reaction sequence afforded anhydrolycorin-7-one (119),which was transformed to hippadine (44)in 90% yield by oxidation with DDQ. Hippadine (a), ungeremine (48)) and anhydrolycorin-7-one (119) were also synthesized by the radical-mediated cyclization approach. Namely, cyclization of 7-bromo-1-[(3,4~~methylenedioxy)benzoyl]-5-nitroindoline (129) in dimethyl sulfoxide (DMSO) in the presence of benzyltriethylammonium chloride (BTAC) at 155°C gave 2-nitroanhydrolycorin-7-one (130), and a regioisomer, in 60% yield (product ratio of 1:1). Catalytic hydro(131) in good yield. genation of 130 led to 2-amino-anhydrolycorin-7-one

n ' 6 OMe O M e

-

126

Me0

-

MeO&

a

b

OHC

127

MeO& Me0

Me0

C1Vasconine (SO)

/ Id Me0

0

Assoanine (45)

Oxoassoanine(46)

Reagenrs and Condirions :a) N-Boc-indoline,s-BuLi, TEMEDA, EtzO. -45OC, CuI. P(OEt)3,rt, then 1M HCI. 65%;b) gaseous HCI, CHC13, quantitative ;c) NaBH.+ EtOH, rt, 93%; d) KMn04, 3M NaOH. CH2C12.2OoC, 84%. SCHEME 14

360

Br

OSAMU HOSHINO

- <"

-("

a

C

0

0 128

I

a

L

0

Ungeremine (48)

< 0 0 " & 0 A ? & Anhydrolycorin-7-one (119)

Hippadine (44)

Reugents and Conditions : a) ~ ~ e 3 , 4 - ( ~ ~ o ~ ) C k H , B ( O Pd(PPh3)4. H ) z , NazC03. DME,reflux.

(4049%) ;b) NaAl(OCHZCH~0Me)~Hz. toluene, reflux. 54%;c) DDQ,dioxanc, reflux, 90%. SCHEME 15

Transformation of 131 to hippadine (a), ungeremine (a), and anhydrolycorin-7-one (119) was accomplished in the usual manner (135)(Scheme 16). The intramolecular Diels-Alder reaction of 5-(3-butynyl)-3H-pyran[2,3c]isoquinoline-3,6-dione (132) in boiling benzene afforded a pyrrolophenanthridone, which yielded 2-methoxy-anhydrolycorin-7-one (136). Hippadine (44) was synthesized by means of l-aza-l'-oxa[3.3]sigmatropic rearrangement of N-(2-methoxycarbonylvinyloxy)-8,9-methylenedioxyphenanthridin-6-one (133)(137) or by palladium-mediated intramolecular cyclization of 7-bromo-N-[(6-bromo-3,4-methylenedioxy)benzoyl]indoline (134)(138) (Fig. 10). C. BIOLOGICAL ACTIVITY Lycorine (1) and pseudolycorine (12) were evaluated to determine their in vitro inhibitory properties against the RNA-containing flaviviruses ( Japanese encephalitis, yellow fever, and dengue type 4 viruses); bunyaviruses (Punta Toro, sandfly fever-Sicilian, and Rift Valley fever); the alphavirus (family Togaviridae); Venezuelan equine encephalomyelitis viruses; the lentivirus; HIV-1; and the DNA-containing vaccinia virus. Antiviral activity was observed against the flaviviruses tested, and to a slightly lesser degree against the bunyaviruses. Also, 1 and l2 showed inhibitory activity against Punta Tor0 and Rift Valley fever viruses, but with low selectivity (139).

4. THE

AMARYLLIDACEAE ALKALOIDS

361

'& (&

('0

0

Anhydrolycorin-7-one (119)

d

'0

0

Hippadine (44)

0

131

(& 0 o

Ungeremine (48) Reugenrs and Conditions : a) BudN'Cl-, K2CO3, M%SO. 155"C, 60% (1 : 1); b) Pd-C, H2, CF3CO2H. 25'C. 93% ; c) aq H3PO4, Cu20, CICH2CH2C1, 7OoC, 50% ; d) DDQ,benzene, 100°C, 76% ;e) ONOS03H. aq. H2SO4, NaBFs, OOC, 76%; f) CF3CO2H. reflux. 40% ;g) NaH, Cd-ISCH2Br,DMF, 7OoC,51% ;h) LiAM4, THF. reflux, 95% ;i) Pd-C. H2, EtOH, 7OoC, then H202, AcOH, Mn02 (HzO),, 25OC, 80% (2 steps).

SCHEME16

132

133 FIG.10

134

362

OSAMU HOSHINO

The pharmacological effects of lycorine (1) have been studied using the guinea pig; it caused concentration-dependent relaxation of the isolated epinephrine-precontacted pulmonary artery. In this study, its effects on heart were suggested to be mediated by the stimulation of P-adrenergic receptors (102).

111. Crinine-Type Alkaloids

A. Isolation and Structural Elucidation Since 1987, the isolation and characterization of several new crinine-type alkaloids have been reported. The structures of the representative alkaloids isolated are depicted in Figs. 11 and 12. It is noteworthy that oxocrinine (138), an intermediate in the biosynthesis of crinine (135)and related compounds in Amaryllidaceae alkaloids, was isolated for the first time from the bulbs of Crinum umericanum (14). Its structure was elucidated by spectroscopic evidence, including 'H-coupled I3CNMR experiments, and finally confirmed by comparison with a sample prepared from crinine (135) by oxidation. The extract of the bulbs of Pancratium maritimum grown in Turkey has been found to contain two new chine-type alkaloids, 3& 1la-dihydroxy-1,Zdehydrocrinane (141)and 8-hydroxy-9-methoxycrinine (172)(98), together with the lycorine-type alkaloids (95). A more hydroxylated crinine-type alkaloid, crinisin (171), was found in the bulbs of C.asiaticurn var. sinicum, accompanied by lycorine (l), crinine (135), and powelline (163) (21). 11-Hydroxyvittatine (152), which hitherto had only been found in plants belonging to the genus Sternbergia (102), has been isolated from the bulbs of Hippeastrum hybrids (42). The structure determination was performed by a comprehensive NMR study of the alkaloids involving 2D techniques such as HOHAHA, ROESY, and HMBC for 'H and '3C assignments, which enabled structural elucidation to be facilitated. Vittatine (147)and 11-hydroxyvittatine (152) were found in the extract of the dried bulbs of Hippeastrum puniceum (43). Hamayne (153), 3-0-acetylhamayne (154), crinamine (156), ambelline (161),and a new alkaloid named josephine (144),together with the lycorinetype alkaloid sternbergine (16), were isolated from the bulbs of Brunsvigia josephinae (11). The mass spectrum of 144 showed the molecular peak at m/z 331, and prominent fragments at m/z 289, 242, and 202 that are characteristic of a 1,Zdisubstituted crinane alkaloid (140).Its spectroscopic ('H and 13CNMR) evidence established the structure as 144. A new alka-

4.

W i n e (Crinidine) (135) R=R~=H 0-Acetylcrinine (136) R = AC, R' = H 6a-Hydroxycrinine (137) R = H. R' = a-OH

363

THE AMARYLLIDACEAE ALKALOIDS

Oxocrinine (138)

Buphanisine (139) R=H 6a-Hydroxybuphanisine (140) R =a-OH

3p.1 la-Dihydroxy-1.2dehydrocrinane (141)

R O&R .

H 0 . A

Flexinine (142) R=OH Augustine (143) R = OMe

Josephinine (1.44) R = P-OAC Amabiline (145) R = a-OH

Alkaloid 13 (151)

, l 'OH

0

Vittatine (147) [(+)-Crinine]

R=H (+)-Buphanisine (148) R=Me

OH

Epi-vittatine (149) R=H Epi-buphanisine(150) R=Me $

Elwesine (146) @ih ydrocrinine)

0 OH

Albiflomanthine (159)

..

ll-Hy&oylvitattine (152) R=a-OH,R'=H Hamayne (153) R = a-OH, R' =H 3-0-Acetylhamayne (154) R = a-OAc, R'= H Haemanthamine (155) R = p-OMe. R' = H

Crinamine (156) R = a-OMt. ' R'=H Haemanthidine (157) R = POMe, 6-Hydro~yR' = OH crinamine (158)

tT=%iMe*

FIG.11

loid, albiflomanthine (159), was found in the bulbs of Haemanthus afbijlos (36). The molecular formula was measured by high-resolution mass spectrometry as CI7Hl9NO5,and the structure was determined as 159 on the basis of spectroscopic (UV and 'H, and 13CNMR) analyses. Interestingly, it possesses the unusual feature: of an oxygen substituent at C-4.

364

OSAMU HOSHINO

R

HO

.OMe

Q 0

0 OMe

OM9

Buphandrine (160) R=H Ambelline (161) R=OH 1I-O-A~etylambelline (162) R = OAC

Powelline (163) R = OH, R' = H 3-O- Acetylpowelline (164)

Crinafoline (166)

powelline (165) R=R'=OH

Bumsbelliie (168)

Me0

Crinafolidine (167)

OH

Crinamidine (169) R=H Undulalinc (170) R=Me

H

Me0 HO OM9

8-HY&OXY-9methoxycrinine (172)

Crinisin (171)

Siculine (173)

H Me0

Me0

HO 8-0-&methylmaritidine (174) R =H, R' = ~e 9-O-Demeth ylmaritidine (175) R=MC,R~=H

Cantabricine(176)

R

Narcidine (177) R

m O M e

Ms.O&, MeO

HO

R

Papyramine (180) R = WOH 6-Epi-papyramine(181) R = &OH 6kO-M~thylpapyramine (182) R = POMe FIG.12

Maritinamine(183) R = p-OH Epi-maritinamine (184) R = a-OH

Maritidine (178) R=H O-Methylmaritidine R = M e (179)

4.

THE AMARYLLIDACEAE ALKALOIDS

365

New crinine-type alkaloids, as well as several known Amaryllidaceae alkaloids, were isolated from two Sternbergiu species of Turkish origin. They are maritinamine (183) and epi-maritinamine (184) (from S. lutea), and (+)-buphanisine (148) and siculine (173) (from S. sicuh) (203).The structure determination of the new alkaloids was performed on the basis of an extensive analysis of 'H NMR spectral data for the known crininetype alkaloids. The spectral data for (+)-buphanisine (148) were in good agreement with those for (-)-buphanisine (139), except for its positive specific rotation. Indeed, the CD curve of (+)-buphanisine was the opposite of that described for (-)-buphanisine in the literature (142).Therefore, (+)-buphanisine was established to be a new alkaloid, enantiomeric with the known (-)-buphanisine. Furthermore, all of the Sternbergiu alkaloids, new as well as known, possess the identical absolute configuration, with the ethano bridge below the mean plane of the molecule.

B. SYNTHETIC STUDIES Since the previously published review (8),some interesting methods for the synthesis of crinine-type alkaloids have appeared. The 2-aza-ally1 anion cyclization method gave (2)-crinine (135) and ( 2 ) epi-crinine (188) ( 1 4 2 ~ Treatment ). of tributylstannylmethylimine 186 [prepared from 6-[(3,4-methylenedioxy)phenyl]-6-methylenehex-4-enal(185) and tributylsannylmethylamine] with butyllithium in THF at -78°C led to formation of the 2-aza-ally1 anion, whose concomitant intramolecular cycloaddition led to 3-0-methoxymethylnormesembrene(187) in 80%yield. The Pictet-Spengler reaction of 187 with formalin using 6 M HC1 in methanol (MeOH) afforded (+)-6-epi-crinine (188). The 6-hydroxy group was epimerized by treatment of the corresponding mesate with cesium acetate to furnish on hydrolysis (+)-crinine (135) (Scheme 17). This methodology was expanded to the synthesis of (-)-amabiline (145)(242c). Namely, 2-aza-allylstannane 189 (derived from 2S,3S-Oisopropylidene-y-butyrolactone) was exposed to butyllithium in THF at -78°C to provide 3a-(3,4-methylenedioxy)phenylhexahydroindoline(190) along with a diastereomer in 74% yield (a 5 : 1 mixture of two diastereomers). The Pictet-Spengler cyclization of 190, followed by acid treatment, afforded (- )-amabiline (145), confirming the absolute stereochemistry of the natural product (Scheme 17). The synthesis of (+)-oxomaritidine (192) and a formal synthesis of (+)-marhidine (178) were achieved by intramolecular oxidative coupling of phenol derivatives using a hypervalent iodine reagent as a key step (2 43). 2-[(4-H ydrox y )phen yl] -hi-[(3,4-dimethoxy)phenyl]4-trifluoroacetylethylamine was treated with phenyliodonium bis(trifluor0acetate) in

366

OSAMU HOSHINO

MOMOc A SArn B u + M O M O e *

f

MOMO

185

186

Ar = 3,4-(CH2O2)%H3 ; MOM = MeOCH2

187

(f)-Epi-crinine (188)

(f)-Crinine (135)

Me

189

190

(-)-Amabiline (145)

Reagents and Conditions : a) Bu3SnCH2NH2, MS4A (50wt%), EbO, rt, 100%; b) BuLi (2.1 equiv.), THF, -78OC. 80%;c) 37% formalin (32 equiv.), MeOH, then 6M HCl. 5OoC, 75% ;d) (MeSO2)20,

Et20, THF, OOC, then CsOAc, rt ; e) KzC03,MeOH. 72% (2 steps) ;F) BuLi (1.9 equiv), THF, -78°C 74% (5 : 1mixture of two diastereomers); g) Me2N+=CH21-,MeCN, reflux ; h) HCl, MeOH, 92% (2 steps). SCHEME 17

CF3-CH20H at -40°C to produce a spirocyclohexadienone 191 in 61% yield, which was converted into (5)-oxomaritidine (192). Application of this methodology to methyl (R)-N-trifluoroacetyl-N-[(3,4-dimethoxy)phenyll-4-hydroxyphenylalanategave the optically active spirocyclodienone 193 in 64% yield, which was previously (144) transformed to (+)-maritidine (178). Hence, this result constitutes a formal synthesis of (+)-maritidine (Scheme 18). Condensation of 2-chloro-A'-pyrrolidinium chloride (prepared in situ from N-benzylpyrrolidin-2-one194 and phosgene) with t-butyl 3-oxo-4pentenoate, followed by acid treatment under ultrasound irradiation condi-

4.

367

THE AMARYLLIDACEAE ALKALOIDS

%e

OH

0

I / OMe

OMe

b

H

~

Me0

CF&O

CF3CO'

191

(f)-Oxomaritidine (192)

OH

OMe

..

CFsCO

CF3CO'

(+)-Maritidhe (178)

193

Reagents and Codifions : a) PhI(OCmCF3)2, CF3CH2OH, -40 'C, 191 (61%), 193 (64%) ; b) K2C03, MeOH-H20 ; c) Ref. 144. SCHEME 18

tions, afforded N-benzyl-A'-mesembren-6-one (195) in 29% yield (three steps). Reduction of 195 with sodium in liquid ammonia gave the known hexahydroindolin-6-one 196, which was earlier (14.5) transformed to (?)dihydromaritidine (197) (146) (Scheme 19). OMe

194

1%

195

Bn = GH5CH2

(f)-Dihydromaritidine (197)

Reagents and Conditions : a) COC12; b:l CH2=CHCOCH2C02r-Bu,Et,N, CH2C12,reflux ;

c) CF3C02H, (3 equiv.), ultrasound, 29%(3 steps) ;d) Na, liq. NH3,76% ;e) Ref. 145. SCHEME 19

368

OSAMU HOSHINO

Starting with 6-allylcyclohexanones 198 and 199, the synthesis of (?)dihydromaritidine (197), (+)-6-epi-dihydromaritidine (202), and ( 2 ) elwesine (146) and (+)-6-epi-elwesine (203) through 200 and 201, respectively, has appeared (147). Also, a formal synthesis of (+)-elwesine (146) by a protocol similar to that noted for (2)-mesembrine (377) has been carried out (Z48)(Fig. 13). C. BIOLOGICAL ACTIVITY

The ethanol extract of the bulbs of Crinum amabile on preliminary biological evaluation was shown to possess cytotoxic and antimalarial properties (13).Although all the isolated alkaloids showed antimalarial activity against two strains of Plasmodium faleiparum, a new crinine-type alkaloid, amabiline (145), was the most effective (lO,OOOX), and augustine (143) the least active (140X). All were significantly more active than the commercial antimalarial drug chloroquine (1.3X).

RO&f2

I

0 RO

RO

R=Me 198 R+R=CH2 199

Bn = C&sCH2

R=Me 200 R+R=CH2 201

RO

RO

(f)-Epi-dihydromaritidine (202) R=Me (*)-Epielwesine (203) R+R=CH2

(f)-Dihydromaritidine (197) R=Me (*)-Elwesine (146) R+R=CH2 FIG.13

4.

THE AMARYLLIDACEAE ALKALOIDS

369

IV. Narciclasine (Lycoricidine)-TypeAlkaloids

A. Isolation and Structural Elucidation 7-Deoxynarciclasine (204),and narciclasine (205),7-deoxypancratistatin (210),and pancratistatin (211)were found in the resting bulbs of Haemanthus kalbreyeii (37). Also, narciclasine (205),7-deoxypancratistatin (210), and pancratistatin (211)have been isolated from the bulbs of Hymenocallis littoralis (45).The glucosidal alkaloids, pancratiside (212)(37),kalbreclasine (206) (108),and 4-O-~-~-glucopyranosylnarciclasine (207) (96), were obtained from resting bulbs of Haemanthus kalbreyeii, the fresh mature seeds of Zephyranthesflava, and the bulbs of Pancratium maritimum, respectively. Elucidation of the structures was performed by spectroscopic and chemical methods. 7-Deoxy-trans-dihydronarciclasine(208)has been isolated from the bulbs of Hymenocallis caribrzea, H. latifolia, and H. littoralis (45). Also, trans-dihydronarciclasine (209) was found in the fresh ground bulbs of Zephyranthes candida (directed by results of a bioassay employing the P388 lymphocylic leukemia) by acetylation (106) (Fig. 14). Plant alkaloids are frequently considered to be protective agents for their hosts; their toxicity and antifeeding properties present a directing environment to predators. An interesting investigation regarding them has been reported (25). One specialized herbivore, Polytela gloriosa Fab (Noctuidae), a smoky-grey moth, utilizes Amaryllidaceae plants, which are avoided by other insects. A remarkable association of alkaloid metabolism by P. gloriosa adapted to a number of Amaryllidaceae species, e.g., Amaryllis, Crinum, and Pancratium, has been noted. The larvae of this insect were found to store large amounts [ca. 0.5-1% (fresh weight)] of the common pyrrolo- and ethano-phenanthridine alkaloids, such as lycorine (l), crinine (135) (and their equivalents), and haemanthamine (155), from the flowers and leaves of Crinum latifolium L. A new isocarbostyri1-Nacetylaminoglucoside conjugate named telastaside (213)was isolated from the insect (P. gloriosa). The structure of the alkaloid was characterized by spectroscopic evidence and chemical transformation. It was treated with hesperidinase in sodium acetate-AcOH buffer (pH 5.1) at 30°C to afford 7-deoxypancratistatin (210)and N-acetylglucosamine, respectively. On the other hand, it was heated with 4 M HCl in 30% aqueous ethanol at 100°C to produce 4-hydroxyphenanthridone (431)and D-glucosamine hydrochloride. A strikingly common association of the alkaloid in the secondary metabolism of the host and the feeder species, during stress, has been discerned. The alkaloid was not present in any part of healthy (uninfested) C. latifolium, nor was it detected in the moth when collected from the natural habitat (earthen cocoon in the rhizosphere of C. latifolium).

370

OSAMU HOSHINO

OH

R

OH

OH

0

7-DeOXYnarciclasine (204) (Lycoricidine)

Narciclasine (205) R = CX-OH Kalbreclasine (206) R = bD-Glucosyl

4-O-P-D-Gl~cosylnarciclasinc (207) R = ~D-Glucosyl

OR

OH

)&Io: NH

R

O

7-hOxytrans-dihydronarciclasine (208) R=H Trans-dihydronatciclasine (209) R-OH

NH

'0

A1

0

7-Deoxypancratistatin(210) R=R~=H Pancratistatin (211) R = H, R*= OH Pancratiside (212) R = P-D-Glucosyl, R' = OH

Telastaside (213)

FIG.14

B. SYNTHETIC STUDIES Regarding the synthesis of the narciclasine (1ycoricidine)-type alkaloids, an important strategic element is how to construct the functionalized ring C in these alkaloids. Therefore, extensive efforts to explore a new method for preparing a key intermediate have been made. Among these extensive studies, the first total synthesis of (+)-pancratistatin (211) has been reported (149) (Scheme 20). Tricyclic 1,2dihydroxy-Slactone 214 was converted into vicinal acetoxy-bromo-6lactone 215 in 88% yield along with the regioisomers. Osmium tetroxide oxidation of 215, followed by introduction of a double bond and selective protection of the hydroxyl groups, gave the corresponding allylic alcohol

4.

Br

OH

214

216

L

371

THE AMAKYLLIDACEAE ALKALOIDS

Bn = C&I5CHz

215

217

219

218

(i)-Pancratistatin(211)

Reagents and Condirions :a) 2-acetoxyisobutyryl bromide, MeCN, rt, 88% ;b) Os04(cat.), NMO, CH2CI2, THF, rt, 88% ;c) (Bu3Snh0, MS3A, toluene, reflux ;d) 4 M e m C H 2 B r . B u ~ ~ I - , a&h,rt, 75 % ;g) Zn,~ Z C ~ Z . 80°C, 84%;e) AgzO, C5H5CH2Br, DMF,rt, 95% ;r) DDQ,4. HzO, AcOH, reflux, 81% ;h) NaH, C13CCN,THF, 0°C to rt, 74%;i) pyrolysis at 100-105°C (0.05-O.lmmHg), 56% ;j) OsOd (cat.), NMO, THF,rt, 75% ;k) KzCO3, dry MeOH-CHzC12 (5 ; 21, reflux, 82% ; I) Pd(OH)2-C, Hz,EtOAc, 90%. SCHEME 20

216 by skillfully stereocontrolled reactions. Following these reactions, the Claisen rearrangement of imino ether 217 (prepared by the reaction of 216 with trichloroacetonitrile in the presence of NaH at 100-105°C under reduced pressure) proceeded effectively to afford the amide 218 in 56% yield, 1,2-cis-dihydroxylationof which, followed by hydrolysis with base, produced 2,7-O-dibenzylpancratistatin(219)by way of an amino acid. Finally, (+)-pancratistatin (211)was synthesized in 90% yield by debenzylation using catalytic hydrogenation.

372

OSAMU HOSHINO

Following this report, a total synthesis of optically active (+)-lycoricidine (204) (150) and (+ )-Zepi-lycoricidine (224) (1506) starting from D-glucose

was described in the literature (Scheme 21). In this case, the modified Heck reaction of amide 220 bearing fully protected functional groups, which was prepared from SS,6S-bis(methoxymethoxy)-4-(4R)-azidocyclohex-2-enone, is a key step. The protected amide 220 underwent intramolecular cyclization with palladium acetate in the presence of thallium(1) acetate and 1,2-bis(diphenylphosphono)ethane OMPM

0

a-c,b

OMOM A3

NMPM

0 0

OMPM

-

0

220

0

221

MPM = 4-MeOC&CH2 MOM = MeOCH2

OAC OH

OH

(100%)

0 0

222

221

(+)-Lycoricidine(204)

223

(+)-2-epi-Lycoricidine(224)

Reogenrs and Conditions :a) NaB%, &C13*7H20, MeOH, OOC, 86% ;b) 4-MeOCaCH2C1, NaH, DMF, rt ;c) LiAW, Et20, OOC. then 6-Br-3,4-(CH2O&J-I3CQH,(EtO)2P(O)CN,Et3N, DMF,O°C, 89%;d) Pd(OAc)? (20 mol%),TlOAc (2 mol%),DIPHOS (40mol %). DMF,140°C, 68% ;e) DDQ. CH2U2-H20(18 : 1). 0°C ;r) P h W H , PPh3, DEAC. THF, rt. 78% ;g) NaOMe, MeOH-THF (5 : 1). rt, 99% ;h) 1N HU, THF-fi20 (1 : 1). 50°C, then AczO, pyrkline, rt, 5 1% ; i) CF3CO2H-CHCl3(1 : 1). It. SCHEME21

4.

373

THE AMARYLLIDACEAE ALKALOIDS

(DIPHOS) in dimethylformamide (DMF) at 140°C to give protected 2-epilycoricidine 221 in 68% yield. Selective deprotection of 221 followed by inversion of a hydroxy group at the 2-position using the Mitsunobu reaction afforded 0-triacetyllycoricidine (222). Hydrolysis of 222 with base led to (+)-lycoricidine (204). On the other hand, 221 was transformed to 2-epilycoricidine (224) through the triacetate 223 by stepwise deprotection. As interesting synthetic approaches toward lycoricidine, starting with optically active tribenzyloxy-5-hexenal or L-arabinose, protected versions 226 (252) or 228 (252) of (+)-lycoricidine have been synthesized through 225 or 227 (Fig. 15). Recently, oxidation of a halobenzene using a microbiological procedure was found to give optically active 3-halo-1,2-cis-dihydroxycyclohexa-3,5diene in good yield. This compound has received the attention of chemists for constructing ring C in the narciclasine-type alkaloids (253). An example is as follows. After protection as a silyl ether, amidation of benzyl N-(5,6-O-isopropylidene-4-hydroxycyclohex-2-enyl)carbamate229 (prepared from 3-bromo-lS, 2S-(3-isopropylidenecyclohexa-3,5-diene) with (6-bromo-3,4-methylenedioxy)benzoylchloride gave the protected N benzyloxycarbonyl-N-(cyclohex-~2-enyl)benzamide230. A modified Heck reaction of 230 in anisole produced the protected lycoricidine 231 in 27% yield (two steps) by N-detosylation. Acid treatment of 231 provided (+)-lycoricidine (204) in 85% yield (Scheme 22).

OBn

p n O-OBn

Bn = C&CH2

225

226

OMe

OM9

0 221

Ts = 4-MeCASO2 FIG.15

0

228

374

OSAMU HOSHINO

OSiMed-Pr

S)SiMe2CPr

- < “d G

0

-

NH

-0

0

0 231

(+)-Lycoricidine (204)

Reagenrs and Conditions :a) i-PrMe2SiC1. imidazole ;b) BuLi, THF, -78OC. then 6-Br-3,4-(a2%)-

C!&COCl; c) Pd(OAc)z, TIOAc, DIPHOS, anisole, 27%; d) Pd-C, cyclohexene, EtOH, 99%;e) C F 3 Q H . OOC. 85%. SCHEME 22

A sequence of reactions similar to those noted previously has been applied to 1,2-cis-dihydroxycyclohexa-3,5-diene, constituting a formal synthesis of (+-)-lycoricidine (204)(154). Since the isolation and discovery of the significant biological activity of 7-deoxypancratistatin (210) and pancratistatin (211), which have more oxygenated functional substituents than lycoricidine (204),synthetic studies have been performed extensively. The total synthesis of optically active (+)7-deoxypancratistatin (210)and (+)-pancratistatin (211)has been reported independently by four research groups. The first group led by Hudlicky reported a synthesis of (+)-7-deoxypancratistatin (210)and (+)-pancratistatin (211)starting with a key intermediate, the optically active aziridine derivative 232 (derived from 3-bromo1S,2S-O-isopropylidenecyclohexa-3,5-diene) (155). A full paper regarding these efforts has been published (256) (Schemes 23 and 24). Reaction of the N-( p-tosy1)aziridine 232 with lithium bis[(3,4-methylenedioxy)phenyl]cyanocuprate in the presence of borontrifluoride etherate (BF3 - Et20) at -78 to -30°C gave rise to stereoselective opening of the aziridine ring to afford methyl N-[SP,6P-dihydroxy-2-(3,4-methylenedioxy)phenylcyclohex-3-enyl]carbamate (233)in 34% yield by deprotection with

4.

232

233

234

OAc NHCQMe

I

~

NH

0

0

235

375

THE AMARYLLIDACEAE ALKALOIDS

236

0

(+)-7-DeOXypancatistatin (210)

Reagents and Conditions : a) dilithium dipiperonylcyanocuprate, BFyEt20, THF,-78 to -30°C, 32%; b) s-BuLi, THF, rt, then (MeOC0)20,76%;c) Na, anthracene, DME, -78OC, 69% ;d) AcOH-THF-H20 (2l:l). 65OC, 94% ; e) r-BuOOH, VO(acac)z, benzene, 7OoC, 85% ; f ) P h 0 2 N a (cat.), H20,100°C, 82%; g) AczO, DMAP, pyridine, 84% ; h) TfZO, DMAP, CH2C12,5°C. 69% ;i) NaOMe, MeOH, THF, rt. 72%. SCHEME 23

acid. Sharpless epoxidation furnished, stereoselectively, methyl N-[3,4pepoxy-5/3,6P-dihydroxy)-2-( 3,4-methylenedioxy)phenylcyclohexyl]carbamate (234)in 45% yield. Ring opening of the epoxide 234 with a catalytic amount of sodium benzoate in boiling water afforded on acetylation methyl N-[3,4,5,6-tetra-acetoxy-2-(3,4-rnethylenedioxy)phenylcyclohexyl]urethane (235).Intramolecular cyclization of 235 with trifluoromethanesulfonic anhydride (Tf20)took place successfully to yield 0-tetra-acetyl-7-deoxypancratistatin (236),which was treated with NaOMe in MeOH-THF to provide (+)-7-deoxypancratistatin (210)in 72% yield. The overall yield was 3% (11 steps from bromobenzene). The synthesis of (k )-pancratistatin (211) has been achieved by application of a sequence of the reactions noted previously to a [3-0-tbutyldimethylsilyl (TBS)-4,5-methylenedioxy]phenyl derivative. Namely, coupling of N-( p-tosy1)aziridine 232 with the cuprate derivative of [3O-TBS-2-(N,N-dimethyIcarboxamido)-4,5-methylenedioxy]benzene,in a manner similar to that noted for 210, produced N-(6-arylcyclohex4-enyl)-N-(p-tosy1)amide as a mixture of atropisomers, reductive N -

376

OSAMU HOSHINO

232

a-Auopisomer (238)

239

Ts = p - M e W S 0 2 TBS = r-BuMezSi BOC= C02Bu-t Bn = C&CH2 HO

0

(+)-Pancratistatin(211) Reagents and Condirionr : a) Liz [2-(MezNCo)-4,5-(CHz@)-3-(r-BuMczsio) C&]2

(CNCu), BF3* THF, reflux, 68% (a mixture of uEt20, THF. -78OC, 75% ; b) s-BuLi, THF, OOC, then (BOC)~O, and p-atropisomers) ;c) Na, anthracene, DME,-78"C, 62% (p-atropisomer), 20% (a-ampisomer) ; d) TBAF, THF,OOC, 93% ;e) SMEAH, morpholine, THF, -45"C, 72% ;f ) C&&HzBr, KzCO3, DMF, rt, 83% ; g) NaC102, KH2P04, 2-methyl-2-butene,r-BuOH, HzO, rt, then CH2N2, EtzO, 98% ; h) AcOH-THF-HzO (2 : 1 : l), 6O"C, 73% ;i) r-BuOOH, VO(a~ac)~, benzene, 6O"C, 53% ; j) H20, PhW2Na (cat), 100aC. 6 days, 51% ;k) H20, PhC@Na (cat), l W C , 48 h ;I) Pd(OH)2, H2, EtOAc. rt, quantitative. SCHEME 24

detosylation of which, followed by N-protection with a Boc group, afforded the N-Boc product 237 (0-atropisomer) and the 0-desilylated N-Boc product 238 (a-atropisomer) in 62 and 20% yield, respectively. 0Desilylation of the former 237 with tributylammonium fluoride (TBAF) in THF at 0°C caused equilibration between the 0-desilylated a- and 0-

4. THE AMAKYLLIDACEAE ALKALOIDS

377

atropisomers to give the 0-desilylated N-Boc product 238 (a-atropisomer) in 93% yield, which was identical with the product obtained by reduction of a mixture of atropisomers. Reduction of the N,N-dimethylcarboxamido group with SMEAH in THF containing morpholine (1 eq)(257) at -45°C followed by 0-benzylation furnished the corresponding 0-benzylated aldehyde, which was converted into 6-[(3-benzyloxy-2 -methoxycarbonyl- 4,5 methy1enedioxy)phenyll- N - Boc- (4,5-epoxy-2,3 -dihydroxy) - cyclohexanecarboxamide (239) by successive oxidation, methylation, deprotection, and Sharpless epoxidation. The reaction of 239 in boiling water containing a catalytic amount of sodium benzoate for 6 days gave spontaneously (+)pancratistatin (211) in 3% yield. Interestingly, when the reaction under similar reaction conditions was quenched after 48 h, 0-benzylpancratistatin (240) was obtained, which was transformed to (2)-panctatistatin (210) in quantitative yield by 0-debenzglation. Therefore, the prolonged reaction under the reaction conditions supported oxirane ring opening, N-deprotection, and cyclization leading to 0-benzylpancratistatin (240). The overall yield was 2% (14 steps from bromobenzene). A second group has synthesized (+)-7-deoxypancratistatin (210) starting from D-glucose (258) by a method involving an intramolecular radicalmediated cyclization of an oxinie as a key step (Scheme 25). 0-TBS-0benzyloxime 241 (derived from D-glucose) was reduced with NaBH4 to afford the corresponding alcohol, reduction of which, followed by treatment with thiocarbonyldiimidazole, afforded a radical precursor 1imidazolylthiocarboxylicester 242. Radical-mediated reaction of O-TBS0-benzyloxime 1-imidazolylthiocarboxylicester 242 with Bu3SnH in boiling toluene containing AIBN gave rise to an intramolecular addition of a carbon radical to the C = N bond in the oxime to provide a cyclized product 243 in 70% yield. Trifluoroacetylation of 243, followed by subsequent 0desilylation and oxidation with tetrapropylammonium perruthenate (TPAP)(259) and N-methylmorpholine N-oxide (NMO), gave the N-benzyloxyamino-N-trifluoroacetyl-Slactone 244. Cleavage of the N-0 bond in 244 was effected with samarium(I1) iodide (SmI,) to afford a trifluoroacetamide, cyclization of which under acidic conditions, followed by hydrolysis with base, provided (+)-7-deoxypancratistatin (209). Furthermore, this methodology was developed to afford the synthesis of ent-lycoricidine (248) using photolysis instead of a chemically mediated radical reaction (260). Photolysis of 4-(4R)-hydroxy-6-[(2-methoxycarbonyl-4,5-methylenedioxy)phenyl]-2S,3S-0-isopropylidenehex-5-ynal0benzyloxime 245 (derived from D-glucose) in the presence of thiophenol under went intramolecular cyclization to produce 1-(N-benzyloxyamino)J-phenylthiocyclohex-5-ene 246. Cleavage of the N-0 bond and reductive elimination of the phenylthio group in 246 with SmIz in THF

378

OSAMU HOSHINO

OMOM

241

MOM = MeOCHz

243

242

TBS = r-BuMe#i Bn = C,HsCH2

v

244

-

(+)-7-Deoxypancratistatin (210)

Reagenrs and Conditions : a) N a B h , MeOH ; b) thiocarbonyldiimidazle, DMAP, ClCH2CH2Cl. 80% (2 steps) ;c) Bu3SnH, AIBN, toluene, 90°C, 70%;d) (CF3CO)20, pyridine, DMAP ; e) Bu4N'F-. THF ; f') TPAP. NMO ;g) Sm12 ;h) Dowex , ' H MeOH, 65OC, 88% ; i) K2CO3, dry MeOH. 70% (3 steps). SCHEME 25

proceeded effectively to give 3,4-0-isopropylidene-ent-lycoricidine (247), deprotection of which with trifluoroacetic acid afforded ent-lycoricidine (248) in 77% yield (Scheme 26). Trost's group has also achieved the synthesis of (+)-pancratistatin (211) starting with the optically active cyclohexenetetraol derivative 249 (161) (Scheme 27). Optically active 6-[(2-bromo-3-methoxy-4,5-methylenedioxy) phenyl]-2,3-0-bis(triethylsilyl)(TES)-cyclohexane (250)(derived from 249) was transformed to isocyanate 251 (by reduction and treatment with phosgene), which was treated with t-butyllithium in ether at -78°C to undergo spontaneous intramolecular addition leading to 3,4-0isopropylidene-7-0-methyl-1-isopancratistatin (252)in 65% yield by way of 251. Conversion of the cis-vicinal dihydroxy groups into trans-vicinal dihydroxy groups was performed through a cyclic sulfonate. Namely, a cyclic sulfonate of the cis-vicinal dihydroxy compound (derived from 252

OH

245

246

H

T ,,

(0-

-

NH

0

0

0

247

ent-Lycoricidine (248)

Reagents and Conditions : a) hv, PhSH, 27OC, 91%; b) Srn12, THF,76% ; c) CF3C02H,77%. SCHEME 26

0 Me Me0

0

252

h, i Me0

0

HO

'

253

0

(+)-Panmatistatin (211)

THF,HzO ;b) COC12, Et3N. M 2 c I 2 ;C) t-BuLi, Et20, -78OC, 62-65%(3 steps) ; d) Bu4N+F-,THF,-78 to O°C ;e) SOCl2, Et3N ; f) RuC13*H20,NaIO4, rt, 72% (2 steps) ; g) PhCQCs, DMF.then workup with THF-H20, HzSO4 CCl,, MeCN,H20,

Reagents and Conditions:a) Me3P,

(cat), 85%;h) K2C03, MeOH, rt ; i)LiI, IMF, 8OoC, 85% (2 steps). SCHEME 21

380

OSAMU HOSHINO

by 0-desilylation with TBAF, treatment with sulfuryl chloride, and oxidation) was treated with cesium benzoate in DMF followed by O-deisopropyli(253). Removal of denation to give 1-0-benzoyl-7-0-methylpancratistatin the benzoyl and methoxy groups of 253 gave (+)-pawratistatin (211). The overall yield was 11%in 15 steps (from 249). The synthesis of (+)-7-deoxy-trans-dihydronarciclasine (208) and (+)7-deoxypancratistatin (210) employing the key intermediate 221 previously reported in the synthesis of (+)-lycoricidine (204) (250) has been published by a fourth group (162) (Schemes 28 and 29). Catalytic hydrogenation of the protected 7-deoxylycoricidine 221, followed by conversion of the 200-(p-meth0xy)phenylmethyl (MPM) group into a 2a-acetoxy substituent, produced the protected (+)-7-deoxy-frans-dihydronarciclasine 254. Stepwise deprotection of 254 afforded (+)-7-deoxy-trans-dihydronarciclasine (208) (Scheme 28). A1(2)-N-MPM-7-deoxypancratistatin (256), which was prepared by elimination and 0-demethoxymethylation of 254, was also transformed to (+)-7-deoxypancratistatin (210) from the epoxide 257 by way of the tetraacetate 236 (Scheme 29). Protected derivatives 259 and 260 of (+)-7-

OAc

254

221

255

MPM = 4-MeOcd-bCH2 MOM = MeOCH2

- (O@Z ff

A

?H O

H

0

0 (+)-7-DcOXy-

WUnS-dihydronarciclasine (208) Reugenrs and Conditionr : a) H2,5%Pd-C,EtOH-EtOAc (14 : 11, rt, 87% ; b) (CF3S02)20,pyridine, CHzClz, OOC ;c) KOAc, 18-crown-6, benzene. n,81%(2 steps) ;d) 1N HCI-THF (1 : 1). 5OoC,then

AczO, pyridine, rt ;e) CF3C02H-CHC13(1 : 1). rt, 64%(3 steps) ; f ) NaOMe, MeOH, OOC. 83%. SCHEME 28

4. THE

236

AMARYLLIDACEAE ALKALOIDS

381

(+)-7-Deoxypancratistatin (210)

Reagents and Conditions : a) NaOMe, MeOH, O°C ; b) (CF3SQ)z0, qyridine, CH2ClZ,O°C ;c) KOAc, 18-crown-6, benzene, rt, 74% (3 steps) ; d) 1N HCl-THF (1 : I), 5OoC, 92% ;e) m-ClCJ-I4CO& C1CHzCH2C1-phosphatebuffer (IM, pH 8)(1 :l), 5OoC,46% ;f) NaOAc, DMF-H20 (4 : 1). 60°C. then AczO, ZnC12, rt, 51% ; g) 5% Pd-C. H2, 1N HCI (cat.), EtOH, rt, 83%. SCHEME29

0-methyl-4a-epi-narciclasine and 7-0-methyl-iso-narciclasine have been synthesized starting with 258 (derived from ~-glucose)(l63). C. BIOLOGICAL ACTIVITY Narciclasine (205) and its glucoside 207 showed similar toxic activity (against Artemia salina), with LDS0values of 0.29 and 0.88 pglml for 205 and 207, respectively. When assayed on a potato disk infested by Agrobacferium

258

(+)-3,4-O-Isopropylidene-7-0methyl-4a-epi-aarciclasine(259) FIG.16

3,4-O-Isopropylidene-7-0methyl-iso-narciclasine(260)

382

OSAMU HOSHINO

tumefucienns, 205 showed a strong antitumor initiation (60% inhibition), and the latter alkaloid, 207,also exhibited similar activity (53% inhibition) in the same assay (96). Antiviral (RNA) activity of narciclasine-type alkaloids and the related compounds have been examined extensively (139). Among these experiments, evaluation of pancratistatin (211)and 7-deoxypancratistatin (210) in two murine Japanese encephalitis mouse models (differing in viral dose challenge, among other factors) has given interesting results. In two experiments (low LDsoviral challenge, variant I), prophylactic administration of 211 at 4 mg and 6 mg/kg/day (2% EtOHhaline, sc, once daily for 7 days, day - 1to +5) increased the survival of Japanese encephalitis-virus-infected mice to 100 and 90%,respectively. In the same model, prophylactic administration of 210 at 40 mg/kg/day in hydroxypropylcellulose (sc, once daily for 7 days, day -1 to + 5 ) increased the survival of Japanese encephalitisvirus-infected mice to 80%.In a second variant (high LDsoviral challenge), administration of 211 at 6 mg/kg/day (ip, twice daily for 9 days, day -1 to +7) resulted in a 50% survival rate. In all cases, there was no survival in the diluent-treated control mice. Thus, 210 and 211 demonstrated activity in mice infected with Japanese encephalitis virus, but only at near-toxic concentrations. This represents a rare demonstration of chemotherapeutic efficacy (by a substance other than an interferon inducer) in the Japanese encephalitis-virus-infected mouse model. Telastaside (213)showed dose-dependent biphasic immunomodulatory responses (25). Its effects suggested inhibition or augmentation of enzyme (proteinase) and membrane integrity, as revealed from the viability or inhibition of growth of both normal and tumor cells (164).

V. Galanthamine-Type Alkaloids A. ISOLATION AND STRUCTURAL ELUCIDATION

Extraction of the flowers of Lycoris incarnata (58) led to the isolation of galanthamine (261),sanguinine (272),lycoramine (276),O-demethyllycoramine (277),and galanthamine N-oxide (281),along with l-palmitoyl2-linoleoylphosphatidylethanolamineand 1-palmitoyl-2-linoleoylphospatidylmethanol sodium salt. In addition, the extract of the bulbs and aerial parts of Narcissus leonensis grown in Northern Spain, and closely related to N. nobilis and N. primigeninus, has been found to contain two new alkaloids, epi-norgalanthamine (267) and epi-norlycoramine (280) (72). (-)-N-Demethyllycoramine (278)has been also isolated for the first time from the bulbs of Hymenocallis rotuta (50).

4.

383

THE AMAKYLLIDACEAE ALKALOIDS

Sanguinine (272), reported previously as a constituent of Leucojum aestivum sub. was obtained from Leiucojum aestivum sub. pulchelum (54).The structures of the representative alkaloids isolated are shown in Fig. 17. R

Me0 N. CH&I

Galanthamine (261) R =H,R' =Me 0-A~etylgalanthamine (262) R = Ac, R' = Me N-Allylgalanthamine (263) R = H,R' = ~ i i y i Norgalanthaminc (264) R=R~=H N-Fmylgalanthamine (265) R =H, R' = CHO

N-Chloromethylgalanthaminium chloride (266)

Epi-norgalanthamine(267)

R=H Narcisine (268) R=Ac

Nanvedine (269)

Leucotamine (270) R=H 0-Methylleucotamine (271) R=Me

R

HO

Sanguinine (272) R = H. R'= Me 2-O-A~~tylchlidanthine (273) R =Ac,R'=Me Nmanguininc (274) R =R~=H Norbutsanguinine. (275) R = COCH2CH(OH)Me, R'=H

R Lycoraniine (276) R = R' = M e O-Demtthyllycoramine (277) R =Me,R'=H Norlycoramine (278) R =H,R'=Me

0 Galanthamine N-oxide (281) R =R,R'=Me 0-Acetylgalanthamine N-oxide (282) R =Ac,R'=Me Sanguinine N-oxide (283) R =R'=H

FIG. 17

Epi-lycoramine (279) R=Me Epi-norlycoramine (280) R=H

Lycoramine N-oxide (284)

384

OSAMU HOSHINO

B. SYNTHETIC STUDIES Galanthamine (261) has been characterized as an acetylcholinesterase inhibitor, and its epimer epi-galanthamine and its oxidized analog narwedine (269) have been evaluated as potential agents for the treatment of Alzheimer’s disease. However, supply of the alkaloids has been limited, although they are found in several Amaryllidaceae species. Therefore, supply by synthesis is a necessary requirement. The synthesis of 261 was initiated using phenolic oxidative coupling as a biomimetic method, and extensive synthetic studies have been performed. Since 1987,some reports on the synthesis of 261 and related compounds using phenolic oxidation and radical-mediated cyclization have appeared. Phenolic oxidation of the diphenolic amide 285 using potassium ferric (111) cyanide afforded (+)-N-formyldibromonarwedine (286), which was reduced successively with lithium tri-s-butylborohydride (L-Selectride) and with LiA1H4 to afford (?)-261.Resolution of (2)-261 using d-camphoric acid provided (-)- and ( +)-galanthamines (261) through the camphanate derivatives 287 and 288 (265) (Scheme 30). Phenolic oxidation of the phenolic palladium complex 290 (prepared by N-methylation and metallation of 289) using thallium(111) trifluoroacetate gave (t)-narwedine (269) in 51% yield by way of the cyclized intermediates 291 and 292 (166) (Scheme 31). The synthesis of ( t)-lycoramine (276) and ( t)-epi-lycoramine (279) using radical-mediated reactions as key steps has been reported (167) (Scheme 32). Dehydration of ethyl 2-[1-(6-bromo-2-methoxy)phenoxy-4, 4-ethylenedioxy-l-hydroxycyclohexyl]acetate(293) [prepared from ethyl (6-bromo-2-methoxy)phenoxyacetateand 4,4-ethylenedioxycyclohexanone] with phosphoryl chloride in pyridine at 90°C produced a radical precursor cyclohexene derivative 294, along with a regioisomer. Radical reaction of 294 with Bu3SnH in boiling o-xylene containing AIBN provided the cyclic spirobenzofuran derivative 295 in 91% yield, which was transformed to Bseco-oxolycoramine 2% in four steps (cleavage of benzofuran ring with Sm12,deprotection, introduction of a double bond, and amidation, followed by concomitant cyclization). The modified Pictet-Spengler reaction of 296 with paraformaldehyde in CF3C02H in dichloroethane led to (2)-0x0dihydronarwedine (297), whose reduction with LiA1H4 in boiling THF yielded ( t)-lycoramine (276) and (2)-epi-lycoramine (279) in 85% yield (a product ratio of 5 :1). A practical and total spontaneous resolution process for the asymmetric transformation of (?)-narwedine (269) into either of its enantiomers, depending on which enantiomer is used as the seeds, and a highly stereospecific conversion of (-)-narwedine (269) into (-)-galanthamine (261) by reduc-

4.

THE AMARYLLIDACEAE ALKALOIDS

a

&OH

Me0$H !O OH

b c

MeO.@&

IMe

286

(+)-Galanthaminyl (-)-camphanate (287)

e

(*)-Galanthamine (261)

MeO@*oH Me

(+)-Galanthamine (261)

+ (-)-Galanthaminyl (-)-camphanate (288)

. . o B o H

CHO

Rr

285

385

~

(-)-Galanthamine(261) Reagents and Conditions : a) K3Fe(CN)6.NaHC03, CHC13,H20, 60°C, 37% ;b) Zn, EtOH,

reflux, 98%;c) L-Selectride@, THF, -78OC, then LiAM4, THF, reflux, 70% ;d) (1s)(-)-camphanicchloride, Et3N, THF-CHC13, (4 : 15), then chromatography, 287 (45%), 288 (43%); e) LiAlH4, THF, 0 ° C then dry HCl, MeOH, (+)-261*HC1(96%),(-)-261*HC1 (92%). SCHEME 30

tion have been reported (168). (+)-Narwedine was dissolved in a solvent mixture of 95% ethanol-triethylamine (9: 1) at 80°C. (-)-Narwedine seeds (2.5%) were added to the supersaturated solution at 68°C. The suspension was kept at 40°C to afford a highly enriched (-)-narwedine in 80% yield from (+)-narwedine. A similar process was successfully employed to prepare (+)-narwedine in 85%yield from (2)-narwedine by seeding the supersaturated racemic solution with (+)-namedine. The concept was expanded to achieve a total spontaneous resolution of (2)-narwedine using either enantiomer of galanthamine as the “catalyst.” (?)-Narwedine was dissolved into a solvent mixture similar to that noted previously at 80°C in the

OSAMU HOSHINO

386

290

289

Reagenrs and Condirions :a) fonnalin. NaCNBH3, MeOH, 90%(from isovanillin) ;b) LiFdC14, Et Ni-R2, -78OC, 95%(1 : 1 mixture of diastereomers) ;c) n ( o 2 c a 3 ) 3 , THF-CH2C!12 (2 : 1). -lO°C;then Ph3P, -10' to 25OC, 51%. SCHEME 31

presence of a catalytic (1%)amount of natural (-)-galanthamine. The resulting suspension gave enantiomerically pure (+)-namedine in 75% yield from ( ?)-namedine. Similarly, optically pure (-)-namedine was obtained from (2)-narwedine, using a catalytic (1%)amount of (+)-galanthamine, in 76% yield. Moreover, (-)-namedine obtained from the above process was reduced stereoselectively by L-Selectride at -78°C to produce (-)galanthamine in 99% yield (99% ee). The process is considered to be attributable to the unique conglomerate nature of narwedine. C. BIOLOGICAL ACTIVITY Galanthamine (261) has been prominent in the popular and general scientific press because of its purported usefulness in healing Alzheimer's disease, presumably due to its acetylcholinesterase and muscarinic activity.

4.

THE AMARYLLIDACEAE ALKALOIDS

293

2%

294

297

387

295

(f)-Lycoramine(276) R=OH,RI=H (i)-Epi-lycoramine (279) R = H, R1 =OH

Reagents and Conditions :a) FOCI3.pyridme, 9OOC ;b) Bu3SnH, AIBN, o-xylene, xeflux. 91%; C) SmIz, HMPA, MeOH, THF, rt, 81% ;d) 3NHCI. 81% ; e) (PhSeOhO, toluene, 76%; f) 40% aq. MeNH2. THF, n, 97% ;g) paraformaldehyde,CF3C02H. CICHzCHzCl. n,81% ; h) THF, nflux, 85% (276 :279 = 5 : 1).

w,

SCHEME 32

VI. Tazettine-Type Alkaloids A. ISOLATIONAND STRUCTURAL ELUCIDATION Tazettine (298) has been isolated from Crinum americanum (leaves) (16), C. giganteum (27),Hippeastrum eyuestre (bulbs) (40),Hippeastrum hybrids (bulbs) (42),Hymenocallis expansa (bulbs and leaves) (48), Lycoris radiata (bulbs) (60),Narcissus tazetta (901, N. cantaricus (whole plants) (65),Pancratium maritinum (bulbs) (%), and Sternbergia sicula (whole plants) (103). Pretazettine (300)has been found in N. pallidiflorus (whole plants) (76), N. panizzianus (whole plants) (79)(aerial and bulbs) (80),S. culsiani (bulbs) (102), and Zephyranthes flava (fresh mature seeds) (108). Tazettine (298), pretazettine (300), littoraline (301), and marconine (302) have been isolated

388

OSAMU HOSHINO

from Hymenocullis littorutu (bulbs), in which littoraline (301) is a new tazettine-type alkaloid (49). A new tazettine-type alkaloid, zeylamine (304),was isolated in 0.18%yield from the air-dried rhizomes of C. zeylunicum (34). Continuing exploration of the extracts of the Amaryllidaceae plants has established the presence of tazettine (298), pretazettine (300), and 3-epi-marconine (303) in Hymenocullis rotutu (50);of tazettine (298) and pretazettine (300)in N. tuzettu (bulbs) (89) and S. luteu (whole plants) (203); and of criwelline (299) in C. firmifolium var. hygrophilum (whole plants) (26).The alkaloids isolated are shown in Fig. 18.

B. SYNTHETIC STUDIES The syntheses of (2)-pretazettine (300) and (%)-haemanthidine (157) (169) (Scheme 33) and (2)-tazettine (298) and 6a-epi-pretazettine (314) (270) (Scheme 34) have been reported. In the one case (269),a key intermediate, the ally1 N-methylcarbamate 305, was transformed to N-methyl-3pivaloyloxy-3a-[(3,4-methylenedioxy)phenyl]-3a,6,7,7a-tetrahydro-6-oxo-

r!

Tazettine (298) R = PQMe Criwelline (299) R = aQMe

Pretazettine (300)

$2-

R

Q 0

0 Maxonine (302) R = a-OMe 3-Epi-macronine (303) R = P-OMe

0 Zeylamine (304)

FIG.18

Littoraline (301)

4.

t-Bucoo.

t.Buc00

-<

0

t-BuCOO

0

0

Q

389

THE AMARYLLIDACEAE ALKALOIDS

ac

0 0

305

0

306

307 R = M e

308 R=CHO t-&COO

Q

Me

h

0

OH

309

OH (f)-Haemanthidine (157)

OH

(f)-Preulzettine (300)

Reagemand Conditons :a) conc. HzS04. EtOAc, rt, then PhN+mBr3-, rt ;b) DBU, benzene, rcflux,

77%(2 steps) ;c) 2cthylhexanoic acid, (Ph$).,Pd. Ph3P, CHzC12,rt, 90% (1.5 : 1) ;d) DIBALH, THF, -78OC (3 :2 :5 :3) ;e) (MeSO&O, EbN, THF. OOC. then MeOH, 0°C to rt, 59% (35 : 24) ;r) 9, Pt black, aq. dioxane, rt, then AcOCHO, pyridine. rt, 57% ; g) POCl,, 8VC, then THF-Hp (1 : I), rt, 7 1% (2 steps) ;h) LiOH. &OH, rt, 78%; i) MeI, MeOH, rt. 66%. SCHEME 33

indoline (306) by oxidation followed by an intramolecular Michael addition. Conversion of the 6 0 x 0 group in 306 to a 6fl-methoxy group produced the methoxy compound 307, oxidative N-demethylation of which, followed by treatment with acetic4ormic anhydride, furnished the N-formyl product 308. The Bischler-Napieralski reaction and continuous hydrolysis of 308 provided (?)-haemanthidine (157). Treatment of 157 with methyl iodide in MeOH led to rearrangement of the skeleton to lead to (5)-pretazettine (300) in 66% yield (Scheme 33). In the other synthesis (270),the modified Heck reaction served as a key step for the construction of the spiro compound 311. Namely, the reaction of N-methoxycarbonyl-2-[(2-iodo-4,5-methylenedioxy)phenyllmethoxy]-2(cyclohexeny1)ethylamine 310 with palladium(0) in boiling THF in the presence of silver carbonate caused an intramolecular cyclization to give the spiro compound 311 in 90% yield. Michael reaction of 311 with 1 N HC1 in boiling THF, followed by introduction of a double bond through a

390

OSAMU HOSHINO

bH

(&)-6a-Epipretazettine(314)

k TBS = t-BuMQSi

OTBS

315

(f)-Tazettine (298)

Reagem and Condirions :a) ClCOzMe ;b) Pd(0Ac)z (lOmol%),Ph3P (4Omol%), AgzC03 (2 eqUiV.), THF, =flux, 90% re ~tatc63-70%) ;C) 1N HCI, THF, reflux, 94% ;d) CF3SQTMS. E t g , CHzC12,OOC, then Pd(0Ac)z. MeCN, rt, 67% (2 steps) ;e) NaBH4, CeC13.7Hz0. MeOH, -78OC. 95% (p :a = 36 : 1) ;f) KH. MI, THF, rt, 75% ;g) C Q , 3,5-dirncthylpyrazole, CH2C12,._~. 400 to -45'C, 63% ;h) LiA& THF-EtzO, rt, 98% ;i) De.ss-Maxtin oxidation,73% ;j) Swern oxidation,298 (61%). 315 (90%) ;k) TBSCl, 76% ;I) B u 4 M , 93%. SCHEME34

silyl enol ether, afforded the spirocyclohexenone 312 in 63% yield (three steps). After the transformation of an 0x0 group to a methoxy group and subsequent oxidation, LiAlH4 reduction of the resulting spiro Slactone led to the dihydroxy compound 313. Interestingly, Swern oxidation of 313 afforded (2)-tazettine (298) in 61% yield, whereas Dess-Martin oxidation of 313 produced (2)-6a-epi-pretazettine (314) in 73% yield (Scheme 34).

4.

THE AMARYLLIDACEAE ALKALOIDS

391

On the other hand, 0-silylation and Swern oxidation of 313 provided Nmethyl-3a-[(2-O-TBS-4,5-methylenedioxy)phenyl]-3-oxo-3a,6,7,7a-tetrahydroindoline (315)in 68%yield, 0-desilylation of which with TBAF gave rise to a spontaneous intramolecular hemiacetalization to afford ( 5 ) tazettine (298)in 93% yield. Intramolecular 2-aza-ally1anion cycloaddition was employed for the synthesis of the crinine-type alkaloids (t)-crinine (135) ( 1 4 2 ~ and ) (-)amabiline (145)( 2 4 2 ~and ) has been reported to provide potential precursors of 6a-epi-pretazettine (314)and 6a-epi-precriwelline (methoxy epimer of 314) (142b). C. BIOLOGICAL ACTIVITY

The extracts of the bulbs and leaves of Hymenocaflis expansa have been re-examined for cytotoxic activity. Both plant parts showed significant activity against different human and murine tumor cell lines. Tazettine (298) showed activity, to varying extents, against the cell lines tested (48). Pretazettine (300)has also been reported to exhibit marginal activity (TIs0 < 4.5)(239).

W.Lycorenine-Type Alkaloids A.

ISOLATION A N D

STRUCTURAL ELUCIDATION

Six new lycorenine-type alkaloids, 5a-methoxy-9-0-demethylhomolycorine (323), galwesine (333),9-0-demethylgalwesine (334),16-hydroxygal(336),and galasine (337), wesine (335),16-hydroxy-9-O-demethylgalwesine have been isolated from whole plants of Galanthus efwesii accompanied by 12 known Amaryllidaceae alkaloids, including lycorine and galanthamine. Of these alkaloids, only lycorine and galanthamine were found previously in this plant. Identification and structural elucidation of these alkaloids were achieved using spectroscopic ('H and 13C NMR, CD, UV) techniques coupled with X-ray crystallographic analyses (for 334,335,and 337) and chemical transformation (35).Interestingly, although the known alkaloid, 9-0-demethylhomolycorine (321),was isolated as five different crystalline samples from five different subfractions of this plant, two of them were nitrogen inversion conformers and the other samples were compounds including different solvent molecules in the crystals (35,171). This is the first time that it has been demonstrated by X-ray crystallographic analyses that, depending on the crystallization conditions, both nitrogen inverted

392

OSAMU HOSHINO

isomers of the same natural alkaloid could be crystallized. In solution, the interchange between the axial and equatorial forms are too fast to be observed. The representative lycorenine-type alkaloids isolated since 1987 are shown in Fig. 19.

'R

RO

Lycmnine (316) R=H 0-Meth yllycmnine (317) R=Me

n

Homo1 corine (318) R = R7 =Me 8-O-Demeth y lhomolycorine (319) R = H, R' = Me

8-0-Acetylhomolycorine (320) R = Ac,R' =Me 9-0-Demethylhomolycorine (321) R = Me, R' = H

a0"

Q

1

0

0

0

OEt

Nobilisine (326)

Q

Me0

'OR

0

Me0

0

0

Clivatine (327) R = COCHZCH(0H)Me

Hippeastrine (328)

0

Me0 RO

OMe

0-Methyllycmnine N-oxide (329)

Me0

'OH

'OMe

0

Homolycorine N-oxide (330) R=Me 8-O-Demeth ylhomo1ycorine N-oxide (331) R=H

R'O

0

Hippeastrine N-oxide (332)

S~-Hydroxy9-O-demeth ylhomolycorine (322) R =OH, R' = Me, R* = H Su-Methoxy9-Odemethylhomolycorine (323) R = OMe, R' = Me, R~=H Dubiusine (324) R = OAc, R' = Me, R2 COCHzCH(0H)M~

0

-

Galwesine (333) R = H, R' Me 9-0-Demethylgalwesine (334) R R' = H

-

1 1-Hydroxygalwesine (335) R = OH, R' = Me 16-Hydroxy9-0-&methylgalwesine (336) R = OH, R' = H

FIG.19

Me0 Meo

0

Galasine (337)

4.

THE AMARYLLIDACEAE ALKALOIDS

393

VIII. Montanine-Type Alkaloids A. ISOLATION AND STRUCTURAL ELUCIDATION The montanine-type alkaloids possess a unique structure, called the 5, 11-methanomorphanthridine skeleton 343, and are a minor group in the Amaryllidaceae alkaloid family, of which only seven representatives had been isolated until recently. Montanine (338) and pancracine (339) were isolated from the bulbs of Hippeastrum hybrids (42). The eighth montaninetype alkaloid montabuphine (340), with a P-5,11-methanomorphanthridine skeleton was found for the first time in the bulbs of Boophaneflava (9) growing in the winter rainfall area in South Africa. The structure was determined by physical and spectroscopic [COSY and ROESY (172)]experiments in the 'H NMR, and HMQC (173) and HMBC (174) correlations in the 13C NMR spectra. The molecular ellipticity of the alkaloid (342) showed a CD curve that was qualitatively the reverse of the known 5,11methanomorphanthridine alkaloids with an a-configuration for the methano-bridge (141,175). Therefore, the 5,11-methano bridge was established to have a /3-configuration (42). As they do not show remarkable biological activity, their synthesis had not been performed, excluding synthetic studies for structure elucidation. The structures of the montaninetype alkaloids isolated are listed in Fig. 20. B. SYNTHETIC STUDIES Although synthetic approaches toward the montanine-type alkaloids had been made by intramolecular cyclization of 3-(3,4-methylenedioxy)phenylhexahydroindoline derivatives (I76), these attempts were thus far unsuccessful. The 5,11-methanomorphanthridinering systems 341-343 (Fig. 21)

'0

Montabuphine (340)

Montanine (338) R = p-OMe, R' = a-OH Pancracine (339) R = &OH, R' = P-OH FIG.20

394

OSAMU HOSHINO

342

341

&g

NH

343

Ts = 4-MeC!&SO2

344

FIG.21

were found to be effectivelyformed by intramolecular reductive cyclization of 11-hydroxymethyl-N-(p-tosy1)morphanthridines 344 using SMEAH (177,178) in boiling toluene. Afterwards, a total synthesis of this type of alkaloid was achieved independently by two research groups; a key step in one of the syntheses involves stereoselective hydroboration-oxidation and cyclization with SMEAH (178,179) as a result of development of a method for the synthesis of $11-methanomorphanthridine343. In the other, a tandem aza-Cope rearrangement-Mannich cyclization and the PictetSpengler reaction (180) are key synthetic steps. A third research group has reported the enantioselective total syntheses of this type of alkaloid by means of an intramolecular allenylsilane ene reaction coupled with the intramolecular Heck reaction (181). The synthetic route used by the first research group is depicted in Schemes 35-37 (178,179). Namely, 2-[(3,4-methylenedioxy)benzoyl]cyclohex-4-ene carboxylic acid (345) (prepared from 1,2-cis-cyclohex-4-ene dicarboxylic anhydride and the Grignard reagent of 6-bromo-3,4-methylenedioxybenzene) was transformed to 3,4-diacetoxy-6-[1-(3,4-methylenedioxy)phenylvinyll-N-(p-tosy1)cyclohexylamine (346) in six steps. (Curtius rearrangement, hydrolysis, N-tosylation, Os04 oxidation, acetylation, and Wittig reaction). Hydroboration-oxidation of 346 in the usual manner proceeded stereoselectively to produce a hydroxymethyl product, acetylation of which gave 2~,3~-diacetoxy-llcr-acetoxymethyl-N-(ptosy1)morphanthridine (347) in good yield. Hydrolysis and successive 0benzylidenation of 347 afforded 2,3-0-benzylidene-llcr-acetoxymethyl-N(p-tosyl)morphanthridine, treatment of which with SMEAH in boiling o-xylene led to smoothly intramolecular cyclization to give 2,3-O-benzyli-

4.

THE AMARYLLIDACEAE ALKALOIDS

345

395

346

/OAc

OAC

-

Ts

347

348

Bn = Ca5CHZ Ts = p-MeC&I4S0z

Y 0

OH

(f)-Coccinine (351) Reagents and Conditions :a) ClC@Et, Et3N. acetone, then aq. NaN3,5OC ;b) t -BuOH, reflux, 94% (3 steps) ;c) CF~COZH,CHzClz,xt ;d) p-TsC1, Et3N, CHzClz, rt, 71% (2 steps) ; e) Os04 (cat.), NMO, dioxane-HZO (4 :1 ) ;f ) AczO, pyridine. DMAP, rt ;,g) Ph3PMeBr, KOt-Bu, THF,rt, 71% ; h) BH3, THF,then 30% Hz@. aq. NaOH, O°C, quantitative ;i) AczO, MeSO$I, (CHZO),,CICHzCHzCl,rt, 81% ;j) NaOMe, MeOH, rt, quantitative ;k) PhCH(OMeh,p-TsOH* HzO, CHC13,rt, 83% ;I) SMEAH, o-xylene, reflux, 91% ;m) DIBAL-H, toluene, rt. 347 (75%). a regioisomer (22%) ;n) Jones oxidation, 59% ;0 ) DDQ, NazHP04, dioxane, reflux, 26%; p) CH(OMe)3,p-TsOH*H20,MeOH, rt, 99% ;q ) MeSSiI, C H C l 3 , rt, 87%. SCHEME35

dene-5,ll-methanomorphanthridine348 in 91% yield. Selective cleavage of 348 with diisobutyl aluminum hydride (DIBALH) in toluene at room tem(349) perature produced 3-benzyloxy-2-hydroxy-5,ll-methanomorphanthridine

396

OSAMU HOSHINO

along with a regioisomer. Jones oxidation of 349, followed by oxidation with DDQ, afforded 3-benzyloxyd1(11a)-5,11-methanomorphanthridin-2one (350). Finally, 350 gave (&)-coccinine (351)in 68% yield (three steps) through dimethyl ketalization, stereoselective removal of a methoxyl group, and 0-debenzylation (Scheme 35) (178,179). The same intermediate 349 was also converted into (+)-montanine (338), (+)-parmacine (339), and (+)-brunsvigine (356).Dehydroxylation of 349 by way of a mesate gave 3-benzyloxy-A1~-5,11-methanomorphanthridine (352), along with the regioisomer, in 70% yield. Chlorophenylselenylation-dephenylselenylation of 352 gave 3-benzyloxy-2-chloro-A1~11a)-5,11-

0 [ & NH OBn a,b

~

C

p&

MH

0

349

OBn

___)

352

Bn = GHsCHz

r

r

OH

(*)-Montanine (338) 353

354

t

(*)-Pancracine (339) H

H

'OAc (f)-0-Diacetylbrunsvigine (355)

0

NH

'OH

(f)-Brunsvigine (356)

Reagents am Conditions : a) leS02C1, Et3N, CH2C12,5OC, 100% ; b) KOt-Bu, Me$O, rt, 70% ;c)

PhSeC1, MeOH, ultrasound, 15-20°C, then NaIO4,82% ; d) Me3Si1, CHC13, rt, 87% ;e) BFpEt20, MeOH, 5OC, 94% ;9 H2SO4, THF- H 2 0 (1: l), reflux. 78% ; g) Me3SiC1, NaI, MeCN, rt, 55% ;h) Os04 (cat.), NMO, dioxane-Hz0, rt ;i) Ac20, DMAP, pyridine, 86% ;j) NaOMe, MeOH, n, 90%. SCHEME 36

4.

THE AMARYLLIDACEAE ALKALOIDS

397

methanomorphanthridine (353), which was treated with iodotrimethylsilane to lead spontaneously to 2,3-P-epoxy-A1("")-5,11-methanomorphanthridine 354. Treatment of 354 with BF3 Et20 in MeOH, or aqueous sulfuric acid, brought about oxirane ring opening to produce (?)-montanine (338) or (+)-pancracine (339). On the other hand, 354 was transformed into (?)brunsvigine (356) through (2)-0-diacetylbrunsvigine (355) (prepared by exchange of the oxirane ring to a double bond, Os04 oxidation, and acetylation) (Scheme 36) (179). Radical-mediated reaction of a radical precursor tetrahydroisoquinoline derivative has been found to produce the $11-methanomorphanthridine ring system (182).Thus, a formal total synthesis of this type of alkaloid was performed by means of the present methodology. Namely, the reaction of 1,2,3,4-tetrahydro-N(4-oxocyclohex-2-enyl)-4-phenylthioisoquinoline (357) with Bu3SnH in boiling o-xylene containing AIBN led to 5,llmethanomorphanthridin-2-one (358) in 80%yield, which was transformed to A2~3-5,11-methan~m~rphanthridine 359 by way of a mesate. In continuation, 359 provided the 2,3-O-benzylidene derivative 349 in two steps (Os04 oxidation and 0-bemylidenation), which was previously (179)converted into this type of alkaloid (Scheme 37).

-

-

H

(f)-Montanine (338) (f)-Pancracine (339) (f)-Coccinine (351)

0

349

Reagenrs and Conditions : a) BqSnH, AIBN, o-xylene, reflux, 80%;b) N a B a , MeOH, 5OC, quantitative (a mixture of a-and P-alcohols) ; c) MeSO2C1, EgN, CHC13, 5OC, 95% (1 : 1mixture of a-and pmesates) ; d) KOr-Bu, DMSO, rt, 82% (1 : 1 mixtutre of regioisomers from p-mesate) ; e) OsO4 (cat.), MNO, dioxane-HzO (4 : l), n ; f) PhCH(OMe)?, p-TsOH, CHC13, rt, 75% (2 steps) ; g) Ref. 179. SCHEME 37

398

OSAMU HOSHINO

The synthetic route in the second report (180) is as follows. Reaction of the N-benzyloxazoline derivative 361 {prepared from cis-2-benzylamino-l[(3,4-methylenedioxy)phenylethynyl]-l-cyclopentanol (360) by reduction and treatment with formalin} with BF3 Et20 in CH2C12at -20 to 23°C consisted of a tandem aza-Cope rearrangement-Mannich reaction to furnish 3-[(3,4-methylenedioxy)phenyl]-N-benzylhexahydroindol~n-4one (362).Interestingly, N-debenzylation of 362, followed by the PictetSpengler reaction using formalin and camphorsulfonic acid, afforded the 5,ll-methanomorphanthridin-1-onering system 363. The present finding may be attributable to the stereochemistry of 3-arylhexahydroindoline ring system. Compound 363 was converted into the A'(''a)-5,11-methanomorphanthridin-2-one 364 in four steps (reduction of an 0x0 group with LSelectride, dehydration of a hydroxyl group with thionyl chloride, hydroxylation with Se02, and Swern oxidation). Finally, 3P-hydroxylation of 364 through the silyl enol ether gave 3P-hydro~y-A~("~)-5,1 l-methanomorphanthridin-2-one, which was reduced with NaBH4 in acetic acid at -35°C to produce (2)-pancracine (339)in 53% yield (three steps) (180) (Scheme 38). e

361

360 Ar = 3,4-(CH2O&H3 Bn = C6H5CH2

363

364

362

(f)-Pancracine(339)

Reagents and Conditions : a) LiAIH4, EtzO, -20% then reflux, 94% ; b) 37% formalin, Na2S04, camphorsulfonic acid, CH~CIZ,2 3 T , 81% ;c) BF3*OEt2, CH2ClZ,-20 to 2 3 T , 97% ;d) Pd-C,

H2, HCI, MeOH, 96% ;e) 37% formalin,Et3N, MeOH, 23'C, then HC1, MeOH, 23"C, 67% ; r) [email protected], -78'C. 99% ;g) SOC12, CHC13, -30 to 23'C, then S e a , dioxanc, 85"C, 62% ; h) Swern oxidation, 91% ; i) MeS03SiMe3, EgN, EtzO, -60to O°C, then Os04(cat), NMO, r-BuOH, HzO. pyridine, -5 to 23°C 82% ;j) NaBh, AcOH, MeCN (1 : l), -35'C. 65%.

SCHEME38

4.

THE AMARYLLIDACEAE ALKALOIDS

399

Starting with optically active cis-2-[N-cyanomethyl-N-(lS-phenethyl]-l[(3,4-methylenedioxy)phenylethynyl]cyclopentanol (365), 3-[(3,4-methylenedioxy)phenyl]-N-[(1S-phenethyl[hexahydroindolin-4-one (366) was synthesized in a manner similar to that noted previously. Thus, the synthesis of (-)-pancracine (339) was achieved in 25% overall yield through 366 by a sequence of reactions similar to those noted for (+)-339 (Z80b) (Scheme 39). Also, the same intermediate 364 employed for the synthesis of (+)339 was transformed to (2)-desmethyl-a-isocrinamine (368) by way of the 3a-acetoxy derivative 367. Intramolecular imino ene reaction of an allenylsilane has recently been found to generate cyclohexyl systems with adjacent cis-amino and -alkynyl moieties. This enantioselective ene cyclization was developed for the enantioselective total syntheses of (-))-montanine (338), (-)-coccinine (351), (-)pancracine (339), and (-)-brunsvigine (356) (a formal total synthesis) by the same research group (181) (Schemes 40 and 41). A precursor allenylsilanealdehyde 370 for the enantioselective ene cyclization was synthesized from scalemic epoxy alcohol 369 in nine steps. The allenylsilane-aldehyde 370 thus obtained reacted with N-triphenylphosphinyl-(2-bromo-4,5-methy1enedioxy)phenylmethylimine in boiling mesitylene to lead to a cyclized product 371 in 63% yield after protodesilylation. Hydrogenation of 371

364

367

WDesmethyla-isocrinamine (368)

Reugents and Condirionr :a) AgN03. aq. EtOH, 23OC, sonicaaon, 95% ;b) Red-A1 (100%) or LiAlH,, (89%). Et20. 23OC ;c) 37%formalin. Na2S04.camphorsulfonic acid, CH2C12, 23OC, 75% ; d) BFp 0Et2. CH2C12. 5OC. 95% ;e) Pd-C, H2 (50 psi), HCl, MeOH, 96% ; 9 in a manner similar ~ O , nflux. 86% ;h) to that noted for (i)-pancracine, 25% overall yield ;g) M ~ ( O A C ) ~ - Wbenzene, DBU, acetone, 23'C, then NaBh. CeCI3*7H20.n. 75% (2 steps) ;i) K2CO3, MeOH, 23OC, 69%. SCHEME 39

400

OSAMU HOSHINO

369

370

371

Bn = G H Q I z ; TBS = t-BuMe$i ;Ts = p-MeC&I.,S&

374

375

376

(-)-Panmacine(339)

0

I-m( 0

Reagents and Conditions : a) nine steps ;b) 2-Br-4,5-(CHzOz)CN=PPh3, mesitylene, 50°C to nflux ;c) TBAF, THF, 0°C 63% (2 steps) ;d) Lindlar catalyst, Hz. quinoline. MeOH, 93% ;e) Pd(PPh3),. Mc$TTI-I$'ha',Et3N, MeCN, 1U)oC.74% ;f) p-TsCl, pyridine, DMAP, l W C , 92% ;g) dimethyldioxirane, acetone,-u)oC, 89% (2 : 1 mixture of two diastemmers) ;h) FeC13, CH& -78OC. then DIBALH, OOC, 88% ; i) 10% Pd-C, Hz,MeOH. 97% ; j) Na, naphthalene, DME,-78OC, 63% ; k) 12, PPb3, imidazole, MeCN, EtzO, O O C , 82% ;I) "PAP, NMO,CH2C!lz, MS 4A,%% ;m) LDA, Mc$iCl, THF, -78'C ;n) Pd(OAc)z, MeCN, 67% ; 0 ) TBAF, THF,OOC to R,98% ;p) NaBH(OAc)3, -35°C. SCHEME 40

over Lindlar catalyst in MeOH containing quinoline, followed by an intramolecular Heck reaction, provided an N-(p-tosy1)-1l-methylenemorphanthridine ring system 373 by N-tosylation. Hydroxylation of 373 was per-

4.

0

THE AMARYLLIDACEAE ALKALOIDS

401

BS

376

377

Bn =C&CH2 TBS = r-BuMe$i Ts =p-MeC&i4S4

374

(-)-Montanine (338)

378

(-)-Brunsvigine (356)

Reagents and Conditions : a) TsOH, CH(OMe)3,MeOH, 0 "Cto n, 91%;b) DIBALH, toluene, rt, 81 % ;c) TBAF,T€IF, 0 ' C to rt, 99%;d) DIBALH, toluene, rt. 41 5% ; e) H2,Pd-C,MeOH; f ) TBAF, THF, 97% (2 steps) ; g) Ref. 179. SCHEME41

formed using the corresponding epoxy derivative of 373 to produce protected 1l-hydroxymethylmorphanthridine374 in 78%yield (three steps). The structure of 374 was confirmed by its conversion into 3P-acetoxy2~-benzyloxy-5,11-methanomorphanthridine, a racemic form of which was previously (I79)transformed to the montanine-type alkaloids. Transformation of 374 to the $11-methanomorphanthridine ring system 375 was successfully achieved in 96% yield by treatment of 3-O-TBS-2-hydroxy-11hydroxymethylmorphanthridine (derived from 374 by O-debenzylation and N-detosylation) with a mixture of imidazole, triphenylphosphine, and iodine in MeCN-ether at 0°C. Thus, (--)-pancracine (339) was synthesized from 375 by way of 376 in five steps (oxidation, formation of 376 through a silyl enol ether, deprotection, and reduction) (Scheme 40). Furthermore, synthesis of ( -)-montanine (338) and (-)-coccinine (351) was carried out in 41 and 91% yield, respectively, from the same intermediate 376 by way of the dimethyl ketal377. Also, the key intermediate 374 was converted into 2~,3/3-dihydroxy-ll-hydroxymethyl-N-( p-tosyl) morphanthridine 378, a racemic form of which was previously (179)trans-

402

OSAMU HOSHINO

formed to (2)-brunsvigine (356). Thus, the present result constitutes an enantioselective formal total synthesis of (-)-brunsvigine (356) (181) (Scheme 41).

IX. Mesembrine-Type Alkaloids A. ISOLATION AND STRUCTURAL ELUCIDATION Few isolations of mesembrine-type alkaloids have been reported. Two examples are the isolation of amisine (379)(from Hymenocallis arenicolu) (183) and of mesembrenol(380) (from Crinum oliganthum) (184) from the Amaryllidaceae family. A third example is the isolation of mesembrenone (Ml), belonging to the mesembrine group, from the aerial parts of Narcissus palladulus (77) growing in Iberia. The structure was elucidated by spectroscopic and chemical methods (Fig. 22). Although both the Amaryllidaceae and Sceletium-type alkaIoids have common biogenetic precursors, further investigations have revealed that the biosyntheses of these two classes of alkaloids are fundamentally different (185). Therefore, the presence of mesembrenone in Narcissus plants is of chemotaxonomic interest because mesembrines seem to be restricted to Aizoaceae-Mesembrylanthemoidaceae (Dicotyledons) (186). The present finding reveals the presence in the Amaryllidaceae of such unexpected alkaloids as those found in some Scefetium species.

B. SYNTHETIC STUDIES The synthesis of mesembrine-type alkaloids belonging to the Sceletium alkaloid family has been carried out extensively in order to seek a

OoMe 6""' OMe

Q

Amisine (379)

q?

HO

0

Mesembrenol(380)

Mesembrenone (381)

FIG.22

4.

THE AMARYLLIDACEAE ALKALOIDS

403

new method for the construction of quaternary carbon centers. As shown in Scheme 42 (187), a formal synthesis of natural (-)-mesembrine (387), in which a key step involves the enantiospecific ring expansion of 2-cyclopropylidene-2-[(3,4-dimethoxy-6-trimethylsilyl)phenyl]ethanol (382) to ( -)-(S)-2-hydroxymethyl-2-[(3,4-dimethoxy)phenyl)cyclobutanone (383), has been reported. Namely, 382 was exposed under asymmetric epoxidation conditions to give 383 in 65% yield. Allylation of 383 through a phenylsulfonyl derivative gave ZS-(but-3-enyl)-2-[(3,4-dimethoxy)phenyl]cyclobutane (384), which was converted into (-)-2S-(but-3-enyl)-2-[(3,4dimethoxy)phenyl]-y-butyrolactone (385) through ozonolysis of the silyl enol ether. Finally, Wacker oxidation of 385 provided (-)-2S-(3-oxobutyl)2-[(3,4-dimethoxy)phenyl]-y-butyrolactone (386), transformation of which to (-)-mesembrine (387) was previously (188) achieved. The synthesis of unnatural (+)-mesembrine (387) through the asymmetric synthesis of methyl (R)-l-[(3,4-dimethoxy)phenyl]-4-oxocyclohex-2-enyl acetate (390) by cycloaddition of enantiomerically pure vinyl sulfoxide with dichloroketene has been performed (189) (Scheme 43). Vinyl sulfoxide 388 [prepared by conjugate addition of enantiopure acetylenic sulfoxide with (3,4-dimethoxy)phenylcopper] reacted with trichloroacetyl chloride in the presence of freshly prepared zinc-copper couple in THF at 0°C to produce a mixture of mono- and dichloro lactones 389. Reduction of 389 with zinc in acetic acid followed by cyclization and methylation afforded methyl 1R[(3,4-dimethoxy)phenyl]-4-oxocyclohex-2-eny1acetate (390), treatment of which with methylamine brought about amidation and concomitant intramolecular Michael addition to provide 2-0x0-mesembrine (391). Successively, 391 was transformed to (+)-mesembrine (387) in 79% yield (three steps; ketalization of an 0x0 group, reduction of lactam, and deketalization)(189). (-)-Mesembrine (387) has been synthesized using thermolysis of an aziridine ester (190). A diastereomeric mixture of 2-[(3,4-dimethoxy)phenyl]-4-(4R)-benzyloxymethyl-y-butyrolactone(392) [obtained from ( S ) - 0 benzylglycidol] was transformed to the lS-benzyloxy-3-[(3,4-dimethoxy) phenyllbut-3-enyl N-benzylaziridine carboxylate 393, thermolysis of which in degassed toluene (in a sealed tube) at 250°C gave, in 85% yield, the pyrrolidine Slactone derivative 394 bearing a quaternary carbon center. Conversion of 394 into 6-benzyloxy-3a-[(3,4-dimethoxy)phenyl]A6*7-tetrahydro-N-methylindolin-5-one (395) was performed in four steps (N-debenzylation, N-methylation and spontaneous reduction of the S lactone, Swern oxidation, and aldol reaction) through intramolecular aldol condensation of a keto-aldehyde. After reduction and subsequent acetylation of 395, Birch reduction gave (-)-mesembrine (387) (Scheme 44) (190). A formal synthesis of (+:)-mesembrine (387) has been performed by means of an intramolecular conjugate addition (146).Namely, condensation

OMe

OMe

382

383

384

60Me - 0

OMe

DL0

0

385

386 (-)-Mesembrine (387) Reagents and Conditions : a) L-(+)-DIPT,Z-BuOOH,Ti(Oi-R)4, MS 4A. CHzClz, -40°C. 65% ( 9 5 % ~;)b) (PhQZ,Bu~P, THF, nflpx. 91% ;c) ethylene glyco1,p-TsOH, benzene. reflux, 88% ; d) m-ClC&CQH, NaHC03, CHzClz,H20, rt ;e) BuLi, ally1 bromide, THF, rt, 91% ;f) p-TsOH, acetone, HzO, reflux, then N a b , MeOH. rt, quantitative ; g) f-BuMqSiOTf, Et3N ;h) Na Wg). NazfIP04, MeOH, R ;i) ByN+F-, THF, rt ;1) Swern oxidation, -78°C.82% ; k) Et3SiOSOZMe, rt ;I) 03, CH2Cl2, -78OC;m) NaBh ;n) 10% H a . rt ;0 ) &,PdClz. CuCl, 2,6-lutidine, CH2CI2. DMF,HzO (Wacker oxidation), rt, quantitative; p) Ref. 187. SCHEME 42

390

389: X = H or CI

388 Ar = 3,4-(MeO)&& M

e

g

o

e

_____)

O

H Me

f-i

M

-

e

0

H Me

391 (+)-Mesembrine (387) Reagents and Conditions : a) %I3CCOCl(3equiv.), Zn-Cu, THF, 0°C ;b) Zn, AcOH, 0°C;c) AcOH,H20, 60°C;d) K2C03, MeOH ; e) CH2N2. Et2O ;f') M e w 2 (excess), THF, reflux, 83% ;g) pyridinium p-toluenesulfonate, EtC(0Me)zMe ;h) LiAW, THF ;i) H30+,then NH3, HzO, 79% (3 steps). SCHEME 43

4.

392

THE AMARYLLIDACEAE ALKALOIDS

393

Bn = C&IsCHz

394

Jq-Q

0

f-i P

405

j-I

BnO

0

H

395

(-)-Mesembrine (387)

Reagents and Conditions : a) LiAW, THF, 0°C ;b) o-N02Q&9eCN, B u g . THF, rt ;i)Br-

CHzCHzBrCOCl, Et3N, CHzCl,, -lO°C, then CfjH5cI%H,m2, rt ; d) 30%Hz@. CHzClz,0°C to rt ;e) 250°C degassed xylene (sealed tube), 85% ;f) 20%Pd(OH)z-C, Hz, MeOH, rt ; g) formalin, MeOH, 0°C then N a b 4 ,0°C to rt ; h) Swern oxidation, -71°C to rt ;i) 0.5N NaOH, EtOH, rt, 75% (2 steps) ;j) N a b , CeCly7Hz0, MeOH, O°C ;k) AczO, Et3N, DMAP, CH~CIZ, 0°C to rt. 76% (2 steps) ;I) Li. liq. N H 3 , -33"C, (27%overall yield). SCHEME 44

of 3-[(3,4-dimethoxy)phenyl]N-methyl-2-methylthiopyrrolidinium iodide (generated by the reaction of pyrrolidine-2-thione 3% with methyl iodide in MeOH) with t-butyl3-oxo-4-pentenoateunder basic conditions produced pyrrolidine derivative 397 and t-butyl A7(7a)-tetrahydroindolin-5-one-7carboxylate (398) in 56 and 17% yield, respectively. Each of 397 and 398, when exposed to CF3C02H under ultrasonication, afforded the same A7mesembrenone (399), which was already (245) transformed to ( 2 ) mesembrine (387) (Scheme 45) (246). There is a report on the synthesis of (2)-mesembrine (387) by a reaction involving aryl rearrangement and Robinson annulation through an enamine (191) (Scheme 46). Reaction of 3-bromo-N-methoxycarbonyl2-methoxypyrrolidine (400) with 1,2-dimethoxybenzene under acidic conditions gave 3-bromo-N-methoxycarbonyl-2-[(3,4-dimethoxy)phenyl]pyrrolidine (401), treatment of which, with silver ion in MeOH, caused

406

OSAMU HOSHINO C

OMe

396

397

398

399

OMe

(k)-Mesembrine (387) Reagents and Conditions : a) MeI, CHzClz ; b) CH2=CHCOCHzC@r-Bu, Et3N, CH2C12, rt, 397 (56%), 398 (17%) ; e) CF3C02H (neat), ultrasound, 71% ;d) C F s Q H (3 equiv.), CHC13, ultrasound, 82% ;e) Ref. 145. SCHEME 45

rearrangement of an aryl group to afford N-methoxycarbonyl-2-[(3,4-dimethoxy)phenyl]-2,3-dehydropyrrolidine(402) in 66%yield. LiAlH4 reduction of 402 gave an enamine, Robinson annulation of which, with methyl vinyl ketone, produced (2)-mesembrine (387). OMe

400

401

402

OMe

(f)-Mesembrine (387)

Reagents and Conditions : a) 1,2-dimethoxybenzene,Htor Lewis acid, 83% ;b) AgN03, MeOH, then H+or reflux, 66%;c) LiALH,, THF, 67% ;d) methyl vinyl ketone, 93%. SCHEME 46

4.

6

8

+

$cozEt

b.f

OUe OMe

OM0

403

407

- g

'

OMe-

COzEt

THE AMARYLLIDACEAE ALKALOIDS

H Me

OMe OMe

405

404

o&

(*)-Mesembrine (387)

Reagenrs and Conditions : a) CHCl3,1,10-phenanthroline,55OC,57% ; b) ethylene glycol,p-TsOH, toluene, rtflux, 88% ; c) LiAH4, EtzO, n, 84%; d) p-TsC1. pyridine. rt, 79% ;e) Bu4N+CN-, HMPA, 8OoC,77% ; f) aq. HCI, THF,rt,94%;g) Ref. 191. SCHEME47

Formation of the quaternary carbon center was also carried out by the reaction of ethyl 4-oxo-cyclohex-~2-ene carboxylate with 3,4-dimethoxyphenyllead triacetate (403) in chloroform containing 1,lO-phenanthroline at 55°C to give ethyl 4-[(3,4-dimethoxy)phenyl]-4-oxocyclohex-2-ene carboxylate (404) in 57% yield. Thus, 4-[(3,4-dimethoxy)phenyl]-4-oxo-cyclohex2-ene carbonitrile (409,which was previously (192) transformed into ( 2 ) mesembrine (387),was obtained in 61% yield from 404 (193) (Scheme 47). The synthesis of (-)- and (+)-mesembrines (387)from 406 by way of 407 using a sequence of reactions involving double Sharpless asymmetric addition and radical-initiated reaction has appeared (194) (Fig. 23). The synthesis of ( -) and (2)-mesembranol (413) has been described in two reports; construction of the quaternary carbon center in the former involved Claisen rearrangement (195) (Scheme 48), whereas that in the latter case was performed by radical-mediated cyclization (148) (Scheme 49). The former synthesis (195) proceeds as follows. (2S,3S,4R))-2-Benzyloxy3,4-O-bis(MOM)-cyclohex-2-enone(408) (derived from D-glucose) reacted OMe

OMe

406

407

Me

0

FIG.23

408

OSAMU HOSHINO

- OMe

OMe

"'"*J$

a, b

MOMO'

f

c-e

MOMO'

HO

Ho& OMOM

MOM0

MOM = MeOCHz BZ = QH&O

408

OMOM

409

410

OMe

OMe

MeHNf18 OMe

OMe

i, I

09 h

b

HO'

OMOM

411

OMOM

(-)-Mesembranol(413)

412

Reagents and Condirions : a) (3,4-MeO)zC&&i, EtzO, -78OC, then NaOMe, McOH, 56%;

b) Pd(OH)Z, H2, EtOAc, 100%;c) l,l'-thiocatgonyldiimidazole,acetone, &lux, 95% ; d) P(OMe)3, EtOAc, reflux, 74% ; e) 30% aq. H Q H , 3OoC, then KzCO3, MeOH. a-OH (39%), POH (18%) ; f) MeCH(OEt)3, E t w H , MS 3A, 135OC. 56% ; g) DIBALH, toluene, -78OC, 82% ;h) 30% aq. MeNH2-MeOH, NaBCNH,, MeOH, rt, 65% ;1) H ~ ( O A C ) ~ , THF,rt, then NaBH4, aq. NaOH, THF, rt, quantitative ;j) aq. Ha-MeOH (1 : 2), rt, 68%.

SCHEME 48

with (3,4-dimethoxy)phenyllithium in ether at -78°C followed by catalytic hydrogenation to afford (lR,2S,3S,4R)-1,2-dihydroxy-3,4-0-bis(MOM)cyclohexanone (409). Conversion of the cis-1,2-dihydroxy groups in 409 into a double bond, followed by selective cleavage of a protecting group, gave a mixture of (4R)-3-hydroxy-4-0-MOM-cyclohexanones (410).The Claisen rearrangement of 410 with triethyl orthoacetate at 136°Cproduced ethyl 4-(1R,4R)-0-MOM-1-[(3,4-dimethoxy)phenyl]cyclohex-2-enyl acetate (411) in 56% yield. Reduction of 411 with DIBALH, followed by reductive amination, furnished (lR,4R)-4-0-MOM-l-[(3,4-dimethoxy) phenyl]-l-[2-(N-methylamino)ethyl]cyclohex-2-enol(412). Acetoxymercuration of 412 with mercury(I1) acetate and treatment with NaBH4 provided 0-MOM-mesembranol, deprotection of which with acid produced (-)-mesembranol (413)in 68% yield (195) (Scheme 48).

4.

'NHMe

414

409

THE AMARYLLIDACEAE ALKALOIDS

-

415

BnO

'ie 0

416

Bn = C&15CH2

(f)-mesembranol(413)

417

Reagents ond Conditions : a) NBS, MeCN-H20 (4 : l), 83% and 10%(regioisomer) ;b) K2CO3, MCOH, rt ;c) 40% aq. MeNH2, MeOH, 100°C, 78% ; d) Cl2CHC0Cl, Et3N, CH2Cl2. rt, 79 9%;

e) p-TsOH, benzene, reflux, 80%and 15% (regioisomer);f) BgSnH, AIBN. toluene, reflux, 51%; g) BH3, THF,reflux ;h) 5% Pd-C, H2 (4 kg/cm2), 68% ;i) Raney Ni (W-2). EtOH, reflux, 81% (3.7 : 1 mixture of a-and p-isomers) ;j) AlH3, THF, rf, 413 (71%), 418 (19%).

SCHEME 49

The second synthetic procedure (148) is shown in Scheme 49. Namely, 4-benzyloxy-l-[(3,4-dimethoxy)phenyl]-2-methylaminocyclohexanol (415) {prepared from 4-benzyloxy-l-~(3,4-dimethoxy)phenyl]cyclohexene(414) by epoxidation and subsequent oxirane ring opening with methylamine} was converted into the N-(methy1)dichloroacetamide 416 in two steps (dichloroacetylation and dehydroxylation with acid). Radical cyclization of 416 with Bu3SnH in boiling toluene containing AIBN produced, in 51% yield, 6-benzyloxymesembran-2-~one (417), reduction of which with borane, followed by catalytic hydrogenation, gave (*)-mesembranol (413) in 68% yield. However, reduction of 417 with Raney nickel gave rise to partial epimerization of a hydroxyl group to yield a mixture of a-and P-hydroxy

410

OSAMU HOSHINO

isomers, which was reduced by combined LIA1H4and aluminum( 111) chloride in THF to afford (t)-mesembranol (413) and (2)-epi-mesembranol (418) in 71 and 17% yield, respectively.

X. Miscellaneous A. PALLIDIFORINE A new heterodimer alkaloid named pallidiforine (419) was isolated as a yellow crystalline compound from whole plants of Narcissus pallidiflorus (76) belonging to the Pseudonarcissus DC section. Its high-resolution mass spectrum indicated the molecular formula CxH40N207 (M', dz.588.2775), suggesting a dimeric structure. The I3C NMR spectrum appeared to be almost exactly superimposable on those of lycoramine (276) (57) and tazettine (298) (296). However, the presence of one carbonyl carbon at 210.5 ppm and the disappearance of the C-11 of the tazettine moiety and that of the N-methyl protons of tazettine or lycoramine were observed. As a result of further examination of the NMR spectrum using 'H-'H (COSY) and lH-13C 2D experiments, its structure 419 was elucidated to be a heterodimer formed by lycoramine and tazettine units linked together. The formation of the alkaloid 419 can be explained by the attack of the nitrogen of N-demethyllycoramine (278) on C-6' of tazettine (298) with opening of the B ring and formation of the keto group (Fig. 24).

Pallidiflorine (419)

Obesine (420) FIG.24

Augustamine (421)

4. THE AMARYLLIDACEAE

ALKALOIDS

411

B. OBESINE Phytochemical studies on Narcissus obesus have resulted in the isolation of a new alkaloid named obesine (420) (see Fig. 24), accompanied by several known Amaryllidaceae alkaloids (74). The stereochemistry and structural determination of the alkaloid 420 have been carried out by spectroscopic analyses and by application of 2D NMR techniques. Although the H-6P proton (6 4.38) is masked by the H-3 proton (6 4.30-4.40), the H-6a proton (6 4.02) was assigned at higher field on the basis of the nuclear Overhauser effect (NOE) with H-12 endo (63.10) observed in the 2D NMR experiment. On the other hand, the a disposition of H-3 was confirmed by the NOE between H-3 (6 4.30-4.40) and H-12 ex0 (6 3.01). In the 13C-NMRspectrum of 420 a characteristic signal due to the C-11 carbon was observed at 82.7 (singlet) ppm. Also, a comparison of the 'H and 13C NMR spectra of obesine (420) with those of the related alkaloid 3-epi-marconine (303) (50) was performed. C. AUCUSTAMINE

Augustamine (421) (see Fig. 24) has been found in Crinum augustum and characterized (8), and its pharmacological properties have received attention (22). However, its absolute stereochemistry remained uncertain. The synthesis of the alkaloid 421 has been achieved using intramolecu) 50). Namely, the relar 2-aza-ally1 anion cycloaddition ( 1 4 2 ~ (Scheme action of the (2-aza-ally1)stannane 189 in a way similar to that reported for the synthesis of (-)-amabiline (145) (see Scheme 17) and subsequent N-methylation with methyl iodide produced 3a-[(3,4-methylenedioxy) phenyl]-4,5-O-isopropylidene-N-methylhexahydroindoline(422) in 82% yield as a 5 : 1 mixture of two diastereomers. Removal of the isopropylidene group with methanolic HC1, followed by treatment with trimethyl orthoformate, afforded the corresponding orthoformate 423, which, without purification, was exposed to methanesulfonic acid in CH2ClZat room temperature to provide (-)-augustamhe (421) in 78% yield (three steps). Thus, this finding established the absolute stereochemistry of the natural alkaloid. D. PHENANTHRIDINE-TYPE ALKALOIDS Ismine (424) and three new phenanthridine derivatives, N-methylcrinasidine (425), 8,9-methylenedioxyphenanthridine (426) and N-methyl-8,9methylenedioxyphenanthridiniumchloride (427), were found in the leaves and bulbs of Lapiedra martinezii (53).The co-occurrence of ismine (424) in the plant gives an indication of the biosynthetic relationship between the four alkaloids (53).The three alkaloids isolated are not artifacts since

412

OSAMU HOSHINO

Ar = 3,4-(CH20z)C,H3

d

____t

r (-)-Augustamine (421)

Reagents and Conditions: a) BuLi (1.9 equiv), THF,-78OC, then Me1 (1.9 equiv), 82% (5 : 1 mixture of two diastereomers) ; b) conc. HCI, MeOH ; c) PPA, CH(OMe)3 ; d) M e S w , CH2C12.78%(3 steps). SCHEME 50

ismine (424) was not metabolized under the extraction conditions employed in this work. Buflavine (428) and 8-demethylbuflavine (429) were isolated for the first time from the bulbs of Boophane$ova. Their structures have been established by spectroscopic ('H and I3CNMR) methods and are representative of the unusual natural Amaryllidaceae alkaloids with an eight-membered Nheterocyclic ring, which had been previously reported only from Galonthus nivalis (197). A new alkaloid phamine (430),which is a phenanthridone alkaloid belonging to the narciclasine group, has been isolated from the bulbs of Hippeastrum equestre along with known Amarylldaceae alkaloids (47). Its structure was determined by spectroscopic (MS, UV, 'H and I3C NMR) analyses. Also, phamine indicated interesting antimitotic activity. The alkaloids isolated since 1987 are shown in Fig. 25. With respect to the synthesis of phenanthrine type alkaloids, 5,6dihydrobicolorine (432) (198),crinasiadine (199),and N-methylcrinasiadine (425) (199) were synthesized using combination of the Suzuki cross coupling reaction and the Bischler-Napieralksi reaction.

4. THE

413

AMARYLLIDACEAE ALKALOIDS

0 OH

Ismine (424)

N-Methylcrinasiadine (425)

Trisphaeridine (426)

427

RO Buflavine (428) R=Me 8-0-Demethylbuflavine (429)

Phamine (430)

431

R=H

("0. 5,dDihydrobicolorine (432)

Bicolorine (433) FIG.25

E.

4-ARYLTETRAHYDROISOQUINOLINE-TYPE ALKALOIDS

Since the previously published review (8), novel 4-aryltetrahydroisoquinoline type alkaloids have not been found in the Amaryllidaceae plants. Only latifine (437) has been isolated from the bulbs of Crinum lafifolium (200). The structure was confirmed by spectroscopic evidence, X-ray crystallographic analysis, and synthesis (198). Regarding synthetic studies, the syntheses of (?)-latifine (437) (200), of (?)-cherylline (440) and (+)-latifine (437) (201), and of (?)-O,Odimethylcherylline (445) and (2:)-0,O-dimethyllatifine (446)(202) have been performed using the Pomeranz-Fritsch-type cyclization (Scheme 51), the Bischler-Napieralski-type reaction (Scheme 52), and intramolecular nucleophilic addition of aryllithium (generated by butyllithium) to a carbony1 group (Scheme 53).

414

OSAMU HOSHINO

OH

OH

a

Me0

Me0

b,c

___)

Meo

H -

Me

Br

BI

43s

(f)-Latifhe (437)

436

Reagenfs and Conditions : a) conc. HCl, EOH, reflux. 63.8%;b) HCQEt, EtOH, K Z W ,MS 3A, reflux ;c) Lim,MeOCH2CHz0Me,reflux, 35.4%. SCHEME 51

F.

JOUBERTIAMINE-TYPE ALKALOIDS

In order to prove the biosynthesis of the Sceletium alkaloids, an extensive study has been carried out using Sceletium subvelutinum L. Bolus that were grown from seed, and the six alkaloids (447-452) (Fig. 26) produced by S. subvelutinum (101) isolated. These six alkaloids were separated chromato-

8-

Me0

d-f

8-c

Me0

Me0

ChH

438

Me0

8-C

___)

M

HO

0 439

e

O

a

(i)-Cherylline (440)

H

C02H

d-f

M e 0 d M e

0

441

442

(*)-Latifine (437)

Reagents and Conditions : a) (COCI)z, benzene, rt ;b) aq. NaN3, acetone, then benzene, reflux ;c)

FOCI3, 90-95"C, then SnCI4,CH&!lz, IT,67%(3 steps) ; d) NaH, benzene, reflux, then MeI, reflux; e) Me& MeSO3H, 5OoC, 50% ; f) LiAIH,, THF, reflux. SCHEME 52

4.

443

THE AMARYLLIDACEAE ALKALOIDS

444

415

(st)-0,O-Dimethylcherylline (445)

OMe

M e 0 a N M e

(k)-0,O-Dimethyllatifine (446) Reagents and Conditions : a) BuLi, THF, -78"C, 77% ; b) HCl, EtOH ;c) NaBH4, 70% (2 steps). SCHEME 53

graphically in order of increasing polarity: 0-methyldehydrojoubertiamine (452), 0-methyljoubertiamine (450), 0-methyldihydrojoubertiamine(448), dehydrojoubertiamine (451), joubertiamine (449), and dihydrojoubertiamine (447). The structures of the alkaloids were characterized by 'H

Dihydrojoubertiamine (447) R=H O-Methyldihydrojoubertiamine (448) R=Me

Joubertiamine (449) R=H O-Methyljoubertiamine (450) R -: Me

FIG. 26

Dehydrojoubertiamine (451) R=H O-Methyldehydrojoubertiamine (452) R=Me

416

OSAMU HOSHINO

NMR and mass spectrometric evidence. Based on the results, the incorporation of radioactivity into the alkaloids was examined, and a key, late biosynthetic intermediate, or a compound that is closely related to that intermediate, was deduced to be the N-methylamine 454 formed from 4hydroxydihydrocinnamic acid by way of the corresponding aldehyde 453 (Scheme 54). As for the synthesis of the joubertiamine-type alkaloids, (-+)-Omethyljoubertiamine (450) has been produced using a transition-metalmediated reaction (203), in which a key step involves the introduction of aryl and 2-dimethylaminoethyl groups by a sequence of two nucleophilic additions to a cationic ($-cyclohexadienyl) iron (1+) intermediate. Namely, treatment of 1,4-dimethoxycyclohexa-1,3-dienecomplex 455 with triphenylmethylium hexafluorophosphate, followed by addition of (4methoxy)phenyllithiumto the resulting cationic complex at -78"C, afforded the (4-methoxy)phenyl adduct 456. The adduct 456 was treated with CF3C02H and then ammonium hexafluorophosphate (NH4PF6)to produce the salt, cyanomethylation of which with the lithium enolate of triethylsilyl cyanoacetate and subsequent treatment with TBAF afforded the cyanomethyl complex. Catalytic hydrogenation of the cyanomethyl complex with hydrogen and Raney nickel in the presence of dimethylamine afforded the 2-dimethylaminoethyl complex 457 in 60% yield, demetalation of which, using anhydrous trimethylamine N-oxide, followed by hydrolysiswith oxalic

9 $= OH

+ NHMe

0

CHO

453

, ,,

454

SCHEME 54

4.

455

417

THE AMARYLLIDACEAE ALKALOIDS

456

457

(k)-O-Methyljoubertiamine (450) Reagents and Conditions : a) Ph+?PFi, then 4-Me0w4Li, 85% ;b) CF3C$H, W P F 6 , 94%; c) Li’[CN~C02(CH2hSiMe,]-, then f-Bu4NF, 84%;d) Raney Ni, H2, MQNH, 609%; e) Et3N0, then (C02H)2,92%. SCHEME 55

acid, furnished (2)-O-methyljoubertiamine (450) in 92%yield. The overall yield was 40% (seven steps from 455) (Scheme 55) (203). In another report (193), (+)-O-methyljoubertiamine (450) has been prepared from the intermediate 404 (see Scheme 47) employed for the synthesis of (2)-mesembrine (387).

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I

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418

OSAMU HOSHINO

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4.

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419

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420

OSAMU HOSHINO

70. J. Via, M. I. Arriortua, L. E. Ochando, M. M. Reventos, J. M. Arnigo, and J. Bastida, Acta Crystullogr., Secr. C 45, 2020 (1989). 71. J. Bastida, F. Viladomat, J. M. Llabrks, C. Codina, and M. Rubiralta, Pluntu Med. 54, 362 (1988). 72. J. Bastida, F. Viladomat, S . Bergoiion, J. M. Ferndndez, C. Codina, M. Rubiralta, and J.-C. Quirion, Phytochemistry 32, 1656 (1993). 73. C. M i a , J. Bastida, F. Viladomat, J. M. Fernandez, S . Bergonon, M. Rubiralta, and J.-C. Quirion, Phyrochemistry 32, 1345 (1993). 74. J. Bastida, F. Viladomat, J. M. Llabrks, S . Quiroga, C. Codina, and M. Rubiralta, Pluntu Med. 56,123 (1990). 75. F. Viladomat, J. Bastida, C. Codina, M. Rubiralta, and J.-C. Quirion, J. Nut. Prod. 55, 804 (1992). 76. C. Codina, F. Viladomat, J. Bastida, M. Rubiralta, and J.-C. Quirion, Phytochemistry 29,2685 (1990). 77. J. Bastida, J. M. Llabrds, F. Viladomat, C. Codina, G. Ramirez, and M. Rubiralta, J. Nut. Prod. 52, 478 (1989). 78. J. Bastida, C. Codina, F. Viladomat, M. Rubiralta, J.-C. Quirion, and B. Weniger, J. Nut. Prod. 55, 134 (1992). 79. J. Bastida, C. Codina, F. Viladomat, M. Rubiralta, J.-C. Quirion, H. P. Husson, and G. Ma, J. Nut. Prod. 53, 1456 (1990). 80. C. Codina, F. Viladomat, J. Bastida, and J.-C. Quirion, Plunta Med. 56,515 (1990). 81. R. Suau, R. Rim, A. I. Garcia, and A. I. Gbmez, Heterocycles 31,517 (1990). 82. J. Bastida, S. Bergoilon, F. Viladomat, and C. Codina. Pluntu Med. 60,95 (1994). 83. M. Kreh, R. Matusch, and L. Witte, Phyrochemistry 40,1303 (1995). 84. M. Kreh, R. Matusch, and L. Witte, Phytochemistry 38,773 (1995). 85. E. Tojo, J. Nut. Prod. 54, 1387 (1991). 86. J. Bastida, J. M. Llabrb, F. Viladomat, C. Codina, M. Rubiralta, and M. Feliz, Pluntu Med. 54,524 (1988). 87. G. M. Tokhtabaeva, V. I. Sheichenko, I. V. Yartseva, and 0. N. Tolkachev, Khim. Prir. Soedin. 872 (1987); Chem. Abstr. 109,89687 (1988). 88. A. Evidente, R. Lanzelta, A. H. Abou-Donia, M. E. Amer, F. F. Kassem, and F. M. Harraz, Arch. Phurmucol. 327,595 (1994); Chem. Abstr. 120,200918 (1994). 89. 0. M. Abdallah, Phytochemistry 34,1447 (1993). 90. A. A. Abou-Donia, F. A. Darwish, and N. M. Ghazy, Alexandria J. Phurm. Sci. 3,122 (1989); Chem. Absrr. 112,95556 (1990). 91. J. Bastida, C. Codina, F. Viladomat, M.RubiTalta, J.-C. Quirion, and H.-P. Husson, Phytochemistry 29,2683 (1990). 92. J. Bastida, J. M. Femlndez, F. Viladomat, C. Codina, and G. de la Fuente, Phytochemistry 38,549 (1995). 93. J. Bastida, C. Codina, F. Viladomat, M. Rubiraka, J.-C. Quirion, and B. Weniger, J. Nut. Prod. 55, 122 (1992). 94. S. KOnUkol and B. Sener, J. Fac. Phurm. Guzi Univ. 9, 89 (1992): Chem. Abstr. 118, 241047 (1993). 95. B.Sener,S.KOnUkol,C.Kruk, andU.K.Pandit,Arch. Pburm. (Weinheim)326,61(1993). 96. A. H. Abou-Donia, A. De Giulio, A. Evidente, M. Gaber, A.-A. Habib, R. Lanzetta, and A. A. Seif El Din, Phytochemistry 30,3445 (1991). 97. M. P. V. Tato, L. Castedo. and R. Riguera, Heterocycles 27,2883 (1988). 98. B. Sener, S. KOnUkol, C. Kruk, P. Cornelis, K. Upendra, Nut. Prod. Lett., 287 (1993); Chem. Absrr. 119,221660 (1993). 99. B. Sener, S . KOnUkol, C. Kruk, and U. K. Pandit, J. Fuc. Phurm. Guzi Univ. 10, 83 (1993); Chem. Absrr. 120,319346 (1994).

4.

THE AMARYLLIDACEAE ALKALOIDS

42 1

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422

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J. Nut. Prod. 47, 796 (1984); S. Ghosal, R. Lochan, Ashutosh, Y. Kumar, and R. S . Srivastava, Phytochemistry 24, 1825 (1985). 131. R. H. Hutchings and A. I. Meyers, J. Org. Chem. 61,1004 (1996). 132. S. Ghosal, P. H. Rao, D. K.Taiswal, Y. Kumar, and A. W. Fraham, Phytochemistry u),

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THE AMARYLLIDACEAE ALKALOIDS

423

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424

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200. S . Kobayashi, T. Tokumoto, S. Iguchi, M. Hihara, Y. Imakura, and Z. Taira, J. Chem. Res. ( S ) , 280 (1986). 201. J. Katakawa, H. Yokomatsu, M. Yoshida, Y. Zhang, H. Irie, and H. Yajima, Chem. Pharm. Bull. 36,3928 (1988). 202. M. Kihara, M. Kashimoto, Y. Kobayashi, and S. Kobayashi, Tetrahedron Lett. 31, 5347 (1990). 203. G . R. Stephenson, H. Finch, D. A. Owen, and S.Swanson, Tetrahedron 49,5649 (1993).

CUMULATIVE INDEX OF TITLES

Aconitum alkaloids, 4,275 (1954), 7,473 (1960), 34, 95 (1988) CI9diterpenes, 12,2 (1970) C ~ diterpenes, O 12,136 (1970) Acridine alkaloids, 2, 353 (1952) Acridone alkaloids, experiment a1 antitumor activity of acronycine, 21, 1 (1983) N-Acyliminium ions as intermediates in alkaloid synthesis, 32, 271 (1988) Ajmaline-Sarpagine alkaloids, 8,789 (1965), 11,41 (1968) enzymes in biosynthesis of, 47,116 (1995) Alkaloid chemistry, synthetic studies, 50, 377 (1998) Alkaloid production, plant biotechnology of, 40, 1 (1991) Alkaloid structures spectral methods, study, 24,287 (1985) unknown structure, 5,301 (1955), 7,509 (1960), 10,545 (1967), 12,455 (1970), 13,397 (1971), 14, 507 (1973), 15,263 (1975), 16,511 (1977) X-ray diffraction, 22,51 (1983) Alkaloids biosynthesis, regulation of, 49,222 (1997) biosynthesis, molecular genetics of, 50,258 (1998) containing a quinolinequinone unit, 49, 79 (1997) containing a quinolinequinoneimine unit, 49,79 (1997) ecological activity of, 47, 227 (1995) forensic chemistry of, 32, 1 (1988) histochemistry of, 39, 1 (1990) in the plant, 1, 15 (1950), 6, 1 (1960) plant biotechnology, production of, 50,453 (1998) Alkaloids from amphibians, 21,139 (1983), 43,185 (1993) ants and insects, 31, 193 (1987) Chinese traditional medicinal plants, 32, 241 (1988) mammals, 21,329 (1983), 43,119 (1993) marine organisms, 24,25 (1985), 41,41 (1992) medicinal plants of New Caledonia, 48, 1 (1996) plants, 49,301 (1997) plants of Thailand, 41, 1 (1992) Allelochemical properties or the raison d’Ctre of alkaloids, 43, 1 (1993) 425

426

CUMULATIVE INDEX OF TITLES

A110 congeners, and tropolonic Colchicum alkaloids, 41, 125 (1992) Alsfonia alkaloids, 8,159 (1965), 12,207 (1970), 14,157 (1973) Amaryllidaceae alkaloids, 2,331 (1952), 6,289 (1960), 11,307 (1968), 15, 83 (1975), 30,251 (1987), 51,323 (1998) Amphibian alkaloids, 21,139 (1983), 43,185 (1983), 50,141 (1998) Analgesic alkaloids, 5, 1 (1955) Anesthetics, local, 5,211 (1955) Anthranilic acid derived alkaloids, 17, 105 (1979), 32,341 (1988), 39,63 (1990) Antifungal alkaloids, 42,117 (1992) Antimalarial alkaloids, 5, 141 (1955) Antitumor alkaloids, 25,l (1985) Apocynaceae alkaloids, steroids, 9, 305 (1967) Aporphine alkaloids, 4,119 (1954), 9 , l (1967), 24,153 (1985) Aristolochiu alkaloids, 31,29 (1987) Aristotelia alkaloids, 24, 113 (1985), 48,249 (1996) Aspergillus alkaloids, 29, 185 (1986) Aspidosperma alkaloids, 8,336 (1965), 11,205 (1968), 17,199 (1979) synthesis of, 50,343 (1998) Aspidospermine group alkaloids, 51, 1 (1998) Azafluoranthene alkaloids, 23, 301 (1984) Bases simple, 3,313 (1953), 8, 1 (1965) simple indole, 10,491 (1967) simple isoquinoline, 4, 7 (1954), 21, 255 (1983) Benzodiazepine alkaloids, 39, 63 (1990) Benzophenanthridine alkaloids, 26,185 (1985) Benzylisoquinoline alkaloids, 4, 29 (1954), 10, 402 (1967) Betalains, 39, 1 (1990) Biosynthesis in Cutharunthus roseus, 49,222 (1997) isoquinoline alkaloids, 4, 1 (1954) pyrrolizidine alkaloids, 46,l (1995) quinolizidine alkaloids, 46,1 (1995) tropane alkaloids, 44,116 (1993) in Rauwolfia serpentinu, 47, 116 (1995) Bisbenzylisoquinoline alkaloids, 4, 199 (1954), 7,429 (1960), 9, 133 (1967), 13,303 (1971), 16,249 (1977), 30, 1 (1987) synthesis, 16,319 (1977) Bisindole alkaloids, 20, 1 (1981) noniridoid, 47, 173 (1995)

CUMULATIVE INDEX OF TITLES

427

Bisindole alkaloids of Catharunthus C-20’ position as a functional hot spot in, 37, 133 (1990) isolation, structure elucidation and biosynthesis, 37, 1 (1990) medicinal chemistry of, 37, 145 (1990) pharmacology of, 37,205 (1990) synthesis of, 37,77 (1990) therapeutic use of, 37,229 (1990) Buxus alkaloids, steroids, 9,305 (1967), 1 4 , l (1973), 32,79 (1988) Cactus alkaloids, 4,23 (1954) Calabar bean alkaloids, 8,27 (1965), 10,383 (1967), 13,213 (1971), 36, 225 (1989) Calabash curare alkaloids, 8, 515 (1965), 11,189 (1968) Calycanthaceae alkaloids, 8,581 (1965) Camptothecine, 21,101 (1983), 50,509 (1998) Cancentrine alkaloids, 14,407 (1973) Cannabis sativa alkaloids, 34,77 (1988) Canthin-6-one alkaloids, 36, 135 (1989) Cspsieurn alkalds, 23, 227 (1984) Carbazole alkaloids, 13,273 (1971), 26, 1 (1985) chemistry and biology of, 44,257 (1993) Carboline alkaloids, 8,47 (1965), 26, 1 (1985) P-Carboline congeners and Ipecac alkaloids, 22,l (1983) Cardioactive alkaloids, 5, 79 (1955) Catharanthus roseus biosynthesis of terpenoid indole alkaloids in, 49,222 (1997) Celastraceae alkaloids, 16,215 (1977) Cephalotaxus alkaloids, 23, 157 (1984), 51, 199 (1998) Cevane group of Veratrum alkaloids, 41,177 (1992) Chemosystematics of alkaloids, 50, 537 (1998) Chemotaxonomy of Papaveraceae and Fumariaceae, 29,l (1986) Chinese medicinal plants, alkaloids from, 32,241 (1988) Chromone alkaloids, 31,67 (1988) Cinchona alkaloids, 3,l (1953), 14, 181 (1973), 34,332 (1988) Colchicine, 2, 261 (1952), 6, 247 (1960), 11,407 (1968), 23, 1 (1984) Cofchicum alkaloids and all0 congeners, 41, 125 (1992) Configuration and conformation, elucidation by X-ray diffraction, 22,51 (1983) Corynantheine, yohimbine, and related alkaloids, 27, 131 (1986) Cularine alkaloids, 4,249 (19541, 10,463 (1967), 29,287 (1986) Curare-like effects, 5,259 (1955) Cyclic tautomers of tryptamine and tryptophan, 34, 1 (1988) Cyclopeptide alkaloids, 15, 165 (1975)

428

CUMULATIVE INDEX OF TITLES

Daphniphyllum alkaloids, 15,41 (1975), 29,265 (1986) Delphinium alkaloids, 4,275 (1954), 7,473 (1960) Clo-diterpenes,12,2 (1970) Go-diterpenes, 12,136 (1970) Dibenzazonine alkaloids, 35, 177 (1989) Dibenzopyrrocoline alkaloids, 31, 101 (1987) Diplorrhyncus alkaloids, 8,336 (1965) Diterpenoid alkaloids Aconitum, 7,473 (1960), l2,2 (1970), 12,136 (1970), 34,95 (1988) Delphinium, 7,473 (1960), l2,2 (1970), 12, 136 (1970) Garrya, 7,473 (1960), l2,2 (1960), 12,136 (1970) chemistry, 18,99 (1981), 42,151 (1992) general introduction, 12, xv (1970) structure, 17, 1 (1970) synthesis, 17, 1 (1979) Eburnamine-vincamine alkaloids, 8,250 (1965), 11, 125 (1968), 20,297 (1981), 42, 1 (1992) Ecological activity of alkaloids, 47,227 (1995) Elaeocarpus alkaloids, 6,325 (1960) Ellipticine and related alkaloids, 39,239 (1990) Enamide cyclizations in alkaloid synthesis, 22, 189 (1983) Enzymatic transformation of alkaloids, microbial and in vitro, 18, 323 (1981) Ephedra alkaloids, 3, 339 (1953) Epibatidine, 46, 95 (1995) Ergot alkaloids, 8,726 (1965), 1 5 , l (1975), 38 1 (1990), 50,171 (1998) Erythrina alkaloids, 2, 499 (1952), 7, 201 (1960), 9,483 (1967), 18, 1 (1981), 48,249 (1996) Erythrophleum alkaloids, 4,265 (1954), 10,287 (1967) Eupomatia alkaloids, 24,1 (1985) Forensic chemistry, alkaloids, 12,514 (1970) by chromatographic methods, 32,l (1988) Galbulimima alkaloids, 9,529 (1967), 13,227 (1971) Gardneria alkaloids, 36, 1 (1989) Garrya alkaloids, 7,473 (1960), 12,2 (1970), 12, 136 (1970) Geksospermum alkaloids, 8, 679 (1965) Gelsemiurn alkaloids, 8, 93 (1965), 33,84 (1988), 49,l (1997) Glycosides, monoterpene alkaloids, 17,545 (1979) Guatteria alkaloids, 35, 1 (1989)

CUMULATIVE INDEX OF TITLES

429

Haplophyton cimicidum alkaloids, 8,673 (1965) Hasubanan alkaloids, 16,393 (1977), 33,307 (1988) Histochemistry of alkaloids, 39, 165 (1990) Holarrhena group, steroid alkaloids, 7,319 (1960) Hunteria alkaloids, 8,250 (1965) Zboga alkaloids, 8, 203 (1965), 11, 79 (1968) Imidazole alkaloids, 3,201 (1953), 22,281 (1983) Indole alkaloids, 2, 369 (1952), 7, 1 (1960), 26, 1 (1985) biomimetic synthesis of, 50,415 (1998) biosynthesis in Carharanthus roseus, 49,222 (1997) biosynthesis in Rauwolfia serpenfina, 47,116 (1995) distribution in plants, 11, 1 (1968) simple, 10,491 (1967), 26,l (1985) Reissert synthesis of, 31, 1 (1987) Indolizidine alkaloids, 28, 183 11986), 44, 189 (1993) In vitro and microbial enzymatic transformation of alkaloids, 18,323 (1981) 2,2’-Indolylquinuclidinealkaloids, chemistry, 8,238 (1965), 11,73 (1968) Ipecac alkaloids, 3,363 (1953), 7,419 (1960), 13,189 (1971), 22,l (1983), 51,271 (1998) Isolation of alkaloids, 1, 1 (1950) Isoquinoline alkaloids, 7,423 (1960) biosynthesis, 4 , l (1954) I3C-NMR spectra, 18,217 (1981) simple isoquinoline alkaloids. 4, 7 (1954), 21,255 (1983) Reissert synthesis of, 31, 1 (1987) Isoquinolinequinones, from Actinomycetes and sponges, 21, 55 (1983) Khat (Catha edulis) alkaloids, 39, 139 (1990) Kopsia alkaloids, 8, 336 (1965) Lead tetraacetate oxidation in alkaloid synthesis, 36,70 (1989) Local anesthetics, 5, 211 (1955) Localization in the plant, 1, 15 (1950), 6 , l (1960) Lupine alkaloids, 3, 119 (1953), 7,253 (1960), 9,175 (1967), 31,16 (1987), 47,2 (1995) Lycopodium alkaloids, 5,265 (1955), 7,505 (1960), 10,306 (1967), 14, 347 (1973), 26,241 (1985), 45,233 (1994) Lythraceae alkaloids, 18, 263 (1981), 35, 155 (1989) Macrocyclic peptide alkaloids from plants, 26,299 (1985) 49,301 (1997) Mammalian alkaloids, 21,329 (1 983), 43, 119 (1993) Manske, R. H. F., biography of 50,3 (1998) Marine alkaloids, 24,25 (1985), 41,41 (1992)

430

CUMULATIVE INDEX OF TITLES

Maytansinoids, 23, 71 (1984) Melanins, 36,254 (1989) Melodinus alkaloids, 11,205 (1968) Mesembrine alkaloids, 9,467 (1967) Metabolic transformation of alkaloids, 27, 323 (1986) Microbial and in vitro enzymatic transformation of alkaloids, 18, 323 (1981) Mitragyna alkaloids, 8,59 (1965), 10,521 (1967), 14,123 (1973) Monoterpene alkaloids, 16,431 (1977) glycosides, 17, 545 (1979) Morphine alkaloids, 2, 1 (part 1, 1952), 2, 161 (part 2, 1952), 6,219 (1960), 13,l (1971), 45,127 (1994) Muscarine alkaloids, 23, 327 (1984) Mushrooms, alkaloids from, 40,190 (1991) Mydriatic alkaloids, 5,243 (1955) a-Naphthophenanthridine alkaloids, 4,253 (1954), 10,485 (1967) Naphthylisoquinoline alkaloids, 29,141 (1986), 46,127 (1995) Narcotics, 5, 1 (1955) New Caledonla, alkaloids from the medkhai plants of, 48,l (1996) Nuphar alkaloids, 9,441 (1967), 16,181 (1977), 35,215 (1989) Ochrosia alkaloids, 8,336 (1965), 11,205 (1968) Ourouparia alkaloids, 8,59 (1965), 10, 521 (1967) Oxaporphine alkaloids, 14,225 (1973) Oxazole alkaloids, 35,259 (1989) Oxindole alkaloids, 14,83 (1973) Papaveraceae alkaloids, 19,467 (1967), 12,333 (1970), 17,385 (1979) pharmacology, 15,207 (1975) toxicology, 15,207 (1975) Pauridiantha alkaloids, 30,223 (1987) Pavine and isopavine alkaloids, 31,317 (1987) Pentaceras alkaloids, 8,250 (1965) Peptide alkaloids, 26,299 (1985), 49,301 (1997) Phenanthrene alkaloids, 39, 99 (1990) Phenanthroindolizidine alkaloids, 19, 193 (1981) Phenanthroquinolizidine alkaloids, 19,193 (1981) 6-Phenethylamines,3,313 (1953), 35,77 (1989) Phenethylisoquinoline alkaloids, 14,265 (1973), 36,172 (1989) Phthalideisoquinoline alkaloids, 4, 167 (1954), 7,433 (1960), 9, 117 (1967), 24,253 (1985) Picralima alkaloids, 8, 119 (1965), 10, 501 (1967), 14, 157 (1973)

CUMULATIVE INDEX OF TITLES

431

Piperidine alkaloids, 26, 89 (1985) Plant biotechnology, for alkaloid production, 40, 1 (1991), 50,453 (1998) Plant systematics, 16, 1 (1977) Pleiocarpa alkaloids, 8,336 (1965), 11,205 (1968) Polyamine alkaloids, 22,85 (1983), 45,l (1994), 50,219 (1998) biology of, 46,63 (1995) Pressor alkaloids, 5,229 (1955) Protoberberine alkaloids, 4,77 (1954), 9,41 (1967), 28,95 (1986) biotransformation of, 46,273 (1995) transformation reactions of, 33,141 (1988) Protopine alkaloids, 4,147 (1954), 34,181 (1988) Pseudocinchorna alkaloids, 8, 694 (1965) Pseudodistomins, 50,317 (1998) Purine alkaloids, 38,226 (1990) Pyridine alkaloids, 1, 165 (1950), 6, 123 (1960), 11, 459 (1968), 26, 89 (1985) Pyrrolidine alkaloids, 1,91 (1950), 6, 31 (1960), 27, 270 (1986) Pyrralizidine alkaloids, 1,107 (1950), 6,35 (1960), 12,246 (1970), 26,327 (1985) biosynthesis of, 46,1 (1995) Quinazolidine alkaloids, see Indolizidine alkaloids Quinazoline alkaloids, 3, 101 (1953), 7,247 (1960), 29, 99 (1986) Quinazolinocarbolines, 8, 55 (1965), 21, 29 (1983) Quinoline alkaloids related to anthranilic acid, 3, 65 (1953), 7, 229 (1960), 17, 105 (1979), 32,341 (1988) Quinolinequinone alkaloids, 49,79 (1997) Quinolinequinoneimine alkaloids, 49, 79 (1997) Quinolizidine alkaloids, 28, 183 (1985), 47, 1 (995) biosynthesis of, 46, 1 (1995) Rauwolfia alkaloids, 8,287 (1965) biosynthesis of, 47,116 (1995) Reissert synthesis of isoquinoline and indole alkaloids, 31, 1 (1987) Reserpine, chemistry, 8,287 (1965) Respiratory stimulants, 5, 109 (1955) Rhoeadine alkaloids, 28, 1 (1986) Salarnandra group, steroids, 9,427 (1967) Sarpagine-type alkaloids, 49, 1 ( 1997) Sceletiurn alkaloids, 19, 1 (1981)

432

CUMULATIVE INDEX OF TITLES

Secoisoquinoline alkaloids, 33, 231 (1988) Securinegu alkaloids, 14,425 (1973) Senecio alkaloids, see Pyrrolizidine alkaloids Simple indole alkaloids, 10,491 (1967) Simple indolizidine alkaloids, 28, 183 (1986), 44, 189 (1993) Sinomenine, 2, 219 (1952) Solunum alkaloids chemistry, 3,247 (1953) steroids, 7,343 (1960), 10,l (1967), 19,81 (1981) Sources of alkaloids, 1, 1 (1950) Spectral methods, alkaloid structures, 24,287 (1985) Spermidine and related polyamine alkaloids, 22, 85 (1983) Spermine and related polyamine alkaloids, 22,85 (1983) Spider toxin alkaloids, 45,l (1994), 46,63 (1995) Spirobenzylisoquinolinealkaloids, 13, 165 (1971), 38, 157 (1990) Sponges, isoquinolinequinone alkaloids from, 21,55 (1983) Stemonu alkaloids, 9, 545 (1967) Steroid alkaloids Apocynaceae, 9,305 (1967), 32,79 (1988) Buxus group, 9,305 (1967), 14, 1 (1973), 32,79 (1988) chemistry and biology, 50,61 (1998) Holurrhenu group, 7,319 (1960) Sulumundru group, 9,427 (1967) Solunum group, 7,343 (1960), 10,l (1967), 19,81 (1981) Verufrum group, 7,363 (1960), 10,193 (1967), 14,l (1973), 41,177 (1992) Stimulants respiratory, 5, 109 (1955) uterine, 5,163 (1955) Structure elucidation, by X-ray diffraction, 22, 51 (1983) Strychnos alkaloids, 1,375 (part 1, 1950), 2, 513 (part 2, 1952), 6, 179 (1960), 8,515, 592 (1965), 11,189 (1968), 34,211 (1988), 36,1 (1989), 48,75 (1996) Sulfur-containingalkaloids, 26,53 (1985), 42, 249 (1992) Synthesis of alkaloids, Enamide cyclizations for, 22, 189 (1983) Lead tetraacetate oxidation in, 36, 70 (1989) Tubernuemontuna alkaloids, 27, 1 (1983) Taxol, 50,509 (1998) Taxus alkaloids, 10, 597 (1967), 39, 195 (1990) Terpenoid indole akaloids, 49,222 (1997) Thailand, alkaloids from the plants of, 41, 1 (1992)

CUMULATIVE INDEX OF TITLES

433

Toxicology, Papaveraceae alkaloids, 15,207 (1975) Transformation of alkaloids, enzymatic microbial and in vitro, 18, 323 (1981) Tropane alkaloids biosynthesis of, 44,115 (1993) chemistry, 1,271 (1950), 6,145 (1960), 9,269 (1967), 13,351 (1971), 16,83 (1977), 33,2 (1988), 44,1 (1993) Tropoloisoquinoiine alkaloids, 23,301 (1984) Tropolonic Colchicum alkaloids, 23, 1 (1984), 41, 125 (1992) Tylophoru alkaloids, 9, 517 (1967) Unnatural alkaloid enantiomers, biological activity of, 50, 109 (1998) Uterine stimulants, 5, 163 (1955) Verutrum alkaloids cevane group of, 41,177 (1992) chemistry, 3,247 (1952) steroids, 7,363 (1960), 10,193 (1967), 14,l (1973) Vincu alkaloids, 8,272 (1965), 11,99 (1968), 20,297 (1981) Voucungu alkaloids, 8,203 (1965), 11,79 (1968) Wasp toxin alkaloids, 45,l (1994), 46,63 (1995) X-ray diffraction of alkaloids, 22, 51 (1983) Yohimbe alkaloids, 8,694 (1965), 11,145 (1968), 27,131 (1986)

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INDEX

Alancine, chemistry and synthesis, 281-285 Alangicine, chemistry and synthesis, 288 Alangimarckine, chemistry and synthesis, 290-291 Alangiside, chemistry and synthesis, 291-292 Alangium plants, chemistry and synthesis, 292-296 Amaryllidaceae alkaloids, 324-417 crinine-type alkaloids, relationship, 362-368 biological activity, 368 isolation and structure elucidation, 362-365 synthetic studies, 365-368 galanthamine-type alkaloids, relationship, 382-386 biological activity, 386 isolation and structure elucidation, 382-383 synthetic studies, 384-386 introduction and botanical sources, 324-342 lycorenine-type alkaloids, relationship, 391-392 isolation and structure elucidation, 391-392 lycorine-type alkaloids, relationship, 342-362 biological activities, 360-362 isolation and structure elucidation, 342-347 synthetic studies, 348-360 mesembrine-type alkaloids, relationship, 393-410 isolation and structure elucidation, 402 synthetic studies, 402-410 miscellaneous, 410-417 4-aryltetrahydroisoquinoline-type alkaloids, 413 augustamine, 411 jouvertiamine-type alkaloids, 414-417 435

obsesine, 411 pallidiforine, 410 phenanthridine-type alkaloids, 411-412 montanine-type alkaloids, relationship, 393-402 isolation and structure elucidation, 393 synthetic studies, 393-402 narciclasine-type alkaloids, relationship, 369-382 isolation and structure elucidation, 369 synthetic studies, 370-381 tazettine-type alkaloids, relationship, 387-391 biological activity, 391 isolation and structure elucidation, 387-388 synthetic studies, 388-391 Anhydroharringtonine, cephalotaxine esters, 235-236 Ankorine, chemistry and synthesis, 281-285 4-Aryltetrahydroisoquinoline-type alkaloids, Amaryllidaceae alkaloids, relationship, 413 Aspidofractinine isolation and structure determination, 41-49 total synthesis, 152-159 seco-Aspidofractinine,isolation and structure determination, 49-52 2,7-seco-Aspidospermidinederivatives, oxidized, isolation and structure determination, 28-30 Aspidospermine group, 2-186 introduction, 2-21 isolation and structure determination, 21-55 alkaloids, 24-28 seco-aspidofractininegroup, 49-52 aspidofractinine group, 41-49 (2,7-seco)aspidospermidine derivatives, oxidized, 28-30

436

INDEX

Aspidospermine group (continued) derivatives degraded, 30 rearrangement, 28 seco-fruticosine alkaloids, 55-56 fruticosine derivatives, 55 seco-kopsine derivatives, 55-56 kopsine derivatives, 55 quebrachamine group, 21-24 quinoline alkaloids, biogenetically related, 52-55 secodine derivatives, 21 vincadifformine derivatives, rearranged and oxidized, 38-40 -tabersonine group, 30-38 vindolinine group, 40-41 rearrangement and transformation, 56-92 baloxine, partial synthesis, 79-80 kitraline, partial synthesis, 68-70 kitramine, partial synthesis, 68-70 meloscine, partial synthesis, 80-85 minovincine, partial synthesis, 68-70 pachysiphine, partial synthesis, 88 quebracharnine, 56-57 ring C, enlargement, 92 rings D and E, functionalization, 71-75 scandine, partial synthesis, 80-85 strempeliopine, synthesis and configuration, 89-92 tabersonine, reactions, 76 vincadifformine conversion into goniomitine ring system, 78-79 reactions, 76 vincamine and derivatives, 63-68 vincatine, structure and stereochemistry, 76-78 vincoline, partial synthesis, 68-70 vindoline and derivatives, 57-60 fragmentation, 61-63 vindolinine, fragmentation, 61-63 vindorosine, partial synthesis, 85-88 total synthesis, 92-163 aspidofractinine group, 152-159 derivatives, 110-127 kopsine group, 159-163 meloscine group, 159 quebrachamine, 102-110

secodine, synthesis, 94-102 vallesamidine group, 152 vincadifformine group, 132-150 vindoline, 127-132, 150-152 vindolinine group, 150-151 vindorosine, 127-132 Augustamine, Amaryllidaceae alkaloids, relationship, 411

Baloxine, partial synthesis, 79-80

Cephaeline, chemistry and synthesis, 289 Cephalotaxine esters anhydroharringtonine, 235-236 deoxyharringtonine, 231-233 harringtonine, 224-227 homoharringtonine, 228-230 isoharringtonine, 233-234 neoharringtonine, 235-236 synthesis, 224-236 Cephalotarine ring system, synthesis, model studies, 236-254 Cephalotaxus alkaloids, 199-264 analytic and spectroscopic studies, 261-262 cephalotaxine esters, synthesis, 224-236 anhydrohamngtonine, 235-236 deoxyhamngtonine, 231-233 harringtonine, 224-227 homohamngtonine, 228-230 isoharringtonine, 233-234 neoharringtonine, 235-236 cephalotaxine ring system, synthesis, model studies, 236-254 esters, antitumor activity, 254-261 introduction, 199-200 isolation and structures, 200-207 pharmacological and clinical studies, 262-264 synthesis, 208-224 Cephulotuxus esters, antitumor activity, 254-261 Crinine-type alkaloids Amaryllidaceae alkaloids, relationship, 362-368 biological activity, 368

INDEX

isolation and structure elucidation, 362-365 synthetic studies, 365-368

Demethylcephaeline, chemistry and synthesis, 289 10-Demethyldeoxytubulosine,chemistry and synthesis, 290-291 9-Demethylprotoemetinol,chemistry and synthesis, 281-285 10-Demethylprotoemetinol, chemistry and synthesis, 281-285 9-Demethylpsychotrine,chemistry and synthesis, 288 9-Demethyltubulosine,chemistry and synthesis, 289-290 10-Demethyltubulosine,chemistry and synthesis, 289-290 Deoxyhamngtonine, cephalotaxine esters, 231-233 Deoxytubulosine, chemistry and synthesis, 290-291

Emetamine, chemistry and synthesis, 285-288 Emetine, chemistry and synthesis, 285-288

seco-Fruticosine alkaloids, isolation and structure determination, 55-56 Fruticosine derivatives, isolation and structure determination, 55

Galanthamine-type alkaloids Amaryllidaceae alkaloids, relationship, 382-386 biological activity, 386 isolation and structure elucidation, 382-383 synthetic studies, 384-386 Goniomitine ring system, vincadifformine conversion into, 78-79

437

Hamngtonine, cephalotaxine esters, 224-227 Homoharringtonine, cephalotaxine esters, 228-230

Ibophyllidine chemistry, 169 -iboxyphylline group, synthesis, 180-186 Occurrence and structure, 168 Iboxyphylline -ibophyllidine, synthesis, 180-186 occurrence and structure, 168-169 19-Iodotabersonine, solvolysis, 61-63 Ipecac alkaloids, 271-321 addendum, 307-308 analytical methods, 299 biological activity, 305-307 biosynthesis, 300-305 chemistry and synthesis, 281-296 alancine, 281-285 alangicine, 288 alangimarckine, 290-291 alangiside, 291-292 Alungium plants, related alkaloids of, 292-296 ankorine, 281-285 cephaeline, 289 demethylcephaeline, 289 10-demethyldeoxytubulosine,290-291 9-demethylprotoemetinol, 281-285 10-demethylprotoemetinol,281-285 9-demethylpsychotrine,288 9-demethyltubulosine, 289-290 10-demethyitubulosine,289-290 deoxytubulosine, 290-291 emetamine, 285-288 emetine, 285-288 ipecoside, 291-292 isocephaeline, 289 isotubulosine, 289-290 0-methylpsychotrine, 285-288 0-methyltubulosine, 289-290 monoterpene alkaloid glucosides, relationship, 291-292 protoemetine, 281-285 protoemetinol, 281-285 psychotrine, 288 tubulosine, 289-290 introduction, 271-278

438

INDEX

Ipecac alkaloids (continued) occurrence, 279-281 related compounds, 296-299 Ipecoside, chemistry and synthesis, 291-292 Isocephaeline, chemistry and synthesis, 289 Isoharringtonine, cephalotaxine esters, 233-234 Isotubulosine, chemistry and synthesis, 289-290

Jouvertiamine-type alkaloids, Amaryllidaceae alkaloids, relationship, 414-417

Kitraline, partial synthesis, 68-70 Kitramine, partial synthesis, 68-70 Kopsine isolation and structure determination, 55 total synthesis, 159-163 seco-Kopsine derivatives, isolation and structure determination, 55-56

Leuconolam, reactions, 60-61 Lycorenine-type alkaloids Amaryllidaceae alkaloids, relationship, 391-392 isolation and structure elucidation, 391-392 Lycorine-type alkaloids Amaryllidaceae alkaloids, relationship, 342-362 biological activities, 360-362 isolation and structure elucidation, 342-347 synthetic studies, 348-360

Meloshe partial synthesis, 80-85 total synthesis, 159 Mesembrine-type alkaloids Amaryllidaceae alkaloids, relationship, 393-410

isolation and structure elucidation, 402 synthetic studies, 402-410 0-Methylpsychotrine, chemistry and synthesis, 285-288 0-Methyltubulosine, chemistry and synthesis, 289-290 Minovincine, partial synthesis, 68-70 Monoterpene alkaloid glucosides, chemistry and synthesis, 291-292 Montanine-type alkaloids Amaryllidaceae alkaloids, relationship, 393-402 isolation and structure elucidation, 393 synthetic studies, 393-402

Narciclasine-type alkaloids Amaryllidaceae alkaloids, relationship, 369-382 biological activity, 381-382 isolation and structure elucidation, 369 synthetic studies, 370-381 Neoharringtonine, cephalotaxine esters, 235-236

Obsesine, Amaryllidaceae alkaloids, relationship, 411

Pachysiphine, partial synthesis, 88 Pallidiforine, Amaryllidaceae alkaloids, relationship, 410 Pandoline -pseudoaspermidine group alkaloids, 163-186.169-186 ibophyllidine group, occurrence and structure, 168 ibophyllidine-iboxyphylline group, synthesis, 180-186 iboxyphylline group, occurrence and structure, 168-169 occurrence and structure, 163-167 Phenanthridine-type alkaloids, Amaryllidaceae alkaloids, relationship, 411-412 Protoemetine, chemistry and synthesis, 281-285

INDEX

Protoemetinol, chemistry and synthesis, 281-285 Pseudoaspermidine -ibophyllidine group, chemistry, 169 -pandoline group alkaloids, 163-186 ibophyllidine group, occurrence and structure, 168 ibophyllidine-iboxyphylline group, synthesis, 180-186 iboxyphylline group, occurrence and structure, 168- 169 occurrence and structure, 163-167 synthesis, 169-186 Psychotrine, chemistry and synthesis, 288

Quebrachamine isolation and structure determination, 21-24 rearrangement and transformation, 56-57 total synthesis, 102-110 Quinoline alkaloids, isolation and structure determination, 52-55

Scandine, partial synthesis, 80-85 Secodine derivatives, isolation and structure determination, 21 synthesis, 94-102 Solvolysis, 194odotabersonine, 61-63 Strempeliopine, synthesis and configuration, 89-92

439

Tabersonine, rearrangement and transformation, 76 Tazettine-type alkaloids Amaryllidaceae alkaloids, relationship, 387-391 biological activity, 391 isolation and structure elucidation, 387-388 synthetic studies, 388-391 Tubulosine, chemistry and synthesis, 289-290

Vallesamidine, total synthesis, 152 Vincadifformine conversion into goniomitine ring system, 78-79 group reactions and rearrangements, 63 reactions, 76 -tabersonine group, isolation and structure determination, 30-38 total synthesis, 132-150 Vincamine, rearrangement and transformation, 63-68 Vincatine, structure and stereochemistry, 76-78 Vincoline, partial synthesis, 68-70 Vindoline fragmentation, 61-63 rearrangement and transformation, 57-60 total synthesis, 127-132, 150-152 Vindolinine fragmentation, 61-63 isolation and structure determination, 40-41 total synthesis, 150-151 Vindorosine partial synthesis, 85-88 total synthesis, 127-132

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