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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.

@

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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I

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


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


-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)


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)


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)


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.


‘ 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.


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


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.


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.


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.


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


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


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.


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.


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


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


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


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.


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.


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.


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.


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.


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.


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


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


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-


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.


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.


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


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


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


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


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


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


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


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


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.


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


-

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


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


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


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


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


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


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


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.


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


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


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


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


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


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

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