The Alkaloids: Chemistry and Pharmacology, Vol. 33

THE ALKALOIDS Chemistry and Pharmacology VOLUME 33

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THE ALKALOIDS Chemistry and Pharmacology Edited by Arnold Brossi National Institutes of Health Bethesda, Maryland

VOLUME 33

Academic Press, Inc. Harcourt Bmce Jovanwich, Publishers

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1988 BY ACADEMIC PRESS, INC.

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PRINTED IN THE UNITED STATES OF AMERICA 8 8 8 9 9 0 9 1

9 8 7 6 5 4 3 2 1

Contributors ............................................................ Preface .................................................................

vii ix

Chapter 1. The Tropane Alkaloids MAURILOUNASMM Introduction ....................................................... Occurrence ........................................................ Syntheses. ......................................................... Reactions .......................................................... Biosynthesis ....................................................... Spectroscopy. ...................................................... Pharmacology. ..................................................... Perspectives.. ...................................................... IX. Addendum ......................................................... References .........................................................

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

2 3 32 43

46 53 70 71 71 74

Chapter 2. Gelsemiurn Alkaloids ZHU-JIN LIUAND REN-RONG Lu I. 11. 111. IV. V. VI. VII. VIII. IX. X.

Introduction ....................................................... Gelsemine-Type Alkaloids. ........................................... Gelsemicine-Qpe Alkaloids .......................................... Sarpagine-npe Alkaloids ............................................ Humantenine-Qpe Alkaloids. ........................................ Sempe~irine....................................................... Koumine .......................................................... Alkaloids of Unknown Structure ..................................... Biogenetic Considerations ........................................... Biological Activity .................................................. References ......................................................... V

84 85 91 %

99 103 104 131 132 135 138

CONTENTS

vi

Chapter 3. Transformation Reactions of Protoberberine Alkaloids

MIYOJIHANAOKA Introduction ....................................................... Bond Cleavage Reactions of Protoberberines ........................... Oxidation of Protoberberines ........................................ Other Reactions of Protoberberines ................................... V. Transformation of Protoberberines to Related Alkaloids ................. References .........................................................

I. 11. 111. IV.

141 143 156 164 170 224

Chapter 4. Secoisoquinoline Alkaloids MARIA D. ROZWADOWSKA

....................................................... 11. Secoberbine Alkaloids. .............................................. 111. SecophthalideisoquinolineAlkaloids .................................. IV. SecobenzylisoquinolineAlkaloids ..................................... V. Secobisbenzylisoquinolineand Secodimeric Isoquinoline Alkaloids ........ VI. Secobenzophenanthridine Alkaloids ................................... VII. Secocularine and Secoquettamine Alkaloids ............................ References ......................................................... I. Introduction

231 233 262 279 285 294 291 301

Chapter 5. Hasubanan Alkaloids MATAO MATSUI Introduction ....................................................... Occurrence and Physical Constants ................................... Spectroscopy. ...................................................... New Alkaloids ..................................................... Synthesis .......................................................... Biosynthesis ....................................................... Pharmacology ...................................................... References .........................................................

307 308 311 323 335 339 342 344

Cumulative Index of Titles.. .............................................. Index ..................................................................

349 355

I. 11. 111. IV. V. VI. VII.

CONTRIBUTORS

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

MIYOJIHANAOKA (141) Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan ZHU-JIN LIU(84), Shanghai Institute of Organic Chemistry, Academia S i c a , Shanghai 200032, The People's Republic of China (2), Laboratory for Organic and Bioorganic Chemistry, MAURILOUNASMAA Technical University of Helsinki, Espoo, Finland REN-RONGLu (84), Shanghai Institute of Organic Chemistry, Academia Sinica, Shanghai 200032, The People's Republic of China MATAOMATSUI(307), Daiichi College of Economics, Dazaifu, Fukuoka, Japan MARIA D. ROZWADOWSKA (231), Faculty of Chemistry, A. Mickiewicz University, Poznan, Poland

vii

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PREFACE

“The Tropane Alkaloids” reviewed in five preceding volumes (Vols. 1, 6,9, I3,and 16)represent pharmacologically one of the most importantgroups among alkaloids. They have now been updated a sixth time with focus on chemical synthesis and spectroscopic properties. “Gelsemium Alkaloids” discussed earlier in Vols. 8 and 14 of this series and used in Chinese traditional medicine are presented here with emphasis on novel congeners, synthetic approaches, and toxicity. Protoberberine alkaloids, readily available by synthesis, constitute a marvelous playground for organic chemists connecting them with many other isoquinoline alkaloids through cleavage of the C-N bond. These conversions are presented here under the title “’Ifansformation Reactions of Protoberberine Alkaloids.” Isoquinolines with an open heterocyclic moiety originate in nature probably from isoquinoline alkaloids by oxidative cleavage, and these naturally occurring substances are discussed here for the first time as “Secoisoquinoline Alkoloids.” “Hasubaban Alkaloids,” reviewed first as a subgroup of morphine alkaloids in Vol. 13 and presented later in Vol. 16 on their own standing, now comprise 41 individual alkaloids which are discussed. Arnold Brossi

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-CHAPTER 1 -

THE TROPANE ALKALOIDS MAURILOUNASMAA Laboratory for Organic and Bioorganic Chemistry Technical University of Helsinki Espoo. Finland

I. Introduction ......................................................... 11. Occurrence ..............................................

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

............... s

IV.

V.

VI.

VII. VIII. IX.

2

32 33

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

F. Wiger and Rettig Synthesis.. ....................................... G. Macdonald and Dolan Synthesis ........................ H. Noyori Synthesis.. ................................................ 1. Kibayashi Synthesis ........................................... J. Krapcho and Vivelo Synthesis . .. ....................... K. Bick Synthesis of Bellendine ... ................................ L. Lounasmaa Synthesis of 4-Benzyltropane Alkaloids. ................... M. Lounasmaa Synthesis of lsobellendine ............................... N. Lounasmaa C-Acylation Method.. .................................. ............. Reactions ................................. A. Demethylation .................................................... thetic Intermediates ....................... Biosynthesis ........ ............................................ and Similar Compounds.. ................. B. Cocaine and Similar Compounds .... ........... C. Proteaceous Alkaloids. ............. Spectroscopy. ........................................................ A. 'H-NMR Spectroscopy. ................... B. I3C-NMR Spectroscopy C. Mass Spectrometry ................................................ Pharmacology ....................................................... Perspectives.......................................................... Addendum ........................................................... ................................... References ........

1

35 36 37 38 39 40

40 42 42

44 44 46 46

46 50

53

61 70 71 71 74

THE ALKALOIDS. VOL. 33 Copyright 0 1988 by Academic Press. Inc. All rights of reproduction in any form reserved.

2

MAURI LOUNASMAA

I. Introduction The tropane alkaloids have been reviewed on five earlier occasions in this series (Z-5). Since the last review in 1977 the number of known structures has grown markedly, to a present count of 139*. In this chapter, the literature is covered up to the end of 1986. The tropane alkaloids are a well-recognized group of structurally related natural products. Long before elucidation of the structures, the mydriatic and anesthetic action of several compounds was exploited (6).The very extensive literature covering the pharmacological properties of the tropane alkaloids will be considered only briefly in this chapter. Readers with a deeper interest in the subject are referred to other publications (7-14) and to the references given in Section VII. The tropane alkaloids contain as a common structural element the azabicyclo[3.2. lloctane system, and the systematic name of tropane is 8methyl-8-azabicycloC3.2.11octane (Fig. 1). Contradictory results concerning the C-6 and/or C-7 substitution of several C-3,C-6- and C-3,C-7-disubstituted and C-3,C-6,C-7-trisubstituted tropane alkaloids have been presented in the literature. In many cases both optical antipodes of these tropane alkaloids are known, either separately or as a racemic mixture. Applying the uniform numbering system presented in Fig. 1, most disubstituted tropane alkaloids that in the literature have been designated as C-3,C-6 disubstituted become C-3,C-7 disubstituted. The same principle, where applicable, is applied to the C-3,C-6,C-7 trisubstituted tropane alkaloids. The C-3,C-7 notation is also used where the choice between the C-3,C-6 and C-3,C-7 notation in the literature has been arbitrary. Only in cases like (-)-anisodamine 63 (vide infra), where the determination of absolute configuration is on a solid basis and where the structure is correctly presented by the C-3,C-6 notation also in the present numbering system, has the original

Me

1

6

5

4

FIG.1. Ring system of tropane alkaloids.

* See Addendum.

1. THE TROPANE ALKALOIDS

3

C-3,C-6 notation been retained. The other cases are compounds 44,54,64,67 and 72. The strict application of the system adopted here is certainly in several cases a simplification of the real situation and should be regarded as such. By analogy to the proteaceous alkaloid (+)-ferrugine (128) (vide infra), whose absolute configuration is known, and in order to have uniform numbering of the formulas through the present review, all the proteaceous alkaloids (whether optically active or not) are presented as C-4 (rather than C-2) substituted. Caution is thus needed in comparison of the data presented with that in the original papers, where the numbering and the presentation of formulas may vary. Since the systematic names in the tropane series are often long and used by very few authors, the traditional nomenclature is followed. In the text, trivial names, where existent, are used while for other compounds a semisystematic name based on the word “tropane” (vide infra) is adopted. In Tables I and 111, however, the nomenclature is based entirely on the semisystematic names, except for dimers, and the trivial names are given in parentheses.

11. Occurrence The tropane alkaloids occur mainly in the plant family Solanaceae but are also found in the families Convolvutaceae, Erythroxylaceae, Proteaceae, and Rhizophoraceae. In addition, the presence of tropane alkaloids has occasionally been indicated in the families Euphorbiaceae and Cruciferae (cf. Tables I1 and 111).For a detailed account of the distribution of tropane alkaloids among species, interested readers should consult Refs. (15-23) and references therein. The absolute configuration of (- )-anisodine [( -)-3a-(2‘-hydroxytropoyloxy)-6~,7~-epoxytropane, 911, isolated from Anisodus tanguticus by Chinese scientists (24-26), has been shown by chemical means to be (S) at C-2’ (27). Similarly, the ( -)-3a-(2,3-dihydroxy-2-phenylpropionyloxy)6,7-epoxytropane [( -)-3a-(2’-hydroxytropoyloxy)-6~,7~-epoxytropane, 911, isolated by Moorhoff (28)from Datura sanguinea, has been shown by X-ray crystallography to possess the (S)configuration at C-2’ (29).The results would seem to establish the identity of the two samples. It is interesting that the C-2’ configuration of (-)-anisodine (91) is opposite to that of (-)-scopolamine (89), although both are designated as C-2’(S)in the Cahn-Ingold- Prelog nomenclature (Fig. 2). Thus, if ( -)-anisodine (91) is formed from (-)-scopolamine (89), the introduction of the additional OH group must have been accompanied by inversion of the configuration.

TABLE I TROPANE ALKALOID STRUCTURES

&-Monosubstituted tropanes This is the largest group of tropanes, consisting of 39 representatives. All members of the group (1-39) are formally derived from 3a-hydroxytropane ( I ) or from the not yet naturally found 3a-hydroxynortropane.

1

a

2 3 4 5 6

7

8 9

10 11 12 13 14

3%-Hydroxytropane(tropine) 3a-Acetoxytropane 3a-Propion yloxytropane 3~-Butyryloxytropane 3a-Isobut yryloxytropane (butropine) 3a-Isovaleryloxynortropane (poroidine)

3a-(2’-Methylbutyryloxy)nortropane (isoporoidine) 3a-Tigloyloxytropane ( +)-3a-(2’-Methylbutyryloxy) tropane (valtropine) 3a-Isovaleryloxytropane 3a-Benzoyloxynortropane 3a-(2‘-Furoyloxy)tropane 3a-Tigloylox ytropane N-oxide 3a-Benzoyloxytropane

R

=

Me, R,

=H

R = Me, R, = acetyl R = Me, R, = propionyl R = Me, R, R = Me, R,

R

= H,

R

= H,

=

butyryl

= isobutyryl

R, = isovaleryl R, = 2-methylbutyryl

R = Me, R, = tigloyl R = Me, R, = 2-methylbutyryl Me, R, = isovaleryl R, = benzoyl R = Me, R, = 2-furoyl R = Me, 0, R, = tigloyl R = Me, R , = benzoyl

R R

=

= H,

15

16 17 18 19 20 21 22

23 m 2 4 25 26 27 28 29

30 31

3a-Apotropoyloxynortropane (aponoratropine) 3a-Apotropoyloxytropane (apoatropine) 3a-Phenylacetoxytropane 3a-(3’-Hydroxybenzoyloxy)tropane (cochlearine) 3a-Cinnamoyloxytropane ( - )-3a-( 1’,2’-Dithiolane-3‘-carbonyloxy)tropane (brugine) ( )-3a-Tropoyloxynortropane (noratropine) ( - )-3a-Tropoyloxynortropane (norhyoscyamine) 3a-(4‘-Methoxybenzoyloxy)tropane (datumetin) 3a-(3’-Hydroxyphenylacetoxy)tropane 3a-Vanilloyloxynortropane (convolidine) ( f)-3a-Tropoyloxytropane (atropine) ( -)-3a-Tropoyloxytropane (hyoscyamine) ( -)-3a-(2’-Hydroxyl-3’phenyl-propionyl0xy)tropane (littorine) 3a-Vanilloyloxytropane (phyllalbine) 3a-Veratroyloxynortropane (convolvine) 3a-Tropoyloxytropane N-oxide 1 (hyoscyamine N-oxide 1)

R = H, R, R

=

= apotropoyl

Me, R,

= apotropoyl

R = Me, R, = phenylacetyl R = Me, R, = 3-hydroxybenzoyl R = Me, R, = cinnamoyl R = Me, R, = 1,2-dithiolane-3-carbonyl R

= H,

R, = tropoyl

R = H, R, = tropoyl R

=

Me, R , = Cmethoxybenzoyl

R = Me, R, = 3-hydroxyphenylacetyl R = H, R, = vanilloyl

R = Me, R, = tropoyl R = Me, R, = tropoyl R = Me, R,

= 2-hydroxy-3-phenylpropionyl

R = Me, R, = vanilloyl R = H,R, = veratroyl

R = Me, 0, R, = tropoyl (continues)

TABLE I (Continued) 32 33

34 35

36 37

38 39 m

3a-Tropoyloxytropane N-oxide 2 (hyoscyamine N-oxide 2) 3a-Veratroyloxytropane (convolamine) 3a-Veratroyloxy-N-hydroxynortropane (convoline) 3a-Feruloyloxytropane 3a-Veratroyloxy-N-formylnortropane (confoline) 3a-Veratroyloxytropane N-oxide (convolamine N-oxide) 3a-(3',4',5'-Trimethoxybenzoyloxy)tropane 3a-(3',4',5'-Trimethoxycinnmoyloxy)tropane

R

= 0, Me, R, = tropoyl

R

= Me, R, = veratroyl

R = OH, R, = veratroyl

R = Me, R, = feruloyl R = CHO, R, = veratroyl R

= Me, 0, R, = veratroyl

R = Me, R, = 3,4,5-trimethoxybenzoyl R = Me, R I = 3,4,5-trimethoxycinnamoyl

3~-MOn0~~bstituted tropnws

This small group of four representatives comprises the 38-hydroxytropane nortropane derivative 3~-benzoyloxynortropane(42).

(a), its two naturally occurring ester derivatives 41 and 43, and the

H 40 41 42

3B-Hydroxytropane (pseudotropine) 3B-Tigloyloxytropane (tigloidine) 3~-Benzoyloxynortropane (nortropacocaine)

R = Me, R, = H R

= Me, R, = tigloyl

R = H,R, = benzoyl

43

3B-Benzoyloxytropane (tropacocaine)

R = Me, R, = benzoyl

3a,6j- and 3aJj-Disubstituted tropanes The base compound of this large group (32 representatives) is 3a,6j-dihydroxytropane 44. The rest (45-67) are mono- or diesters of 44 or of the corresponding 3a,7fiderivative.

44 45

46 47 48

49 50 51 52

3a,6j-Dihydroxytropane

+ +

( )-3a-Acetoxy-7fi-hydroxytropane ( )-3a-Hydroxy-7~-tigloyloxynortropane

3a-Tigloyloxy-7/3-hydroxynortropane 3a-Isobutyryloxy-7fi-hydroxytropane 3a-Hydroxy-7~-tigloyloxytropane 3a-H ydroxy-78-angeloyloxytropane 3a-Tigloyloxy-7fi-hydroxytropane 3a-Senecioyloxy-7~-hydroxytropane

R = Me, R, = R, = H R = Me, R, = acetyl, R, = H R = H,R, = H,R, = tigloyl R = H, R, = tigloyl, R2 = H R = Me, R, = isobutyryl, R, = H R = Me, R, = H,R2 = tigloyl R = Me, R, = H R, = angeloyl R = Me, R, = tigloyl, R, = H R = Me, R, = senecioyl. R, = H (continues)

TABLE I (Continued) 53 54

m

55 56 57 58 59 60 61 62 63 64

65

66 67

68 69 70

71

( +)-3a-Hydroxy-7j-(2’-methylbutyryloxy)-

tropane 3a-Isovaleryloxy-6/3-hydroxytropane (valeroidine) 3a-Benzoyloxy-7/3-hydroxynortropane 3a-Hydroxy-7/3-benzoyloxytropane 3a-Acetoxy-7j-isobut yryloxytropane 3a-Isobutyryloxy-7/3-acetoxytropane 3a-Phenylacetoxy-7j-hydroxytropane 3a-Tigloyloxy-78-acetoxytropane 3a-Cinnamoyloxy-7j-hydroxytropane 3a-Tigloyloxy-7/3-propionyloxytropane ( - )-3a-Tropoyloxy-6/3-hydroxytropane [( -)-anisodamine] ( f)-3a-Tropoyloxy-6j-hydroxytropane (68-hydroxyatropine) 3a-Phenylacetoxy-78-acetoxytropane 3a,7/3-Ditigloyloxytropane 3a-Tropoyloxy-61-hydroxytropaneN-oxide (6/3-hydroxyhyoscyamineN-oxide) 3a-Tigloyloxy-7fl-(2’-methylbutyryloxy)tropane 3a-(4’-Methoxyphenylacetoxy)-7j-hydroxytropane (physochlaine)

3a-(Pyrrolyl-2‘-carbonyloxy)-7j-(N”-methylpyrrolyl-2”-carbonyloxy)tropane (catuabine C) 3a-(3’-Ethoxycarbonylmethacryloyloxy)-7/3senecioyloxytropane (schizanthin A)

R = Me, R,

=

H,R,

R = Me, R,

= isovaleryl, R, = H

= 2-methylbutyryl

= H, R, = benzoyl, R2 = H R = Me, R , = H, R, = benzoyl R = Me, R, = acetyl, R, = isobutyryl R = Me, R, = isobutyryl, R2 = acetyl R = Me, R, = phenylacetyl, R, = H R = Me, R, = tigloyl, R, = acetyl R = Me, R, = cinnamoyl, R, = H R = Me, R, = tigloyl, R2 = propionyl R = Me, R, = tropoyl, R, = H

R

R

=

Me, R, = tropoyl, R,

=

H

R = Me, R, = phenylacetyl, R, = acetyl R = Me, R, = R, = tigloyl R = Me, 0, R, = tropoyl, R2 = H R = Me, R, = tigloyl R2 = methylbutyryl R = Me, R, = 4-methoxyphenylacetyl, R, = H

R

= Me,

R, = pyrrolyl-2-carbonyl, R2 = N methylpyrrolyl-2-carbonyl

R = Me, R, = 3-ethoxycarbonylmethacryloyl,R,

= senecioyl

72 73 74

75

3a-Acetyltropoyloxy-6~-acetoxytropane (68-hydroxyhyoscyamine diacetate) 3a-(3’,4’,5‘-Trimethoxybenzoyloxy)-7jbenzoyloxytropane (catuabine B) 3a-(3’,4‘,5’-Trimethoxybenzoyloxy)-7~-(N”methylpyrrolyl-2”-carbonyloxy) tropane (catuabine A) 3a-(3’,4’,5’-Trimethoxycinnamoyloxy)-7jbenzoyloxytropane

R

=

Me, R ,

= acetyltropoyl,

R

=

Me, R,

= 3,4,5-trimethoxybenzoyl,R, = benzoyl

R

=

Me, R, = 3,4,5-trimethoxybenzoyl,R, = N-methylpyrrolyl-2-carbonyl

R = Me, R ,

R,

=

acetyl

= 3,4,5-trimethoxycinnamoyl,

R,

= benzoyl

3a,6fi,7/?-Trisubstittedtropaws The nine members of this group (76-84) are formally derived from the not yet naturally found 3a,6j,7j-trihydroxytropane(vide infra, compound 170) (or from the corresponding nortropane).

76 77 78 79 80

81

3a,7j-Dihydroxy-6j-tigloyloxytropane 3a-Tigloyloxy-6j,7j-dihydroxytropane (meteloidine) 3a-Benzoyloxy-6/?,7jdihydroxytropane 3a-Phenylacetoxy-6j,7j-dihydroxytropane 3a-(2’-Hydroxy-3’-phenylpropionyloxy)6j.7jdihydroxytropane (6j,7,9dihydroxylittorine) 3a-Tigloyloxy-6~-hydroxy-7j-isovaleryloxytropane

R R

= =

Me, R , = R, = H, R, = tigloyl Me, R, = tigloyl, R, = R, = H

R = Me, R , = benzoyl, R, = R, = H R = Me, R , = phenylacetyl, R, = R, = H R = Me, R , = 2-hydroxy-3-phenylpropiony1,R, R

=

Me, R ,

= tigloyl,

R,

= H,

=

R,

=

H

R, = isovaleryl (continues)

TABLE I (Continued) 82 83 84

3a,7~-Ditigloyloxy-6/3-hydroxytropane 3a-(3’,4’,5‘-Trimethoxybenzoyloxy)6~,7~dihydroxytropane (+)-3a-(2’-Hydroxy-3’-phenylpropionyloxy)6~-hydroxy-7~-tigloyloxynortropane

R = Me, R , R = Me, R ,

R

=

= =

R, = tigloyl, R, = H 3,4,5-trimethoxybenzoyl, R,

-

0

86

87 88

89 90 91

R,

=

H

H,R, = 2-hydroxy-3-phenylpropionyl, R, = H, R,

3a-Substituted 6/?,7/?-epoxytropanes This group of eight representatives (85-92) is characterized by the 6/?,7B-epoxyring.

85

=

R = Me,R, = H 3a-Hydroxy-6/?,7b-epoxytropane (scopine) R = H, R, = apc 3a-Apotropoyloxy-6~,7~-epoxynoi opane (aponorscopolamine,aponorhyoscine) R = Me, R, = apotropoyl 3a-Apotropoyloxy-6~,7~-epoxytropane (aposcopolamine,apohyoscine) R = H, R, = tropoyl 3a-Tropoyloxy-6~,7~-epoxynortropane (norscopolamine,norhyoscine) R = Me, R, = tropoyl ( -)-3a-Tropoyloxy-6~,78-epoxytropane (scopolamine,hyoscine) R = Me, R , = tropoyl ( )-3a-Tropoyloxy-6~,78-epoxytropane (atroscine) ( - )-3a-(2‘-Hydroxytropoyloxy)-6/3,7~-epoxy- R = Me, R, = 2-hydroxytropoyl tropane [( -)-anisodine, daturamine]

=

tigloyl

92

3a-Tropoyloxy-6fl,7~~poxytropane N-oxide (scopolamine N-oxide, h yoscine N-oxide)

R

= Me,

0, R, = tropoyl

3j?-SubstitutedZj?-carboxytropaws The seven representatives of this group (93-99) may be considered derivatives of 2j-carboxy-3B-hydroxytropane (ecgonine, 95) or of the corresponding, not yet naturally found 2fi-carboxy-3~-hydroxynortropane(norecgonine).

H

-

93

w

94

95 96

97 98

99

( -)-2~-Carboxy-3~-formyloxynortropane

(norecgonine formyl ester) 2,3-Dehydro-2~-methoxycarbonyltropane (anhydroecgonine methyl ester) ( -)-2B-Carboxy-3fi-hydroxytropane (ecgonine) (-)-2~-Methoxycarbonyl-3fl-hydroxytropane (ecgonine methyl ester) ( - )-2~-Carboxy-3B-benzoyloxytropane (be.nzoylecgonine) ( - )-2~-Methoxycarbonyl-3~-be.nzoyloxytropane (cocaine) (-)-2~-Methoxycarbonyl-3~-cinnamoyloxytropane (cinnamoylcocaine)

R

= H,

R

= Me, R, = H,

R, = formyl, R,

R = Me, R, = R, R

= Me, R, = H,

R,

=H

= Me, A’

=H

R,

= Me

R = Me, R, = benzoyl, R, = H R

=

Me, R, = benzoyl, R,

R

=

Me, R, = cinnamoyl, R,

=

Me =

Me (continues)

TABLE I (Continued) k-Substituted 4a-benzyltropanes This five-member group of 4a-benzyltropanes (100-104) is without functionality at C-6 and C-7.

100 +

101

N

102 103 104

3n-Acetoxy-4a-benzyltropane (alkaloid KD-B) 3a-Acetoxy-4a-hydroxybenzyltropane (knightinol) 3a-Acetoxy-4a-acetoxybenzyltropane (acetylknightinol) 3a-Benzoyloxy-4a-benzyltropane (alkaloid KD-A) 3a-Benzoyloxy-4a-hydroxybenzyltropane

R

=

Me, R ,

R

= Me,

= acetyl,

R,

R, = acetyl, R,

R = Me, R, = acetyl, R, R

=

=

= OH =

Me, R , = benzoyl, R,

R = Me, R ,

= benzoyl,

H

R,

acetoxy =H =

OH

k,6&Disubstituted 4rr-benzyltropanes The two members of this group (105 and 106) are 3a-substituted 4a-benzyltropanes with an additional functionality at C-6.

105 106

3a-Acetoxy-4a-benzyl-6/3-hydroxytropane (knightoline) 3a-Cinnamoyloxy-4a-benzyl-6fi-hydroxytropane (alkaloid KD-D)

R

=

Me, R, = acetyl, R,

= R, =

R

= Me, R, = cinnamoyl,

R,

H

= R, =

H

3~,7/?-Disubstituted 4a-benzyltropanes The members of this group (107-109) are similar to those of the preceding group except that the additional functionality is at C-7instead of C-6.

107 e W

108

109

3a-Hydroxy-4a-benzyl-7fi-benzoyIoxytropane R (alkaloid KD-C) R 3a-Cinnarnoyloxy-4a-hydroxybenzyl-7fibenzoyloxytropane (alkaloid KD-E) 3a-Hydroxy-4a-hydroxybe1~yl-7/3-benzoyloxy-R tropane (alkaloid KD-F)

R,

= H,R, = benzoyl

= .Me,

RI

= Me,

R I = cinnamoyl, R,

=

=

Me, R, = H, R,

=

= OH, R, = benzoyl

OH, R, = benzoyl

3/?,6/?-Disubstituted4a-benzyltropnnes This small group of two representatives (110 and 111) contains the only 4a-benzyltropanes where the C-3 substituent is 8.

(continues)

TABLE I (Continued) 110 111

3fl-Hydroxy-4a-hydroxybenzyl-6fl-acetoxy(knightalbinol) 3fl-Benzoyloxy-4a-hydroxybenzyl-6flhydroxytropane (knightolamine)

R = Me, R , = H, R, = OH, R,

R

= Me,

R, = benzoyl, R,

= acetyl

= OH, R, = H

Pyranotropaws The natural products 112-115 contain a y-pyrano group attached to the 3,4position of the tropane rhg.

0

r

P

112 113 114 115

Pyranotropane (strobiline) 10-Methylpyranotropane (bellendine) 11-Methylpyranotropane (isobellendine) 10,ll-Dimethylpyranotropane (darlingine)

Ri

R1

R, = R, = H R, = Me, R, = H R, = H, R, = Me R, = R, = Me

3,4Dihydropyra1wtropaoes Compounds 116 and 117 are y-pyranotropane derivatives in which the 3,4double bond is reduced.

Me

116 117

1l-Methyl-3a,4adihydropyranotropane (5,ll-dihydroisobellendine) 141l-Dimethyl-3a,4adihydropyranotropane (5,l ldihydrodarlingine)

R, = H, R,

R, = R,

= Me

= Me

10,1l-DihydropymnotropaWs The members of this group (118-123) are y-pyranotropanes in which the 10,ll double bond is reduced. It has not been possible to deduce from the available data whether the C-10 and/or C-11 substituents, when present, are a or p.

Me

e

VI

118 119 120 121 122 123

10,ll-Dihydropyranotropane (dihydrostrobiline) 10-Methyl-10,l ldihydropyranotropane (dihydrobellendine) lCLMethyl-lO,lldihydropyranotropane (epidihydrobellendine) 10,ll-Dimethyl-10,1ldihydropyranotropane (dihydrodarlingine) 11-Phenyl-141ldihydropyranotropane (strobamine) 7~-Hydroxy-ll-phenyl-l0,1ldihydropyranotropane (strobolamine)

R, = R,

= R, = H

R, = Meeq,R,

= R, = H

R,.= Me,,., R, = R, = H R, = R,

= Me,,,

R, = R,

= H,R, = Ph,,

R, = H,R,

R,

= Ph,,,

=

R,

H

= OH

(continues)

TABLE I (Continued)

-

Miscellaneous tropnnes

This heterogeneous group contains eight “monomeric”compounds (124-131) not falling in any Of the 13 preceding groups. some of them, however, are apparent precursors for compounds mentioned earlier [e.g., chalcostrobamine(131)for strobamine (122)].

124

p + O

3-Oxotropane (tropinone)

124

125

1-Hydroxytropane(hydrochloride) (physoperuvine)

e

m

Me. 126

+

( )-3,4-Dehydro-4-acetyltropane

(ferruginine) L

O5 ‘Me

OAMe 126

127

( - )-2/?-Hydroxy-6~-acetoxynortropane (baogongteng A)

;

Me-C-0

~ y H

H : $ G H

127

Me-C-0 H

=

f

"0

Jj$ z

/

a,

t

r

a I o=uI

z

z

'

I c u t

;t

I

17

li" Ill I 0 I

a,

t

I

&-,+a z

Ill

TABLE I (Continued) “Dimeric” tropaoes Eight “dimeric” tropane alkaloids (132-139) have been found so far.

132

a-Belladonnine

133

/?-Belladonnine

134

a-Scopodonnine

135

p-Scopodonnine

134

0

a

II

E, ,g II

U I

I

I

o=u

z

X

I

a

“b

z

o=u I

I

‘t c /

o=u

\ I

0

$. o=u

E

% = %

e

.-2 B

v)

n

p.

2 19

/

a II

co

I?

TABLE I (Continued)

-0 H f 3 ” ” ’ 139

P-Truxilline

-0 139 N

Acyl group

0

Structure

Formyl

0 II H-C-

Acetyl

0 II Me-C-

0I I

Propionyl

Me - CH2-C -

Butyryl

0 I! Me -CH, -CH2-C-

Me 0 I

Isobutyryl

Me-CH

II

- C0

Me I

II

Isovaleryl

Me-CH-CH2-C-

2-Methylbut yryl

Me 0 I II Me-CH2-FH-CMe

Tigloyl

‘/c = c

H

H Angeloyl

Senecioyl

0

\I1

C-

Me

\c=c/o / \ll Me

C-

Me

H

\c=c’o

/ Me

s-*s 1,2-Dithiolane-3-carbonyl

Me

/

\I1

C0

C(3) 5 (continues)

TABLE I (Continued) Acyl group

Structure

0 EtO-? 3-Ethoxycarbonylmethacryloyl

Me

\

H

/

C-

2-Furoyl

g

Benzoyl

0;-

HO 3-Hydroxybenzoyl

CMethoxybenzoyl

Vanilloyl

Veratroyl

3,4,5-Trimethoxybenzoyl

Pbenylacetyl

W h)

3-Hydroxyphenylacetyl

4MethoxyphenylacetyI

Cinnamoyl

(continues)

TABLE I (Continued) Structure

Acyl group

Me0 FeruloyI

HOQ

,c=c

H, 0 \‘I

H

C-

Me0 3,4,5-Trimethoxycinnamoyl N

M e O o ,

c=cH, 0 \I1

Me0

P

2-H ydroxy -3-phenylpropiony l

C-

OH 0 I II C H2- C H - C3

Apotropoyl

Tropoyl

2

0 CHp-O-C- Me Acetyltropoyl

O

F

IH!-C-!

CHzOH 0 II

2-Hydroxytropoyl

E3 VI

Pyrrolyl-2-carbonyl

N-Methylpyrrolyl-2-crbonyl

PIhe

26

MAURI LOUNASMAA

TABLE I1 BOTANICAL CLASSIFICATION OF PLANTSCONTAINING TROPANE ALKALOIDS' Family

Subfamily

Solanaceae

Solanoideae

Cestroideae

Erythroxy laceae Proteaceae

Grevilleoideae

Rhizophoraceae Convolvulaceae Euphorbiaceae

Persoonioideae Rhizophoroideae Phyllanthoideae

-

-

Cruciferae a

Genus A tropa. A tropanthe, Cyphomandra. Datura, Hyoscyamus. Latua, Mandragora, Nicandra. Physalis. Physochlaina, Przewalskia, Salpichroa , Scopolia. Solandra. Withania Anthocercis. Anthotroche, Duboisia. Schizanthus Erythroxylon Darlingia. Knightia Bellendena Bruguiera Convolvulus Actephila (syn. Peripentadenia), Phyllanthus Cochlearia

From Ref. 23a-d.

Incl. Anisodus tanguticus.

0

'A

CH20H

- c I" Il.c*IIl

Q

0

OH

2'

CH20H

H

89

C(2') S

91

C(2')

s

FIG. 2. C-2' configuration of (-)-scopolamine (89)and (-)-anisodine (91).

27

I. THE TROPANE ALKALOIDS

TABLE I11 TROPANE ALKALOIDS OF PLANT

ORIGIN'

~~

MW 139

Compound

Formula C,H13N0

141

C,H,,NO

141

C8H15N0

141

CgH15NO

155

CsH13NOz

157 165

C,H,,NO, CloHl,NO

171

CgH13NO3

181

C,,HI5NOz

183 185

C1oH17NOZ C9H15N03

185

C9Hl,N0,

191

C11H13NOz

193

C11H1,NOZ

197 199 199

C11H19NOz CloH1,NO3 C,oH,7NOj

205

C1zH15NOz

205

C1zH1,NOz

207

C,zH,7NOz

207

C,,H,7N0z

124 3-Oxotropane

(tropinone) 1 3a-Hydroxytropane (tropine) 40 3j-Hydroxytropane (pseudotropine) 125 1-Hydroxytropane (hydrochloride) (physoperuvine) 85 3a-Hydroxy-6j,7j-epoxytropane (scopine) 44 3a,6j-Dihydroxytropane 126 ( +)-3,4Dehydro4acetyltropane (ferruginine) 93 ( -)-2j-Carboxy-3j-foryloxynortropane (norecgonine formyl ester) 94 2,3-Dehydro-2-methoxycarbonyltropane (anhydroecgonine methyl ester) 2 3a-Acetoxytropane 95 ( -)-2a-Carboxy-3j-hydroxytropane (ecgonine) 127 ( -)-2j-Hydroxy-6j-acetoxynortropane (baogongteng A) 112 Pyranotropane (strobiline) 118 10,ll-Dihydropyranotropane (dihydrostrobiline) 3 3a-Propionyloxytropane 45 ( +)-3a-Acetoxy-7j-hydroxytropane 96 ( -)-2j-Methoxycarbonyl-3j-hydroxytropane (ecgonine methyl ester) 113 10-Methylpyranotropane (bellendine) 114 11-Methylpyranotropane (isobellendine) 116 1 l-Methyl-3,4dihydropyranotropane (5,ll-dihydroisobellendine) 119 10-Methyl-10,ll-dihydropyranotropane (dihydrobellendine)

Familyb

Refs.

S

1.5.30

S

1.2s

S, Er

1.2.5.31

S

5,32-34

S

1

S,Er

I

P

5.35.36

Er

1

Er

1

S,R

5

Er

12

co

37

P

22.38

P

22.38

R Eu, P Er

5 5.39 1

P

5,22.39

P

5.22.39

P

22.39

P

22.39

The compounds are listed in order of increasing molecular weight: In most cases the references refer to articles where the Occurrence of the compound was indicated for the first time or its rediscovery in a new plant family was announced. Where the compound has been mentioned in earlier chapters of this treatise, the review reference is usually given, together with some recent supplementary references. Key to Families: Co, Convolvulaceae; Cr. Cruciferae; Er, Erythroxylaceae; Eu, Euphorbiaceae; P, Proteaceae; R, Rhizophordceae; S , Soldndceae. (continues)

28

MAURl LOUNASMAA

TABLE 111 (Continued)

MW

Formula

207

C,2H,,N0,

211 211 211

CIZH,,NO, C,,H,,NO, C,ZH,,NOZ

211

C,,H,,NO,

219

C,,H,,NO,

221

C,,H,,NO,

221

C,3Hl,N0,

223 223 225

C,3H,,N0, C,,H,,NO2 C,,H,,NO,

225 225 225 227 229 231 231

C,,H,,NO, C,zH,,NO, ClzH19N03 C12H2,N03 C,,H,,NO CI4Hl7NO2 C,4H,,N0,

235 239 239 239 239 239 241

C,3H,,N03 CI3H2,NO, C,3H,,NO3 C,,Hz,NO, C,jH,,NO3 C13H,,N03 C,,HZ3NO3

241

CI3H2,NO,

245 245 247 247 255 255

C,,H,,NO, CISHl9NO2 C,,H,,N03 CI4Hl7NO3 CljH21N04 C,3H,,N0,

Compound 120 10-Methyl-10,l l-dihydropyranotropane

(epidihydrobellendine) 4 3a-Butyryloxytropane 5 3rr-Isobutyryloxytropane(butropine) 6 3a-Isovaleryloxynortropane ~. (poroidine) 7 3a-(2’-Methylbutyryloxy)nortropane (isoporoidine) 115 1411-Dimethylpyranotropane (darlingine) 117 10,ll -Dimethyl-3,4-dihydropyranotropane (5.1 l-dihydrodarlingine) 121 10,l I-Dimethyl-141 1-dihydropyranotropane (dihydrodarlingine) 8 3a-Tigloyloxytropane 41 3/l-Tigloyloxytropane (tigloidine) 9 ( )-3a-(2’-Methylbutyryloxy)tropane (valtropine) 10 3a-Isovaleryloxytropane 46 ( )-3a-Hydroxy-7/?-tigloyloxynortropane 47 3a-Tigloyloxy-7j-hydroxynortropane 48 3a-Isobutyryloxy-7B-hydroxy tropane 128 ( +)-4a-Benzoyltropane (ferrugine) 11 3a-Benzoyloxynortropane 42 3j-Benzoyloxynortropane (nortropacocaine) 12 3a-(2‘-Furoyloxy)tropane 13 3a-Tigloyloxytropane N-oxide

+

+

3a-Hydroxy-7~-tigloyloxytropane 3a-Hydroxy-7~-angeloyloxytropane 3a-Tigloyloxy-7/3-hydroxytropane 3a-Senecioyloxy-7/?-hydroxytropane ( +)-3a-Hydroxy-7B-(2’-methylbutyryloxy)tropane 54 3a-Isovaleryloxy-6/?-hydroxytropane (valeroidine) 14 3a-Benzoyloxytropane . . 43 3/3-Benzoyloxytropane(tropacocaine) 129 ( + )-2a-Benzoyloxy-3/3-hydroxynortropane 55 3a-Benzoyloxy-7~-hydroxynortropane 76 3q7B-Dihydroxy-6~-tigloyloxytropane 77 3a-Tigloyloxy-6~,7~-dihydroxytropane (meteloidine) 49 50 51 52 53

Familyb

Refs.

P

22.39

S, R S, R S

5.40 1.4S.41 1.42

S

1,42

P

5,22,35.36.39

P

22.35

P

22.39

S S S, R

4.5.32 5,32

Er, R Er S S

5.42 43 44 45 5.36 31 46

P

Er Er

1.4.5

Er S S S S

42 5 3.4

S

S

47 5

S

1.3

Er, R Er Eu Er S S

5.30.32 I ,5.31,46 5 31

47

4.5

5 M 1.4.5

I . THE TROPANE ALKALOIDS

29

TABLE 111 (Continued) ~

MW 257

Formula

C,,H,,NO,

259

C,,H,,NO,

259 259

CI6H,,NO2 C,,H,,NO,

261

CI5H,,NO,

261 269 269 269

C15H,,N0, C,,H,,NO, C14H,,N0, C,,H,,NO,

269

C,,H,,N02

271 271

C,,H,,NO, C,,HI,N03

273

C,,H,,NO,S,

275

C,,H,,N03

275

C,,H,,NO,

275

C,,H,,NO,

275

C,,H,,N02

275 275 277

C16H,,N03 C,,H,,N03 ClSH,,NO,

277 281 285

C,,H,,NO, Cl5H,,NO, C,,H,,NO,

285

CI7Hl9NO3

287 289 289

C,,H,,NO, CI,H,,NO3 C,,H,,NO,

Compound 15 3a-Apotropoyloxynortropane

(aponoratropine) 16 3a-Apotropoyloxytropane (apoatropine) 17 3a-Phenylacetoxytropane tropane 130 6,7-Dehydro-3a-(4’-hydroxybenzoyloxy) [3a4 p-hydroxybenzoyloxy)trop-6-ene] 18 3a-(3’-Hydroxybenzoyloxy) tropane (cochlearine) 56 3a-Hydroxy-7/?-benzoyloxytropane 57 3a-Acetoxy-7/?-isobutyryloxytropane 58 3a-Isobutyryloxy-7f3-acetoxytropane 122 11-Phenyl-l0,ll-dihydropyranotropane (strobamine) 131 ( + )-3,4-Dehydro4cinnamoyl-3-hydroxytropane (chalcostrobamine) 19 3a-Cinnamoyloxytropae 86 3a-Apotropoyloxy-6~,7Bepoxynortropane (aponorscopolamine, aponorhyoscine) 20 ( -)-3a4 1’,2‘-Dithiolane-3’-carbonyloxy)tropane (brugine) 21 ( & )-3a-Tropoyloxynortropane (noratropine) 22 ( -)-3a-Tropoyloxynortropane (norh yoscyamine) 23 3a-(4‘-Methoxybenzoyloxy)tropane (datumetin) 100 2a-Benzyl-3a-acetoxytropane (alkaloid KD-B) 24 3a-(3’-Hydroxyphenylacetoxy) tropane 59 3a-Phenylacetoxy-7~-hydroxytropane 25 3a-Vanilloyloxynortropane (convolidine) 78 3a-Benzoyloxy-6fl,7~dihydroxytropane 60 3a-Tigloyloxy-7~-acetoxytropane 87 3a-Apotropoyloxy-6~,7~-epoxytropane (aposcopolamine, apohyoscine) 123 78-Hydroxy- 1l-phenyl-10,l ldihydropyranotropane (strobolamine) 61 3a-Cinnamoyloxy-78-hydroxytropane 26 (+)-3a-Tropoyloxytropane (atropine) 27 ( - )-3a-Tropoyloxytropane

Familyb

Refs.

S

45

S

1.5.41

Er P

40,42 49

Cr

50

P

P P

46.51 5.39 5.39 22.51

P

22.38

R

S

30 45

R

4.5.30

S

1.5.41

S

1,4

S

52

P

5,2233

Er Er

40 40 54.55

P

co

Er

s, p S

43 5.49 1.4.41

P

22,51

P

38 1.5 13.4

S S

(hyoscyamine) (continues)

30

MAURI LOUNASMAA

TABLE I11 (Continued) MW 289 289 289 289 289 291 291 291 295 303 303 303 305 305 305 305 305 305 307 317 317 319 319 319

Formula

Compound

28 ( -)-3a-(2’-Hydroxy-3’-phenylpropionyloxy)tropane (littorine) C I ~ H I ~ N O ~88 3a-Tropoyloxy-6~,7B-epoxynortropane (norscopolamine, norhyoscine) 97 ( -)-2/3-Carboxy-3~-benzoyloxytropane C,,H,,NO, (benzoylecgonine) C,,H23NO3 101 3a-Acetoxy4a-hydroxybenzyltropane (knightinol) 105 3a-Acetoxy-4a-benzyI-6~-hydroxytropane Cl7Hz,NO3 (knightoline) Cl6Hz1NO4 29 3a-Vanilloyloxytropane(phyllalbine) CI6Hz1NO4 30 3a-Veratroyloxynortropane (convolvine) C16Hz1NO4 79 3a-Phenylacetoxy-6b,7fi-dihydroxytropane C16HzsNO4 62 3a-Tigloyloxy-7j?-propionyloxytropane CI7HZ1NO4 89 ( -)-3a-Tropoyloxy-6/3,-7~-epoxytropane (scopolamine,hyoscine) C17Hz1NO4 90 ( f )-3a-Tropoyloxy-6~,7~-epoxytropane (atroscine) CI7Hz1NO4 98 ( -)-2~-Methoxycarbonyl-3/3-benzoyloxytropane (cocaine) CITH23N04 31 3a-Tropoyloxytropane N-oxide 1 (hyoscyamineN-oxide 1) C17HZ3N04 32 3a-Tropoyloxytropane N-oxide 2 (hyoscyamineN-oxide 2) C17Hz3NO4 38 3a-Veratroyloxytropane (convolamine) 63 ( - )-3a-Tropoyloxy-6~-hydroxytropane CI7H2,NO4 [( - )-anisdaminel 64 ( f )-3a-Tropoyloxy-6/?-hydroxytropane Cl7HZ,NO4 (6b-hydroxyatropine) CI7Hz3NO4 110 3~-Hydroxy-4a-hydroxybenzyl-6~-acetoxytropane (knightalbinol) C16Hz1NO5 34 3a-Veratroyloxy-N-hydroxynortropane (convoline) Cl8Hz3NO4 35 3a-Feruloyloxytropane C,,HZ,NO4 65 3a-Phenylacetoxy-7/t-acetoxytropane C17HzlN05 36 3a-Veratroyloxy-N-formylnortropane (confoline) C17HZ1N0, 91 ( -)-3a-(2‘-Hydroxytropoyloxy)-6/3,7~-epoxytropane [( -)-anisdine, daturamine] C17Hz1NO5 92 3a-Tropoyloxy-6~,7~-epoxytropane N-oxide (scopolamineN-oxide, hyoscine N-oxide)

C17H23NO3

Familyb

Refs.

S

4

S

1.4

Er

I

P

22.28

P

22.38

Eu

3 9 I ,55

co

Er

S S

40 5 14

S

I

Er

1.2

S

5

S

5

co

I

S

5

S

56

P

22.51

co

57

R Er co

40

S

5.26.28.58.59

S

5

30 55

I.

THE TROPANE ALKALOIDS

31

TABLE 111 (Continued)

MW

Formula

321 321

Cl8HZ7NO4 C17H,,N0,

321

C17H,,N0,

321

C,,H,,NO,

323 323

C,,H,,NO, CI8Hz9NO4

329

C19Hz3N04

Compound

Familyb

66 3a,7j-Ditigloyloxytropane 67 3a-Tropoyloxy-6j-hydroxytropaneN-oxide

(6j-hydroxyhyoscyamine N-oxide) 80 3a-(2’-Hydroxy-3‘-phenylpropionyloxy)-68,7/?dihydroxytropane (6/3,7B-dihydroxylittorine) 37 3a-Veratroyloxytropane N-oxide (convolamine N-oxide) 68 3a-Tigloyloxy-7j-(2’-methylbutyryloxy)tropane 81 3a-Tigloyloxy-6j-isovaleryloxy-7~-hydroxytropane 99 ( -)-2j-Methoxytrocarbonyl-3jcinnamoyloxy-

331

C,,H,,NO,

tropane (cinnamoylcocaine) 102 3a-Acetoxy-4a-acetoxybenzyltropane (acetylknightinol)

335 335

Cl8HZ5NO, C,,H,,NO,

38 3a-(3’,4‘,5‘-Trimethoxybenzoyloxy)tropane 103 3a-Benzoyloxy-4a-benzyltropane

337 351 351

C18H,,N05 C,,H,,N03 C,,H,,NO,

82 3a,7~-Ditigloyloxy-6j-hydroxytropane 104 3a-Benzoyloxy-4a-hydroxybenzyltropane 107 3a-Hydroxy-4a-benzyI-7j-benzoyloxytropane

353

CI7Hz3NO7

Refs.

S S

3 5.60

S

48

Co

60

S S

5 61

Er

I

P

22.38

Er P

5 5.22.53

S

P P

5 22.36 5.22.38

S

5.60

Er

62

Er Er

4.5 5

P

5.22.63

P

22.51

P

5.22.38

S

64

S

56

Er

43

(alkaloid KD-A)

(alkaloid KD-C)

357

C19H23N304

361 367

C,,H,,NO, C,8Hz5N07

367

C2,H,,N0,

367

C22H25N04

377

C,,H,,NO,

379

C,,H,,NO,

389

CZ1Hz7NO6

389

C21H,,NO,

69 3a-(4‘-Methoxyphenylacetoxy)-7~-hydroxy-

tropane (physochlaine) 70 3a-(Pyrrolyl-2‘-carbonyloxy)-7~-(N”-methylpyrrolyl-2”carbonyloxy) tropane (catuabine C) tropane 39 3a-(3’,4‘,5’-Trimethoxycinnamoyloxy) 83 3a-(3’,4‘,5’-Trimethoxybenzoyloxy)6B,7Bdihydroxytropane 109 3a-Hydroxy-4a-hydroxybenzyl-7j-benzoyloxytropane (alkaloid KD-F) 111 3j-Benzoyloxy-4a-hydroxybenzyl-6j-hydroxytropane (knightolamine) 106 3a-Cinnamoyloxy-4a-benzyl-6j-hydroxytropane (alkaloid KD-D) 71 3a-(3’-EthoxycarbonyImethacryloyloxy)-7jsenecioyloxytropane (schizanthin A) 72 3a-Acetyltropoyloxy-6~-acetoxytropane (6j-hydroxyhyoscyamine diacetate) 84 ( +)-3a-(2’-Hydroxy-3’-phenylpropionyloxy)-6jhydroxy-78-tigloyloxynortropane

(continues)

32

MAURI LOUNASMAA

TABLE 111 (Continued) MW

Formula

419

CZ2H2,NO,

458 481

497

Compound

Familyb

73 3a-(3',4',5'-Trimethoxybenzoyloxy)-7~-benzoyloxytropane (catuabine B) 74 3a-(3',4',5'-Trimethoxybenzoyloxy)-7~-(N"C24H30N207 methylpyrrolyl-2"carbonyloxy)tropane (catuabineA) CZ7H3,NO7 75 3a-(3',4',5'-Trimethoxycinnamoyloxy)-7~benzoyloxytropane C3,H3,N0, 108 3a-Cinnamoyloxy-4a-hydroxybenzyl-7~benzoyloxytropane (alkaloid KD-E) 132 a-Belladonnine 133 B-Belledonnine 134 a-Scopodonnine 135 B-Scopodonnine 136 Schizanthin B 137 Subhirsine 138 a-Truxilline 139 8-Truxilline

Refs.

Er

62

Er

62

Er

5

P

5.22.63

S

56.60 56,60 41 41 64 65

S S S S co Er Er

I 1

111. Syntheses

A number of new synthetic approaches to the tropane skeleton have been developed during recent years. The more characteristic ones are described in this section. In order to provide a representative picture of the whole field, a few of the earlier syntheses, starting from the classic ones of Willstatter and Robinson, are briefly reviewed. The earlier methods based on the transformation of the preformed tropane skeleton are noted only occasionally. However, the recently developed syntheses of the proteaceous tropane alkaloids based on new C-acylation methods for tropinone (124) are included.

A. WILLSTATTER SYNTHESIS

The first synthesis of tropinone (124), which was presented by Willstatter and consisted of a route of 16 steps from cycloheptanone to tropinone (124) (Scheme l), has been thoroughly discussed by Holmes (I) and will not be further noted. 0

0

--

pG->O 124

SCHEMEI . Willstatter synthesis of tropinone (124).

1.

33

THE TROPANE ALKALOIDS

B. ROBINSON-SCHOPF SYNTHESIS The original Robinson synthesis(66)of tropinone (124), which consists of a reaction between succinaldehyde (140), methylamine (141), and the calcium salt of acetonedicarboxylic acid (142), proceeds in low yield (Scheme 2). However,it has the great merit of being the pioneering achievement in the field of biomimetic syntheses of natural products.

140

141

142

124

SCHEME 2. Robinson-Schopf synthesis.

Later, Schopf et al. (67,68)found that the yield could be raised to 83% by using, at 25"C,dilute solutions buffered at pH 5 (physiological conditions). Despite this relatively high yield the reaction was not very suitable for the production of tropinone (124), especially in large scale, because of the lack of a convenient method to obtain succinaldehyde (140). This obstacle was later circumvented when it was found that succinaldehyde (140) could be replaced by its synthetic equivalent, 2,5-dimethoxytetrahydrofuran (143) (Scheme 3).

dMeLCHO OMe

143

AL

CHO

140

SCHEME 3. Transformation of 2.5-dimethoxytetrahydrofuran(143) to succinaldehyde (140).

The basic principle of the synthesis involving 143 has been applied for the preparation of many tropane derivatives [e.g., 6-hydroxytropinone (144) and (+)-cocaine (98)] (69- 71). During recent years, especially in China, considerable attention has been paid to practical applications and modifications of this long known method (70- 77),illustrated here by the scheme leading to anisodamine (63) (Scheme 4). It should be noted that Fodor has cast some doubt on the success of using acetyltropoyl chloride as an acylating agent in the conditions described (9f 1.

34

MAURI LOUNASMAA

...

"L

p + O

HO

AcO

rp+o

'v_

rp$oHV

AcO

144

63

SCHEME 4. Chinese synthesis of anisodamine (63). Reagents: i, HCI, HzO; ii, MeNH,, HOOCCH,COOH, pH 5,25"C; iii, Ac,O, py; iv, H,/Pd; v, C6H5CH(CH,OAc)COCI;vi, 5% HCI, 1 hr.

C. PARKER, RAPHAEL, AND WILKINSON SYNTHESIS

Parker, Raphael, and Wilkinson have investigated a synthetic approach to tropinone(124),which they call the acetylenic route (78).Reaction of hexa-1,5diyne-1,6-dicarboxylate (145) with methylamine yields the pyrrolidine derivative (I&), which by catalytic hydrogenation affords the diester 147 (79,80).

c

- qeCOOEt

CEC-COOEt

C f C-COOEt

ii

COOEt 145

146

COOEt @e

COOEt 147

124

SCHEME 5. Parker, Raphael, and Wilkinson synthesis of tropinone (124). Reagents: i, MeNH,, EtOH; ii, H,/PtO,, AcOH; iii, t-BuOK, t-BuOH.

1. THE TROPANE ALKALOIDS

35

Dieckmann cyclization of 147, followed by hydrolysis and decarboxylation, leads to tropinone (124) (Scheme 5). D. BOTTINIAND GALSYNTHESIS Bottini and Gal (81) added 2,6-cycloheptadienone (148), prepared from cycloheptanone in four steps (82),to a solution of methanolic methylamine and obtained tropinone (124)in 64% yield (Scheme 6). This reaction was suggested long ago by Robinson (66).

0

0

I

p:N-n,).o

/

148

124

SCHEME6. Bottini and Gal synthesis of tropinone (124). Reagents:i, MeNH,, MeOH, 20°C.

E. TUFARIELLO SYNTHESIS Tufariello and co-workers have used an interesting new approach in their synthesis of tropane alkaloids (83-86). The addition of 1-pyrroline I-oxide (149) to methyl 3-butenoate affords isoazolidine (150), oxidative opening of which with MCPBA produces the nitrone 151. This is transformed to its methyl acrylate cycloadduct 152, which is converted to' the unsaturated isooxazolide 153 via the corresponding methanesulfonate. Cycloreversion of 153 to the nitrone ester 154 is accompanied by concomitant intramolecular cycloaddition to give the tricycloadduct 155. After alkylation of 155, the resulting methiodide 156 is subjected to reductive scission of the N-0 bond, affording ecgonine methyl ester (W), which by benzoylation is transformed to (&)-cocaine (98) (Scheme 7). The nitrone-induced oxidative cyclization of the same type has also been applied with success to the preparation of pseudotropine (40).

F. WIGERAND RETTING SYNTHESIS The preparation of N-carbethoxy-8-azabicyclo[5.1.0]oct-3-ene (158) from ethyl azidoformate (157) and 1,Ccycloheptadiene through a photolytic reaction, and its palladium(I1)-catalyzed multistep rearrangement to Ncarbethoxynortropidine (159), has been presented by Wiger and Retting as a new route to the 8-azabicyclo[3.2.l]octene skeleton (87)(Scheme 8).

-$?

36

MAURI LOUNASMAA

I

I

-

0-

\r

Me02C 149

ii

150

C02Me

OH 151

. C02Me T C O 2 M e

C02Me w C 0 2 M e

OH 152

153

154

155

156

96

m

Me\N

C02Me OCOCbHs

98

SCHEME7. Tufariello synthesis of cocaine (98). Reagents: i, CH,=CHCH,CO,Me; ii, MCPBA; iii, CH,=CHCO,Me; iv, MsCI; v, xylene, reflux; vi, MeI; vii, Zn, AcOH; viii, C,H,COCI.

G. MACDONALD AND DOLAN SYNTHESIS

Macdonald and Dolan have reported a new route to the tropinone system (88). 2-Cyclohexenone (160) is transformed to 2-[(trimethylsilyl)oxyl]-1,3cyclohexadiene (16Q and then by dichlorocyclopropanation to 162 and by acid-catalyzed hydrolysis to 2-chloro-2,6-cycloheptadienone(163). Addition

37

1. THE TROPANE ALKALOIDS

157

158

159

SCHEME 8. Wiger and Rettig synthesis of N-carbethoxynortropidine(159). Reagents: i, v Hg lamp: ii, PdCI,(PhCN),, C6H6, RT, 60 hr.

Q

I

6"" ii

[ C y j H ]

161

160

163

iii

162

Go- 6; iv

-

0- v

164

124

SCHEME 9. Macdonald and Dolan synthesis of tropinone (124). Reagents: i, LDA, O M S , Et3N, DMF; ii, DME, CCI,COONa, A; iii, HCI; iv, MeOH, WC, MeNH,; v, (n-C,H,),SnH.

of methylamine gives 2B-chloro-3-tropinone (la), which by reduction with tributyltin hydride is converted to tropinone (124) (Scheme 9). H. NOYORI SYNTHESIS Noyori and co-workers have developed a new and useful general synthesis of the tropane alkaloids (89- 92). The Fe,(CO),-aided reaction of tetrabromoacetone and N-carbomethoxypyrrole (165)(3: 3: 1 ratio) in benzene at

38

MAURI LOUNASMAA

50°C gives a mixture of dibromoketones 166a and 166b, and when these are treated with zinc-copper in methanol saturated with ammonium chloride at room temperature, the debromination product 167is obtained in quantitative yield. Reduction of 167 with an excess of DIBAH in THF at - 78°C and then at room temperature leads to a mixture of the 6,7-dehydro-3-hydroxytropanes 168 and 169 (93:7 ratio) (Scheme 10). It was pointed out that 6,7-dehydro-3a-hydroxytropane (168),in particular, is a very important intermediate for the synthesis of several tropane alkaloids (e.g., 1,26,44,and 85), as well as of their congener 170 (Scheme 11).

166 a 166 b

165

MeOOCN

m 0 167

SCHEME10. N o y d synthesis of 6,7-dehydro-3-hydroxytropanes168 and 169. Reagents: i, Fe,(CO),, C6H6, 50°C; ii, Zn-Cu, NH,CI, 20°C; iii, DIBAH, THF, -78 -+ 20°C.

I. KIBAYASHI SYNTHESIS

A new and interesting synthetic approach to the tropane alkaloids has been developed recently by Kibayashi and co-workers (92,93).The reaction of cyclohepta-3,5-dienyI benzoate (171)with 1-chloro-1-nitrosocyclohexane (172)in CC1,EtOH (3:2) solution generates the oxaazabicyclononene hydrochloride 173, which is transformed by catalytic hydrogenation to the amino alcohol hydrochloride 174. Selective N-acylation of 174 (EtOCOCI, aq Na2C03,CHCI,, 0°C + RT) furnishes the carbamate 175,and chlorination of this with thionyl chloride (py, CHCI,, 0°C + reflux) gives 176. Intramolecular cyclization of 176 by treatment with t-BuOK in benzene-HMPA (1:1) affords 177. Reduction of 177 with LiAIH4 yields pseudotropine (40) (Scheme 12). Alternatively,benzyloxycarbonylation of 174 gives the carbamate 178,and

39

I. THE TROPANE ALKALOIDS

1

R=H

/

26 R = C O - { - H

168 I

44

170

SCHEME 11. 6,7-Dehydro-3a-hydroxytropane(168) as an intermediate in the synthesis of several tropane alkaloids.

chlorination of this with thionyl chloride yields 179. Intramolecular cyclization of 179, induced by t-BuOK treatment, leads to 180. Catalytic hydrogenation (Pd/C, MeOH) of 180 affords N-nortropacocaine (181), which subsequently undergoes Eschweiler- Clarke reaction (HCO,H, HCHO, reflux) to provide the desired tropacocaine (43) (Scheme 12). J. KRAPCHO AND VIVELO SYNTHE~IS

Krapcho and Vivelo have described a new formal total synthesis of tropinone (124) and (+)-cocaine (98)(94). Cycloaddition of N-methylpyrrole (182) and acetylenedicarboxylic acid leads to 183, which is hydrogenated to 184. The diacid mixture 184 is refluxed in MeOH/HCI to yield the diester mixture 185. Addition of this to an excess of metallic sodium in liquid ammonia at - 78°C leads to the N-methylpyrrolidinederivative 186 (cf.95), whose diethyl analog 147 has earlier been converted to tropinone (124) and (+)-cocaine (98) (78-80) (Scheme 13).

40

MAURI LOUNASMAA

CL

OCOPh

OCOPh

N=O

H 172

171

174

175 178

'k-*OCOPh

vi

R

177 R = 180 R = 181 R =

C02Et Cbz H

173

R=COzEt R=Cbz

-

176 179

Me,

40

OC0 P h 43

SCHEME 12. Kibayashi synthesis of pseudotropine (40)and tropacocaine (43). Reagents: i, CC1,-EtOH (3:2), -20°C. 2 weeks;ii, H,/Pd-C, MeOH; iii, EtOCOCl or PhCH,OCOCI, aq Na,C03,0"C + RT;iv,SOCI,,py,CHCI,,O"C -t reflux;,v,r-BuOK,C,H,-HMPA,0-5"C; vi, LiAIH,, THF, reflux; vii, (1) H,/Pd-C, MeOH, (2) HCO,H, HCHO, reflux.

K. BICKSYNTHESIS OF BELLENDINE

Bick and co-workers (96) have described the C-acylation of tropinone (124) with 3-methoxymethacryloylchloride leading to a tautomeric mixture of 187a and 18%. Acid-induced cyclization of the mixture produces bellendine (113) (Scheme 14). L. LOUNASMAA SYNTHESIS OF ~BENZYLTROPANE ALKALOIDS Lounasmaa and Johansson have developed a synthetic route useful for the preparation of 4-benzyltropane alkaloids (97). The base-catalyzed condensation of tropinone (124) with benzaldehyde under carefully controlled

41

1. THE TROPANE ALKALOIDS

- r[ I cooe

B - M e

IH-N-Me

I

-

II

COOH 182

183

-

COOMe

...

iv

Ill

COOMe 184

185

COOMe @e

-<

124

COOMe

COzMe OCOPh

186

H 98

SCHEME 13. Krapcho and Vivelo synthesis.. Reagents: i, HOOCC=CCOOH, Et,O, reflux; ii, H,/Pd; iii, MeOH/HCI, reflux; iv, Na, liq NH,, -78°C.

p

=

&

o

._ I

.._

p

II

OMe

0 187 a

124

0'

0

Me

Me

187 b

Me

113

SCHEME 14. Bick synthesis of bellendine (113). Reagents: i, (1) NaH, (2) MeOCH= C(Me)COCI;ii, H2S0,, H,O.

42

MAURI LOUNASMAA

conditions yields trans-4-benzylidenetropane(188). Catalytic hydrogenation of 188 to 4-benzyltropinone (189a and 189b), followed by LiAlH, reduction and isomer separation, affords 4-benzyltropanol(190). This is esterified with benzoyl and acetyl chloride to yield 3a-benzoyloxy-4a-benzyltropane(alkaloid KD-A, 103) and 3a-acetoxy-4a-benzyltropane(alkaloid KD-B, IN), respectively (Scheme 15).

190

103 100

R = C6H5 R=Me

SCHEME 15. Lounasmaa synthesis of 4-benzyltropane alkaloids. Reagents: i, benzaldehyde, KOH; ii, H,/Pd; iii, LiAIH,; iv, RCOCI.

M. LOUNASMAA SYNTHESIS OF IsoBELLENDINE An effective two-step synthesis of isobellendine (114) starting from tropinone (124) has been described by Lounasmaa and co-workers (98).Tropinone (124) is transformed to the corresponding enamine (191),which is then treated with diketene to yield isobellendine (114) in over 30%total yield (Scheme 16).

N. LOUNASMAA C-ACYLATION METHOD Lounasmaa and co-workers have found that the treatment of tropinone (124) with acyl cyanides leads to facile C-acylation (99,100).Application of this method has permitted effective total syntheses of ( f)-knightin01 (IOI), ( &)acetylknightinol (102), ( f)-chalcostrobamine (131), ( +)-dihydrodarlingine (121), and (f)-strobamine (122) (Scheme 17).

191

124

n

0 -

y-yH2 @

0

O

H

F/bMe 0 114

SCHEME16. Lounasmaa synthesis of isobellendine (1 14). Reagents:i, morpholine;ii, diketene.

121 R, = R 2 = M e

101

102

122 R1= H; R 2 = c 6 c 5

SCHEME17. Lounasmaa synthesis of knightinol (101), acetylknightinol (102). chalcostrobamine (131), dihydrodarlingine (121), and strobamine (122). Reagents: i, THF, NaH, reflux, RCOCN; ii, From 19211or 131, H2S04, H,O, 50°C; iii, from 192b, H2/Pt02;iv, Ac,O, 5 drops of BF,-Et,O, 20°C; v, Ac,O, DMAP, reflux.

44

MAURI LOUNASMAA

IV. Reactions Since most of the fundamental chemical transformations of the tropane alkaloids were discovered during the pioneering elucidation of the structures, the most important reactions have been described in earlier chapters in this treatise (1-5). Two developments will be discussed here: the recent progress in the demethylation of tropane derivatives and the use of tropinone enamines as synthetic intermediates. A. DEMETHYLATION

The classic methods for the demethylation of tropane derivatives to the corresponding nortropanes (KMnO, oxidation, CNBr treatment, Polonovski reaction, etc.) have been thoroughly described in earlier reviews (1-5). Very little new information has appeared since. Although the classic methods are still valuable, the use of chloroformic esters, especially those of 2,2,2trichloroethyl chloroformates and vinyl chloroformates, has become increasingly common during the last decade (101-105). This is mainly due to the relatively mild conditions under which the reaction takes place, which permit the presence of fragile functional groups (e.g., ester groups). Treatment of atropine (26) with trichloroethyl chloroformate leads to the formation of a mixture of compounds 194 and 195, which when treated with zinc dust in acetic acid yields noratropine (21) (103)(Scheme 18). Similarly, the Me\

H

O

,

Lr+H &

,

- E-+H R\

I

Ph

O

0

'N

II

Ph

O

A

O

R

'

0 CI3CCHZOCO; R ' = H 195 R = R ' = C13CCHZOCO

26

H

N

194 R

m& 0

OH

21

SCHEME 18. Demethylation of atropine (26).Reagents: i, CI,CCH,OCOCI; ii, Zn, AcOH.

45

I . THE TROPANE ALKALOIDS

reaction of cocaine (98) with an excess of 2,2,2-trichloroethyl chloroformate and vinyl chloroformate produces the carbamates l%a and 196b, respectively. Reductive removal of the carbamate groups with zinc/acetic acid gives norcocaine (197) in 85 and 55% total yield (102) (Scheme 19). A new and interesting chloroformate reagent, a-chloroethyl chloroformate, was recently introduced for selective N-dealkylation of tertiary amines (106). When it was applied to the demethylation of 3a-acetoxytropane (2), the corresponding nor salt (198) was obtained in 97% yield (Scheme 20). R\ I __c

Ns COOMe

II

OCOC~HS

H

196a 196b

H\

R = CI3CCH20CO R = CH2=CH-OCO

COOMe OCOC~HS

N=

197

SCHEME 19. Demethylation of cocaine (98). Reagents: i, CI,CCH,OCOCI or CH,= CHOCOCI; ii, Zn, AcOH.

0 II

C-OFH-Me

CP

OAc

198

SCHEME 20. Demethylation of 3a-acetoxytropane (2). Reagents: i, CH,CHCIOCOCI, CICH,CH,Cl, 0°C -+ A, 1 hr; ii, MeOH, A.

46

MAURI LOUNASMAA

The use of ultraviolet irradiation to transform cocaine (98), 3abenzoyloxytropane (14), and tropacocaine (43) to the corresponding Ndemethylated products has been described (107).

B. TROPINONE ENAMINESAS

SYNTHETIC INTERMEDIATES

The enamines 199 and 191, prepared by condensation of tropinone (124) with piperidine and morpholine, respectively, have proved to be useful synthetic intermediates (98,108). Addition of acrylonitrile to enamine 199, followed by hydrolysis, produced cyanoethyltropinone (200) in 43% yield (108) (Scheme 21). The reaction of the enamine 191 with diketene permitted the preparation of isobellendine (114) (vide supra) in 53% yield (98).

n

I

124

F

,

k

N

n X

u CHz -CHz CN

199

X = CHz

191

x=0

II

...

- Po Ill

CHz-CHzCN

2 00

SCHEME21. Preparation of cyanoethyltropinone (200). Reagents: i, piperidine, C,H,, p TsOH, reflux, 20 hr, H,O separation;ii, CH,=CHCN, dioxane, reflux, 20 hr; iii, H,O, HCI.

V. Biosynthesis The main lines of the biosynthesis of tropane alkaloids have been settled (109- 113).

A. HYOSCYAMINE, SCOPOLAMINE, AND SIMILAR COMPOUNDS

Extensive tracer experiments over more than three decades have established that ornithine (201), as a precursor of hyoscyamine (27), is incorporated asymmetrically into the pyrrolidine ring of the tropane moiety in Datura

1.

47

THE TROPANE ALKALOIDS

species and Atropa belladonna. [2-'4C] Ornithine leads to hyoscyamine (27) that is labeled only at the C-1 bridgehead carbon [having the ( R ) configuration] (5,224,215). By analogy with the asymmetrical incorporation of [2-14C]~rnithineit was proposed (5,116,217) (Scheme 22) that to avoid the formation of putrescine

201

203

204

205

f

c:

E t Me Xe

202

F ) - o Me

-

p

>

-

o Me

210

206

F

>

O Me

209

124

I

S

COSCoA

E

208

COOMe

-7po

-

COOH

0

-

207

COOMe

p + o

Me

-

213

214

COOMe

F

>

27

~ H ~ O H

Me

o

212

.COOMe

1

0

96

SCHEME22. Biosynthetic formation of the tropane alkaloids.

SOOMe

98

48

MAURI LOUNASMAA

(202), which is a symmetrical intermediate and which would lead to equal labeling of the C-1 and C-5 bridgehead carbons, ornithine (201) should first be methylated to 6-methylornithine (203). This has been shown to be a direct precursor of hyoscyamine (27) in Datura stramonium and A. belladonna (116,117). Radioactive 6-N-methylornithine (203) has also been isolated after feeding of [5-'4C]- or [5-3H]ornithine to A. belladonna, and shown thereby to be a natural plant constituent (118). Decarboxylation of 6-Nmethylornithine (203) affords N-methylputrescine (204) (an asymmetrical

intermediate), which is an established precursor of the tropane nucleus of hyoscyamine (27) (119-121). N-Methylputrescine (204) is oxidized to 4methylaminobutanal (205), detected in Datura plants fed [2-14C]ornithine (122). Condensation of N-methyl-A'-pyrrolinium salt (206) [cyclized form of 4-methylaminobutanal (205)] with acetyl coenzyme A leads to the coenzyme A ester of hygrine-1'-carboxylic acid (207), which by hydrolysis to 208 and decarboxylation yields hygrine (209). Hygrine (209) has been demonstrated to be a precursor of tropine (1) (123),which in all probability is formed from 209 through dehydrohygrine (210) and tropinone (124). The @)-tropic acid, the acid moiety found in hyoscyamine (27) and scopolamine (89), is formed from phenylalanine by an intramolecular 2,3carbonyl shift (5,124). Feeding of the four possible stereoisomers of [1-'4C,3-3H] phenylalanine to Datura innoxia and D. stramonium was used to prove that during the 2,3-carbonyl shift a 3,2-hydrogen shift takes place as well (125)(Scheme 23). With D. innoxia, the 2,3-carbonyl shift was shown to Ph C H C ,,H -

COOH

k--I

(&

kH2

--

Ph

I

HOOC-C-CHzOH

I H

SCHEME 23. Formation of tropic acid from phenylalanine.

involve the migration of the carboxyl group of phenylalanine to its pro-chiral C-3 position with retention of configuration (126). Incorporation of cinnamic, phenylpyruvic, and phenyllactic acids into tropic acid has also been claimed (5,127). On the other hand, Leete (128)has shown, using D. stramonium plants, that 3-hydroxy-3-phenylpropionicacid and cinnamic acid are not intermediates between phenylalanine and tropic acid. Datura innoxia shows a distinct preference for D( +)-hygrine (209a) (129), whereas Physalis alkekengi, Atropa belladonna, and Hyoscyamus niger are able to use D( + )-hygrine (209a) and L( -)-hygrine (209b)(130) equally well (Scheme 24). It was established with Datura species that esterification occurs

I.

THE TROPANE ALKALOIDS

49

H 209 b

SCHEME24.

D( +)-Hygrine

(ma)and L( -)-hygrine (209b) as synthetic intermediates.

after the formation of the tropane ring (131).The proposed intermediacy of hygroline (210) (131)was disproved (132).

210

It has been confirmed that isoleucine but not 3-hydroxy-2-methylbutanoic acid is a precursor for the tiglic acid which is the esterifying acid in some tropane alkaloids [e.g., meteloidine (77) (133)].In the biosynthesis of meteloidine (77) from 3a-hydroxytropane (I), the hydroxyl groups at C-6 and C-7 are most probably introduced after esterification at C-3 (5)(Scheme 25). In this connection we would point out that scopolamine (89)is a well-known (2,3) metabolite of hyoscyamine (27) and that the reaction proceeds via 6hydroxyhyoscyamine [( -)-anisodamine (6311 and 6,7-dehydrohyoscyamine (211) (Scheme 26). The mechanism of acetoacetate coupling in the biosynthesis of hygrine (m) has been studied by feeding sodium [3-14C]- and [4-14C]acetoacetate to Nicandra physaloides (134).

50

MAURI LOUNASMAA

OH

- F l H7'

-

,Me

0-c-c=c

'H

8

1

ye 0-c-c=

,Me

c

-

0-c-c=

HO

H'

'H 51

c /Me

77

SCHEME 25. Biosynthesis of meteloidine (77).

SCHEME 26. Biosynthesis of scopolamine (89)from hyoscyamine (27).

B. COCAINE AND SIMILAR COMPOUNDS

An analogous biogenetic scheme was predicted for cocaine (98)(Scheme 22) although convincing experimental evidencs was lacking for a long time (109). Recently, a significant incorporation of [5-14C]ornithine into cocaine (98), using the leaf-painting technique and Erythroxylon coca plants, provided this evidence (135-138). Systematic degradation of the cocaine (98) showed that, in contrast to hyoscyamine (27) (uide supra), it was equally labeled at the C-1 and C-5 bridgehead carbons. In view of this finding, it was proposed (135-138) (Scheme 22) that in the case of cocaine (98)the ornithine (201) is incorporated through free putrescine (202), which is a symmetrical intermediate and therefore would afford the pyrrolinium salt 206 equally labeled at C-2 and C-5. As above, condensation of the N-methyl-A'-pyrrolinium salt (206) with acetyl coenzyme A leads to the coenzyme A ester of hygrine-1'-carboxylic acid (207), which by transester-

1.

THE TROPANE ALKALOIDS

51

ification yields the corresponding methyl ester (212). Dehydrogenation of the ester to the iminium salt 213 followed by cyclization leads to 2-carbomethoxy-3-tropinone (214). The intermediacy of 2-carbomethoxy-3-tropinone (214) in the biogenetic formation of cocaine (98)was recently demonto strated by feeding 2-[9-' 3C,14C,0-methyl-3H]carbomethoxy-3-tropinone Erythroxylon coca plants (139). Reduction of 2-carbomethoxy-3-tropinone (214) leads to the corresponding alcohol, methylecgonine (%) (Scheme 22), which has been detected in E. coca as a minor component (25). Moreover, feeding experiments with ( &)-3-[4-3H]benzoyloxy-2-[carbonyl'3C,'4C]carbomethoxy-2-tropene (2,3-dehydrococaine) have indicated that cocaine (98) is not formed by the direct reduction of 2,3-dehydrococaine (140).

The benzoic acid, the acid moiety found in cocaine (98), is also derived from phenylalanine (141). Feeding of [4-3H] phenylalanine to E. coca led to the benzoyl moiety, where 96% of the 3H was located at the para position (138). The intermediacy of cinnamic, 3-hydroxy-3-phenylpropionic, and benzoylacetic acid in the formation of benzoic acid has been suggested (138).

C.

PROTEACEOUS

ALKALOIDS

All evidence so far suggests that the proteaceous alkaloids (e.g., 104,112, 114, 122, 126) are derived from N-methyl-A'-pyrrolinium salt (206). No

labeling experiments have yet been carried out to determine the mode of biogenesis of these alkaloids, but on the analogy of the tropane bases (e.g., 14) occurring in the Solanaceae and related families, it has been suggested (22) that the pyrrolidine ring is derived from a unit of ornithine (201) and that the rest of the structures are built up from units of acetic, benzoic, or other simple acids available from the pool of primary plant metabolites. The general reactions depicted in Scheme 27 have been tentatively proposed [the formation of 3a-benzoyloxytropane (14) is included by way of analogy] (22).

The biogenesis of all the proteaceous alkaloids listed above can be accounted for with Scheme 27, or with simple and obvious modifications of it. The scheme suggests a problem for future study. In which of the several possible ways does the formation of bellendine (113) and its dihydro derivatives take place: by methylation of strobiline (112), from isobellendine (114) directly by the 2,3-shift of a methyl group, or by methylation of isobellendine (114) to darlingine (115) followed by demethylation? Strobiline (112) and its dihydro derivative could also be formed by demethylation of isobellendine (114) (22) (Scheme 28).

52

MAURI LOUNASMAA

Me \

Me \

lb

N

14

114

OCOPh OH 104

SCHEME27. Proposal for the biogenesis of the proteaceous tropane alkaloids.

I . THE TROPANE ALKALOIDS

crs J$L

0

2.3-shift 'Me

O

53

-

v Me he 115

SCHEME28. Possible biogenetic transformations among strobiline (1 12). bellendine (1 13). isobellendine (I 14), and darlingine (115).

VI. spectroscopy Only 'H NMR, I3C NMR, and mass spectrometry, the three most important spectroscopic methods for the tropane alkaloids, will be treated here. A. 'H-NMR SPECTROSCOPY

The 'H-NMR technique has proved to be a valuable tool for structural determinations of tropane alkaloids and their synthetic analogs, and 'HNMR data are now available for most of the basic tropane alkaloid structures (42J9.142-146).Recent high-frequency 'H-NMR data of some basic tropane alkaloids are summarized in Table IV. Lounasmaa et al. (51,53,148,149)have recorded and interpreted the 'HNMR spectra of several 4-benzyltropane alkaloids and their hydrolysis

54

MAURI LOUNASMAA

TABLE IV 'H-NMR DATA OF BASIC TROPANE ALKALOIDS' ~

Proton H-1 H-2a H-2e H-3 H-4a H-4e H-5 H-6n H-6x H-7n H-7x H-2' H-3'a H-3'b Benzoyl 2~ 0-H 2x m-H lx pH Cinnamoyl 5x H -CH=CH-COO-CH=CH-COOCH,-N,

a

/

1(146,147)

26 (146.147)

56 (38)

61 (38)

89 (146,147)

3.08 2.10 1.67 4.03 2.10 1.67 3.08 2.0 2.0 2.0 2.0 -

2.9 1 2.02 1.47 5.02 2.10 1.68 3.03 1.74 1.86 1.17 1.68 3.82 3.79 4.16

3.26 2.10 1.90 4.08 2.14 1.64 3.34 2.78 2.27 5.94 -

3.33 2.20 1.70 5.14 2.24 1.54 3.07 2.65 2.34 4.64

2.97 2.02 1.33 5.02 2.11 1.58 3.1 1 3.38 2.16

-

-

-

-

-

-

7.98 7.37 7.50

-

-

-

-

6.42 7.66

2.26

2.19

2.54

2.50

2.45

-

-

-

-

-

The spectra were recorded at 400or 240 MHz, using tetramethylsilane as internal standard (TMS = 0)and CDCI, as solvent. The coupling constant between the cinnamoyl protons (-CH=CH-COO-) in 61 was 16 Hz (38). The coupling constants for I, 26, and 89 were not given (146.147).

products (Fig. 3) (Table V). The signals were assigned and the stereochemical conclusions made by reference to the spectral data of the hydrolysis product (215) of the Knightia deplanchei alkaloid KD-A 103. The 'H-NMRspectra of cocaine 98 and its three possible, not naturally occurring diastereoisomers, pseudococaine (217), allococaine (218), and

1.

55

THE TROPANE ALKALOIDS

1

6

-

215

216

0-C-Me Me -C-0 102

105

110

111 FIG.3. CBenzyltropane structures for Table V.

allopseudococaine (219) (Fig. 4), have been recorded and interpreted by Carroll et al. (150) (Table VI). A discrepancy exists in Ref. 150 between the chemical shifts indicated for C-1 H and C-4 Ha of cocaine (98) in the table (63.5 and 2.5 ppm, respectively) and the visual reproduction of the recorded spectrum (- 63.6 and 2.4 ppm, respectively). The 'H-NMR spectra of pyranotropanes 112-115 and dihydropyranotropanes 118, 119,121, and 123 and the spectrum of chalcostrobamine 131 (Fig. 5) have been recorded (35,38,39,51).The data are summarized in Tables VII and VIII.

-

TABLE V 'H-NMR DATAOF ~BENZYLTROPANES" Proton H- 1 H-2a H-2e H-3 H-4 H-5 H-6n H-6x H-7n H-7x H-9 H-9' CH,-N< Benzyl 2~ 0-H 2 x m-H I X p-H CH3-COOCH3-COOCH3-COO-

215 (148.149)

107 (148,149)

216 (148,149)

101 (38)

102 (38)

105 (38)

110 (51)

111 (51)

3.10 m 1.86 br dd 1.72 br dd 5.32 ddd 2.58 br dd 2.44 br d 2.00 m 1.80 m 2.46 dd 1.80 m 5.75 d

3.26 m 1.94 ddd 1.50 ddd 4.88 ddd 2.36 m 2.86 br d 4.28 dd 2.46 dd 2.04 m 2.68 dd 2.66 dd 2.48 s

3.18 br d 1.84 m 1.70 br dd 3.78 ddd 2.06 m 3.12 br d 4.88 dd 2.32 dd 1.84 m 4.92 d

3.17 br d 2.30 ddd 1.75 rn 5.17 ddd 1.90 br dd 3.07 br d 4.20 dd 2.82 dd 1.75 m 4.75 d

2.34 s

2.42 s

7.25 m 7.25 m 7.25 m 2.10 s

7.30 def. 7.30 def. 7.30 def. -

7.28 d 7.22 t 7.06 t -

3.00 m 1.91 br dd 1.58 br dd 3.66 m 2.13 m 2.76 m 1.90 m 1.78 m 2.13 m 1.90 m 2.72 dd 2.58 dd 2.16 s

3.29 m 2.10 ddd 1.93 ddd 3.84 m 2.27 m 3.12 br d 2.98 dd 2.17 m 5.83 dd 2.87 dd 2.66 dd 2.56 s

3.10 m 1.86 br dd 1.48 br dd 3.66 br dd 2.11 dddd 2.83 br d 4.93 br d 2.15 m 1.91 m 2.82 dd 2.70 dd 2.42 s

3.01 m 1.84 br dd 1.54 br d 4.17 ddd 2.37 br dd 3.55 m 2.00 m 1.80 m 2.15 m 1.80 m 4.60 d 2.28 s

7.20 def. 7.20 def. 7.20 def. -

7.20 def. 7.20 def. 7.20 def.

7.27 def. 7.27 def. 7.27 def.

7.28 def. 7.28 def. 7.28 def. 1.96 s -

-

-

-

-

-

-

-

2.12 s 7.22 def. 7.22 def. 7.22 def. 1.94 s 2.04 s -

-

-

-

-

1.96 s

-

The spectra were recorded at240 MHz, using tetramethylsilaneasinternalstandard (TMS = 0)and solvents CDCI, (215,107,102,105, and 110), CDCI,/C,D,N ( I : 1) (216), and CDzCIz (101 and 111).

58

MAURI LOUNASMAA

98

217

.C02Me

COzMe

p-j(;-;o p-,$;-pg -

218

219 FIG.

4. The four cocaine structures for Table VI.

TABLE VI 'H-NMR DATAOF COCAINES' Proton H- 1 H-2 H-3 H-4a H-4e H-5 CH3-N, CH3-0-

/

98 (150)

217 (150)

218 (150)

219 (150)

3.5 m 3.0 ddd 5.3 ddd 2.5 ddd 1.8 dddd 3.3 m

3.5 m 3.1 dd 5.5 ddd 1.8 dd(d) 2.1 ddd 3.3 m

3.5 m 3.2 dd 5.6 ddd 2.2 ddd 1.9 ddd 3.3 m

2.2s

2.4 s

3.1 m 2.8 ddd 5.6 ddd 2.4 ddd 1.8 dddd 3.2 m 2.2 s

3.1 s

3.6 s

3.8 s

3.5 s

2.3 s

Coupling constants 98: J1,2 = 3.3 Hz; J2.3 = 6.0 Hz; J2.4e = 0.8 Hz; J3.4a = 12 Hz; = 1.8 Hz; J4c,5= 3.0 HZ J3.4e= 6.0 Hz;J4a,4c= 12.9 Hz; 217: J1,2= 2.9 Hz; J2.3 = 10.9 Hz; 53.4. = 10.5 Hz; 53.4. = 6.6 Hz; J4n,4c= 12.5 Hz; J4c,5= 3.0 HZ 218: J1,2= 2.2 Hz; J2.3 = 1.0 Hz; J2.4c = 2.2 Hz; J3,4a= 5.2 Hz; J3.4c = 1.1 Hz; J4p.4c= 15.0 Hz; J4*,5 = 3.8 Hz; J4c.5 = 2.2 HZ 219: J1,2= 3.1 Hz; J2.3 = 4.8 Hz; J3.4a= 4.8 Hz; J3.de = 1.1 Hz; = 15.8 Hz; J4a.5= 4.8 Hz; J4=,5= 2.2 HZ

" The spectra were recorded at 250 MHz in CDC13,using tetramethylsilane as internal standard (TMS = 0). The multiplicities have been added by the reviewer and are based on the coupling constants indicated and examination of the visually reproduced spectra. The C-6 and C-7 protons and the aromatic protons resonating between 2.4 and I .8 ppm. and 7.9and 7.2 ppm, respectively. were not differentiated.

59

I . THE TROPANE ALKALOIDS 7

1

6

9

2

5

113

0 112

p

@

M

0

Me

e

0 114

9 0

118

HO

F b

r F b 0

F,m 122

0 123

0 131

FIG.5. Pyranotropanes(plus chalcostrobamine)and 10,ll-dihydropyranotropanestructures for Tables VII, VIII and XII.

B. I3C-NMR SPECTROSCOPY The 13C-NMR spectra have been recorded for a large number of tropane alkaloids and their synthetic analogs (42,43,51,59,99,149-162).Table IX lists the 13C-NMR shifts of the basic tropane alkaloids 1,16,21,25,26,30,33,34, 40,64,87,89, and 124 (Fig. 6). For general signal assignments, the interested reader is referred to previous reviews (144,145,163-165).

60

MAURI LOUNASMAA

TABLE VII 'H-NMR DATAOF F'YRANOTROPANES AND CHALCOSTROBAMINE' Proton

112 (38)

113 (39)

114 (39)

115 (35)

131 (51)

3.48 dd 2.16 m 3.05 dd 4.24 d na na na na

3.43 m 2.13 m 3.05 dd 4.18 d na na na na 6.06 s

3.48 m 2.12 d 3.02 dd 4.19 d na na na na

2.35 s

3.42 m 1.94 d 2.80 dd 4.06 dd 1.82 ddd 2.18 m 1.62 ddd 2.18 m 6.84 d 7.68 d 2.42 s

H-1 H-2a H-2e H-5 H-6n H-6x H-7n H-7x H-10 H-11

3.50 m 2.18 d 3.04 dd 4.18 dd 1.87 ddd 2.25 m 1.56 ddd 2.25 m 6.27 d 7.62 d

7.60 s

CH,-N( C-10 CH3 C-11 CH, Benzyl 2 x 0-H 2 x m-H 1 x p-H

2.37 s

2.38 s

2.37 s

1.93 s

-

-

2.23 s

1.92 s 2.25 s 7.35 d 7.34 m 7.34 m

Lounasmaa et al. (152) have analyzed the I3C-NMR spectra of several 4benzyltropane alkaloids. The analyses and the stereochemical conclusions were based on the preliminary correct interpretation of the I3C-NMR spectra of 3~-benzoyloxytropane(14) and 3B-benzoyloxytropane (43), and of their hydrolyzed counterparts 3a-hydroxytropane (1) and 3B-hydroxytropane(40), respectively. The chemical shifts of 4-benzyltropanes and 4-hydroxybenzyltropanes (100-103,105-107,109,110,220-223) (Fig. 7) are listed in Table X. The I3C-NMR spectra of the four diastereoisomericcocaines (98 and 217219) (Fig. 4) have been described by Carroll et. al. (150) (Table XI).The 13CNMR spectra measured for the pyranotropanes 112-115, for 10,l l-dihydropyranotropane (122), and for chalcostrobamine (131) (Fig. 5) are summarized in Table XII.

61

I . THE TROPANE ALKALOIDS

TABLE VIII 'H-NMR DATAOF 10,l 1-DIHYDROPYRANOTROPANE~ 118 (38)

119 (39)

121 (39)

H-1 H-2a H-2e H-5 H-6n H-6x H-7n H-7x H-lOa H-lOe H-1 l a H-1 le

3.33 m 1.90 d 2.75 dd 3.98 dd 1.70 ddd 2.20 m 1.50 ddd 2.20 m 2.56 ddd 2.52 ddd 4.42 ddd 4.44 ddd

3.35 m 1.93 d 2.78 dd 4.00 m na na na na

3.32 m 2.10 d 2.74 dd 3.97 m na na na na -

4.41 dd 4.00 m

4.1 m

CH,-N( C-10 CH, C-11 CH3 C-11 C6H5

2.33 s

2.35 s

-

1.10 s -

2.33 s 1.10 s 1.43 s

Proton

-

-

-

-

-

~

122 (51)

123 (51)

3.40 m 2.02 d 2.82 br d 4.06 d 1.75 ddd 2.20 m 1.55 ddd 2.20 m 2.85 dd 2.62 dd 5.36 dd -

3.27 br d 1.96 d 2.68 dd 4.10 d 4.13 m 2.04 m 2.26 m 2.85 dd 2.62 dd 5.36 dd -

2.37 s

2.33 s 7.35 (5H)

-

7.37 (5H)

~~

The spectra were recorded using tetrarnethylsilane as internal standard (TMS = 0).The signals for the protons marked with na were no1 reported.

C. MASSSPECTROMETRY The mass spectral behavior of tropane alkaloids is well documented (53,63,142,166-171), and only the most characteristic points will be noted

here. The general fragmentation pattern of the 3-hydroxytropane esters can be described in terms of the following five routes (Routes A-E) (Scheme 29) (53). Route A. Cleavage of the 5,6 and 1,7 bonds (or vice versa) eliminates an ethylene unit. This elimination is generally followed by the loss of a hydrogen radical and the ester function, leading to the relatively stable N-methylpyridinium cation ( m / z 94).

TABLE IX "C-NMR DATA OF SOMESIMPLE TROPANE ALKALOIDS' Carbon

c-1 c-2 c-3 c-4 c-5 C-6 c-7 \ ,N-CH, \

,c=o a-C

8-c

53.0 36.8* 68.4 37.0* 53.0 28.5** 28.8**

60.9 47.6 208.2 47.6 60.9 27.9 27.9 38.4

60.0 39.6 64.5 39.6 60.0 25.8 25.8

60.4 39.8 64.0 39.8 60.4 26.9 26.9

40.4

38.6

-

-

-

-

-

-

-

-

54.6 63.7 135.9 127.9 128.5 127.3

54.1 63.6 135.5 127.6 128.4 127.3

142.0 126.6 136.9 128.1 128.4 128.1

141.9 126.8 136.7 128.2 128.3 128.0

54.8 63.6 136.0 128.1 128.6 127.5

171.8

171.7

165.9

165.4

172.0

171.9

208.2 -

0-c

-

m-C PC

-

-

,c=o

64 (149,162)

(159)

-

c-1' C-2' c-3' C-4' c-5' C-6' -O-CH, -O-CH,

21 (41)

1 (159)

i-C

0,

40

124 (153)

-

-

16 (41)

59.4 35.8' 67.6 36.0' 59.4 25.2** 24.8** 40.0

57.3 29.9* 66.1 30.1, 57.3 55.8,. 55.1** 41.3

59.9 36.4 68.1 36.4 59.9 25.5 25.5 40.3

57.9 31.3 67.0 31.3 57.9 56.5 56.5 42.3

-

(162)

25 (162)

58.4 30.5 67.4 29.2 67.0 75.1 39.1 36.8

59.1 35.9 67.0 35.9 59.1 25.1 25.1

52.5 36.8 68.0 36.8 52.5 28.9 28.9

52.8 36.9 67.9 36.9 52.8 28.8 28.8

64.3 37.4 66.3 37.4 64.3 25.9 25.9

-

-

-

-

54.6 63.6 135.6 128.2 128.7 128.0

-

-

-

-

-

-

33

-

-

-

-

-

164.3 122.7 122.4 111.4 152.3 148.0 109.8 55.1 55.0

The spectra were recorded in CDC13 exceptthat of compound 25 (DMSO-d,). The chemical shifts are given in ppm (TMS = 0).

-

164.8 121.0 123.1 115.3 151.6 147.4 112.5 55.5 -

164.7 122.8 122.5 111.4 152.3 148.1 109.9 55.2 55.2

-

-

165.4 123.1 123.2 112.0 153.1 148.8 110.5 55.9 55.9

63

I . THE TROPANE ALKALOIDS

pG-=b-Me)O 124

1

40

H 0 CH20H 0-C-CH \--I

89

26

H 0

H 0 CH2

CH2

0-c-C

0-c-c 16

87

H E rH20H F ) O - C - C H O 21

64

030

0-C-CH

HO

c

OMe 34

FIG.6. Basic tropane alkaloid structures for Table IX.

64

MAURI LOUNASMAA

223

0-C-CH=CH

0

Fob -

106

101

Me-5-0

yob 0

102

!

Me-C-0

110

FIG.7. CBenzyltropane structures for Table X.

109

TABLE X ',C-NMR DATA OF 4-BENZYLTROPANFS AND ~HYDROXYBENZYLTROPANE~

Carbon

c-1 c-2 c-3 c-4 C-5 C-6 c-7 c-9 i-C

0-c

m-C PC \

,N-

CH,

220 (149, 152)

100 (149, 152)

103 (149, 152)

22 1 (149, 152)

107 (149, 152)

222 (149, 152)

223 (149, 152)

105 (149)

106 (149, 152)

101 (100)

60.0 39.9 65.6 46.3 63.8 21.8 25.3 35.4 140.1 127.9 128.7 125.5 40.3

59.8 37.0 69.3 45.4 63.3 21.6 25.3 35.1 139.2 128.1 128.7 125.8 40.4

59.6 37.0 69.7 45.8 63.2 21.9 25.3 35.2 139.0 127.9 128.7 125.7 40.3

67.4 32.7 66.0 40.0 62.8 37.1 76.2 35.1 139.8 128.3 128.7 125.8 36.8

66.5 36.9 65.4 44.9 64.2 32.2 80,5 35.2 140.0 128.1 128.8 125.7 40.6

65.8 34.0 69.3 44.3 63.5 32.7 80.0 35.1 138.7 128.1 128.7 126.0 40.6

58.8 34.4 66.1 40.1 71.6 73.3 40.8 35.1 139.8 128.3 128.7 125.8 37.1

58.4 31.2 69.3 38.5 70.6 72.7 40.8 34.9 139.1 128.4 128.8 126.8 36.8

58.3 31.0 69.3 38.6 70.7 72.8 40.9 35.0 138.9 127.9 128.7 126.0 36.7

59.8 36.7 68.5 50.4 61.2 22.0 25.6 73.1 142.0 126.7 128.6 128.2 40.6

(100)

109 (149, 152)

110 (149)

60.0 36.7 66.1 47.9 61.2 22.1 25.4 73.6 138.3 127.5 128.6 128.6 40.2

66.3 36.0 64.6 49.4 62.5 33.1 80.3 74.2 142.7 126.4 128.4 127.8 40.3

64.6 33.8 65.9 49.3 64.6 78.2 34.0 73.2 143.1 126.1 128.6 127.6 37.1

102

The acetate carbons of l00,101,102,105,and 110 exhibit the following signals: 100, C=O 169.9, CH,-COO 21.3; 105, C=O 169.8. C_,--COO 21.3; 101, C=O 169.4, C_H3-CO0 21.4; 102, C=O 170.1 (ZC), cH,-COO 21 .O and 21.3; 110, C=O 170.9,C_H,-COO 21. I . The benzoatecarbons of 103,107,109, and 222exhibit thefollowingsignals: 103,C=O 165.4, i-C 130.4.0-C 129.2(2C),m-C 128.2(2C),p-C 132.5; 107,C=O 166.3,;-C 129.7,o-C 129.3(2C),m-C128.2(2C).p-C132.7: 222, C=O 165.7 (ZC), i-C 130.3 (2C). 0-C 129.5 (4C). m-C 128.3 (4C), p-C 132.8 and 133.0; 109, C=O 166.1, i-C 130.0.0-C 129.3 (2C). m-C 128.2 (2C). p-C 132.9. The cinnamate carbons of 106 exhibit the following signals: C=O 165.5, a-C 118.0, P-C 144.8, i-C 134.0.0-C 128.7 (2C), m-C 128.3 (2C). p-C 130.2. The spectra were recorded in CDCI,. In the case of 221 some (CH,),SO was added to enhance the solubility. The 6 values are given in ppm (TMS= 0).

TABLE XI "C-NMR DATAOF COCAINES" Carbon

c-1 c-2 c-3 c-4 c-5 C-6 c-7 \

,N-CH, -COOcH, --C_OOCH3

c=o i-C

0-c m-C P-C a

'

98 (150)

217 (150)

218 (150)

219 (150)

64.76 50.14 66.82 35.48 61.45 25.32' 25.17'

62.38 48.38 67.64 33.56 59.50 26.63 23.86

62.87 51.80 67.69 36.15 60.48 24.97 24.44

61.01 49.41 68.18 36.63 59.60 25.32 24.05

41.02 51.26 170.63 166.04 130.20 129.57 128.16 132.74

37.36

41.51

40.38

51.55 171.95 165.22 129.26 129.18 127.91 132.49

51.65 171.80 165.26 130.15 129.18 128.26 132.74

51.40 171.31 165.41 130.06 129.23 128.40 132.89

The spectra were recorded in CDCI,. The chemical shifts are given in ppm (TMS = 0). The assignment for these signals may be reversed.

TABLE XI1 I3C-NMR DATAOF PYRANOTROPANES, 10,l I-DIHYDROPYRANOTROPANE, AND CHALCOSTROBAMINE' 112 (38)

113 (39)

114 (149)

115 (35)

122 (99)

131 (99)

55.6 29.2 161.6 127.8 58.2 33.7 33.4 176.9 116.7 154.8

56..2 29.8 161.6 125.8 58.4 34.1 34.1 178.0 125.2 151.5

55.3 29.0 164.9 124.8 57.9 33.2 33.2 177.5 113.5 160.4

56.1 29.8 161.1 123.9 58.4 34.0 34.0 177.9 120.7 159.9

55.7 28.3 168.6 116.8 58.0 35.4 32.6 189.2 42.7 80.5

57.6 29.0 172.7 112.4 58.9 36.8 33.3 196.8 117.5 141.1

,N-CH3 C-10 CH3 C-I1 CH3 i-C

37.2

31.6 11.9

-

-

36.6 19.7

-

-

-

37.3 10.4 18.3 -

-

-

m-C P-C

-

-

-

-

-

-

-

-

37.4 138.0 128.4 125.8 128.4

40.6

-

Carbon

c-1 c-2 c-3 c-4 c-5 C-6 c-7 c-9 c-10 c-11 \

0-c

The spectra were recorded in CDCI,. The chemical shifts are given in ppm (TMS = 0)

-

135.1 128.7 128.0 129.9

67

I . THE TROPANE ALKALOIDS

‘F)ycO

-RCOOH

R

C7H9N02R rnlz 139+R

[bH6N

rnlz 94, g

1

1

-H.

-H.

H

H

c7H10N02R

c6H9N

rnlz 95,

t

WH

OR

’

d

-CH2

rnlz 140+R,

CH2

t

p

‘

6H11N

C6H10N

rnlz 97

rnlz 96

t

A -CH2=CH2

A

H

-C 3H3OzR

F>(” i 1 ) . ’‘g

-‘kHs0ZR

OCOR

OCOR

-RCOOH

c 5H9N rnlz 83,f

9H lkN O2

C8H13N

rnlz 123

rnlz 168+R

Cl-RCOO-

H

/

.

2D t M e

1’

-

0 C8H14NO

C8H14N

C5H7N

C5H8N

rnlz 140,b

mlr 124, c

rnlz 81

rnlz 82, g

SCHEME29. General fragmentationpattern of 3-hydroxytropaneesters.

Route B. Cleavage of the 4,5 (or 1,2) bond is followed by several further fragmentations. Routes C, D, and E. In these routes the C-3 ester function is cleaved under forms of RCOO., RCO., and RCOOH, respectively. In the last case, ionized tropidine is formed. Concomitant losses of ethylene and hydrogen radical lead again to the N-methylpyridinium ion (cf. Route A).

68

MAURI LOUNASMAA

TABLE XI11 RELATIVE INTENSITIES (INPARENTHESES) OF THE MOSTCHARACTERISTIC PEAKSIN THE MASSSPECTRA OF TROPANE ALKALOIDS"

Ion M+ a b C

d e

f g

21

26

63

89

91

289 (29) 261 (< 1) 140 (8) 124(100) 95 (8) 94 (14) 83 (20) 82 (18)

305 ( 19) 261 (14) 156 (3) 140 (41) 95(100) 94 (82) 83 (2) 82 (6)

303 (68) 261 ( < 1 ) 154 (32) 138 (100) 95 (14) 94 (77) 97 (22) 96 (10)

319 (51) 277 (< 1) 154 (14) 138 (100) 95 ( 5 ) 94 (36) 97 (15) 96 ( 5 )

From Ref. / 7 / . The mass spectra were recorded with a Jeol JMS-02-B mass spectrometer using an ionization potential of 75 eV. Unfortunately, the exact recording conditions, especially the ion source temperature, were not given ( 1 7 / ) .

In the case of asymmetrical tropanes (e.g., 103), where the $6 and 1,7 and the 4,5 and 1,2 bonds, respectively, are not equal, there are two possibilities for the Routes A and B. The five routes presented (A-E) can be detected in the mass spectra of all 3hydroxytropane esters. However, their contribution to the general fragmentation may vary widely. Table XI11 shows the relative intensities of the characteristic peaks, corresponding to the ions a-g given below for atropine 26 (Fig. 8). Route A strongly dominates the fragmentation of pyranotropane alkaloids, leading in the case of strobiline (112), for example, to the ion m/z 162 (ion e) (base peak) (Scheme 30). As can be seen in Table XIII, the presence of supplementary functional groups often strongly influences the fragmentation pattern. For example, a hydroxyl group at C-6 or C-7 position generally strongly favors the cleavage of the ethylene derivative (Routes A and E) (53,63,166,171).The substituents

112

SCHEME 30. Main fragmentation of strobiline (112).

I.

THE TROPANE ALKALOIDS

69

a

m/z 261

e -

m l z 94

b -

m/z 140

-f

m/z 83

c m l z 124

g -

m I z 82

-d

m/z 95

FIG.8. The most characteristicions in the mass spectral fragmentation of atropine (26).

may be partly or totally cleaved, which will influence the general fragmentation (53,Z71). Thus tropic acid derivatives [e.g., atropine (26)] and similar compounds lose formaldehyde due to the McLafferty rearrangement (142) (Scheme 31). In the case of tropic acid derivatives, there is a relatively easy thermal loss of water before ionization, leading to the corresponding apo compounds, which then give fragments of their own. Quadrupole electron-impact (EI) and chemical ionization (CI) mass spectral behavior of some principal tropane alkaloids (e.g., 1,14,19,26,43,89, 96-98, and 124) has recently been reported (172).

70

MAURI LOUNASMAA

SCHEME 3 I . McLafferty rearrangement of tropic acid derivatives.

VII. Pharmacology Tropane alkaloids, long known to have anticholinergic, antiemetic, parasympatholytic, anesthetic, and many other actions, have been featured in an extremely wide number of pharmacological reports. The section “Pharmacology” in Chemical Abstracts (Vols. 90-105) lists over 600 articles. To deal in an adequate way with these articles would go far beyond the scope of the present chapter, and interested readers are referred to Chemical Abstracts. Many of the same articles are mentioned in Periodical Reports (9a-9h).Only a few papers (oide infra) will receive comment here. A special issue of The Journal of Ethnopharmacology in 1981 (Vol. 3, Nos. 2-3) was devoted to coca and cocaine (98).Several other, more general articles on the pharmacological effects of tropane alkaloids have recently appeared (173-185). The Chinese have shown great interest in the pharmacology of tropane alkaloids, especially anisodamine (63)and anisodine (91).Because of the poorer accessibility of the Chinese papers to Western readers, most of these papers are listed here (186-221).The antishock action of anisodamine (63)has been investigated (187,189-195), and it has been proposed (187) that it operates in rabbits by preventing the production of a shock-causingintestinal factor. Anisodamine (63)has been found (192,197,200,203)to reduce acute myocardial infarction. Possibly its Ca2+-antagonistaction (207)is related to its protective effect against myocardial damage (uide supra). The expectorant effects of anisodamine (63)have been studied and found to be mainly due to a the peripheral action (188). The effect of anisodine (91) on the release of acetylcholine has been investigated (211-213). Investigation of the pharmacological effects of anisodine (91) on the central nervous system in rabbits has shown a strong depressant effect (210).The effect was antagonized by physostigmine and

I . THE TROPANE ALKALOIDS

71

andrenomimetics,whereas regitine was found to be synergistic. A comparative EEG study of anisodine (91), scopolamine(89),anisodamine (63), and atropine (26) in rabbits after intracerebroventricular injection suggested that anisodine (91) and scopolamine (89) are mainly depressants of the central nervous system (vide supra), whereas anisodamine (63) and atropine (26) are stimulants (214-216).

VIII. Perspectives Altogether 139* tropane alkaloids (sensu stricto) have been isolated from different plant sources. The intensity of the search for new tropane alkaloids can be expected to continue. Although chemical syntheses have been developed for the basic tropane alkaloids, most of the pharmaceutically important alkaloids are more economically obtained in an industrial scale by extraction from plant material. This will probably be true in the immediate future as well. Recently, considerable effort has been directed toward the production of tropane alkaloids with plant cell cultures (222-235). Unfortunately, the alkaloid content in cultured cells has so far proved lower than in intact plants (225-227), and a breakthrough in the procedure is still awaited. The high variability in the production of tropane alkaloids by cell cultures would suggest the possibility of improving the alkaloid production through a continuous selection of high-production cell lines. Some interesting results have recently been reported (235).Genetic manipulations in plant cells can be expected some day to provide revolutionary possibilities for the production of tropane alkaloids by plant cells. Several serious problems in the gene technology will have to be solved, however, before this attractive goal is reached.

IX. Addendum Since the completion of the original manuscript (literature covered up to the end of 1986, uide supra), the isolation of 12 new tropane alkaloids 224-235, listed in Tables XIV and XV, has been reported (236-239). This brings the

*

See Addendum.

TABLE XIV

TROPANE ALKALOIDSTRUCTURES &-Monosubstituted tropanes 3a-Senecioyloxytropane (R = Me, R, = senecioyl) 3a-(3’,4’,5‘,-Trimethoxybenzoylox~~-nortropane (R = H, R, = 3,4,5-trimethoxybenzoyl) ( f)-3a-Veratroyloxy-N-isopropylnortropane (R = i-Pr, R, = veratroyl) (convosine)

224 225 226

&,7j’I-Dkubstituted tropanes 227 3a-(3’,4’,5’-Trimethoxybenzoyloxy)-7jhydroxynortropane 228 ( )-3a-(3’,4’,5’-Trimethoxybenzoyloxy)7j-hydroxytropane

+

3

&,6j’I,7j’I-Trisubstituted tropanes 229 3a,6j-Dihydroxy-7~-benzoyloxytropane 230 3a-(3’,4’,5’-Trimethoxycinnamoyloxy)-6jhydroxy-7~-benzoyloxytropane 231 3a-(3’,4’,5’-Trimethoxycinnamoyloxy)-6jacetoxy-7j-benzoyloxytropane

(R = H,R, = 3,4,5-trimethoxybenzoyl) (R = Me, R,

= 3,4,5-trimethoxybenzoyl)

(R = Me, R, = R, = H, R, = benzoyl) (R = Me, R, = 3,4,5-trimethoxycinnamoyl, R, = H, R, = benzoyl) (R = Me, R, = 3,4,5-trimethoxycinnamoyl, R, = acetyl, R, = benzoyl)

“Dimeric tropaws” Schizanthine C

232

c

I Me

n

I

o=u

xa

a

u-x I I

w

x N

o=u

I U

I

a

u-z s

13

74

MAURI LOUNASMAA

TABLE XV LISTOF TROPANE ALKALOIDS OF PLANT ORIGIN

.

MW

Formula

Compound

Family”

Refs.

~

223 277

cl 3H2 1 ‘1

,H19N04

321

c l 7HZ3N0S

333

C19H27N04

337

‘1

351

C18H25N06

7H23N06

474 490 490 497

230 3a-(3’,4’,5’-TrimethoxycinnamoyI-

539

C2,H33N0,

608

C34H44N208

”

224 3a-Senecioyloxytropane 229 3a,6fl-Dihydroxy-7fl-benzoyloxytropane 225 3a-(3’,4’,5’-Trimethoxybenzoyloxy)-nortropane 226 ( +)-3a-Veratroyloxy-N-isopropylnortropane (convosine) 227 3or-(3’,4‘,5’-Trimethoxybenzoyloxy)-7/&hydroxynortropane 228 (+)-3a-(3’,4’,5’-Trimethoxybenzoyloxy)-7fl-hydroxytropane 232 Schizanthine C 233 Schizanthine D 234 Schizanthine E

oxy)-6fl-hydroxy-7fl-benzoyloxytropane 231 3a-(3’,4‘,5’-Trirnethoxycinnamoyloxy)-6fl-acetoxy-7~-benzoyloxytropane 235 Convolvidine

Er

236 23 7

Er

23 7

co

238

Er

23 7

Er

23 7

5 5 5

Er

236 236 236 23 7

Er

23 7

co

239

5

Key to families: C o , Convolvulaceae; Er, Erythroxylaceae; S,Solanaceae.

total number of known tropanealkaloids to 151(139 1987).

+ 12)(asof December 1,

Backvall et al. (240)have described a method which permits the stereocontrolled preparation of 3a- and 3B-hydroxytropane derivatives at will. The approach is related to the Kibayashi synthesis (92,93).

References H. L.Holmes, Alkaloids ( N . Y . ) 1,271 (1950). G. Fodor, Alkaloids ( N . Y . ) 6, 145 (1960). G. Fodor, Alkaloids ( N . Y . ) 9,269 (1967). G. Fodor, Alkaloids ( N . Y . ) 13,351 (1971). 5. R. L.Clarke, Alkaloids ( N . Y . ) 16,83 (1977).

1. 2. 3. 4.

I.

THE TROPANE ALKALOIDS

75

6. See, for example, G. A. Swan, “An Introduction to the Alkaloids,” pp. 50-52. Blackwell Scientific Publications, Oxford, 1967. 7. K. Nador, in “Recent Development in the Chemistry of Natural Carbon Compounds,” (G. Fodor, ed.) Vol. 1, pp. 163-235. Publishing House of Academy of Sciences, Budapest, 1965. 8. L. N. Bereznegovskaya, “Physiology and Biochemistry of Tropane Alkaloids.” Izd. Tomsk. Gos. Univ., Tomsk. (U.S.S.R.), 1974; Chem. Absrr. 82, 121987f(1975). 9a. G. Fodor and J. Butterick, Alkaloids (London) 9,46 (1979). 9b. G. Fodor and J. Butterick, Alkaloids (London) 10,41 (1981). 9c. G. Fodor and R. Dharanipragada, Alkaloids (London) 11,36 (1981). 9d. G. Fodor and R. Dharanipragada, Alkaloids (London) 12.45 (1982). 9e. G. Fodor and R. Dharanipragada, Alkaloids (London) 13.55 (1983). 9f. G. Fodor and R. Dharanipragada, Nor. Prod. Rep. 1,231 (1984). 9g. G. Fodor and R. Dharanipragada, Not. Prod. Rep. 2,221 (1985). 9h. G. Fodor and R. Dharanipragada, Nar. Prod. Rep. 3, 181 (1986). 10. C. C. Fang, J. Erhnopharmacol. 2, 57 (1980). 11. A. T. Weil, J. Erhnopharmacol. 3,367 (1981). 12. P. G. Xiao, J . Erhnopharmacol. 7,95 (1983). 13. P. G. Xiao and L. Y. He, J . Ethnopharmacol. 8,1(1983). 14. M. Novak, C. A. Salemink, and I. Khan, J. Erhnopharmacol. 10,261 (1984). 15. A. Romeike, Bot. Noriser 131, 85 (1978). 16. W. C. Evans, in “The Biology and Taxonomy of the Solanaceae”(J. G. Hawkes, R.N. Lester, and A. D. Skelding, eds.),pp. 241-254. Linnean Society Symposium Series, No. 7, Academic Press, London, 1979. 17. W. C. Evans and K. P. A. Ramsey, Phyrochemistry 22,2219 (1983). 18. Y. M. A. El Imam and W. C. Evans, Planta Med., 50,86 (1984). 19. W. C. Evans, J. Erhnopharmacol. 3,265 (1981). 20. R. Hegnauer, J. Erhnopharmacol. 3,279 (1981). 21. I. R. C. Bick and H.-M. Leow, J. Indian Chem. SOC.55,1103 (1978). 22. I. R. C. Bick, J. W. Gillard, H.-M. Leow, M. Lounasmaa, J. Pusset, and T. Svenet, Planta Med. 41, 379 (1981). 23a. W. G. DArcy, in “The Biology and Taxonomy of the Solanaceae” (J. G. Hawkes, R. N. Lester, and A. D. Skelding, eds.), pp. 3-47. Linnean Society Symposium Series, No. 7, Academic Press, London, 1979. 23b. R. Hegnauer, “Chemotaxonomie der Pflanzen,” Vols. 1-7. Birkhauser, Bade and Stuttgart, 1962- 1986. 23c. R. von Wettstein, in “Die Naturlichen Pflanzenfamilien” (A. Engler and K. Prant, 4s.). Englemann, Leipzig, 1885. 23d. “Index Kewensis.” The Royal Botanical Gardens, Kew, Clarendon Press, Oxford, 1893-1987. 24. P. Hsiao, K. Hsia, and L. Ho, Chih. Wu Hsueh Pa0 15, 187 (1973); Chem. Absrr. 81.355451 (1974). 25. C. Hsieh, L. Wang, Y. Liu, T. Shang, F. Hsieh, and T. Ka, K b Hsueh Tung Pa0 20.52 (1975); Chem. Absrr. 83,93824~(1975). 26. P. Xiao and L. He, Planra Med. 45, 112 (1982),and references therein. 27. J. Xie, J. Yang, Y. Zhao, and C. Zhang, Sci. Sin.Ser. B (Engl. Ed.) 26,931 (1983); Chem. Absrr. 100, 139413~ (1984). 28. C. F. Moorhoff, PIanra Med. 28,106 (1975). 29. J. Bode and C. H. Stam, Acra Crystallogr. Sect. B 38,333 (1982). 30. D. H. Gnecco Medina, M. Pusset, and H.-P. Husson, J. Nar. Prod. 46,398 (1983). 31. M. S. Al-Said, W. C. Evans, and R.J. Grout, Phyrochemisrry 25,851 (1986). 32. M. Sahai and A. B. Ray, J. Org. Chem. 45,3265 (1980).

76

,

MAURI LOUNASMAA

33. A. R. Pinder, J. Org. Chem. 47,3607(1982). 34. A. B. Ray, Y. Oshima, H. Hikino, and C. Kabuto, Heterocycles 19, 1233 (1982). 35. I. R. C. Bick, J. W. Gillard, and H.-M. Leow, Aust. J. Chem. 32,2523 (1979). 36. 1. R. C. Bick, J. W. Gillard, and H.-M. Leow, Aust. J. Chem. 32,2537 (1979). 37. T.Yao, Z.Chen, D. Yi, and G. Xu, Yaoxue Xuebao 16,582 (1981);Chem. Abstr. %, 48972c (1982). 38. M. Lounasmaa, J. Pusset, and T. Sivenet, Phytochemistry 19,949 (1980). 39. 1. R. C. Bick, J. W. Gillard, and H.-M. Leow, Aust. J . Chem. 32, 1827 (1979). 40. M. S.Al-Said, W. C. Evans, and R. J. Grout, J. Chem. Soc.. Perkin Trans. I, 957 (1986). 41. K. Kagei, M. Ikeda, T. Sato, Y. Ogata, T. Kunii, S. Toyoshima, and S . Matsuura, Yakugaku Zusshi 100,216 (1980);Chem. Absfr.92, 194445s(1980). 42. M. A. I. A-Yahya, W. C. Evans, and R. J. Grout, J. Chem. Soc.. Perkin Trans. I , 2130 (1979). 43. W.J. Griffin, Aust. J. Chem. 31, 1161 (1978). 44. W. C. Evans and V. A. Woolley, Phytochemistry 17, 171 (1978). 45. W.C. Evans and K. P. A. Ramsey, Phyrochemistry 20,497 (1981). 46. Y. M. A. El-Iman, W. C. Evans, and T. Plowman, Phytochemistry 24,2285 (1985). 47. A. San Martin, J. Rovirosa, V. Gambaro, and M. Castillo, Phytochemistry 19,2007 (1980); see also V. Gambaro, C. Lab&, and M. Castillo, Bol. SOC.Chil. Quim. 27,296 (1982),and V.Gambaro, C. LabW, and M. Castillo, Phytochemistry 22, 1838 (1983). 48. W.J. Griffin, Aust. J. Chem. 29,2329 (1976). 49. I. R. C. Bick, J. W. Gillard, H.-M. Leow, and N. W. Preston, Aust. J . Chem. 32,2071 (1979). 50. V. 1. Muraveva, A. G. Mamedova, and A. 1. Bankovskii, Zh. Obshch. Khim. 33,1690 (1963); Chem. Ahstr. 59, 131 14g(1963). 51. M. Lounasmaa, J. Pusset, and T. Sevenet, Phytochemistry 19,953 (1980). 52. S. Siddiqui, N.Sultana, S. S. Ahmed, and S. I. Haider,J. Nut. Prod. 49, 511 (1986). 53. C. Kan-Fan and M. Lounasmaa, Actu Chem. Scund. 27,1039 (1973). 54. S. F.Aripova, V. M. Malikov, and S. Y. Yunusov, Khim. Prir. Soedin, 290 (1977);Chem. Ahstr. 87,98864d (1977). 55. E. G.Sharova, S. F. Aripova, and S. Y. Yunusov. Khim. Prir. Soedin, 672(1980);Chem. Abstr. 94,117787~(1981). 56. R. T.Mirzamatov, V. M. Malikov, K. L. Lutfullin, and S. Y. Yunusov, Khim. Prir. Soedin, 493 (1972);Chem. Ahstr. 78, 13742d (1973). 57. S.F.Aripova, E. G. Sharova, U. A. Abdullaev, and S. Y. Yunusov, Khim. Prir. Soedin, 749 (1983)[Chem.Nut. Compd. (Engl. Trans.) 19,712(1983)];Chem.Abstr. 100,171549y(1984). 58. R. Pfleger, Mitt. Dfsch. Pharmaz. Ges. 34, 182 (1964). 59. S.A. Minina, T. V. Astakhova, and D. A. Fesenko, Khim. Prir. Soedin, 712 (1977);Chem. Ahsrr. 88, 6 0 0 9 7 ~(1978). 60.S. F. Aripova, Khim. Prir. Soedin. 275 (1985)[Chem. Nut. Compd. (Engl. Trans.) 21,261 (1985)l;Chem. Ahstr. 103,682741 (1985). 61. W . C. Evans and V. A. Major, J. Chem. SOC.C , 2775 (1968). 62. E. Graf and W. Lude, Arch. Pharm. ( Weinheim. Ger.) 311,139 (1978);see also E.Graf and W. Lude, Arch. Pharm. (Weinheim. Ger.) 310, 1005 (1977). 63. M. Lounasmaa, PIunta Med. 27,83 (1975). 64. H. Ripperger, Phytochemistry 18,717 (1979). 65. S.F. Aripova, E. G. Sharova, and S. Y. Yunusov, Khim. Prir. Soedin. 640(1982);Chem. Abstr. 98, 160979e (1983). 66. R. Robinson, J. Chem. SOC.111,762 (1917). 67. C. Schopf and G. Lehmann, Liebigs Ann. Chem. 518, 1 (1935). 68. C. Schopf, Angew. Chem. 50,779,797(1937). 69. R. Willstatter, 0, Wolfes, and H. Mader, Liebigs Ann. Chem. 434,111 (1923).

1.

THE TROPANE ALKALOIDS

77

P. Nedenskov and N. Clauson-Kaas, Acfu Chem. Scund. 8, 1295 (1954). G. Fodor, S. Kiss, and J. Rakoczi, Chim. Ind. (Paris) 90,225 (1963). N. Clauson-Kaas, F. Limborg, and K. Glens, Acfu Chem. Scund. 6,531 (1952). T. S. Chou and W. J. Cheng, Bull. Insf. Chem. Acod. Sin.29,9(1982); Chem. Absrr. 98,72506r (1983). 74. J. Xie, J. Zhou, X. Jia, C. Liu, H. Xu, A. Fang, J. Wang, and B. Xia, Yuo Hsueh Hsueh Puo 15, 403 (1980); Chem. Absfr.94, 121757b (1981). 75. J. Xie, J. Yang, and C. Zhang, Yuoxue Xuebuo 16, 762, (1981); Chem. Absrr. %, 1629909 (1982). 76. J. Xie, J. Xhou, C. Zhang, and J. Yang, Yuoxue Xuebuo 16, 767 (1981); Chem. Absrr. %, 143127q (1982). 77. J. Xie, J. Zhou, C. Zhang, J. Yang, and X. Chen, Zhongguo Y i x w Kexueyuun Xuebuo 4,92 (1982); Chem. Abstr. 97,216529e (1982). 78. W. Parker, R. A. Raphael, and D. I. Wilkinson J. Chem. SOC.,2433 (1959). 79. R. Willstatter and M. Bommer, Liebigs Ann. Chem. 422, 1 (1921). 80. P. Karrer and H. Alagil, Helv. Chim. Acra 30, 1776 (1947). 81. A. T. Bottini and J. Gal, J. Org. Chem. 36, 1718 (1971); see also B. Gutkowska and R. Kmiotek, Pol. J. Chem. 54,1579 (1980); Chem. Absfr.94, 192519111(1981). 82. E. W. Garbisch, Jr, J. Org. Chem. 30,2109 (1965). 83. J. J. Tufariello and E. J. Trybulski, J. Chem. Soc., Chem. Commwt., 720 (1973);see also J. B. Bapat, D. St. C. Black, R. F. C. Brown, and C. Ichlov, Ausf.J . Chem. 25,2445 (1972). 84. J. J. Tufariello, J. J. Tegeler, S. C. Wong, and I. A. Ali, TefruhedronLeft., 1733 (1978). 85. J. J. Tufariello, G. B. Mullen, J. J. Tegeler, E. J. Trybulski, S. C. Wong, and 1. A. Ali, J. Am. Chem. Soc. 101,2435( 1979);see also J. J. Tufariello and G. B. Mullen,J. Am. Chem. SOC.100, 3638 (1978). 86. J. J. Tufariello, Acc. Chem. Res. 12, 396 (1979). 87. G. R. Wiger and M. F. Rettig, J. Am. Chem. SOC.98,4168 (1976). 88. T. L. Macdonald and R. Dolan, J. Org. Chem. 44,4973 (1979). 89. R. Noyori, S. Makino, Y. Baba, and Y. Hayakawa, TefruhedronLerr., 1049 (1974). 90. R. Noyori, Y. Baba, and Y. Hayakawa, J. Am. Chem. SOC.%, 3336 (1974). 91. Y. Hayakawa, Y. Baba, S. Makino, and R. Noyori, J. Am. Chem. SOC.100,1786(1978). 92. H. Iida, Y. Watanabe, and C. Kibayashi, TefruhedronLerr. 25,5091 (1984). 93. H. Iida, Y. Watanabe, and C. Kibayashi, J . Org. Chem. 50, 1818 (1985). 94. A. P. Krapcho and J. A. Vivelo, J. Chem. SOC.,Chem. Commun., 233 (1985). 95. M. E. Jung and J. C. Rohloff, J. Chem. Soc.. Chem. Commun., 630 (1984). 96. I. R. C. Bick, J. B. Bremmer, and J. W. Gillard, Tetrahedron Letf., 5099 (1973). 97. M. Lounasmaa and C.-J. Johansson, Tetrahedron Leff., 2509 (1974). 98. M. Lounasmaa, T. Langenskiold, and C. Holmberg, Tetrahedron Left., 5179 (1981). 99. M. Lounasmaa, C. Holmberg, and T. Langenskiold, J. Nur. Prod. 46,429 (1983). 100. M. Lounasmaa, C. Holmberg, and T. Langenskiold, Plunru Med. 48,56 (1983). 101. R. A. Olofson, R. C. Schnur, L. Bunes, and J. P. P e p , Tetrahedron Lerr.. 1567 (1977). 102. S. W. Baldwin, P. W. Jeffs, and S. Natarajan, Synfh. Commun. 7,79 (1977). 103. J. R. Pfister, J . Org. Chem. 43,4373 (1978). 104. J. L. Wallace, M. R. Kidd, S. E. Cauthen, and J. Woodyard, J. Pharm. Sci. 69, 1357 (1 980). 105. E. S. Lazer, N. D. Naranjan, G. J. Hite, K. A. Nieforth, R. T. Kelleher, R. D. Spealman, C. R. Schuster, and W. Wolverton, J. Phurm. Sci. 67, 1656 (1978). 106. R. A. Olofson, J. T. Martz, J.-P. Senet, M. Piteau, and T. Malfroot, J. Org. Chem. 49,2081 (1984). 107. S . P. Singh, D. Kaufman, and V. I. Stenberg, J. Hererocycl. Chem. 16,625 (1979). 70. 71. 72. 73.

78

MAURI LOUNASMAA

108. R. G. Glushkov, N. I. Koretskaya, A. I. Ermakov, G. Y. Shvarts, and M. D. Mashkovskii, Khim.-Farm. Zh. 9,6 (1975);Chem. Abstr. 84, 180439r(1976). 109. E. Leete, Planta Med. 36,97 (1979). 1 10. T. Robinson, “The Biochemistry of Alkaloids,” pp. 58-66. Springer Verlag, Berlin, Heidelberg, New York, 1981. 111. E. Leete, Biosynthesis (London) 7, 102 (1983). 112. G. R. Waller and 0.C. Dermer, “The Biochemistry of Plants” (P. K. Stumpf and E. E. Conn, eds.), Vol. 7, pp. 317-402. Academic Press, New York, 1981. 113. H. W. Liebisch and H. R. Schiitte, in “Biochemistry of Alkaloids”(K. Mothes, H. R. Schiitte, and M. Luckner,eds.),pp. 107-127. VEB Deutscher Verlagder Wissenschaften, Berlin, 1985. 114. E. Leete, J. Am. Chem. SOC.84,55 (1962). 115. E. Leete, Tetrahedron Lett., 1619 (1964). 116. F. E. Baralle and E. G. Gros, Chem. Commun., 721 (1969). 117. A. Ahmad and E. Leete, Phytochemistry 9,2345 (1970). 118. S. H. Hedges and R. B. Herbert, Phytochemistry 20,2064 (1981). 119. H. W. Liebisch, W. Maier, and H. R. Schiitte, Tetrahedron Lett., 4079 (1966). 120. H. W. Liebisch, A. S. Radwan, and H.R. Schiitte, Liebigs Ann. Chem. 721, 163 (1969). 121. E. Leete and J. A. McDonell, J. Am. Chem. SOC.103,658 (1981). 122. S. Mizusaki, T. Kisaki, and E. Tamaki, Plant Physiol. 43.93 (1968). 123. D. G. ODonovan and M. F. Keogh, J. Chem. SOC.C , 223 (1969); see also E. Leete, Phytochemistry 24,953 (1985). 124. E. Leete, N. Kowanko, and R. A. Newmark, J . Am. Chem. SOC.97,6826 (1975). 125. E. Leete, J. Am. Chem. SOC.106,7271 (1984). 126. E. Leete, Can. J. Chem. 65, 226 (1987); see also R. V. Platt, C. T. Opie, and E. Haslam, Phytochemistry 23,221 1 (1984). 127. B. A. McGaw and J. G. Woolley, J. Pharm. Pharmacol. 30,Suppl. 83P (1978). 128. E. Leete, Phytochemistry 22,933 (1983). 129. B. A. McGaw and J. G. Woolley, Phytochemistry 17,257 (1978). 130. B. A. McGaw and J. G. Woolley, Phytochemistry 18, 189 (1979). 131. B. A. McGaw and J. G. Woolley, Phytochemistry 21,2653 (1982). 132. B. A. McGaw and J. G. Woolley, Phytochemistry 22,1407 (1983). 133. B. A. McGaw and J. G. Woolley, Phytochemistry 16,1711 (1977). 134. B. A. McGaw and J. G. Woolley, Tetrahedron Lett., 3135 (1979). 135. E. Leete, J. Chem. SOC.,Chem. Commun.. 1170(1980). 136. E. Leete, J. Am. Chem. SOC.104,1403 (1982). 137. E. Leete, Rev. Lutinoumer. Quim. 14, l(1983). 138. E. Leete, Phytochemistry 22,699 (1983). 139. E. Leete, J . Am. Chem. SOC.105,6727 (1983). 140. E. Leete, J. Nut. Prod. 50,30 (1987). 141. D. Gross and H. R. Schiitte, Arch. Pharm. ( Weinheim, Ger.) 296, 1 (1963). 142. J. Parello, P. Longevialle, W. Vetter, and J. McCloskey, Bull. SOC.Chim. Fr., 2787 (1963). 143. V. I. Stenberg, S. P. Singh, and N. K. Narain, J. Org. Chem. 42,2244 (1977). 144. T. A. Crabb, Annu. Rep. NMR Spectrosc. 8,85 (1978). 145. T. A. Crabb, Annu. Rep. NMR Spectrosc. 13, 119 (1982). 146. W. J. Chazin and L. D. Colebrook, J. Org. Chem. 51,1243 (1986). 147. W. J. Chazin, Ph.D. Thesis, Concordia University, Montreal, Quebec, Canada, 1983. 148. M. Lounasmaa and G. Massiot, Planta Med. 34,66 (1978). 149. M. Lounasmaa, unpublished results. 150. F. 1. Carroll, M. L. Coleman, and A. H. Lewin, J. Org. Chem. 47, 13 (1982). 151. K.-H. Pook, W. Schulz, and R. Banholzer, Liebigs Ann. Chem.. 1499 (1975).

I.

THE TROPANE ALKALOIDS

79

152. M. Lounasmaa, P. M. Wovkulich, and E. Wenkert, J. Org. Chem. 40,3694(1975). 153. P. Hanisch, A. J. Jones, A. F. Casey, and J. E. Coates, J. Chem. SOC.Perkin Trans. 2, 1202, 1977. 154. V. I. Stenberg, N. K. Narain, and S. P. Singh, J. Heferocycl. Chem. 14,225 (1977). 155. J. Feeney, R. Foster, and E. A. Piper, J. Chem. SOC.,Perkin Trans. 2,2016,(1977). 156. J. K. Baker and R. F. Borne, J. Heterocycl. Chem. 15,165 (1978). 157. A. M. Taha and G. Rucker, J. Pharm. Sci. 67,775 (1978). 158. G. G. Trigo, M. Martinez, and E. Galvez, J. Pharm. Sci. 70,87 (1981). 159. H. W. Avdovich and G. A. Neville, Can. J. Specfrosc.28,l (1983). 160. R. Uusvuori and M. Lounasmaa, Org. Magn. Res. 22,286 (1984). 161. R. Uusvuori and M. Lounasmaa, Magn. Res. Chem. 24,1048 (1986). 162. M. R. Yagudaev and S . F. Aripova, Khim. Prir. Soedin. SO, (1986)[Chem. Nor. Compd. (Engl. Trans.) 22.74 (1986)l;Chem. Abstr. 105,24479a(1986). 163. E. Wenkert, J. S. Bindra, C.-J. Chang, D. W. Cochran,and F. M. Schell,Acc. Chem. Res. 7,46 ( 1974). 164. F. W. Wehrli and T. Nishida, in “Progress in the Chemistry of Organic Natural Products” (W. Herz, H.Grisenbach, and G. W.Kirby, eds.), Vol. 36,pp. 157-158. Springer-Verlag, Wien, New York, 1979. 165. T. A. Broadbent and E. G. Paul, Heterocycles 20,863 (1983). 166. E. C. Blossey, H.Budzikiewicz, M. Ohashi, G. Fodor, and C. Djerassi, Tefrahedron 20.585 ( 1964). 167. S. R. Johns, J. A. Lamberton, and A. A. Sioumis, Ausf.J. Chem. 24,2399(1971). 168. D.H.Smith, A. M. Duffield, and C. Djerassi, Org. Mars.Specrrom. 7,367 (1973). 169. H.-F. Griitzmacher and G. Lange, Chem. Ber. 111,1962(1978). 170. M. Hesse and H. 0. Bernhard, in “Progress in Mass Spectrometry” (H. Budzikiewicz, ed.), Vol. 3,pp. 40-47. Verlag Chemie, Weinheim, 1975. 171. P. Z. Cong, Hua Hsueh Hsueh Pa0 39,75 (1981);Chem. Absfr.95,43425~ (1981). 172. J. C. Ethier and G. A. Neville, Can. J . Specfrosc. 31,81 (1986). 173. J. Scheel-Kruger, C. Braestrup, M. Nielson, K. Golembiowska, and E. Mogilnicka, Adu. Behau. Biol. 21, 373 (1977);Chem. Absfr.91,6k (1979). 174. V. V. Zakusov, Pharmacol. Res. Commun. 12,233 (1980);Chem. Abstr. 93,368311(1980). 175. J. Kanto, Inf. J. Clin. Pharmacol. Ther. Toxicol. 21, 92 (1983);Chem. Abstr. 98, 209436q (1983). 176. J. H.van Epen, Ned. Tgdschr. Geneeskd. 128,2220 (1984);Chem. Abstr. 102,89555e (1985). 177. R. T.Jones, NIDA Res. Monogr. 50,34 (1984);Chem. Absfr. 102,124918~(1985). 178. A. J. Altman, D. M. Albert, and G. A. Fournier, Suru. Ophthalmol. 29,300 (1985);Chem. Absfr. 102, 159901r (1985). 179. K. Kuba and S . Minolta, Seifaino Kagaku 35,464 (1984);Chem. Absrr. 102,197338~(1985). 180. S. P. Clissold and R. C. Heel, Drugs 29,189 (1985);Chem. Abstr. 103,16251~(1985). 181. J. Grabowski, Gou. Rep. Announce. Index (US.)85,56 (1985);Chem. Absrr. 103,116080a (1985). 182. A. A. Al-Badr and F. J. Muhtadi, Anal. Profiles Drug Subsr. 14,325 (1985);Chem. Absrr. 103, 188991~(1985). 183. S . Castellani and E. H. Ellinwood, Psychopharmacology (Amsferdum) 2,442(1985);Chem. Absrr. 104,61309~(1986). 184. R. T. Jones, NIDA Res. Monogr.68, 142 (1986);Chem. Absfr. 105,202565k (1986). 185. R. Seeger and H.G. Neumann, Dfsch. Apofh. Zfg. 126, 1930 (1986);Chem. Absfr. 105, 218119d (1986). 186. T. Yue, G. Wang, and Z. Song, Yao Hsueh Hsueh Pa0 14,208(1979);Chem. Absrr. 92,51661~ (1980).

80

MAURl LOUNASMAA

187. C. Tang, L. Wu, and J. Su, Kexue Tongbao 26, 1402 (1981); Chem. Abstr. %, 97378x (1 982). 188. S. Yu and J. Ma, Zhongguo Yixue Kexueyuan Xuebao 4,258 (1982); Chem. Abstr. 98,32911 (1983). 189. H. Guo and R. Sun, Kexue Tongbao 27.320 (1982); Chem. Abstr. 9 7 , 4 5 4 (1982). 190. R. Sun, H. Guo, C. Zhou, and Y. Yan, Zhonghua Yixue Zazhi62,458 (1982);Chem. Abstr. 97, 207978~(1982). 191. X. Chen, Z. Wang, and Y. Yan, Zhonghua Yixue Kexueyuan Xuebao 4, 57 (1982); Chem. Abstr. 97,85060~(1982). 192. J. Shi, Z. Miao, S. Zhang, X. Zhou, and Z. Yu, Tianjin Yiyao 11,540(1983);Chem. Abstr. 100, 114755~ (1984). 193. H. Guo and R. Sun,Kexue Tongbao 28, 142 (1983); Chem. Abstr. 99,98995 (1983). 194. J. Su, Ziran Zazhi 7, 638 (1984); Chem. Abstr. 101, 222297~(1984); see also J. Su, Shengli Kexue Jinzhan 16,317 (1985); Chem. Abstr. 104, 161368g(1986). 195. J. Su, C. Hock, and A. Lefer, Naunyn-Schmiedeberg’s Arch. Pharmacol. 325, 360 (1984); Chem. Abstr. 101, 17065b (1984). 196. W. Wang, Zhongguo Yaoli Xuebao 6,26 (1985); Chem. Abstr. 102, 160243j(1985). 197. Y. Fan, L. Yang, X. Wang, H. Sun, Y. Sun, F. Hu, W. Zhou, Y. Xiao, Zhongguo Yaoli Xuebao 7, 117 (1986); Chem. Abstr. 104,179916~(1986). 198. X. Yu, Z. Luo, J. You, and H. Luo, Hunan Yixueyuan Xuebao 10,13 (1985); Chem. Abstr. 103, 32152n (1985). 199. T. Yao, Y. Xiao, X. Sun, H. Tong, M. Yuan, Z. Xu, and Z. Dai, Chin. Med. J. (Beijing, Engl. Ed.)97,871 (1984); Chem. Abstr. 103,81445~(1985). 200. Q. Han, H. Hao, and X. Wang, Xi’an Yixueyuan Xuebao 6, 12 (1985); Chem. Abstr. 103, 115958f(1985). 201. P.Wang and L. Shi, Shanghai Diyi Yixueyuan Xuebao 12, 309 (1985); Chem. Abstr. 103, 389445h (1985). 202. D. Yin, B. Yu, and R. Ji, Yiyao Gongye 16,302 (1985); Chem. Abstr. 103,206231e (1985). 203. Q. Han, B. Huang, and Y. Wu, Beijing Yike Daxue Xuebao 17,253 (1985); Chem. Absrr. 105, 202992~(1986). 204. F. Huang, Y. Wu, and D. Wen, Kexue Tongbao (Foreign Lang. Ed.) 31,211 (1986); Chem. Abstr. 105,492~(1986). 205. S. Lu, J. Yu, Y. Li, W. Zhao, S. Zheng, D. Zou, S. Liu, S. Yu, and Z. Zheng, Zhonghua Neike Zazhi(Beijing)25, 10 (1986); Chem. Abstr. 105, 1816933(1986). 206. Y. Sun and S. Wang, Kexue Tongbao (Foreign Lang. Ed.) 31,413 (1986); Chem. Abstr. 105, 353332 (1986). 207. C. Tang, X. Yang, X. Wang, Q. Zhao, and J. Su, Beijing Yixueyuan Xuebao 17, 165 (1985); Chem. Abstr. 105,145922~(1986). 208. Y. Zhu and Y. Su, Eeijing Yixueyuan Xuebao 17, 161 (1986); Chem. Absrr. 105, 145921~ ( 1986). 209. Q. Han and Y. Xi, Beijing Yixueyuan Xuebao 17, 101 (1986); Chem. Abstr. 105, 164684~ (1986). 210. C. Bian and S. Duan, Yaoxue Xuebao 16,801 (1981); Chem. Absrr. 96,46211e (1982). 21 1. X. Niu and Z. Ren, Yaoxue Xuebao 16,545 (1981); Chem. Abstr. 97, 16995s (1982). 212. J. Huang, Z. Chen, and X. Chen, Zhongguo Yaoli Xuebao 4,1(1983); Chem. Abstr. 99,16425~ (1983). 213. J. Huang, Z. Chen, and G. Wang, Zhongguo Yaoli Xuebao 7,293 (1986); Chem. Abstr. 105, 7260711(1986). 214. J. Peng, L. Jin, X. Chen, and Z. Chen, Zhongguo Yaoli Xuebao 4,81(1983); Chem. Abstr. 99, 642358 (1983).

I . THE TROPANE ALKALOIDS

81

215. J. Peng, Z. Chen, and X . Chen, Zhongguo Yuoli Xuebuo 3,78(1982);Chem. Absfr.97,852421 (1982). 216. D. Li, F. Sun,and L. Ning, Zhongguo Yuoli Xuebuo 6,225 (1985);Chem. Absfr. 104,81876f (1986). 217. M. Yang and Y. Shi, Zhonghuu Muzuixue Zuzhi 3, 136 (1983); Chem. Abstr. 100, 61526f (1984). 218. Z. Wang, B. Peng, Q. Wan, and Y. Shen, Zhonghuu Muzuixue Zuzhi 3, 138 (1984);Chem. Abstr. 100,61527g (1984). 219. J. Yu, Y. Yang, G. Xiong, and M. Chen, Zhonghuu Mazuixue Znzhi3,3 (1983); Chem. Absfr. 100,61626~(1984). 220. D. Dai, J. Ma, Y. Wang, and H. Zhang, Nunjing Yuoxueyuun Xuebuo. 1(1983); Chem. Absfr. 100, 185673~ (1984). 221. G. Hong, J. Li, and G. Jin, Shengli Xuebuo 36, 149(1984);Chem. Absfr. 101,83898b (1984). 222. M. Tabata, in “Plant Tissue Culture and Its Biotechnological Application” (W. Herz, E. Reinhard, and M. H. Zenk, eds.), pp. 3-16. Springer-Verlag, Berlin, Heidelberg, New York, 1977. 223. G. K. Dhoot and G. G. Henshaw, Ann. Eot. (London) 41,943 (1977). 224. S. Eapen,T. S. Rangan, M. S. Chadha, and M. R. Heble, Can. J. Eot. 56,2781 (1978). 225. W. J. Griffin, Nuturwissenschuften 66, 58 (1979). 226. Y. Yamada and R. Hashimoto, Plant Cell Rep. 1, 101 (1982). 227. S. Koul, A. Ahuja, and S. Grewal, Pluntu Med. 47, 11 (1983). 228. T. Hashimoto and Y. Yamada, PIuntu Med. 47, 195 (1983). 229. N. Hiraoka and M. Tabata, Phytochemisfry 22,409 (1983). 230. Y. Yamada and T. Endo, PIunt Cell Rep. 3, 186 (1984). 231. T. Endo and Y. Yamada, Phytochemistry 24, 1233 (1985). 232. H. Kamada, N. Okamura, M. Satake, H. Harada, and K. Shimomura, PIanf Cell Rep. 5,239 (1986). 233. K.-M. Oksman-Caldentey and A. Strauss, PIunfu Med. 52.6 (1986). 234. T. Hartmann, L. Witte, F. Oprach, and G. Toppel, PIunfuMed. 52,390( 1986),and references therein. 235. L. Simola, S. Nieminen, A. Huhtikangas, M. Ylinen, T. Naaranlahti, and M. Lounasmaa, J. Nut. Prod., 51, 234(1988). 236. A. San Martin, C. Lab&, 0.Munoz,M. Castillo, M. Reina, G. de la Fuente, and A. Gonzdes, Phytochemistry 26,819 (1987). 237. Y. M. A. El-Iman, W. C. Evans, R. J. Grout, and K. P. A. Ramsey, Phyfochembtry 26,2385 (1987). 238. S . F. Aripova and S . Y. Yunusov, Khim. Prir. Soedin. 618 (1986); Chem. Nut. Compd. (Engl. Truns.) 22,581 (1986);Chem. Absfr. 106, 135238111(1987). 239. S. F. Aripova and S. Y. Yunusov, Khim. Prir. Soedin. 657 (1986); Chem. Nut. Compd. (Engl. Trans.) 22, (1986);Chem. Abstr. 106,643521(1987). 240. J. E. Backvall, Z. D. Renko, and S . E. Bystrom, Tetrahedron k f t .28,4199 (1987).

This Page Intentionally Left Blank

. CHAPTER 2.

GELSEMZUM ALKALOIDS ZHU-JINLIU* AND REN-RONGLu Shanghai Institute of Organic Chemistry Academia Sinica Shanghai 200032. The People's Republic of China

I . Introduction ......................................................... I1. Gelsemine-Type Alkaloids ............................................. A . Gelsemine .................................. B. Gelsevirine ....................................................... C . 21-Oxogelsemine .................................................. D. 21-Oxogelsevirine ................................................. 111. Gelsemicine-Type Alkaloids ............................................ A . Gelsedine........... ............................... B. Hydroxygelsemicine. . ............................... C . 14P-Hydroxygelsedine.............................................. D. Gelsenicine (Humantenmine) ...... .... E. Humantenidine .................................................... IV . Sarpagine-Type Alkaloids .............................................. A . Koumicine (Akuammidine).......................................... B. Akuammidine N-Oxide .............................................. C. Koumidine (16-Epinormacusine B) ... ............... V. Humantenine-Type Alkaloids .......................................... A. Humantenine (Gelsenidine) .........................................

84 85 86 88 88

90

91 91 92 93 94 95 96 91 91 98 99 99 ..................... ..... I 0 0 C . Rankinidine ...................................................... 102 ......................................... 103 VII . Koumine .......... ........ ..................... 104 A . Structure ......................................................... 104 B. Stereochemistry ................................................... 110 C. Reactions ........... ............................. 115 D . Synthetic Approaches ............................. 1 I9 131 VIII . Alkaloids of Unknown Structure ........................................ A . Kouminidine ...................................................... 131 B. Kounidine ........................................................ 132 IX . Biogenetic Considerations 132 X . Biological Activity .................................................... 135 A . Pharmacological Studies ............................................ 135 B. Clinical Applications ..................... .......... ... 137 References ........................................................... 138

* Also known as Chu-tsin Liu. 83

.

THE ALKALOIDS VOL . 33 Copyright i d ' 1988 by Academic Press. Inc . All rights of reproduction in any form rewrved.

84

ZHU-JIN LIU AND REN-RONG LU

I. Introduction Since the first review of the chemistry of Gelsemium alkaloids by Saxton in this treatise in 1965,two rather brief accounts of this topic have appeared, one in a section of Bindra’s contribution “Oxindole Alkaloids” in Vol. 14 of this treatise (1973) and the other in a section of Joule’s chapter, “The Sarpagine Ajmaline Group,” in lndoles, Part 4 , The Monoterpenoid lndole Alkaloids, edited by Saxton (1983),where the literature survey was up to mid-1981. The latest significant advances mainly involve four areas. First, there have been the isolation and structure elucidation of 14j?-hydroxygeIsedinefrom yellow jasmine (Gelsemium sempervirens Ait.) and especially a series of significant indole alkaloids from the less explored Chinese species Kou- Wen (G. elegans Benth.) and the previously uninvestigated species G. rankinii Small of the southeastern United States. These include the sarpagine-type alkaloids koumicine (akuammidine), koumidine (16-epinormacusine B), and akuam-

TABLE I Gelsemium ALKALOIDS

Name

Molecular formula

Source“

Gelsemine (1) Gelsevirine (2) 21-Oxogelsemine (3) 21-Oxogelsevirine(4) Gelsemicine (5) Gelsedine (6) H ydroxygelsemicine(7) 14/3-Hydroxygelsedine(8) Sempervirine (9) Koumicine (akuammidine, 10) Akuammidine N-oxide (11) Koumidine (16-epinormacusine B, 12) Gelsenicine (humantenmine, 13) Humantenidine (14) Humantenine (gelsenidine, 15) Humantenirine (16) Rankinidine (17) Koumine (18) Kouminidineb Kounidineb Key lo sources: S,Gelsemium sempervirens; E, G. elegans; R, C . rankinii. Structure unknown.

Ref. I .2,39 3.4 5 6 7.6 3.4.9,19 10 11

12-16,30 17-20 21 17.19 20.21 21.22 20.21.23.24 21.23.24 24 25-29 25 25

2. GELSEMIUM ALKALOIDS

85

midine N-oxide, the 4,20-dehydrogelsedine-typealkaloids gelsenicine (humantenmine) and humantenidine, as well as the novel oxindole alkaloids humantenine (gelsenidine) and humantenirine from G. elegans, and also rankinidine and 2 1-oxogelsevirine from G. rankinii. Second, some progress has been achieved in gelsemine chemistry, especially approaches to its total synthesis. Third, a fairly extensive study has been conducted on the chemistry of koumine, the principal alkaloid of G. elegans isolated in 1931. This includes the elucidation of its novel type of hexacyclic cage structure, the determination of its relative and absolute configuration, the study of some of its interesting reactions, as well as some synthetic approaches including a successful biomimetic synthesis from vobasine. Finally, a plausible biogenetic pathway for the two principal and most evolved Gelsemiurn alkaloids, koumine and gelsemine, has been proposed based on the isolation of some presumed precursors such as koumicine and koumidine from G. elegans as well as the existence of 18-hydroxygardnutin in nature. These proposals have been supported by the facile biomimetic synthesis of koumine from vobasine and 1I-methoxykoumine from 18hydroxygardnerine. Pharmacological studies and clinical applications of individual Gelsemiurn alkaloids or of the total alkaloids have never been reviewed before, so a preliminary treatment is presented in this chapter based on the limited data collected so far. For the convenience of identification, the names, molecular formulas, sources, as well as main references of all the Gelsemiurn alkaloids reported in the literature to date are listed in Table I.

11. Gelsemine-Type Alkaloids

R' Gelsemine ( I ) Gelsevirine (2) 21-Oxogelsemine (3) 21-Oxogelsevirine (4)

H OCH3

H

OCH,

R' H2 H2

0 0

86

ZHU-JIN LIU AND REN-RONG LU

A. GELSEMINE

The 'H- and ',C-NMR spectra of gelsemine (1) have been reinvestigated with 2D homonuclear NOESY and heteronuclear COSY techniques (31).As a result some of the original assignments (4,32)have been revised. Thus the bH of values of H-14a, H-14e, H-15, and H-16 are revised from 2.37, -2.0,2.83, and -2.30 to 2.83, 2.01, -2.30, and 2.43 ppm, respectively, while the most significant corrections of bc values involve that of C-6 from 40.2 to 50.47 ppm and N-CH, from 50.4 to 40.40 ppm. These adjustments will be helpful in future studies of alkaloids in this series. i n e to gelsemine in The in uiuo transformation of [ 6 - ' 4 C ] ~ t r i ~ t ~ ~ i d(19) Gelsemium semperuirens was claimed with an incorporation of 0.47% (33).This provides another experimental support to the proposal that strictosidine appears to be the original precursor in the biosynthesis of monoterpenoid indole alkaloids, although the detailed pathway of this biosynthetic process still remains obscure.

T7" --

Gelsemine (1)

--.-H

Me02C Strictosidine (19) SCHEME 1

Since the elucidation of its complex hexacyclic cage structure in 1959(2,39), gelsemine has been an intriguing target for synthetic chemists. However, no total synthesis has ever been reported, nor there is any sign that anyone has even gotten close to this target (34).Not until 1986 did Fleming describe an elegant study on the total synthesis of gelsemine (35).The synthetic plan is based on the preferred disconnection indicated below: H

N-l-l

I 21

N-l-l

I

m

SCHEME 2. Reprinted with permission from 1. Fleming in "New Trends in Natural Products Chemistry 1986" (A. U. Rahman and P. W. Le Quesne, eds), p. 84, 89-92, Pergamon Books Limited, 1986.

OTH P 1. AIH8,McOH 2. EtOzCCI. EtjN 3. LiAIH4 4. AcCI.DMAP 5. PyH’TsO-.EtOH

0,N-

OH OEt Et0,CHN’

OEt OEt

+M@r,

*olEt

90% 30

80% 29

97%

84%

31

32

SCHEME 2 (Continued)

.D

SOCLz, El3N DMF

88

ZHU-JIN LIU AND REN-RONG LU

The synthesis of the key intermediate 20 has been achieved after great effort, as shown in the synthetic sequence of Scheme 2. The elegant synthesis started from a Diels- Alder reaction between Bnitroacrylate and the tetrahydropyranyl enol ether to give a crystalline adduct (22)easily separated from the reaction mixture. The nitro group in 22 was then reduced with aluminum amalgam, and the resulting amine protected as the urethane; meanwhile the ester group of 22 was reduced with lithium aluminium hydride and the resulting alcohol protected as the acetate, and finally the T H P protecting group in 22 was removed to afford product 23 in 76% yield. The rearrangement of the bicyclo[2.2.l]octane system (23)to the bicyclo[3.2. lloctane system (26)was accomplished by successive epoxidation of 23 and then treatment of the resulting epoxide (24) with magnesium bromide, and presumably occurred through intermediate 25.At this stage, the desired bicyclic skeleton (26)with the four functional groups properly located was in hand. The next two steps were designed to effect the formation of the cyclic ether linkage, while the other two oxygenated functions were properly modified to yield 28 on which the desired vinylation could readily be introduced; the resulting tricyclic intermediate 30 was obtained in excellent yield. At this stage, the technique of allylsilane chemistry was chosen to effect the configuration inversion of the introduced vinyl group and consequently to facilitate the formation of the pyrrolidine ring in 33 which can be converted readily to 20. However, the oxindole synthesis from 33 to yield the target molecule gelsemine (1) has not yet been worked out. As observed by Fleming, “It seems that we had no luck in this work: every step has been a hard won battle” (35).

B. GELSEVIRINE Gelsevirine (2)was first isolated in 1953 from G. sempervirens as a minor component (3). Its structure was later elucidated on the basis of mass spectrometry as well as ‘H-NMR and 13C-NMR studies (4). Gelsevirine has been found to be the predominant alkaloid in G. rankinii (24), and it was claimed that some of the previously reported ‘H-NMR and 13C-NMR data should be revised. Thus the previous assignments of H-16, H-15, H-l4a, H - l k , and H-6 for gelsevirine should be changed to H-15, H-l4a, H-16, H-6, and H-14e, respectively, from the evidence of the more accurate homonuclear 2D COSY experiments. Similarly, from the heteronuclear 2D correlation spectrum, the assignments for C-16, C-15, C-6, and N-CH, should be revised to C-15, C-16, N-CH3, and C-6, respectively. c . 2 1-0XOGELSEMINE The minor alkaloid 21-oxogelsemine (3)was isolated from G. sempervirens by the combination of column chromatography, TLC, and preparative gas

89

2. GELSEMIUM ALKALOIDS

R1 1

H

2

OCH,

3

H

R2

mje

H2

108 108 122

H2

0

SCHEME 3. Reprinted with permission from ref. 5.

chromatography (5). The structure of 21-oxogelsemine [mp 148-150°C, /I,,,(CH,OH) 252 nm (loge 3.7), 282 nm (log E 3.25)]. has been determined on the basis of high-resolution mass spectrometry. Since the fragmentation of gelsemine (M' 322) and gelsevirine (M+ 352) had been studied previously (4.10)and the fragmentation pathway of the key fragment m/z 108 rationalized as shown in Scheme 3, the new isolate 3, which showed a parent ion at 336.148 and a key fragment m/z 122.060 corresponding to C,H8N0, appears to indicate a difference of 14 mass units between gelsemine ( M + 322) and the 3 (M' 336) as well as between their key fragments m/z 108and 122. On the basis that they possess the same molecular skeleton (as indicated by the fragmentation pattern and also by the similarity of their CD curves), it is most probable that the m/z 122 fragment has structure identical to that of m/z 108 except that the two hydrogen atoms on C-21 have been substituted by an oxygen atom. Further mass spectral evidence has been provided by the fragmentation pattern of 3 and its dihydro derivative 3' (i.e., the vinyl group of 3 is saturated), in which fragments of m/z 254 and 256 are observed, respectively (Scheme 4).

3 3'

-CH=CH, -CH,CH,

SCHEME 4. Reprinted with permission from Ref. 5.

254 256

90

ZHU-JIN LIU AND REN-RONG LU

Gelsemine, owing to the absence of the C-210x0 group, does not give this kind of fragmentation. Furthermore, 3‘ can split off a CH2CH3group and give an m/z 277 fragment while 3 would not. D. 21-0XOGELSEVIRINE

21-Oxogelsevirine(4) was isolated as the principal alkaloid from a methanol extract of the stem of Gelsemium rankinii Small, a previously uninvestigated Gelsemium speciesnative to the southeastern United States. 21-Oxogelsevirine exhibits a molecular ion peak at m/z 366, 30 amu more than that of 21oxogelsemine, and a base peak at m/z 122,characteristic of the fragmentation of 21-oxogelsemine, thus suggesting a molecular formula of C21H22N,0,. The observation in the ‘H-NMR spectrum of a 3H singlet at 3.96 ppm reveals a methoxy group. The general similarity of all its spectra with those of 21-oxogelsemine,except for the chemical shifts of the aromatic protons which TABLE I1 13C-NMR SPECTRA OF GELSEMINE-TYPE ALKALOIDS”.~ Gelsemine (1)

21-Oxogelsemine (3)

Gelsevirine (2)

21-Oxogelsevirine

Carbon c-2 C-13 C-19 C-8 c-9 c-11 c-10 C-18 c-12 c-5 c-3 c-21 N-OCH, C17 c-7 c-20 C-6 N-CH, C-16 C-15 C-14

179.3 140.5 138.5 131.7 128.0 127.7 121.4 111.9 108.8 71.8 69.2 65.9 61.3 54.0 53.8 50.5 40.4 37.9 35.5 22.7

177.3 140.1 133.1 131.8 127.8 128.4 121.9 117.3 109.4 66.1 68.9 176.8 60.6 53.2 60.4 53.7 27.9 42.6 31.6 23.1

172.5 138.8 137.8 127.6 127.8 127.8 122.3 112.5 106.7 71.8 69.0 65.8 62.8 61.1 51.8 53.7 50.6 40.2 37.6 35.5 22.7

171.8 139.5 132.7 126.4 127.6 128.7 122.8 117.9 107.5 66.2 68.8 176.7 63.3 60.6 51.4 60.4 54.0 27.9 42.5 31.7 23.3

From Ref. 6. Chemical shifts are given in ppm; a,,

= 0 ppm; solvent CDCI,.

(4)

91

2. GELSEMIUM ALKALOIDS

are nearly identical with those of gelsevirine (2), points to this new isolate being 21-oxogelsevirine (4) (6). Detailed study of the 13C-NMR spectrum of the new isolate and its comparison with those of gelsemine (I), 21-oxogelsemine (3), and gelsevirine (2) (Table 11)provide strong support for the proposed structure 4. Thus, while both 3 and 4 display an amido C-21 at 6176.8 and 176.7 ppm and the corresponding C-20 at 660.4 ppm, respectively, 1 and 2 show an amino C-21 at 665.9 and 65.8 ppm and a corresponding C-20 at 653.8 and 53.7 ppm, respectively. On the other hand, 2 and 4 reveal an N-OCH, signal at 662.8 and 63.3 ppm, respectively, whereas 1and 3 appear to lack it. It is also evident from Table I1 that the 21-0x0 substitution of gelsemine produces a significant downfield shift in C-18, C-6, and C-16 but an upfield shift for C-19, C-5, N-CH, ,and C- 15. The 'H-NMR spectra of 21-oxogelsemine and gelsevirine have also been assigned by a 2-D COSY experiment (6).The absence of H-21, the downfield shifts of H-18, H-5, H-14, H-15, N-CH,, and upfield shifts of H-19 and H-16 also support the presence of the 21-0x0 group.

111. Gelsemicine-Type Alkaloids

OCH,

R Gelsemicine(5) Geldine (6) Hydroxygelsemicine (7) 14/?-Hydroxygelsedine(8)

R'

OCH, H

H H

OCH,

OH

H

OH (B)

A. GELSEDINE

The minor alkaloid gelsedine, originally isolated from G . semperuirens in 1953(3),has also been found in G. elegans (19).The structure of gelsedine (6) has been determined by means of 'H-NMR and mass spectral analysis (4.9)

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ZHU-JIN LIU AND REN-RONG LU

Pathway 1

&cH2cH,

O

I

OCH, Pathway 2

OCH,

H

--+

+og

i ~ : +

I

HZCH~

m/e 152

OCH,

6CH3 H GN+

I

-[R OCH,

+ CHflCH\a”CH

&cHzcH,

I OCH3

N

I

‘CZH,

mle 84

OCH3 SCHEME 5. Reprinted with permission from Ref. 10.

and on the basis of the structure determination of gelsemicine (1 l-methoxygelsedine, 5) by X-ray crystallography (8).Rationalization of the fragmentation pathways of gelsedine has also been presented (4,lO).Thus the characteristic fragments m/z 152,84, and 122 (10)for both gelsedine and gelsemicine are supposed to arise from two pathways (Scheme 5). The probability of the two pathways has been shown shown to be roughly 1:1 by substitution of the N-H with ’H (35). B. HYDROXYGELSEMICINE

Hydroxygelsemicine (7, C20H26N205) was isolated from G. sempervirens. Its molecular formula indicated the presence of an extra oxygen atom in gelsemicine (C20H26N204), most likely in the form of a hydroxy group. The

93

2. GELSEMIUM ALKALOIDS

compound was identified as hydroxygelsemicine through comparison of its 'H-NMR spectrum with that of gelsemicine (10). It is clear from examination of the 'H-NMR data of each proton of 7 and 5 (including the chemical shifts, spliting pattern, and J values) that all protons are very similar except at C-14 where 5 exhibits a 1H signal at 62.8-3.0 while 7 shows a signal of l H a t 64.38 indicating a HO-CH proton. However, the 60-MHz NMR spectrum did not allow the configuration of the 14-OH group and even its location to be unambiguously assigned. So it was designated with reservation, only as hydroxygelsemicine. The situation concerning the location of the hydroxy group has been clarified by recent work on the structure of 148hydroxygelsedine (22).

c. 14B-HYDROXYGELSEDINE As in the case of correlation of gelsemicine (5) and gelsedine (6), coexistence of 14-hydroxygelsemicine(7) and 14/3-hydroxygeIsedine(8) in G.semperuirens was also established in 1985(22). The fact that the molecular ion of 8 at m/z 344 is 30 amu less than that of 7 suggests the possibility that 8 might be demethoxyhydroxygelsemicine. The 360-MHz 'H-NMR spectrum of 8 is nearly identical with that of hydroxygelsemicine reported at 220 MHz (10) except for the presence of an unsubstituted aromatic ring, i.e., the presence of the 67.29 (ddd) H-11 signal and the absence of the 63.80 (s) 11-OCH, signal in 8. Since there is exceptional similarity between the 'H-NMR data of the aromatic regions of 8 and gelsedine (6), both having an unsubstituted reveal aromatic ring, the H-14 signals of 7 and 8 C64.28 (s)versus 64.42 (MA)] the presence of the O H substituent at C-14. The stereochemistry of the hydroxyl group at C-14 has been determined through decoupling experiments (12). Irradiation of H-3 at 63.42 ppm sharpens H-14 to a doublet (J = 1.0 Hz), and irradiation of H-15 collapses both H-3 and H-14 to doublets (J= 0.7 Hz). The small coupling constants between H-3 and H-14 (J = 0.7 Hz) as well as those between H-14 and H-15 (J = 1.0 Hz) indicate that the dihedral angles between them are approximately 70" and 105", respectively. The 14-hydroxyl group therefore has the axial configuration. The stereostructures of 5,6,7, and 8 can be represented by the following formula (22): 17

R' 18 /

8 7 6 5

R3 bCH

,

R2

H O H H OH H H H H

R' H OCH, H OCH,

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ZHU-JIN LIU AND REN-RONG LU

The proton assignments of H-l7e, H-l7a, H-6a, and H-6e are made by examination of the dihedral angles with Dreiding models and the J values. These and the other proton assignments are confirmed by 2D COSY experiments. In the study of 13C-NMR spectra of 8 and 6, the presence of the hydroxyl group at C-14 is also evident since a downfield shift of 43 ppm from 6 (621.2) to 8 (663.87) is observed. The previously ambiguous assignments of C-15, C-16, C-5, and C-20 are also clarified through irradiation of H-16, H-5, and H-20 with low-power single-frequency off-resonance decoupling (SFORD) experiments.

D. GELSENICINE (HUMANTENMINE)

I

OCH,

R Gelsenicine (13) Humantenidine(14)

H OH

A new alkaloid was isolated from G.eleguns by column chromatography and TLC. Its structure was identified as 13, and it was designated as gelsenicine (20) and humantenmine (21) independently by two groups. Gelsenicine forms colorless cubic crystals from acetone and displays the following physical characteristics: mp 171-3°C (20) C166-168"C (21)], - 117" (0.576, CH3Cl) (20), [a];' - 147" (0.46, EtOH) (24, hydrochloride mp 182-184"C, and hydrobromide mp 208-210°C (22). The molecular formula was determined as C1,Hz2NZO3by elemental analysis as well as by high-resolution mass spectrometry. Its UV spectrum and the aromatic region of its 'H-NMR spectrum are very similar to those of gelsedine, suggesting the presence of the same chromophore. However, the IR spectrum of gelsenicine displays a C=N absorption at 1640cm-', and there is no D,O-exchangeable signal in the 'H-NMR spectrum of 13. Also, the fragment ion m/z 150 of gelsenicine appears to correspond to the characteristic m/z 152 peak of gelsedine. These results indicate that gelsenicine might be a C-N dehydrogelsedine. Furthermore, the I3C-NMR spectra show that the

2. GELSEMIUM ALKALOIDS

95

C-20 signals of 6 and 13 appear at 659.6 and 172.2 ppm, respectively, suggesting that gelsenicine is a A4*20-gelsedine. The structure proposed above on the basis of spectral analysis has finally been confirmed by the transformation of gelsenicine to gelsedine (6) by saturation of the C=N double bond. When 13 was reduced with sodium borohydride in methanol at - 10°C,two products were obtained. One was the known alkaloid gelsedine, in which only the C=N bond of 13 was reduced, while the other product had both the C=N and the C=O functions reduced (20). On the other hand, catalytic hydrogenation over PtOz gave gelsedine as the sole product. These results confirm the structure of gelsenicine as 13. It is noteworthy that gelsenicine is the most toxic alkaloid isolated so far from G . elegans. The LD,, value is 185 pg/kg for mice on intraperitoneal injection.

E. HUMANTENDINE Humantenidine (14) was isolated along with humantenmine (13) from G. elegans in 1983 (22),and its structure was determined as 14 in 1984 (22). It is significant that so far there are three pairs of Gelsemiurn oxindole alkaloids which exist in the same relationship, namely, 14-hydroxygelsemicine (7), 14P-hydroxygelsedine (8), and humantenidine (14) are all 14-hydroxyl derivatives of gelsemicine (5), gelsedine (6), and humantenmine (gelsenicine, 13), respectively. Humantenidine (C,,H,,N,O,) is a colorless transparent resinous material and displays the following: - 123" (0.107, EtOH), hydrochloride hydride mp 159-164"C, M+ 342. Its UV absorption pattern at 210 nm (log E 4.38) and 257 nm (log E 3.78) is reminiscent of the known N-methoxy oxindole alkaloid gelsedine (6) having the same chromophore. The IR spectrum displays the presence of a hydroxyl(3400-3200 an-'), acarbonyl(171Ocm-') and a C=N bond (1640 cm-'). The 'H-NMR spectrum exhibits the same aromatic signals and the N-methoxyl resonance at 63.96 ppm ad once again indicates the close similarity between the aromatic moieties of humantenidine, gelsedine (6),and humantenmine (13). However, an extra 1H signal was found in the 64.20-4.55 region which should be assigned to a proton connected to an oxygen-bearing secondary carbon. Considering the existence of 14-hydroxygelsemicine in Gelsemium spp., the oxygen function in humantenidine might also be present in the form of a hydroxyl group. This is in accord with the 3400-3200 cm-' absorption in the IR spectrum of humantenidine. The M+ of humatenidine is 342 and that of humantenmine (13) is 326, a difference of 16 amu, while the characteristic fragment ion of the alicyclic portion of the former (m/z 166)is also 16amu larger than that of the latter (m/z

96

ZHU-JIN LIU AND REN-RONG LU

150),indicating that there might be one more hydroxyl group in the molecular structure of the alicyclic moiety of the former. Comparison of the 13C-NMR spectra of 13 and 14 reveals that there is one less secondary carbon in 13, suggesting further that one of the secondary carbons in 13 is connected to a hydroxyl group. This secondary carbon can only be C-6, C-14, C-17, or C-19, and, since the chemical shifts of C-6, C-17, and C-19 in 14 do not show significant change with respect to those of 13 while there is a large downfield shift of C-14 from 13 (625.6) to 14 (665.9), the hydroxyl group must attach to C-14 in 14. As a consequence the neighboring protons C-3 and C-15 in 14 also exhibit significant downfield shifts of 5.6 and 12.6 ppm, respectively. The spectroscopic data all favor the proposed structure 14 for humantenidine. Conventional catalytic hydrogenation of 14 affords a dihydro derivative (34),mp 216-219°C. This dihydro derivative displays a fragmentation pattern similar to that of 14-hydroxygelsemicine (7), giving a strong peak of the fragment ion m/z 168, supposedly from the alicyclic part of the molecule. Furthermore, humantenidine (14) yields only an M - 31 fragment ion but not an M - 29 fragment ion while the dihydro derivative (34)yields both. This also indicates that the double bond is situated between (2-20 and N-4. The high-field region of the 'H-NMR spectrum of 34 is almost identical with that of 7, suggesting they have a common alicyclic structure and further supporting the proposed structure 14 for humantenidine. It is interesting that the 'H-NMR data of the dihydro derivative (34)are practically identical with those of l4g-hydroxygelsedine (8)which was isolated from G. semperuirens in 1985 (ZZ), although the latter data were, recorded at 360 MHz while the former at 90 MHz in the same solvent (CDCI,). Since it appears humantenidine has been proved to be 14-hydro~y-A~*~~-gelsedine, that 34 and 8 are the same material.

IV. Sarpagine-Type Alkaloids

To date, the extensively investigated species G. sempervirens gives only oxindole type alkaloids with the exception of the oxygen-free alkaloid sempervirine (9). On the other hand, the less extensively studied species G. elegans native to China and southeast Asia yields beside the C-20 and C-19 oxindole alkaloids and sempervirine the less evolved sarpagine-type alkaloids koumicine (akuammidine), koumidine (16-epinormacusine B), and akuammidine N-oxide. Furthermore, the principal alkaloid of this species, koumine, has been proved to belong to a novel class of alkaloids having a unique hexacyclic cage structure.

97

2. GELSEMIUM ALKALOIDS

R'

Koumicine (10) Akuammidine N-oxide (11) Koumidine (12)

R'

R2

Nb

C0,Me C0,Me CH,OH

CH,OH CH,OH H

-0

-

A. KOUMICINE (AKUAMMIDINE) Koumicine (10) was first isolated from G. elegans in 1961 but in an impure form, mp 232-234°C. Initially, although no further structural work had been done, its UV spectrum suggested the presence of an indole chromophore (17). About 20 years later, in the course of reinvestigations of the alkaloids of G. elegans, it was isolated in the pure form independently by two groups (19,20).The molecular formula was revised to CZ1H,,N,0,, and the melting point was corrected to 252-254°C (20) and 248-249°C (19), respectively. The structure of koumicine in pure form was finally identified with that of akuammidine (19),which had been isolated from other sources, and the structure determined as 10 independently by two groups in 1961 (18). The mass spectrum of koumicine [CZIHz4N2O3, colorless leaflets,mp 248249"C, [CY];' -5" (1.40, CH,OH), M + 3541 was identical with that of akuammidine (36), and the acetyl derivative also had a mass spectrum identical with that of acetylakuammidine (37). The 'H-NMR spectrum of the acetyl derivative is consistent with structure 10: SiFd;,,,9 (lH, m, H-3), 3.20-3.40 (lH, m, H-5), 2.76-2.90 (2H, m, H-6), 6.92-7.36 (4H, m, H-9, H-12), 1.44-1.64 (Obscured, H-14), 2.44-2.64 (lH, m, H-15), 4.16 (2H, AB,

16-CH~OOCCH~),1.53(3H,d,J~6H~,H-18),5.20(1H,~,J~6H~, 3.50 (2H, br s, H-21), 8.08 (N-H), 1.92 (3H, s, OOCCH,), 2.92 (3H, s, COOCH,). These data are very similar to those of the diacetyl derivative of the LAH reduction product of polyneuridine, a C-16 epimer of akuammidine.

B. AKUAMMIDINE N-OXIDE The presence of akuaammidine N-oxide [ll, CzlH2,Nz0,, mp 270°C (dec.)] in G. elegans was reported in 1983 (38).The structure was proposed on

98

ZHU-JIN LIU AND REN-RONG LU

the basis of IR and mass spectral analysis and was confirmed by hydrogen peroxide oxidation of akuammidine, which produced a compound identical with the isolate based on IR and mass spectral data. c . KOUMIDINE (16-EPINORMACUSINE B) Koumidine (12, C,,H2,N20, mp 202-204°C) was first isolated from the root of G.elegans in 1961. The presence of an indole moiety in the molecule was suggested on a UV spectrum basis (27).Some 20 years later, it was also isolated from the same source by two other groups (29,20).In the course of mass spectrometricstudy (29)it was found that the fragmentation pattern of koumidine was extremely similar to that of normacusine B (36)except for the presence of a strong dehydration ion (M - 18) at m/z 276 in koumidine. Ohasi's group has studied the fragmentation pathway of this type of alkaloid by means of the deuteration method, and they found that when the (2-16 CH20H was in the endo position a strong M - 18 dehydration peak always resulted, presumably from the interaction between the OH group with the indole N-H on heating, whereas this phenomenon would not occur when this group was in the exo position. Therefore the presence or absence of a strong dehydration peak can be used as a criterion for the determination of stereochemistry at C-16. On this basis, it was suggested that koumidine is the C-16 epimer of normacusine B (19).The probable fragmentation pathway of 12 to form the m/z 276 ion has been rationalized as follows: 17

21

18

M' mi: 294

m / z 216

R'

R'

35

H

36

OCCH,

H H

12

The 'H-NMR data of koumidine are in accord with the proposed structure 12. Furthermore, when koumidine was oxidized with Cr0,-H2S0,, the product [35, C19H,oN,0 (M' 292)] which resulted was a dehydrogenated product of koumidine, and the OH signal disappeared from the 'H-acetyl

99

2. GELSEMIUM ALKALOIDS

derivative (36)of this product. In addition, the two C-6 H signalsat 62.56-2.62 of 12 had also disappeared in 36,and a new doublet of 1 H was found at 65.44. It was then evident that the endo-situated C-16 CHzOH had formed an ether linkage with C-6 under the oxidation conditions. This is supported by the IR spectrum which displays a strong absorption at 1090 m-'.

V. Humantenine-Type Alkaloids The humantenine-type Gelsemium alkaloids, which so far include humantenine, humantenirine, and rankinidine, are oxindole alkaloids with a novel skeleton similar to that of gelsemine but lacking a bond between C-6 and C-20. From a biogenetic viewpoint, humantenine-type alkaloids are less evolved than those of the gelsemine series and might well be immediate precursors of them

Humantenine (15) Humantenine (16) Rankinidine (17)

R'

R*

CH, H H

H OCH H

A. HUMANTENINE (GELSENIDINE)

Humantenine [lS, C21H,,N,0,, mp 143.5"C (20), [a]h* - 142" (0.72, CHCI,) (21)] was first isolated from G . elegans in 1982-1983, and later also from G. rankinii in 1986 (24). Gelsemium elegans is known in some parts of China as Kou-Wen and in other parts (e.g., Guangxi Province) as Hu-ManTeng, hence the name humantenine. It was isolated by column chromatography of the total alkaloid fraction, and the free base turned out to be unstable transparent resinous material which deteriorated rapidly on exposure to air, but the hydrochloride [mp 210°C (dec.)], hydrobromide [mp 240°C (dec.)], and picrate (mp 145-6°C) are more stable. High-resolution mass spectrometry reveals a molecular ion at m/z 354.1960,corresponding to a

100

ZHU-JIN LIU AND REN-RONG LU

molecular formula C,,H,,N,O,. Its UV spectrum is similar to those of gelsenicine (humantenmine, 13) and gelsedine (6),suggesting the presence of a 3, 3-disubstituted N-methoxyoxindole chromophore. The IR spectrum displays a carbonyl absorption at 1710 cm-'. The 'H-NMR spectrum exhibits proton signals arising from the aromatic heterocyclic system of gelsedine and gelsenicine, which is in accord with the UV evidence. The structure of the alicyclic portion of the molecule is elucidated by 'Hand I3C-NMR spectroscopy as follows (23). A pair of quartets at 64.19 and 4.00 ppm constituting the AB part of the ABX system may be assigned to the geminal protons on C-17. The multiplets at 63.60 and 3.36 ppm, representing 1H each, may be assigned to the C-5 and C-3 protons, respectively. The multiplet at 6-2.10-2.80 ppm containing six protons might arise from C-6, C14, C-15, and C-16 through analogy to the 'H-NMR spectrum of gelsemicine (5).These data suggest structural similarity of the alicyclic parts of humantenine and gelsemicine or gelsedine. However, the broad singlet at 63.35 ppm (2H) reveals the presence of a methylene attached to the basic nitrogen, lacking in both 5 and 6. So it is reasonable to assume that humantenine possesses a piperidine ring of a C,, alkaloid like gelsemine rather than a pyrrolidine ring of a C, alkaloid like 5 or 6. In addition, the 3H singlet at 6-2.34 ppm indicates the presence of an N-methyl group while the 1H quartet at 65.34 ppm together with the 3H doublet at 61.62 ppm suggests that the side chain at C-20 is an ethylidene instead of a vinyl group (as in 1) or an ethyl group (as in 5 or 6). Thus, all the alicyclic signals have been assigned, and structure 15 can be proposed for humantenine. Finally, the ,C-NMR spectrum of humantenine is in complete agreement with structure 15. Thus among the 21 carbons recorded (cf. Table 111),nine are over 100 ppm, of which six aromatic carbons and one amide carbon can be seen while the remaining two are the C=C carbons of the ethylidene. Of the 12 carbons below 100 ppm, there is one quaternary carbon, four methine carbons, four methylene carbons, and three methyl carbons. From their chemical shifts and by comparison with the 13C-NMR spectra of gelsedine (6) and gelsenicine (13), structure 15 for humantenine is further confirmed. The fragmentation pathway of humantenine can also rationalized according to structure 15. X-Ray crystallography of humantenine hydrobromide has firmly established the novel structure 15 for this alkaloid.

'

B. HUMANTENIRINE

Humantenirine (16, C,,H,,N,O,, colorless cubic crystals, mp 168- 169"C, M + 370.1944). Its UV spectrum is similar to that of gelsemicine (5); hence both have the same chromophore, 7-methoxy-3,3-disubstituted N-methoxy-

101

2. GELSEMIUM ALKALOIDS

TABLE I11 "C-NMR SPECTRA OF HUMANTENINE (15), GELSENKINE (13), AND GELSEDINE (6)" 15

13

6

174.0 s 71.8 d 61.3 d 38.0 t 54.9 s 129.0 s 125.5 d 122.4 d 127.6 d 106.8 d 138.6 s 25.4 t 34.2 d 37.8 d 66.5 t 12.3 q 118.7 d 137.2 s 45.4 t 42.2 q 63.4 q

182.1 s 74.5 d 72.3 d 38.0 t 55.3 s 131.0s 123.4 d 122.1 d 126.8 d 105.5d 138.0 s 25.6 t 40.0 d 42.6 d 61.7 t 10.3 q 27.2 t 172.2 s 62.6 q

174.7 74.6 65.6 34.0 53.0 132.0 125.5 123.7 128.1 107.2 138.3 21.5 34.8 42.0 63.9 12.0 21.5 59.7

Carbon

c-2 c-3 c-5 C-6 c-7 C-8 c-9 c-10 c-11 c-12 C-13 C-14 c-15 C-16 C-17 C-18 C-19 c-20 c-21 N-CH, OCH, a

-

63.4

From Ref. 23.

oxindole. This is supported by the IR absorptions of an amide carbonyl at 1690 cm-' and an aromatic ring at 1620, 1590, and 1490 cm-'. The 'H-NMR spectrum reveals the presence of an aromatic moiety similar that of to 5 and 14-hydroxygelsemicine (7), but the alicyclic part appears to be like that of humantenine (15). Thus one observes the signals 61.62 (3H, d, J = 7 Hz) and 65.26 (lH, q, the ethylidene side chain), 64.30 and 4.03 ( 2 H , ABX, H-l7a, H-l7b), 63.20-3.42 (2H. m, H-21a, H-21b), 63.70 (1H. m, H-3), and 63.54 (lH, m, H-5); the rest of the protons (H-6a, H-6b, H-15, H-16, H-l4a, and H-14b) are contained in the complex multiplet at 62.102.80 ppm. These account for 16 of the 17 protons of the alicyclic portion of humantenirine. The remaining one proves to be an N-H as supported by the IR absorption at 3300 cm-'. In comparison to humantenine (IS), the structure of which has been confirmed by X-ray diffraction analysis, structure 16 can be assigned to humantenirine with reasonable confidence. The proposed structure is supported by the fragmentation pattern (high-resolution mass spectroscopy and

102

ZHU-JIN LIU AND REN-RONG LU

metastable ion studies). The base peak m/z 164 (loo%, M -206), representing CloH14N0,can be rationalized as the fragment ion produced following loss of the aromatic moiety. This is in complete agreement with the counterpart fragment ion m/z 178 from humantenine (15) in which the Nb has been sustitutedby a methyl group. Furthermore, when humantenirine is submitted to Nb-methylation with formic acid-formaldehyde, the resulting Nbmethylhumantenirine (M' 384) exhibits a completely identical alicyclic portion when compared ('H NMR) to that of humantenine (15). C. RANKINIDME Rankinidine [17, C20H24N203, [a]:' - 126" (0.07, MeOH) was isolated in 1986, together with humantenine and humantenirine, from a methanol extract of the stem of G . rankinii (24).It was obtained as white needles from acetone (mp 175- 178°C).The free base is so labile that it decomposes quite rapidly to 217, an orange-brown amorphous gum even at 5°C. Its UV spectrum (A,, 256 nm) shows the characteristic N-OMe oxindole chromophore. IR absorption at 3300 cm-' indicates the presence of an N-H group, and in comparison with humantenine (15) the 'H-NMR spectrum lacks the N-CH, signal at 62.34 (3H, s). The mass spectrum of rankinidine displays a molecular ion peak at m/z 340, the facile loss of a methoxy group from the molecular ion, m/z 309, and especially an ion at m/z 164 (M - 176), due to the loss of the aromatic portion. Such a fragmentation pattern is in agreement with that of humantenine which exhibits an additional ion involving the loss of an Nmethyl group m/z 339. The 'H-NMR spectrum of rankinidine is in close agreement with that of humantenine reported in literature (23)except for the absence of an N-CH3 group at 62.34 ppm. On the other hand, the 'H-NMR spectra of rankinidine and humantenirine, although appearing similar also, differ in the lack of an OCH, group at 63.83 in the former and the lack of an aromatic H-11 signal in the latter. On the basis of the above-mentioned 'H-NMR comparison and fragmentation pattern studies, and since the structure of humantenine has been established by X-ray analysis (23), structure 17 has been proposed for rakinidine (24). Furthermore, with the use of high-resolution NMR (360 MHz) as well as NOE and homonuclear COSY techniques, it has been possible to clarify the ambiguous signals assigned previously to H-21, H-6, H-14, and H-16 in humantenirine (16). Thus NOE experiments have established the location of the aromatic OCH, group at C-11, and the COSY spectrum suggests the assignment of 63.32 (dd, J = 16.8, 1.1 Hz) to H-21 due to the long range coupling with H-19 and small W coupling with H-15 (consequently the 3.87 ppm signal can be assigned to H-21/?).The assignment of H-17a at 64.29 ppm and H-17/?at 64.02 ppm are in accordance with the observation that only H-

103

2. GELSEMIUM ALKALOIDS

TABLE IV 'H-NMR SPECTRA OF RANKINIDINE (17) AND HUMANTENIRINE (16pb Proton

17

16

H-3 H-5 H-6~ H-6P H-9 H-10 H-11 H-12 H-14a H- 14p H-15 H-16 H-17~ H-17P H-18 H-19 H-21a H-21p Ar-OCH, N-OCH,

3.56 d, 7.7 3.84 m 2.19 dd, 3.3, 15.3 2.30 dd, 3.3, 15.3 7.42 d, 7.4 7.14 t, 7.4 7.41 t, 7.4 6.98 d, 7.4 2.38 dd, 7.0, 13.7 2.30 dd, 7.7, 13.7 2.64 m 2.20 m 4.33 d, 10.6 4.05 dd, 4.3, 10.6 1.61 d, 6.8 5.28 q, 6.8 3.37 dd, 2.7, 16.2 3.93 d, 16.2 4.00 s

3.52 d, 8.4 3.68 m 2.18 dd, 3.3, 15.3 2.30 dd, 3.2, 15.6 7.30 dd, 0.8,8.4 6.62 dd, 1.6, 8.4 6.56 d, 1.6 2.42 dd, 7.3, 15.6 2.30 dd, 8.4, 15.6 2.60 m 2.20 m 4.29 d, 10.5 4.03 dd, 4.2, 10.5 1.59 d, 6.8 5.23 q, 7.0 3.32 dd, 1.1, 16.8 3.87 d, 16.8 3.83 s 3.98 s

From Ref. 24. Recorded at 360 MHz in CDCI,.

178 couples with H-16 at 62.2 ppm. On the other hand, H-17a is the only proton exhibiting an NOE effect on H-68 at 62.30 ppm. Consequently the signal at 62.18 ppm is assigned to H-6a and the 62.30 ppm signal to H-6B. Similarly, H- 14a, H- 148, and H-16 are also assigned (cf. Table IV).

VI. Sempervirine

Sempervirine (9)

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ZHU-JIN LIU AND REN-RONG LU

The unique nonoxygenated yellow anhydronium base sempervirine (9)was isolated from G. semperuirens in 191 1 (12) and from G. elegans in 1953 (30). Structure 9 (13,14)has been confirmed by syntheses (15,16).

VII. Koumine

Koumine (18)

A. STRUCTURE

Koumine (18) is the principal alkaloid of the Chinese medicinal plant KouWen (G. elegans Benth.). It was first isolated in 1931 and designated by molecular formula C20H22N20(25).Except for an UV spectrum reported in 1953 (30), however, no information had been available regarding to its molecular structure until 1961 when a partial structure (37)was proposed (17). Twenty years later, the novel type of hexacyclic cage structure was independently elucidated by two groups. The Gif-sur-Yvette group determined the structure mainly by X-ray analysis (28), while the Shanghai group elucidated 22

-CH=CH,

-0-C,H

H’

12

37

R 18

CH=CH,

44

C2H5

45

C,H5

R’

CH, CH3 CHO

2. GELSEMIUM ALKALOIDS

105

I

R” R 38 41 41

CH=CH, CH=CH, C,H,

R’

R”

CH, CH, CH,

H Ac

H

the structure and relative configuration through chemical and spectroscopic studies (26,27)and confirmed it by X-ray crystallography, which also established the absolute configuration as 18 (26,29). The presence of the 2,7,7-trisubstituted indolenene (pseudoindole) moiety has been confirmed by the ‘H-NMR spectrum of koumine, which shows four consecutive aromatic protons with 6$:$l3 7.61 (dd, H-9), 7.36 (td, H-lo), 7.25 (td, H-I]), and 7.55 (dd, H-12) (J, = 7.4 Hz, J, = 1.4 Hz). The 13C-NMR 123.1 (d), 126.0 (d), spectrum of koumine has seven low-field signals, 6$K’l3 128.2 (d), 121.2 (d), 154.9 (s), 143.7 (s), and 185.7 (s), which can be assigned to C-9, C-10, C-11, C-12, C-13, C-8, and C-2, respectively. The high-field signal 658.0 (s)apparently can be assigned to C-7. These assignments are based on the previous determination of the C-9 to C- 12 signals with selective decoupling techniques in addition to the conventional PND and ORD processes as well as by comparison with the I3C-NMR spectrum of gelsemine (4).The C-2 and C-7 absorptions in dihydrokoumine (38) shifted as expected to 675.5 and 41.8, respectively. The presence of a-N=CCH(CH,)OCH,CH-fragment in 18 is deduced from ‘H-NMR studies of 18 and 38. The 65.016 ( I H , ddd, JAx= 3.5 Hz, J,, = 2.4 Hz, JMx = 1.0 Hz) signal in 18 might be assigned to the X part of the ABMX system, since in dihydrokoumine (38) this signal shifts, as expected, upfield to 64.223 (d, br). On the other hand, an ABX system at 63.619 (1H. d, JAB = 12.2 Hz) and 64.258 ( I H , dd, J B A = 12.2 Hz, JBx= 4.4 Hz) is observed in 18, which can be attributed to the presence of an -OCH,CHfragment. Because there is only one oxygen atom and one C=N bond in koumine, both of the above-mentioned fragments must share this oxygen atom, i.e., the presence of a fragment -N=CCH(CH,)OCH,CHis inferred, and the C=N bond in this fragment must also contribute to part of the indolenene nucleus. Consequently, 37 can be expanded as 37’.

106

ZHU-JIN LIU AND REN-RONG LU

Since koumine has been reductively cleaved by nascent hydrogen (sodiumEtOH) to afford a Cz0 primary alcohol (39),the above deduction based on spectroscopic analysis is supported chemically (Scheme 6). N-CHI

n

R 39 40

CH=CH, CZHS

SCHEME6

Dihydrokouminol (39, C20H2,N20, M+ 310) is characterized by the following physical characteristics: IR v, 3390 (NH), 3510, 1035 cm-' 210, 246, 298 nm, Amin 226, 276 nm (dihydroindole (CH20H); UV A,, fragment chromophore). Instead of the S5.016 signal of the -N=CCHOthere appears a multiplet centered at 63.8 (4H, in which one H is exchangeable with D 2 0 ) which can be assigned to a C H 2 0 H group and a -NHCH: group. The fragment ions at m/z 292 (M - H20), 130 (M - 180, C9H8N+), and 180 (M - 130, C,,H,,N;T+O)may be rationalized as shown in Scheme 7. Dihydrokouminol (39)has been hydrogenated to tetrahydrokouminol (40, C20H28N20,M+ 312). The relative position of the vinyl and the Nb-methyl group in 18 has been determined through the results of the oxidation-decarboxylation of Naacetyldihydrokoumine methiodide (41+ MeI-) by aqueous potassium permanganate (39). The formation of amine 42 indicates the presence of a segment CH2=CH-C-CH2NCH, in 18 as formulated in Scheme 8. It can be seen that the oxidation process is accompanied by hydrolysis of the Naacetyl group and is followed by further oxidation of the resulting dihydroindole system to the indolenene system.

2. GELSEMIUM ALKALOIDS

9 Rq-n10

-CzHa,

OH 39 m / z 180 40 m / z 182

I

3 9 m / z 134 40 m / z 136

OH 39 m / z 152 40 m / z 154

I

-Cn20n -n'

-Cwon -n'

3 9 m / z 148

3 9 m / z 120 40 m / z 122

40 m / z 150

107

SCHEME 7

Product 42 (C,,H22N2, M+ 290) possesses the chromophore of a pseu220, 260 nm, Amin 238 nm, v,,, 1580, 1610 cm-'; an exo doindole, A,, methylene group, v,,, 895, 1643, 3070 cm-', 64.72 (lH, s), 4.54 (lH, d, "J = 0.7 Hz); and an -N(CH,), group, 62.39 (6H. s). 42 can be hydrogenated to 43 [C19H24N20, M+ 296, v,,, 1370 ~ m - (-CCH,), ' 60.17 (3H. d, J = 7 Hz, CHCH,)]. As additional evidence for the above rationalization, there is a signal of an isolated AB system in the 'H-NMR spectrum of 18 C63.11 (1H each, d, JAB= 11.4 Hz)] which can be attributed to the presence of a

108

ZHU-JIN LIU AND REN-RONG LU

43

SCHEME 8

>CCH,N: moiety in the ring system. On the other hand, formaldehyde has been formed in the ozonolysis of 41. Also, 18 resists the NBS allylic bromination, and no Hofmann degradation has been observed for N"-acetyldihydrokoumine methyl hydroxide (41+ MeOH-). These results are all consistent with the presence of the structural segment CH,lCH2C2CH2NCH3 (Scheme 9). The result of the attempted Hofmann degradation also provides preliminary structural information concerning the other side of Nb:i.e., the p position of Nb is either a quaternary carbon or it is situated at the bridgehead of a

-

aN&' 16[5°C. H 2 06 . ( mmHg 0)1

ON&,

(-CH,COOH. -CHIOH)

I

H

COCH, 41' MeOH-

-

38 9 SCHEME

109

2. GELSEMIUM ALKALOIDS

C18H;9N0

LC18H;9N0

J

45

46 SCHEME 10

bridged ring system. Actually, the structural information of the other side of Nb in 18 has been obtained from the results of KMnO, oxidation of isodihydrokoumine (44)in acetone at room temperature (40). Under these conditions, a neutral product (45) and a basic product (46)have been obtained (Scheme 10). The structure of the neutral product (45, 22-oxoisodihydrokoumine, C20H22N202,M+ 322)'has been elucidated by IR and I3CNMR analyses: vmaX 1660 cm-' (s) (vc o ) ; 6 , 8.30 (1H. S, N-CHO), bC 160.7 (d,N-CHO); an ABX system -CH2CH-N-CHO, 6,2.26,2.78 (1H each, dd, JAB = 14.2 Hz, JAX = 3.7 Hz, J B X = 2.0 Hz), 3.87 (lH, dt, J X A = 3.7 Hz, JxB= 2.0 Hz). The basic product (46,iso-N-norkoumine, CI9H2,N2O, M + 1 s, 292) has also been characterized: v,, 1605 cm-' (ms) (vCeN); ~ 5 ~ 8 . 4(lH, -CCH=N-); an ABX system -CH,CH-N=CH-, 6" 1.7, 2.68 (1H each, dd, JAB= 13.6 Hz, JAx= 1.9 Hz, J B X = 2.9 Hz), ~ 5 ~ 4 . (lH, 5 3 m). The base peaks in the mass spectra of both koumine (18) and dihydrokoumine (38) are m/z 70.0712, rationalized as C4H8N+ or CH2=N+ (CH3)CH=CH2. This is further evidence for the presence of the segment -CH2-N(CH3)CH-CH, in 18. Therefore, the structure 37" might be further expanded as 37"'. The determination of the linkage of the 10 residual bonds in 37" has been solved by a series of double-irradiation decoupling studies. The linkage of C-15 to C-16 and C-16 to C-5 is proved by decoupling between H-15 and H-16 in compounds 18,42,44, and 43 as well as between H-16 and H-5 in compounds 45, 46, and 18, respectively, while linkage of C-15 and C-20

110

ZHU-JIN LIU AND REN-RONG LU

,CH Z-N-CH

37"

31"'

has been determined by decoupling between H-15 and H-20 in 43. In the further expanded structural formula 37" thus resulting, there are still linking problems among the four remaining bonds at C-7, C-6, and C-20. However, between the two alternative possibilities, it is obvious that the only reasonable choice is the formation of the bond C-7-C-6 and C-7-C-20 (i.e., structural formula 18), since only this arrangement can meet the requirement of a hexacyclic structure (koumine, C,,H,,N,O, has five double bonds and thus requires six rings in the molecule) and be in accord with various spectroscopic data as well as biogenetic considerations. The alternative choice would lead to a pentacyclic structure containing an unstable carbene moiety. The I3C-NMR data of koumine (18) and its derivatives 38 and 45 are all in agreement with the proposed structures. The rationalization of the mass spectra of koumine and its derivatives 38,44,39,40,and 47, regarding the probable fragmentation pathway, is shown in Scheme 11.

B. STEREOCHEMISTRY There are seven chiral centers in koumine (18),and its relative configuration has been determined from 'H-NMR analysis and Dreiding model examination of 18 and its derivatives. The coupling constants between H-3 and H-15 range from 1.Oto 3.2 Hz, indicating a planar W-type coupling (41);hence these two hydrogens should have a cis relationship. The coupling constants between H-15 and H-16 range from 10.0 to 12.0 Hz, which correspond roughly to a dihedral angle of o",and therefore H-15 and H-16 are also cis. The coupling constants between H-16 and H-5 are 2.0-4.1 Hz, corresponding to a dihedral angle of around 5", which suggests these two hydrogen atoms are trans. The signal arising from the methyl in the C-20 ethyl group of 44 appears at extraordinarily high field (60.48), thus indicating that these three protons are within the shielding zone of the aromatic ring (42). On observation of the Dreidingmodel of 44, it can be seen that only the a configuration (i.e., cis to H15) of this ethyl group (corresponding to the vinyl group of 18)would cause a shielding effect. On the other hand, it can also be observed that the Nb-methyl

3

111

2. GELSEMIUM ALKALOIDS

Me

-

Me

Me

I+

I+

/ \

N ’

0

\

N’

0

18 m/r 223 44 m/z 225

Me

Me

Me

Me

18 mn/z 120 44 m/z 122

18 mlz 94 44 mlr 94

18 mn/z 263 44 m/r 265

I

- cn2=cncncno

18 m/z 194 44 m/z 1%

SCHEME 11

R

18 mlr 168 44 mlr 168

112

ZHU-JIN LIU AND REN-RONG LU

Me

38

41

R

mlz

CH,=CH C,H,

308 350

Me

38 m / z 130 41 m / z 136

I

1

Me

Me

Me

L O '

38 m / z 178 (M - 130) 47 m / z 180(M - 130)

38 m/r 94

38 m / z 120 41 m / z 122

41 m/r 94

25

*-.

, . r

__f

H

H m / z 42

SCHEME I 1 (Continued)

group must assume a fl configuration, which is neighboring to H-9 and within an interatomic distance of around 3.1 A, in order to account for the observed result of NOE experiments (i.e., when the proton signals of the Nb-CH3are irradiated, H-9 acquires a 5.3% enhancement). In the case of such a rigid, cagelike molecule, it can also be observed from the Dreiding model that the C-7-C-20 bond should assume an CI configuration while C-7-C-6 bond should be in a fl configuration. The structure and relative configuration of 18 are consistent with the X-ray crystallographic results reported independently by two groups (26,28,29). Khuong-Huu's group (28) described the crystal data as follows: Monoclinic system, space group P2, Z = 2, a = 7.676(2), b = 13.122(3), c = 7.988(2) 8, fl = 103.32(2)",V = 782.95 A3, D, = 1.28 g cm-,, I = 1.5418 A. The inten-

2. GELSEMIUM ALKALOIDS

113

N1 47 Fic. 1. Stereostructural representation of koumine (47) according to Khuong-Huu er al. (28). Reprinted with permission from Ref. 28.

sity data were collected as observed [I > 3a(I)]. The structure was solved by the direct method and refined by the full-matrix least-squares method, using the anisotropic temperature factor. All the hydrogen atoms were located on difference Fourier synthesis and replaced at their theoretical positions except those of the nitrogen atom N-1 and carbon atoms C-18 and C-22. The final R value was 0.036 for the observed reflections. Considering that koumine belongs to the corynantheine group and has been represented with the absolute configuration at C-15 common to all alkaloids known of this type and in agreement with a biogenetic hypothesis of its formation from corynantheine, the absolute stereostructure has been assigned as 47 (Fig. 1). Liang’s group reported (26.29) that the crystal structure of koumine hydrobromide has been solved by Patterson and Fourier methods and refined to an R value of 0.067 by the full-matrix least-squares method. The crystal belongs to the orthorhombic system with the unit cell parameters a = 14.307, b = 12.053, c = 9.862 A, and four molecules are contained in the cell. The space group is P2,2,2,. The positions of all hydrogen atoms have been determined from a difference Fourier map calculated after refinement of the coordinates of all nonhydrogen atoms with anisotropic thermal parameters by the least-square method. Thus the absolute configuration of the molecule has been established as 48, and the three-dimensional projection of koumine hydrobromide is represented as 49. The absolute configuration of koumine has also been confirmed by a biomimetic synthesis of koumine from vobasine (50) (43). The configuration was correlated with L( -)-tryptophan, since vobasine was reduced to dregamine (51) and the latter had been synthesized from L( -)-tryptophan with conservation of the (S)configuration of the amino acid, which corresponds to C-5 of koumine (44).

I

HlOl

..-

48

FIG.2. Stereostructureof koumine (48) according to Liang and co-workers (26.29).Also shown is the threedimensional projection of koumine (49).Reprinted with permissionfrom C. T. Liu, Q. W. Wang and C. H. Wan&J. Am. Chem. Soc., 1981,103,4635, Copyright (1981) American Chemical Society.

E

115

2. GELSEMIUM ALKALOIDS

C. REACTIONS

The rigidity of the hexacyclic cage structure of koumine (18) renders some of its chemical behavior quite unusual, for instance, the resistance to Hofmann degradation shown by Na-acetyldihydrokoumine methyl hydroxide (27). However, owing to the presence of a /3-aromatic imino system in 18, reductive cleavage by sodium-alcohol to yield dihydrokouminol (39) proceeds smoothly. This reaction has been considered to occur through a radicalanion mechanism as indicated in Scheme 12 (27).

H

I8

/N-Me I

H 39 SCHEME 12

Reductive cleavage experiments on a series of synthetic /?-substituted imino ethers have shown that different results would be obtained depending on the nature of the imino system (45).Thus, /?-aryl-substituted imino ethers can be reduced and cleaved with sodium in boiling alcohol whereas /?-aliphatic imino ethers are not susceptible to this kind of reductive fission. The fl-irnino ethers synthesized include types 52 and 53. It appears that this kind of reductive cleavage might be developed into a common degradative method for the similar indolenene alkaloids. Another interesting reaction is the very slow acid-induced rearrangement hydration of kuomine. This reaction results in the formation of a labile hemiacetal, hydrakouminol(54), and its reduction with a borane complex in

116

ZHU-JIN LIU AND REN-RONG LU

the presence of hydrochloric acid to a stable product, neodihydrokoumine (55) (46).

1

R CH3C6H, a-C,,H, 5 3 ~ B-C,H,N 5% c-C~H,~ 53a 53b

R 52a 52b

Sk

C6H, a-C,,H, C-C~H,,

H

18

When a long-stored hydrochloric acid extract of G.elegans is worked up, the main alkaloid isolated proves to be an alcohol (CZOHZ4N2O2) instead of the normally isolated principal alkaloid koumine (18, C20H2zN20). From the molecular formula, it is apparent that some kind of hydration process had been taking place. The UV spectrum of the new alcohol reveals an indole chromophore, and its IR absorption displays the presence of NH and OH groups, although the characteristic absorptions of the ether linkage and the vinyl group of 18 are still present. This new alcohol is designated as hydrakouminol (54), and its methanolic solution appears very unstable, always showing four spots on TLC of which one spot predominates. An isomerization equilibrium has probably been established in the methanolic solution of 54. Similarly, when a deuterated methanolic solution of 54 is subjected to ‘H- or 13C-NMR experiments at room temperature, a useful spectrum cannot be obtained. However, when it is crystallized from cold methanol (- 1OOC) and the NMR experiments run in cold C D 3 0 D solution (- lOOC), useful ‘H- and 13C-NMR spectra have been obtained. Treatment

117

2. GELSEMIUM ALKALOIDS

TABLE V 'H-NMR SPECTRA OF KOUMINE (18), HYDRAKOUMINOL (54). AND NEODIHYDROKOUMINE (55)

4, (PPm) Proton

18

J"-"

55

54

(Ha

54

18

55

-~

H-18a H-18b H-19 H- 17a H-14a H-14b H-6a H-6b H-3 N-H

3.615 (d)

5.361 (d) 5.483 (d) 6.170 (dd) 3.626 (dd)

5.439 (d) 5.392 (d) 6.181 (dd) -

1.878 (dd) 2.610 (dt)

1.2 (dt) 1.779 (dt)

-

-

4.6-4.9 (m)

-

2.786 (m)

5.016 (ddd) -

1.42 (m)

3.239 (dd) 2.957 (dd) 3.76 (m) 7.769 (b, s)

-3 (m) 5.148 (dd) 7.75 (b, s)

TABLE VI SELECTED "C-NMR DATAOF KOUMINE (18), HYDRAKOUMINOL (54), AND NEODIHYDROKOUMINE (55)" ~~

~

-

Carbon

18

54

55

c-2 c-3 c-7

185.7 (s) 71.0(d) 58.0 (s)

136.9 (s) 94.8 (d) 107.8 (s)

134.7 (s) 66.2 (t) 108.2 (s)

6, values are given in ppm. The spectrum of 54 was recorded at - 10°C.

of 54 with borane-triethylamine in hydrochloric acid removes the hydroxyl group. The resulting product (C20H,,N,0), designated as neodihydrokoumine (55), shows remarkable changes in solubility as well as in stability, giving only one spot on TLC. This is in accordance with the speculation that 54 is probably an equilibrated mixture of isomers which would lead to the same product (55) on borane reduction. Comparison of the NMR data of 18,54, and 55 in Table V and VI provides the main evidence leading to the assignment of structures 54 and 55 for hydrakouminol and neodihydrokoumine, respectively: 1. The changes expected for the 6, values of C-2, C-7, and C-3 among 18, 54, and 55 are observed.

118

ZHU-JIN LIU AND REN-RONG LU

2. The proton coupling 33-15 = 0 in 54 and 55 indicates that the original typical W planar structure between H-3 and H-15 in 18 is not present in 54 and 55. 3. Whereas the 317b-16 values in all known derivatives of 18 with cage structures are equal to zero and 317b-16 = 4.5 Hz, the 317a-16 values in 54 and 55 are greater than 6 Hz and the 317b-16 values are over 5 Hz. This would suggest that the dihedral angle between H-16 and H-17 in 18 must be quite different from those in 54 and 55. 4. The remarkable shifts of H-18 and H-19 in 54 and 55 to lower field and the changes in the splitting patterns suggest that the vinyl group in 54 and 55 are no longer under the severe shielding effect of the planar aromatic ring. 5. The signal for C-3 in 54 belongs to a typical -0-CH-0structure type. while that in 55 belongs to a normal -OCH2(2 2 )

(4)

H3C-N

\\

10 11

c-20 +c-2

\ 12

13

17

-H20

3

) ;

H

3

18

Q

54

SCHEME13

2. GELSEMIUM ALKALOIDS

119

From the NMR analysis described above, it may be concluded that the rigid cage structure of 18 has become more flexible in 54 and 55 on account of the cleavage of the C-7-C-20 and C-2-C-3 bonds followed by the formation of a C-7=C-2 double bond, a new C-2-C-20 bond, and C-3-OH bond in sequence, which would lead to structure 54. The preferred cleavage of C-7-C-20 over C-7-C-6 is probably due to the fact that it is mechanistically more plausible, since only the cleavage of the former at (2-20 could lead to a more stable carbonium ion (as illustrated in Scheme 13) which would facilitate the cleavage and prompt the rearrangement. The possible participation of the unshared electron pair on the oxygen in stabilizing the carbonium ion on C-3 would also favor the formation of 54. It is well known that in the cyclization of a y-hydroxy aldehyde to form the corresponding six-membered ring hemiacetal through intramolecular cyclization the hemiacetal form always predominates (48).This might account for the fact that no noticeable carbonyl absorption has been observed in the IR and NMR spectra of 54. However, the equilibrium between the hemiacetal and the aldehyde forms might shift in favor of the aldehyde form as the borane reduction proceeds until 54 is completely transformed to 55. While single crystals of 54 are not readily available for X-ray crystallography, the X-ray diffraction data of 55 have established its stereostructure shown in Fig. 3, in which the plane of the indole ring appears approximately perpendicular to both the piperidine and the tetrahydropyran rings of the alicyclic portion of the molecule. It also reveals that there are four molecules in each unit cell, and they are paired together via intermolecular N-H-0 hydrogen bonds as illustrated in Fig. 3 (47). This would account for the fact that the melting point of 55 is much higher than those of the isomeric compounds dihydrokoumine (38) and isodihydrokoumine (44)by 60 and 70°C respectively (17). D. SYNTHETIC APPROACHES

It may be easily appreciated that a molecule like koumine (18), with seven chiral centers in a rigid compact cage consisting of three boat- and one chairshaped six-membered rings, is likely to present a synthetic challenge no less than gelsemine (1) to organic chemists. There appears to be major approaches to reach the target, depending on whether the synthesis is biogenetic or nonbiogenetic. The biogenetic approach, which is a linear approach, is based on the stepwise disconnection of 18 into a series of biogenetically related alkaloid precursors. The precursors are usually built up in the actual synthesis with the C,, indole chromophore attached from the beginning and with stepwise modification of the alicyclic portion of the molecule later on. An example of this kind of approach is illustrated in Scheme 14 (43).3(R)-Vobasinediol(58)is

c (11) FIG.3. Stereostructureof neodihydrokoumine(55) and intermolecular bonding in the unit cell. (With permission from Ref. 47.)

121

2. GELSEMIUM ALKALOIDS

-

N '%

H

H

Koumine (18)

19

HO

0

II

HOCH,

MeOC

58

0

II

MeOC

59

51

SCHEME 14

ZHU-JIN LIU AND REN-RONG LU

122

known and vobasine (50) is a naturally occurring alkaloid, while dregamine (51) is another natural alkaloid which has been synthesized (44). 16Decarbomethoxyvobasine (59) has also been synthesized (49). Since the transformation of vobasine to koumine has been accomplished recently ( 4 3 , either the total synthesis of 50 or the transformation of 51 or 59 to 50 would then constitute a formal total synthesis of koumine. On the other hand, the nonbiogenetic approach usually adopts a convergent process such as shown in Scheme 15. When 18 is cleaved through C-6-C-7 (as 18 + 60),phenylhydrazine and a tricyclic moiety (61) which contains six chiral centers result. The synthetic problem then becomes synthesis of 61 followed by a Fischer indole synthesis and a final ring closure between C-6 and C-7 (61 + 60 + 18). Me

.. .*

H

H

Koumine (18)

60

HoL(IN-Me 61

SCHEME 15

In another biogenetic approach (Scheme 16) (50,51), a model experiment on the synthesis of 65, an analog of 18-hydroxyvobasinediol(57)without the C-5-C-15 bridge, has resulted in a diastereoisomeric mixture (69), which might be transformed to a 19,20-saturated counterpart of 65. The C-5-C-15 bridge can be introduced at the muconic acid (66) stage (Scheme 17) either by oxidation with mercuric acetate or by the DCCI method (56.57) to produce the C-5=N-4 double bond first (in the latter case, of course, tryptophan instead of tryptamine should be used as the starting material). The bridge cyclization is then effected via a nucleophilic attack at the C-5=N+ moiety by the C-16 anion in the presence of a suitable base. Photooxidation of 63 reveals that when an indole and a catechol system coexist in the same molecule a hydroxy derivative (70) instead of a

2.

GELSEMIUM ALKALOIDS

123

OH

OH 63

62

N-CH,

OR 65

COOH 64

SCHEME16. Reprinted with permission from C. T. Liu, S. C. Sun and Q. S. Yu, J . Org. Chem., 48,44(1983).Copyright (1983),American Chemical Society.

hydroperoxy derivative (71) can be obtained without the presence of a reducing agent. Furthermore, no diketone compound (72) has ever been isolated. This has been rationalized as indicated in Scheme 18. As soon as the type-C compound 71 is formed, it is reduced by thecatechol system to form the more stable 70 whereas the o-hydroquinone system is oxidized to o-quinone, which is known to form muconic acid readily on photooxidation. As a consequence, the equilibrium between 71 and 72 will shift in favor of 71, and the probability of the formation of 72 may be neglected (50). In comparison to the photooxidation of catechol itself, it appears that different substituents on the catechol ring would afford different types of products, probably through different pathways and mechanisms (52). Since it has not proved feasible to differentiate the two allylic double bonds in 68 through LAH reduction and since natural vobasine happened to be available, a new synthetic strategy has been adopted in which the possibility of transforming vobasine to koumine via 3(R)-vobasinediol first and then turning to the total synthesis to the structurally simpler 3(R)-vobasinediol has been studied. A glance at anhydrovobasinediol (73),which can be obtained readily from vobasine (50), reveals its close conformational similarity to koumine (18).The former already has a 20-carbon skeleton very similar to that of 18, including two of the alicyclic rings D and F with the proper chirality of

124

ZHU-JIN LIU AND REN-RONG LU

14

COOH OH

66

62

I I

,CO BU

COOH 67

OH 63

I

II

,, ..

hvlOz Y

COOH 68

69

SCHEME 17

3(R), 5(S), 15(R),and 16(S)(Scheme 19). Consequently, the problem regarding the transformation of 73 to 18 appears to involve simply the formation of the key C-7-C-20 bond from the rear side to construct rings C and E of 18 with the correct stereochemistry and the simultaneous conversion of the ethylidene side chain and the indole chromophore of 73 to the vinyl and the

125

2. GELSEMIUM ALKALOIDS

62

I

I

70

72

71 reducing agent

SCHEME 18. Reprinted with permission from C. T. Liu, S. C. Sun, and Q. S. Yu, J . Org. Chem.. 48,44 (1983).Copyright (1983), American Chemical Society.

18

73

74

SCHEME 19

indolenene system of 18, respectively. This series of transformation might be realized either by a rear side electrophilic attack of the allylic carbonium ion C-18-C-20 to the electron-rich B side of the indole system or by a rear side nucleophilic attack of the n electrons of the C-20=C-19 double bond on the transitional carbonium ion at C-7 formed from a presumable 3-hydroxyindolenene species in ,acid medium. These carbonium ions could supposedly be formed from the oxygenated intermediates 56 and 74, respectively.

126

ZHU-JIN LIU AND REN-RONG LU

In practice, however, all attempts to introduce a hydroxyl group at the allylic position C-18 of 73 in order to acquire 56 have failed. These include the attempted oxidation of 73 by Se02 in various solvent systems within a temperature range of 0-100°C. Attempted allylic oxidation of 73 with SeO,/H,O, in aqueous solution at room temperature results only in the corresponding N-oxide, in which the 6, value of the N-methyl has shifted from 2.20 to 3.03 ppm. Finally, 18 has been obtained directly from 3(R)-vobasinediol(58)in a facile way (Scheme 20). It seems that all the expected reactions mentioned above have been completed in one pot within 2.5 hr and under relatively mild conditions. The substitution of 58 with 73 as the starting material gives similar results. In this case, the yield of 18 is 25%. In this one-pot reaction, control of the reaction conditions seems to be very delicate, and the presence of sulfuric acid as well as mild treatment with H,O, followed by immediate removal of the excess of oxidizing agent prove to be quite crucial. The mechanism of this biomimetic reaction has been proposed (Scheme 21). On the basis of the elucidation of the structure of koumine in 1981 (26,28), a plausible biosynthetic proposal appeared in 1982 (53). It suggested that koumine might be formed in v i m though the unnatural alkaloid 18-hydroxydeoxysarpagine (75, 18-hydroxykoumidine or 18-hydroxy-1Qepinormacusine B) by rupture of the C-3-N-4 bond to afford 18-hydroxyvobasinedioI

HO

''

40% HzSO4.0.5 hr. RT: ScO2.1.5 hr, 54°C; H 2 0 z . 20 min. RT.

P

21

H 18

SCHEME 20

127

2. GELSEMIUM ALKALOIDS

(57) before the final ring closure to form koumine (18) (Scheme 22). However, no further information regarding to the experimental results has been reported since then. The realization of Lounasmaa's biogenetic idea was achieved in 1986 by the Chiba group (54), who claimed success in synthesizing the unnatural

I

OH

OH

SI

75

H

H 57

18

SCHEME 22. (From Ref. 53.)

129

2. GELSEMIUM ALKALOIDS

alkaloid 1 1-methoxykoumine (76). The starting material used by this group was 18-hydroxygardnerine (77) isolated by them from Gardneria nutans (Loganiaceae),and the main pathway to reach 76 included a C/D ring-fission methodology developed by this group and conventional palladium-mediated allylic ring closure, as shown in Scheme 23. Although 76 is an unknown

+CH,CHO 0

-

0

OH

- \lr, 0

OAc

78

H

..

H

80

79 H

18

SCHEME24

130

ZHU-JIN LIU AND REN-RONG LU

compound, the 'H- and I3C-NMRas well as the CD spectra are comparable with those of koumine excepting the aromatic ring portion, thus suggesting that 76 and 18 have the same molecular skeleton and the same absolute configuration. For the moment, the problem of the formal total synthesis of koumine seems to have been simplified to the total synthesis of vobasine (50) or the transformation of dregamine (51) or 16-decarbomethoxyvobasine (59) to vobasine or its derivatives. Following the strategy for the synthesis of dregamine (44) a similar sequence designed to introduce an ethylidine instead of an ethyl group at C-20 has been tested Scheme 24 (55).Unfortunately, this approach to koumidine (12, 16-epinormacusine B) and anhydrovobasinediol (73) have proved unsuccessful, since 78 and 79 reacted directly to give a compound (81) in which the ethylidene side chain at C-20 had been formed. Probably owing to the influence of this exo ethylidene side chain on the conformation of 81, the expected cyclization between C-16 and C-15, in contrast to the case for 80, was no longer possible in 81. The direct formation might follow the mechanism indicated in Scheme 25. Another approach has also been designed (58)in order to realize the crucial cyclization between C-5 and C-16 by the conventional DCC method (56,57). The sequence is outlined in Scheme 26. However, there was no better luck in this approach, and handicaps were encountered at the very beginning. When 82 was treated with NBS, no bromination occurred on the expected methyl group. Instead, only the active methylene reacted to yield the mono- and

OAc

78

0 81

SCHEME 25

131

2. GELSEMIUM ALKALOIDS

COZR

I

R02C+

0

0

-

C02R R 0 2 0 C 4 B r 83

82

84

RO,C

RO,C

0

0

dibromo products; when the keto group was protected as the ethylene ketal, no reaction took place at all (58). No reports of the nonbiogenetic convergent total synthesis of koumine has appeared up to date.

VIII. Alkaloids of Unknown Structure A. KOUMINIDINE

Kouminidine was first isolated from G. elegans in 1931 and given the molecular formula C2,,H2,N20, (25.59).No structural information has been available.

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ZHU-JIN LIU AND REN-RONG LU

B. KOUNIDINE

The water-soluble alkaloid kounidine (C, H,,N,O,) was isolated from G. elegans in 1936 (60),but the structure remains unknown.

IX. Biogenetic Considerations Although the transformation of [6-'4C]strictosidine to gelsemine in Gelsemium sempervirens with 0.47% incorporation has been reported (33), the exact biosynthetic pathway is still vague. However, the isolation and identification of koumicine (akuammidine), koumidine (16-epinormacusine B), and humantenine from G . elegans, coupled with facile biomimetic transformation of vobasinediol to koumine, appear to have shed some light on this problem. On the one hand, it is conceivable that koumicine and koumidine might be derived readily from the corynantheine base 85 which is a C-4=C-5 isomer of 4,21-dehydrogeissoschizine(86) known to be a biosynthetic intermediate involving strictosidine (61) . On the other hand, the transformation of koumidine to vobasinediol and then to anhydrovobasinediol is expected to involve conventional processes only.

The presumed mechanism for the transformation of anhydrovobasinediol to koumine is as follows: However, the proposed in oivo transformation of anhydrovobasinediol to gelsemine might involve a series of more extensive alterations of the molecular skeleton which presumably would include (1) oxidation of the 2,7 double bond, (2) an acid-induced 2,7 shift, and (3) allylic rearrangement of the C-20 ethylidene side chain to a (2-20 vinyl, so that a humantenine-type precursor

133

2. GELSEMIUM ALKALOIDS 17

C *;H \ 3

20

2 3

5 17

15

H

14

2 1 9

18

73

56

16

18

(87) would be formed (Scheme 27). Subsequent oxidative coupling between C-6 and C-20 would be expected to afford the target molecule gelsemine as shown in Scheme 28. The isolation of humantenine and humantenirine from G. elegans seems to support the suggested biosynthetic pathway of gelsemine shown in Scheme 28.

21 14

20

13

N-CH,

OH 87 SCHEME 21

20

134

ZHU-JIN LIU AND REN-RONG LU w

z

I

\

H

I

+

or$..OGlu /

NH, Me0,C

H

L-Tryptophan

\

Secologanin

Strictosidine

9 TH 9 HOH2C

HOH,C

H,

-

'01

Vobasindiol

Koumidine (16-epinormacusine B)

Anh ydrovobasindiol

Koumine

I

Humantenine type (gelsenidine)

Gelsemine

SCHEME28

Koumicine (akuammidine)

2. GELSEMIUM ALKALOIDS

135

X. Biological Activity A. PHARMACOLOGICAL STUDIES

1. Pharmacology of Gelsemicine Owing to its remarkably high toxicity (MLD 0.05-0.06 mg/kg in rabbits, intravenous injection) in comparison to gelsemine (MLD 180 mg/kg), gelsemicine has been considered to be the active principle of G. semperuirens and attracted the attention of pharmacologists soon after its isolation in pure form in 1931. H. C. Hou has studied the pharmacological actions of gelsemicine on respiration (62), circulation (64, the intestine, the uterus, as well as on the urinary bladder (64) and concluded that (1) gelsemicine affects the respiratory center alone, the vagus and higher centers not being involved, (2) as long as artificial respiration is maintained gelsemicine produces no change in the action current, conductivity, or contractibility of the heart, even when the dose injected is twice the MLD; (3) gelsemicine has no action on the spleen or peripheral vessels of the nose, intestine, kidney, or leg. K. K. Chen et al. studied the mode of action of gelsemicine hydrochloride in inducing emesis in rabbits and pigeons (intravenous injection)and concluded that gelsemicine apparently depresses the motor neurons of the brain and spinal cord, resulting in generalized muscular weakness. The respiratory failure after administration of fatal doses is not due to paralysis of the center, but is attributable to paralysis of the spinal motor neurons innervating the respiratory muscles. It has no action on the vagus. The mydriasis, intestinal relaxation, and uterine contractions suggest an action on the sympathetic system (65).Chen et al. also studied the action of gelsemicineon the acid-base balance in rabbits and found an acidosis characterized by an excess of C 0 2 and accumulation of fixed acids. These authors hypothesized that the acidosis resulted from respiratory failure and can be abolished by artificial respiration (66). 2. Pharmacology of Gelsemine Physiological study of gelsemine was first reported as early as 1914 by Chillingsworth (67), who concluded that gelsemine acted on the central nervous system and that the action on the heart was secondary via the vagi. The analgesic action of gelsemine was first reported by Eichler et al. in 1957 (68). Later, in the course of study of the analgesic activity of a mixture of gelsemine and aspirin, some detailed results were reported (69): (1) the acute LDS0 of gelsemine in mice (given orally) is 1240 mg/kg (intraperitoneally 405 mg/kg, intravenously 133 mg/kg); (2) gelsemine does not have a curarelike action, it is not a central nervous system sedative, and it has a very

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ZHU-JIN LIU AND REN-RONG LU

weak serotonin action. It strengthens the hypertensive action of adrenalin but is hypotensive in large doses. It does not act on the heart and is not potentiated by barbiturates. 3. Toxicity of Gelsemium Alkaloids

Symptoms of intoxication in humans caused by accidental ingestion of Kou-Wen plants have been described as follows. The effect on the digestive system starts with loss of appetite and turn of the stomach, and continues to severe abdominal pain and intestinal bleeding. The effect on the respiratory system presents as breathing difficulties which finally lead to death by respiratory failure. The effect on muscle innervation usually results in generalized muscular weakness and paralysis of the limbs. The effect on the circulatory system starts with heartbeat disorders and a drop in blood pressure, but heart failure is not a common cause of death. In addition to dilation of pupils, a drop in body temperature and proliferation of white blood cells have also been observed (70). The traditional and effective emergency treatment of this kind of poisoning in China includes administration of fresh sheep blood as well as Chinese cinnamon oil. Of course immediate detoxification measures such as gastric lavage, application of emetics or laxatives, and administration of active charcoal also prove effective. For those with respiratory problems, oxygen therapy is recommended; In case respiration has ceased but the heart remains beating, application of artificial respiration as well as injection of respiratory center stimulants and administration of large doses of neostigmine and atropine are effective. Chlorpromazine can be used in the case of body spasms, and appropriate infusion and supplementation of electrolytes are necessary for excessive dehydration caused by vomiting and diarrhea (70). It is interesting to note that the toxicity of Gelsemium species depends not only on the individual alkaloids present but also on the route of administration as well as on the animals used. For example, the LD,, values of gelsemine in mice are 1240,405, and 133 mg/kg, respectively, depending on whether the drug is administered orally, intraperitoneally, or intravenously (69). Toxicity also depends on the animals used and on the method of drug administration, as can be seen clearly from the following tabulation (71): Animal Frog Rat Rabbit Dog

Route of administration

MLD (mg/kg)

Injection to abdominal lymph bladder Intraperitoneal or abdominal cavity injection Intravenous injection Intravenous injection

20-30 0.1-0.12 0.05-0.06 0.5- 1.0

The toxicities of gelsemicine (G), aconitine (A), and pseudoaconitine (P) have been compared (72),and it was found again that the toxicity depends on

2. GELSEMIUM ALKALOIDS

137

the animals used. Thus, for mice, G > A > P; for rats, G > P > A; for guinea pigs, P > A > G; and for New Zealand red rabbits, P > A > G. The toxicity of the alkaloids from G. elegans has been studied much less extensively, but it has been found that the toxicity of the principal alkaloid koumine is comparable to that of gelsemine (MLD, 180 mg/kg) (7,25,60). The later isolated compound gelsenicine (humantenmine) proves to be the most toxic of G. elegans alkaloids, the LD50 being 185 pg/kg (mice, intraperitoneal injection)(20). It is also very interesting that one of the ancient Chinese pharmacopeias has described the toxicity of Kou-Wen, “While it proves fatal to human beings as well as to cattle, sheep fed the young plant always become stronger and healthier; that is why fresh sheep’s blood has been used by folks for the detoxification of Kou- Wen.” Another citation, from the modern Magazine of Traditional Chinese Drugs in Guangxi Province, states that Kou- Wen can improve poor appetite in pigs; it appears not only to be harmless but also to have some therapeutic value; therefore, Kou- Wen is also known in Guangxi as “pig’s ginseng.”

-

B. CLINICAL APPLICATIONS

The toxic Gelsernium alkaloids in crude form have been used as analgesic and antispasm agents for a long time. It was also applied in traditional Chinese medicine as a remedy for dangerous skin ulcers, such as miliary vesicles under the nose. In recent years, the pure alkaloid gelsemine has been used in an analgesiccomposition (0.5- 2 mg gelsemine in 300- 500 mg aspirin),and it was claimed that this preparation “has an onset of action of about 15 minutes and lasts about 8 hours. The action of the combination is greater than either drug used alone” (69). Recent preliminary clinical experiments with Kou- Wen on malignant tumors have also given encouraging results. For instance, the therapeutic efficacy of treatment of 38 cases of hepatic cancer, using the crude root powder of Kou-Wen orally, is 60% (73). More recently, a preparation of the total alkaloids,which consists of seven individual Gelsernium alkaloids (as shown by TLC) and which has an LD50 in mice of 0.275 mg/kg (intravenous injection), has been used as an analgesic for the palliation of various acute cancer pains, including hepatic cancer. The normal dosage used was 2-3.5 mg/day (intravenous injection). It was claimed that good analgesic activity usually lasted 4-6 hr and the rate of remarkably effective was 66%, effective 24%, and not effective lo%, thus confirming the analgesic activity of Gelsemiurn alkaloids. Furthermore, the preparation does not show any side effect of addiction and therefore has been recommended as a substitute for morphine or dolantin (73).

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Preliminary observation on 16 cancer patients who have been treated with the above-mentioned total alkaloid preparation indicates that symptoms are improved. Thus hepatic cancer patients have claimed disappearance of pain, improvement of appetite, and reduction of ascites; patients suffering esophageal cancer claimed to have the self-feeling of relaxation of pain and disappearance of vomiting and upset stomach as well as the improvement of appetite. These preliminary results are quite encouraging, but certainly more extensive investigations are needed before the antitumor action of the Gelsemium alkaloids can be established. The order for the Gelsemium alkaloid preparation to be a practical remedy in the chemotherapy of cancers, caution must be paid to the safety problem. Thus, not only should the dosage itself be strictly controlled, but also further investigation of suitable methods of administration as well as the application of combination forms should be initiated.

REFERENCES

1. 2. 3. 4. 5. 6. 7. 8.

A. Gerrad, Pharm. J. 13,641 (1883). F. M. Lovell, R. Pepinsky, and A. J. C. Wilson, Tetrahedron Lett.. 1 (1959). H. Schwarz and L. Marion, J. Am. Chem. SOC.75,4372 (1953). E. Wenkert, C. J. Chang, D. W.Cochran, and R.Pellicciari, Experientia 28, 377 (1972). A. Nikiforov, J. Latzel, K. Varmuza, and M. Wichtl, Monatsh. Chem. 105, 1292 (1974). S.Yeh, G. A. Cordell, and M.Garland, J. Nat. Prod. 49,483 (1986). T. Q. Chou, K. K.Chen,T. P. Pak, and H.C. Hou, Chin. J. Physiol. 5, 131 (1931). M. Przybylska, Acta Crystallogr. 14, 694 (1961); M. Przybylska, Acta Crystallogr. 15, 301

(1962). 9. E. Wenkert, J. C. Orr, S. Garrat, J. H. Hansen, 9. Wickberg, and C. L. Leicht, J. Org. Chem. 27, 4123 (1962). 10. M. Wichtl, A. Nikiforov, S. Sponer, and K . Jentzsch, Monatsh. Chem. 104,87 (1973). 11. S . Yeh and G. A. Cordell, J. Nut. Prod. 48,788 (1985). 12. L. E. Sayre, Pharm. J. 86,242 (191 1). 13. R. B. Woodward and B. Witkop, J. Am. Chem. SOC.71,379 (1949). 14. R. Bentley and T. S. Stevens, Nature, (London) 164, 141 (1949). 15. R. 9. Woodward and W. M. McLamore, J. Am. Chem. Soc. 71,379 (1949). 16 G. A. Swan, J. Chem. Soc.. Chem. Commun., 2083 (1958). 17. C. T. Liu, J. Y. Loh, T. T. Chu, and C. H. Wang, Aeta Chim. Sinica 27,47 (1961); Chem. Abstr. 59, 14041a (1963). 18a. J. Levy, J. LeMen, and M.-M. Janot, Compt. Rend., Ser. C253,131(1961). 18b. A. Chatterjee, C. R.Ghosal, N. Adityachaudhury, and S.Ghosal, Chem. Ind. (London),1034 (1961). 19. H. L. Jin and R. S . Xu, Acta Chim. Sinica 40, 1129 (1982); Chem. Abstr. 98, 104296r (1982). 20. X. B. Du, Y. H. Dai, C. L. Zhang, S.L. Lu, and 2. G. Liu, Acta Chim. Sinica 40, 1137 (1982); Chem. Abstr. 98, 1264300 (1982).

2. GELSEMIUM ALKALOIDS

139

21. J. S. Yang and Y. W. Chen, Acta Pharm. Sinica 18, 104 (1983); Chem. Abstr. 99, 102248~ (1983). 22. J. S. Yang and Y. W. Chen, Acta Pharm. Sinica 19,437 (1984); Chem. Abstr. 103,3678h (1985). 23. J. S. Yang and Y. W. Chen, Acta Pharm. Sinica 19,686 (1984). 24. S. Yeh and G. A. Cordell, J. Nut. Prod. 49,806(1986). 25. T. Q. Chou, T.P. Pak, H. C. Hou, and R. C. Liu, Chin. J. Phpiol. 5,345 (1931). 26. C. T. Liu, Q. W. Wang, and C. H. Wang, J . Am. Chem. Soc. 103,4634(1981); C. T. Liu, Q. W. Wang and C. H. Wang, “Chemistry of Natural Products,” p. 171. Science Press (Beijing) Gordon and Breach Inc. (New York) 1982. 27. C. T. Liu, Q. W. Wang, and C. H. Wang, Acta Chim. Sinica (Engl. Ed.), 73 (1986). 28. F. Khuong-Huu, A. Chiaroni, and C. Riche, Tetrahedron Lett. 22,733 (1981). 29. Z. H. Yao, Z. L. Wan, and D. C. Liang, Acta Physica Sinica 31,547 (1982). 30. M.-M. Janot, R. Goutarel, and M. L. Perezamador y Barron, Ann. Pharm. Fr. 11,602 (1953). 31. S. Yeh and G. A. Cordell, J. Nut. Prod. 48,969 (1985). 32. E. Wenkert, C. J. Chang, A. 0.Clouse and D. W. Cochran, Chem. Commun.. 961 (1970). 33. N. Nagakura, M. Ruffer, and M. H. Zenk, J. Chem. Soc.. Perkin Trans. 1,2308 (1979). 34a. R. D. Guthrie, Diss. Abstr. 24, 1834 (1963). 34b. V. A. Landeryou, Diss. Abstr. 26,2477 (1965). 3412. F. C. Tahk, Diss. Abstr. 27, 118 (1966). 3 4 . E. G. Lovett, Diss. Abstr. 28, 110 (1967). 34e. R. S. Johnson, T. 0. Lovett, and T. S. Stevens, J . Chem. SOC.C, 796 (1970). 34f. K. Jones, M. Thompson, and C. Wright, J. Chem. SOC..Chem. Commun.. 115 (1986). 35. I. Fleming, in “New Trends in Natural Product Chemistry 1986,” (A. U. Rahman and P. W. Le Quesne, eds.) p. 83. Elsevier, Amsterdam, 1986. 36. L. D. Antonaccio, N. A. Pereira, B. Gilbert, H. Vorbrueggen, H. Budzikiewicz, J. M. Wilson. J. L. Durlam, and C. Djerassi, J. Am. Chem. Soc. 84,2161 (1962). 37. M. Ohashi, H. Budzikiewicz, J. M. Wilson, C. Djerassi, J. Levy, J. Gosset, J. Lemen, and M.-M. Janot, Tetrahedron 19,2241 (1963). 38. J. S. Yang and Y. W. Chen, “Proceedings of the Symposium on the Chemistry of Traditional Chinese Medicine and Medicinal Natural Products,” p. 86. Chinese Pharmaceutical Society, Nanning, China, October, 1983. 39. H. Conroy and J. K. Chakrabarti, Tetrahedron Lett., 6 (1959). 40. H. J. Teuber and S . Rosenberger, Chem. Ber. 93,3100 (1960). 41. L. M. Jackman and S. Sternhell, “Application of Nuclear Magnetic Resonance Spectroscopy in Organic Chemistry,” 2nd Ed., p. 334. Pergamon, New York, 1969. 42. L. M. Jackman and S. Sternhell, “Application of Nuclear Magnetic Resonance Spectroscopy in Organic Chemistry,” 2nd Ed., p. 334. Pergamon, New York, 1969. 43. Z. J. Liu and Q. S. Yu, Youji Huaxue (Organic Chem.. Chin. Chem. Soc.). 36 (1986); Chem. Abstr. 105,97773b (1986); 2. J. Liu and Q. S . Yu, Acta Chim. Sinica 45,359 (1987). 44. J. P. Kutney, G. K. Eigendorf, H. Matsue, A. Murai, K. Tanaka, W. L. Sung, K. Wada, and B. Worth, J. Am. Chem. Soc. 100,938 (1978). 45. 2. J. Liu, H. J. Gu, and G. R. Xu,Acta Chim. Sinica (Engl. Ed.), 53 (1984). 46. Z. J. Liu, Q. W. Wang, 2. C. Fan, C. H. Wang, and Y. Q. Pei, Acta Chim. Sinica (Engl. Ed.), 225 (1986); Chem. Abstr. 106, 18909~(1981). 47. 2. C. Fan, Z. J. Liu, and C. H. Wang, J. Struct. Chem. 4, 123 (1985). 48. S. H. Pine, J. B. Hendrickson, D. J. Cram, and G. S. Hammond, “Organic Chemistry,” 4th Ed., pp. 205,250. McGraw-Hill, New York (1980). 49. Y. Langlois and P. Potier, Tetrahedron 31,419 (1975). 50. C. T. Liu, S. C. Sun, and Q. S . Yu, Youji Huaxue (Organic Chem.. Chin. Chem. Soc.). 121 (1982); C. T. Liu, S. C. Sun, and Q. S . Yu,J. Org. Chem. 48,44(1983).

140

ZHU-JIN LIU AND REN-RONG LU

51. Z. J. Liu, Z. Q. Wang, and Q. S. Yu, Acta Chim. Sinica 43,789 (1985) (in Chinese). 52. Z. J. Liu and Q. S. Yu, Acta Chim. Sinica 43, 1110 (1985) (in Chinese). 53. M. Lounasmaa and A. Koskinen, Planta Med. 44, 120 (1982).

54. S. I. Sakai, E. Yamanaka, M. Kitajima, M. Yokota, N. Aimi, S. Wongseripatana, and D. Ponglux, Tetrahedron Lett. 27,4585 (1986). 55. G. B. Rong, Ph.D. Dissertation, pp. 47-52. Shanghai Institute of Organic Chemistry, Academia Sinica, 1986. 56. E. E. Van Tamelen and L. K. Oliver, J. Am. Chem. SOC.92,2136 (1970). 57a. I. G. Csendes, Y. Y. Lee, H. C. Padrett, and H. Rapoport, J. Org. Chem. 44,4173 (1979). 57b. J. E. Johansen, B. D. Christer, and H. Rapoport, J . Org. Chem. 46,4914(1981). 58. G . B. Rong, Ph.D. Dissertation, pp. 29-45. Shanghai Institute of Organic Chemistry, Academia Sinica, 1986; G. B. Rong, Youji Huaxue, 365 (1986). 59. Y. F. Chi, Y. S. Kao, and Y.T. Huang, J . Am. Chem. SOC.60, 1728 (1938). 60. T. Q. Chou, J. S. Wang, and W. C. Tseng, Chin. J. Physiol. 10,79 (1936). 61. R. B. Herbert, in “Indoles, Part Four, The Monoterpenoid Indole Alkaloids” (J. E. Saxton, ed.),pp. 6, 22. Wiley, New York, 1983. 62. H. C. Hou, Chin. J. Physiol. 5,279 (1931); Chem. Abstr. 25, 59344 (1931). 63. H. C. Hou, Chin. J. Physiol. 6,41 (1932). 64. H. C. Hou, Chin. J. Physiol. 6, 281 (1932). 65. K. K. Chen and T. Q. Chou, Chin.J. Physiol. 14, 319 (1939); Chem. Abstr. 34, 48109 (1939). 66. H. M. Lee and K. K. Chen, Chin. J . Physiol. 14, 489 (1939); Chem. Abstr. 34, 4811’ (1939). 67. F. P. Chillingsworth, J. Am. Pharm. Assoc. 3,315 (1914); Chem. Abstr. 8, 1643’ (1914). 68. 0.Eichler, F. Hertle, and 1. Staib, Arzneim. Forsch. 7,349 (1957). 69. Societe Boulonnaise de Recherches et de Diffusion Pharmaceutique “Sobore” S. A., Belg. 639323, April 29, 1964.8 pp.; Chem. Abstr. 62,8949b (1957). 70. Pharmacology Group, Navy Medical School, “Symposium On Pharmacy” Technical Paper No. 49, pp. 1-41, 1982 (in Chinese), Navy Medical School, Beijing. 71. H. C. Hou, Chin. J . Physiol. 5, 181 (1931). 72. K. K. Chen, R. C. Anderson, and B. Q. Robbins, J. Pharm. 11,84 (1938). 73. Z. L. Chen and Y. S. Chen, Med. Info., 36 (1981) (in Chinese). Addendum in proof: 1. The configuration of C-18 in koumidine (p. 97-98) should be revised to be trans to C-15 ( Z configuration instead of the previously assigned E configuration). Yeh Schun and G. A. Cordell, Phytochern. 26 (lo), 2875 (1987). 2. Two novel approachs toward the total synthesis of gelsemine have been described. a, R. T. Vijn, H. Hiemstra, J. J. Kok, M. Knotter, and W. N. Speckamp, Tetrahedron. 43 (21). 5019-5030 (1987). b, G. Stork, M. E. Krafft, and S. A. Biller, Tetrahedron Lett 28 (10) 10351038 (1987).

. CHAPTER 3.

TRANSFORMATION REACTIONS OF PROTOBERBERINE ALKALOIDS MIYOJIHANAOKA Faculty of Pharmaceutical Sciences Kanazawa University Kanazawa. Japan

I . Introduction ........................................................... I1. Bond Cleavage Reactions of Protoberberines .............................. A. C-N Bond Cleavage B. C-C Bond Cleavage ................................................ C. C-0 Bond Cleavage ................................... 111. Oxidation of Protoberberines ............................................ A . Hydroxylation ..................... B. Protoberberinephenolbetaines ....... C. 14-Hydroxy-8.13-dioxotetrahydroberberine(Prechilenine)................. IV. Other Reactions of Protoberberines ...................................... A. 8, 1CCycloberbines .................................................. B. Reaction with Chloroform ............................................ V . Transformation of Protoberberines to Related Alkaloids ..................... A. Benzo[ c ] phenanthridine and 3-Arylisoquinoline Alkaloids ................ B. Secoberbine Alkaloids ............................................... C. Spirobenzylisoquinoline Alkaloids ..................................... D. Phthalideisoquinoline Alkaloids ....................................... E. Protopine Alkaloids ... .......................................... F. lndenobenzazepine Alkaloids ......................................... G . Rhoeadine Alkaloids ................................................ H. Isoindolobenzazepine Alkaloids ....................................... I. Protoberberine and Retroprotoberberine Alkaloids ...................... J . Miscellaneous Alkaloids ............................................. References.............................................................

141 143 143 153 153 156 156 159 163 164 164 169 170 170 180 182 194 201 204 209 213 216 221 224

.

I Introduction The isoquinoline alkaloids (1-4) along with the indole alkaloids are the most abundant groups of alkaloids. Their chemistry and synthesis have been extensively studied . In recent years one of the most interesting features of the chemistry of these alkaloids is the transformation among the different types. 141

. .

THE ALKALOIDS VOL. 33 Copyright 0 1988 by Academic Press Inc. All rights of reproduction in any form reserved.

142

MIYOJI HANAOKA

The protoberberine alkaloids (5-15) play important roles as precursoi-s in the biosynthesis of a variety of related isoquinoline alkaloids such as protopine, phthalideisoquinoline, spirobenzylisoquinoline, rhoeadine, indenobenzazepine, secoberbine, and benzo[c] phenanthridine alkaloids. Chemical transformations of protoberberines to these alkaloids are particularly interesting and exciting from the biogenetic viewpoint and further from ready availability of starting protoberberines in nature or synthesis. The structural relationships of these alkaloids are shown in Scheme 1 (substituents on aromatic rings are omitted for simplicity). Most alkaloids have oxygenated skeletons and are derived through bond cleavage of protoberberine alkaloids. The bond cleavage and oxygenation positions (in parenthesis)are indicated at the arrows in Scheme 1. Two main problems arise for these transformations, namely, how to cleave regioselectively the bond, especially the C-N bond, and how to introduce the oxygen at the proper position of the original protoberberine skeleton. Numerous elegant and marvelous transformations have been developed in these fields and are reviewed in this chapter. Transformations between the

Protopine isoquinoline

/

R Rhoeadine r

Indenobenzazepine

(8,141

,A

.I

I

Benzo [clphenanthridine

. Secobelrbine

SCHEMEI . Biosyntheticrelationshipsbetween protoberberinesand related alkaloids.

3. TRANSFORMATION REACTIONS OF PROTOBERBERINE ALKALOIDS

143

related isoquinoline alkaloids are omitted unless protoberberine alkaloids were used as the starting material, and some reactions of protoberberines are also left out when not related to transformations to the other alkaloids. For these reactions, readers are referred to previous reviews (1,2,5-15).

11. Bond Cleavage Reactions of Protoberberines

The C-N bond cleavage is a fundamental and key reaction in skeletal rearrangements of protoberberines. The remaining two cleavages, that is, of the C-C and C-0 bonds, are not always essential to transformation. A. C-N

BOND CLEAVAGE

1. Hofmann Degradation The Hofmann degradation is the most well-known C-N bond cleavage reaction, and its value to structural elucidation of alkaloids has been demonstrated (16). Hofmann degradation of tetrahydroberberine methohydroxide (1) led to two products: base A (2), the C-14-N bond cleavage product, and base B (3),the C-6-N bond cleavage product (Scheme 2) (Z7J8). The former was the major product when 1 was heated under reduced pressure, but the latter, the thermodynamically controlled product, predominated when the reaction was carried out at atmospheric pressure or in an alkaline medium because base A recyclized back to the starting quaternary base through the transannular reaction. In fact, 2 was heated in aqueous alcohol to afford 1. The mechanism of this recyclization reaction was discussed by Kirby et al. (19). This recyclization reaction has been skillfully utilized for stereospecific labeling at C-13 of tetrahydroberberine with tritium or deuterium for biosynthetic studies of ophiocarpine (20). Base A- and B-type products have

U

1

2

3

SCHEME2. Hofmann degradation of tetrahydroberberine metho salt (1).

O Me

144

MIYOJI HANAOKA

been used for synthesis of protopine (Section V,E,l) and benzo[c]phenanthridine alkaloids (Section V,A). As the Hofmann degradation precedes trans anticoplanar elimination, the reaction is sensitive to the stereochemistry of the substrates. Thus, corydaline (4) or thalictricavine metho salt (5), having 13H,14H-cisconfigurations, gave the 10-membered ring product, whereas mesocorydaline (6)or thalictrofoline metho salt (7),having 13H,14H-trans configurations, afforded the C-6-N bond cleavage product (Scheme 3) (21-23). The stereochemistry of corydalic acid methyl ester (8) was confirmed by correlation with the Hofmann degradation product of mesotetrahydro-

Me

Me 0

+. , , ,

\

12

OMe Me

Me0

13

OMe

14

OMe OMe

SCHEME 3. Hofmann degradation of protoberberines. Reagents: a, MeI; b. Amberlite IRA400; c, 20% KOH, MeOH; d, B,H,; e, H,O,, NaOH; f, LAH, THF; g, 10% NaOH.

3. TRANSFORMATION REACTIONS OF PROTOBERBERINE ALKALOIDS

145

corysamine (9) (24).Namely, the lithium aluminum hydride reduction product of 8 was identical to the alcohol (11) derived through hydroborationoxidation of the C-6-N cleavage product (lo), which was obtained exclusively by Hofmann degradation of 9. Hofmann degradation of 13hydroxyxylopinine (12) afforded phenolbetaines 13 and 14 through oxidation of ring C without participation of the 13-hydroxyl group (25). The C-8-N bond cleavage of protoberberines themselves by the Hofmann degradation is impossible; however, this cleavage was realized by introduction of a benzyl group at C-8 of berberine (15) (Scheme4). Hofmann degradation of 8-benzyltetrahydroberberine (16) effected regioselective C-8-N bond fission to give stilbene 17 (26,27).This reaction was used for a synthesis of secoberbine alkaloids (Section V,B,l).

(86%)

15

16

17

SCHEME 4. C-8-N Bond cleavage by the Hofmann degradation. Reagents: a, PhCH,MgBr; b, NaBH,; c, Mel; d, KOH, MeOH.

Kametani et al. (28-32) found an interesting C-8-N bond cleavage during investigation of the Hofmann degradation of phenolic protoberberines. Heating of quaternary tetrahydroprotoberberines (e.g., 18), having a phenolic hydroxyl group at the 9 or 11 position, in methanolic 20% potassium hydroxide afforded a novel C-8-N bond cleavage product (20) in addition to a normal C-6-N bond cleavage product (19). Compound 21, having one more phenolic hydroxyl group at the 2 position, underwent further cyclization to give rise to a tetracyclic compound (23) in addition to the methoxylated compound (22). Under prolonged reaction times (72 hr) 23 was obtained exclusively in 78% yield. The products were obtained via quinomethides 24 or 25 as shown in Scheme 5. 2. von Braun Reaction

The von Braun reaction (Scheme 6) is another basic reaction for C-N bond cleavage (32).Tetrahydroberberine (26) was heated under reflux with cyanogen bromide in benzene to afford the bromocyanide (28) and the unsaturated cyanide (29) through C-6-N and C-14-N bond cleavage, respectively. The C-8-N bond cleavage product was not obtained because of the steric hindrance of the methoxyl group at C-9 in SN2-typereactions (33).The

146

MH

MIYOJI HANAOKA

e

o

NMe T

a

21

OH

Me Meo%Me HO +

(15%)

(30%)

/ \

HO

\

Me

22

OH

Me

\ / Me0

OH

23

SCHEME 5. Abnormal Hofmann degradation. Reagents: a, KOH, MeOH.

6. The von Braun reaction. Reagents: a, BrCN, benzene; b, BrCN, EtOH or aq SCHEME THF (MgO).

3. TRANSFORMATION REACTIONS OF PROTOBERBERINE ALKALOIDS

147

C-6-N bond cleavage strategy was applied to a synthesis of corydamine (Section V,A,7). Reaction under solvolytic conditions such as in ethanol or aqueous tetrahydrofuran caused exclusive C-14-N bond cleavage and introduction of an ethoxyl or hydroxyl group at C-14, giving 30 in excellent yields (34). Addition of a base such as magnesium oxide to the reaction mixture was found to be useful to avoid the recovery of the starting material as the hydrobromide (35).The reaction was used for a synthesis of protopine alkaloids (Section V,E,5). 3. Birch-Type Reduction

Nagata et al. (36) studied the Birch-type reduction for a synthesis from protoberberines of an analgesic compound having 10-membered ring (Scheme 7). Electron attack occurred at either ring A or D, resulting in the C-14-N or C-8-N bond cleavage product, respectively. Therefore, the cleavage site depends on the substituents on the aromatic ring; for example, 31 and 32 afforded exclusively 33 and 34, respectively.

31 : R1 b C H 2 , R2-PhCH,

32: R l = H

.

33

(91%)

,R*-Me

34

(70%)

SCHEME 7. The Birch reduction. Reagents: a, Li, lig NH,.

On treatment with aerated sodium in liquid ammonia, tetrahydroprotoberberine N-oxides (35a and 35b) afforded the C-14-N bond cleavage products 36 and 37 (Scheme 8) (37). The same trans N-oxides also gave the C-14-N cleavage products 38 and 39 on photolysis (38).

4 . Cleavage with Ethyl Chloroformate Knabe et al. (39)have extensively studied C-N bond cleavage reactions of tertiary amines and alkaloids with ethyl chloroformate. In contrast to other amines, tetrahydroprotoberberines were found to be inert to this reagent under Schotten-Baumann-like conditions. Ronsch (40) and Hanaoka et al. (41) independently reinvestigated the reaction of tetrahydroberberine (26) with ethyl chloroformate and found it to be a useful reagent for regioselective C-8-N bond cleavage of protoberberines (Scheme 9). Ronsch obtained

148

MIYOJI HANAOKA

-

R1O

R10

35

R4

\

b

b : R1=R2=Me,R3=HrR4:OMe

R20 R

R10

36

l

ET : OMe

R4

q

;

(5%)

OMe

38 SCHEME 8. C-N b, hv, MeOH.

(4%)

R4

39

R3

‘ OMe R4

Bond cleavage of protoberberine N-oxides. Reagents: a, Na, air, liq NH,;

___)

R4 R5

R7

R5

R5

R6

41

42

43

SCHEME 9. C-N Bond cleavage with ethyl chloroformate. Reagents: a, CICO,Et, Nal, acetone; b, CIC0,Et.

3. TRANSFORMATION REACTIONS OF PROTOBERBERINEALKALOIDS

149

iodide 40a by using the reagent in acetone in the presence of sodium iodide, and Hanaoka et al. obtained chloride 40b by heating the reagent without solvent. Tetrahydropalmatine also gave the corresponding iodide (42).A variety of tetrahydroprotoberberines (41) were treated with large excess of ethyl chloroformate at 70-80°C to give the C-8-N and/or C-6-N bond cleavage products 42 and/or 43 (Scheme 9) (43).Generally regioselective C-8-N bond cleavage took place regardless of the substitution pattern on ring D, but the presence of an electron-donating group in ring D is necessary because the starting material was recovered unchanged in the case of protoberberines lacking substituents on ring D. The regioselectivity was affected by the substituent at C-1 or C-13,,, which influences the conformation of tetrahydroprotoberberines. The greater the B/C trans conformation, the greater the regioselectivity of C-8-N bond cleavage. This C-8-N bond cleavage reaction was used for synthesis of secoberbine (Section V,B,2) and phthalideisoquinoline alkaloids (Section V,D,5). Prior et al. (44) found that 13-methylprotoberberine (44)gave the C-14-N bond cleavage product 45, and Hanaoka et al. (45)also detected the C-14-N bond cleavage product 47 as a minor product along with 4Ob and 46 in the reaction of tetrahydroberberine (26) (Scheme 10). Finally, the C-8-N bond cleavage reaction was applied to synthesis of benzocycloheptaquinoline 23 (46) and 6’-methyl-l-benzylisoquinoline 50 via 49 (Scheme 11) (47).The bond cleavage was found to proceed smoothly in ethanol-free chloroform under reflux (46).

Me (47%)

44

OMe

45

/ \

OMe OMe

SCHEME 10. Reagents: a, CICO,Et, NaI, acetone; b, CIC0,Et.

150

MIYOJI HANAOKA

AcO /

48

a

' OMe

-M

e AcO (82%)

o

~

\

49

OAc

/

L Me

50

Z

\ /

Me0

OAc

1

~

( 4 9M% )

OH

23

d,e

OH OH

SCHEME 1 1 . Reagents: a, CICO,Et, CHCI,; b, NaOH; c, LAH; d, H,/Pd-C; e, NH,NH,.

5. Cleavage with Other Reagents Treatment of tetrahydroberberine (26) with sodium benzenethiolate (48)or -selenolate (49) in the presence of ruthenium catalyst afforded the C-14-N bond cleavage products 51 or 52 with a phenylthio or phenylseleno group at C-14 (Scheme 12). The latter was converted to the 10-membered amino olefin 53 on treatment with m-chloroperbenzoicacid.

51 X = S (62%) 52 X = S e (67%) SCHEME 12. Reagents:a, PhSNa, RuCl,; b, PhSeNa, RuCI,; c, MCPBA.

Heating of oxyprotoberberine 55, derived from dehydroprotoberberine (54), in methanol saturated with potassium hydroxide effected C-8-N bond cleavage to afford the zwitterionicsalt 56, which was converted to amino ester 57 (Scheme 13) (50).The same reaction, however, could not be performed for oxyberberine (58),which lacks the additional double bond in ring B.

T

M

3. TRANSFORMATION REACTIONS OF PROTOBERBERINE ALKALOIDS

-

15 1

d,e

Me0

OOMe /

67

‘

Me

SCHEME 13. Reagents: a, 20%KOH; b, KOH, MeOH; c. A; d, MeI; e, NaBH,.

Tetrahydroprotoberberines (59) having a phenolic hydroxyl group were heated in trifluoroacetic anhydride in a sealed tube to afford the indene derivatives (60)after treatment with methanol (Scheme 14) (51). The products formed through both C-14-N and C-8-N bond cleavage followed by ring closure.

a : RI= O H , R ~ - H( 2 5 % )

b:

R1:

H ,R*=OH

SCHEME 14. Reagents: a, (CF,C0)20, 180°C;b, MeOH.

On heating with sodium acetate and acetic anhydride under nitrogen, berberine (15) gave the naphthyl derivatives 61 and 62. The reaction proceeds as indicated in Scheme 15. Similar treatment of dehydroprotoberberine (54) gave the aromatized naphthylisoquinoline 63 owing to the presence of the additional double bond in ring B (52,53).

-

___)

OAc Me

OMe ( 3 9 % )

OMe

61

62

-

Me0

(24%)

Me0

54

OMe Me

Me0

/

Me0

‘

\

OAc

(70%)

63

SCHEME15. Reagents: a, AcONa, Ac,O, 110°C

SCHEME16. Synthesis of polyberbine (M),polycarpine (67), and its analog from protoberberines. Reagents: a, MCPBA, NaHCO,, CH,CI,, -78°C; b. MCPBA, NaH, THF.

3. TRANSFORMATION REACTIONS OF PROTOBERBERINE ALKALOIDS

B. C-C

153

BOND CLEAVAGE

Although several oxidative C-C bond cleavages have been observed, the only method useful for transformation is C-8-C-8a bond cleavage. Treatment of berberine (15) with m-chloroperbenzoic acid in dichloromethane in the presence of sodium bicarbonate at - 78°C gave polyberbine (66)and Nformylnoroxyhydrastinine (69, R' + R2 = CH,) in 20 and 15% yield, respectively (Scheme 16)(54). Similar treatment of palmatine (64) and coptisine (65) led to polycarpine (67) and the enamide 68, respectively, in 40-50% yield (55).The yield of polyberbine was improved to 76% whenthe oxidation was carried out in tetrahydrofuran in the presence of sodium hydride; however, the yields of 67 and 68 could not be improved under the,same reaction conditions (56). The products were used for synthesis of tetrahydroprotoberberine (Section V,I,5) and aporphine alkaloids (Section V,J,3). C. C-0

BOND CLEAVAGE

Although C-0 bond cleavage is of little importance for transformations of protoberberines to other types of alkaloids, the selective C-0 bond cleavage reaction provides access to naturally unabundant or nonnatural protoberberines from naturally abundant protoberberines such as berberine. 1. Aluminum Chloride

Berberine (15) was demethylenated and demethylated by heating with aluminum chloride to give berberolme (70), which was methylated with dimethyl sulfate to afford palmatine (64)(Scheme 17) (57).

-

HO

15

Me0

70

OMe

71 : R + R =CH, 72:R=Me

SCHEME17. Reagents:a, AICI,; b, Me,SO,; c, A.

154

MIYOJI HANAOKA

2. Pyrolysis Regioselective 9-O-demethylation of 15 was achieved by pyrolysis at 190°C to give berberrubine (71) (Scheme 17) (58),and 64 was similarly converted to palmatrubine (72), which was derivatized to [9-O-rnethyl-'4C]palmatine for biosynthetic studies (59). 3. Boron Trichloride

Preferential cleavage of a methylenedioxy group in the presence of methoxyl groups was accomplished with boron trichloride (60-62). Thus, tetrahydroberberine (26) was converted to the catechol derivative 73, which was deoxygenated via the tetrazoyl ether to the protoberberine 74 having no substituent in ring A (Scheme 18) (61).The catechol also furnished tetrahydropalmatine (27) on treatment with diazomethane (63).This reagent is also useful for preferential cleavage of a methoxyl group adjacent to a phenolic hydroxyl group in polymethoxylated protoberberines (e.g., 75 + 76). However, a methylenedioxy moiety proved to be more labile to this reagent than a methoxyl group adjacent to a phenol (e.g., 77 + 78) (64).

SCHEME18. Reagents: a, BCI,, CH,CI,; b, 5-chloro-l-phenyl-lH-tetrazole,benzene; c, H,/Pd-C, AcOH; d, CH,N2, MeOH.

3. TRANSFORMATION REACTIONS OF PROTOBERBERINE ALKALOIDS

155

4. Boron Tribromide

Boron tribromide cleaved a methoxyl group (e.g., 79 + 80)(Scheme 19) (65) as well as a methylenedioxy group (66). Tetrahydroberberine (26) was converted to tetrahydrocoptisine (82)by treatment with boron tribromide and subsequent methylenation (67). 5. Sodium in Liquid Ammonia

Tomita et al. (68)found that a methylenedioxy group was cleaved and some methoxyl groups were partially demethylated on treatment with sodium in liquid ammonia (Scheme 20).

OMe Me

79

OH

80

OH

, OMe 26

'

OMe

81

OH

82

SCHEME 19. Reagents: a, BBr,, CH,CI,; b, CH,CI,, NaOH, DMSO.

OMe

26 : R+R=CH, 27 : R=Me OH OMe SCHEME 20. Reagents: a, Na, liq NH,.

Me

156

MIYOJI HANAOKA

86

OMe

88

OMe OMe

87

89

\

OMe

OMe NHCH,Ph

SCHEME 21. Smile rearrangement. Reagents: a, RNH,; b, PhCH,NH,.

6. Smile Rearrangement A variety of protoberberines (86 or 88) were treated with primary or secondary amines in refluxing ethanol or methanol to give (2-9- or C - l l aminated protoberberines (87 or 89) in 60-90% yield (Scheme 21). When bulky amines were used, the demethylation product was also obtained (69,70).

111. Oxidation of Protoberberines

A. HYDROXYLATION 1. Hydrohoration- Oxidation

Introduction of a hydroxyl group into the protoberberine skeleton was successfully carried out by the hydroboration-oxidation method. Dihydroberberine (90) was converted to ( f)-epiophiocarpine (91) as a major product along with (f )-ophiocarpine (92) (Scheme 22) (71). 5-Hydroxyprotoberberines 94 and 95 were obtained from the 5,6-dehydro compound 93 (50) synthesized from papaverine via 54 (72). 2. Oxidation with Lead Tetraacetate

Hydroxylation at C-5 or C-13 has also been successfully achieved by lead tetraacetate oxidation, which was extensively studied in connection with isoquinoline alkaloids by Umezawa’s group. (+)-Govanhe (96) and ( f)discretine (97) were oxidized with lead tetraacetate in acetic acid to afford 5acetoxy products 100,101, and 102 via p-quinol acetates (e.g., 99) (Scheme 23)

3. TRANSFORMATION REACTIONS OF PROTOBERBERINE ALKALOIDS

157

90

93 SCHEME22. Introduction of a hydroxyl group into protoberberines. Reagents: a, B,H,; b, H,O,, NaOH.

(73,75). 10-Hydroxyprotoberberine 59a and (+)-corytencine (98) led to 13acetoxy compounds 104, 105, and 107; moreover, the 2,3,9,10,12-pentaoxygenated protoberberine 108 was also obtained from 98 via the p-quinol acetate 106 through a retro-Mannich reaction followed by recyclization (74,75). Oxidation in dichloromethane instead of acetic acid proceeded differently, namely, 97 and 98 led to pentaoxygenated protoberberines 103 and 109 by introduction of an acetoxyl group at C-4 and C-12, respectively, via o-quinol acetates (76). This oxidation method was applied to determination of the absolute stereochemistry of berberastine (110) and thalidastine (111). (+)-Tetrahydrojatrorrhizine (112) was converted to 5a- and 5B-hydroxyl derivatives 113 and 114 in a 2 : 1 ratio (Scheme 24). The major product 113 was dehydrogenated to give rise to the dextrorotatory quaternary protoberberine 115. Thus, 110 and 111, being dextrorotatory, should have the same absolute configuration as that of 115 (77). Oxidation of oxyberberine (58) with lead tetraacetate effected 13-acetoxylation to give 13-acetoxyoxyberberine(116), which was further oxidized to the 14-alkoxy-8,13-dioxocompounds 117 and 118 (Scheme 25). Reduction of 116 with lithium aluminum hydride followed by sodium borohydride afforded (+)-ophiocarpine (92) (78).

158

MIYOJI HANAOKA

Me0

b

Me+ *

. AcO (91%)

96

0 Me OMe

gg

OMe

-

Me0

loo

0 Me OMe

Me0 (30%)

(66%)

\

0 Me OMe

97

\ P

59a

101 :R ~ = O A C , R ~ = H 102 :R1=H , R2=OAc

O H OMe

-

Me0

AcO

98 I c,bl

OH

OMe

AcO OAc

109

(12.5%)

OMe

Ac

AcO

OMe

(52%)

108

SCHEME23. Oxidation with lead tetraacetate.Reagents:a, Pb(OAc),, AcOH; b, conc H,SO,,, Ac,O; c, Pb(OAc),, CH2Cl,.

3. TRANSFORMATION REACTIONS OF PROTOBERBERINE ALKALOIDS

159

110 : R = M e 111: R = H

Me0

Me

Me0

OMe

OMe

112 SCHEME 24. Determination of absolute configuration using lead tetraacetate oxidation. Reagents: a, Pb(OAc),, AcOH; b, 10% HCI; c, I,, EtOH.

O a Me

58

OMe

SCHEME 25. Oxidation of oxyberberine (58) with lead tetraacetate. Reagents: a, Pb(OAc),, CH,CI,; b, LAH; c, NaBH,; d, Pb(OAc),, CHCI,; e, p-TsOH, MeOH, or EtOH.

B. PROTOBERBERINEPHENOLBETAINES

Protoberberinephenolbetaines are important intermediates in chemical transformations of protoberberines. In this section, their syntheses and some reactions are described.

160

MIYOJI HANAOKA

123

-::%

%I:

k+

-Me e M \

127

OMe OMe

g or h

COCH,

(88 o r 6 7 % )

(100%)

128

0

\

\

OMe OMe

129

OMe OMe

SCHEME 26. Syntheses and reactions of protoberberinephenolbetaines. Reagents: a, CH,COCH,; b, KMnO,; c, HCI; d, LAH; e, OsO,; f, hv, 0,. MeOH; g, MCPBA, CH,CI,; h, hv, 0 , ,Rose Bengal, MeOH; i, NaBH,; j, MnO,; k, EtOH, A.

3. TRANSFORMATION REACTIONS OF PROTOBERBERINE ALKALOIDS

161

1. Berberinephenolbetaineand Its Analogs

Berberinephenolbetaine (121) was first obtained by Pyman and designated as neoxyberberine (79).Acetoneberberine (119) was oxidized with potassium permanganate in aqueous acetone to give neoxyberberine acetone (120), the structure of which was established by Iwasa and Naruto (80).On treatment with hydrochloric acid followed by sodium hydroxide, 120 gave 121 (79-81), which was also obtained directly from 119 by oxidation with potassium permanganate or osmium tetroxide (Scheme 26) (80). Oxidation of dihydrocoptisine (124), derived from protopine, with mchloroperbenzoic acid in dichloromethane afforded coptisinephenolbetaine (125) as the hydrochloride in 78% yield (Scheme 26) (82). This oxidation method was applied to dihydroberberine (90) to produce berberinephenolbetaine (121) (83).Additionally, photooxygenation of 90 in methanol containing Rose Bengal gave 121 in 80% yield, further photooxygenation of which led to the epidioxide 122, a 1,3-dipolar cycloaddition product with oxygen (84,85). Reduction of coptisinephenolbetaine (125) with sodium borohydride in methanol gave ( +)- 13B-hydroxystylopine (126) (82) and that of berberinephenolbetaine (121) afforded ( )-ophiocarpine (92) and ( f)-epiophiocarpine (91) in 80 and 9% yield, respectively (Scheme 26) (85). When the latter reduction was carried out in ethanol, or n-propanol, the ratio of two products (92:91) changed from 9:l to 3 : l or 1:1, respectively (85).Reduction of the epidioxide 122 gave also 92 and 91 (84,85). Oxidation of 92 with manganese dioxide afforded ( )-ophiocarpinone (123) (86).Finally, 7,8-dihydrocoralyne (127) was easily autooxidized in hot ethanol in the dark to give the betaine 128 in quantitative yield, which was further oxidized with irradiation or mchloroperbenzoic acid to give the C-8-N bond cleavage product 129 (Scheme 26) (85,87).

+

+

2. 8-Metho.uyberberinepheno1betuine Oxidation of berberine (15) with potassium ferricyanide followed by treatment with sodium hydroxide afforded oxybisberberine (130) (30%),the structure of which is still unknown (Scheme 27). The product was treated with 10%methanolic hydrogen chloride to give 8-methoxyberberinephenolbetaine (131)(93%) and 15 (77%) (88,89).Alternatively, irradiation of 15 in methanol in the presence of sodium hydroxide and Rose Bengal in a stream of oxygen gave the tetramethoxyketone 132 (5979, which was aromatized to 131 (99%) by removal of methanol on heating in methanol (90.91). 8-Methoxyberberinephenolbetaine(131) possesses an interesting structural feature, namely, an 8,lCdioxygenated berberine skeleton and a masked carboxylic acid at C-8. It has been converted to phthalideisoquinoline alkaloids (Section V,D,l). Treatment of 131 with methyl iodide, hydrochloric

MIYOJI HANAOKA

162 Oxybisberberine

15 OMe

132

0Me

(71%)133: R=Me (85%) 134 : R-(SJ,,,

116:

(12%)

!

R=Ac

(95%) k or 1 7 ( 4 0 or 88%)

OMe MeO& OMe

136

0

137

’-\

0

OMe

\

OMe

Me

0 Me

135

138

SCHEME27. Syntheses and reactions of 8methoxyberberinephenolbetaine(131). Reagents: a, K,Fe(CN),; b, HCl, MeOH; c, hv, O,, Rose Bengal, NaOMe, MeOH; d, MeOH, reflux; e, MeI, THF; f, 6 N HCI; g, Ac,O, py; h, NaBH,; i, air, aq THF; j, hv, 0,. Rose Bengal, MeOH; k, KOH, MeOH; I, aq NH3, MeOH.

acid, or acetic anhydride provided 13-methoxy-, 13-hydroxy-, or 13-acetoxyoxyberberine (133, 134, or 116), respectively, in excellent yields (Scheme 27) (89,91,92).The betaine 131 was reduced with sodium borohydride to give (&)ophiocarpine (92) as a major product along with ( f )-epiophiocarpine (91) (89-91 ).

Hydrolysis of 131 in wet tetrahydrofuran gave methyl isoanhydroberberilate (135) through air oxidation and N - 0 acyl migration (Scheme 27) (89,92).The same ester (135) was also obtained by photooxygenation of 131 in methanol in the presence of Rose Bengal in addition to the spirobenzylisoquinoline 136 and methoxyberberal (137) in 57, 12, and 16% yields, respectively; irradiation without Rose Bengal resulted in the same products but in 10,40, and 1% respective yields (93). Hydrolysis of 13-acetoxyoxyberberine (116) gave methyl anhydroberberilate (138) (89,9f,92).

163

3. TRANSFORMATION REACTIONS OF PROTOBERBERINE ALKALOIDS

c . 14-HYDROXY-8,13-DIOXOTETRAHYDROBERBERINE(PRECHILENINE) The highly oxygenated compound 14-hydroxy-8,13-dioxoberbine (139) possesses a homoannular a-ketocarbinolamide and shows a variety of chemical reactivities. Oxybisberberine (130) was treated with pyridine hydrochloride in pyridine followed by acid to afford 14-hydroxy-8,13-dioxotetrahydroberberine (prechilenine) (139) and berberine (15) in quantitative yield (Scheme 28) (94,96).Oxidation of oxyberberine (58)with pyridinium chlorochromate (PCC) followed by treatment with methanol gave O-methylprechilenine (117) in 53% yield ( 9 9 , which was also obtained in 92% yield from 13-acetoxyoxyberberine (116) by treatment with lead tetraacetate followed by methanol in the presence of p-toluenesulfonic acid (78).Similarly, oxypseudopalmatine gave the analogous diketones corresponding to 139 and 117 (95).

Cleavage of a hydroxyl group of 139 occurred in methanolic hydrogen chloride to give the imminium salt 140 (Scheme 28). Evaporation of the solvent generated 0-methylprechilenine (117) in 96% yield. The imminium salt

138

% ' OM.

\

OMe

58

130

\

a,b

(58%)

139

13&R=H 118:R=Ac j (92%)

I\

e(53%l

c (68%)

SCHEME28. Syntheses and reactions of prechilenine (139).Reagents:a, py * HCI, py; b, HCI; c, NaBH,; d, NaOH; e, PCC then MeOH; f, HCI, MeOH; g, H,O; h, MeOH; i, conc HCI; j, Pb(OAc),; k, CHZN2.

164

MlYOJl HANAOKA

afforded the dimeric product 141 on standing in concentrated hydrochloric acid. Both 117 and 141 reverted back to 139 on treatment with concentrated hydrochloric acid followed by dilution with water. Treatment of 139 with sodium hydroxide effected oxidative C- 13-C- 14 cleavage to give methyl anhydroberberilate (138) after esterification. Reduction of 139 or 117 with sodium borohydride gave 13-hydroxyoxyberberine (134) (94,96). Conversions of 139 to phthalideisoquinoline (Section V,D,4) and isoindolobenzazepine alkaloids (Section V,H,2) are described later.

IV. Other Reactions of Protoberberines A. 8,14-CYCLOBERBINES

Irradiation of berberinephenolbetaine (121), derived from dihydroberberine (W), through Pyrex filter in methanol in a stream of nitrogen effected valence isomerization to afford the 8,14-cycloberbine 146 in 70% yield (Scheme 29) (83,97).The product 146 is unexpectedly stable because conrotatory opening of the aziridine ring is thermally disallowed in this ring system, but on irradiation without the filter 146 reverts back to the starting orange-colored phenolbetaine 121 through photochemically allowed disrotatory ring opening. Similarly, several 8-alkylberberinephenolbetaines were converted to 8-alkyl-8,14-cycloberbines(8-methyl, 147, 85%; %ethyl, 148, 77%; 8-benzyl, 37%; 8-ally1, 82%) (83,97).These unique 8,14-cycloberbines having a reactive aziridine ring in their structures possess great potential to be transformed to spirobenzylisoquinoline and/or indenobenzazepine skeletons through C-N bond cleavage. 1. Spirobenzylisoquinolines

Treatment of cycloberbine 146 with ethyl chloroformate effected regioselective C-8-N bond cleavage to furnish the spirobenzylisoquinoline 149 in 70% yield (Scheme 29). On similar treatment, %methyl derivative 147 gave the methylidene derivative 150 through concomitant dehydrochlorination, and 8-ethyl derivative 148 gave the Z - and E-ethylidene 151 as well as the oxazolidinone 152, the analog 153 of which was obtained from 149 on treatment with silver nitrate (83,97).Reaction of 146 with methyl iodide in methanol produced the indenobenzazepine 154 in 60% yield through C-14-N bond cleavage, whereas 147 and 148 underwent both N-methylation and Hofmann degradation to afford the 8-methylidene 155 and %ethylidene spiro compound 156 in 72 and 66% yield, respectively (83,97).

3. TRANSFORMATION REACTIONS OF PROTOBERBERINE ALKALOIDS

165

SCHEME29. Syntheses and reactions of 8,14-cycloberbines.Reagents: a, MCPBA; b,mhv, N,, MeOH, Pyrex filter; c, hv, N,, MeOH, without filter; d, CIC0,Et; e, AgNO,; f, MeI.

Solvolysis of the 8-alkylcycloberbines 147, 148, and 157 in 10% hydrochloric acid afforded the hydroxyspirobenzylisoquinolines158a, 159a, and 160a and the unsaturated spirobenzylisoquinolines161,162, and 163 through regioselective C-8-N bond cleavage (Scheme 30) in contrast to solvolysis of 8-unsubstituted 8,14-cycloberbine 146, which gave indenobenzazepines through regioselective C- 14-N bond cleavage (Section IV,A,2). Solv‘olysisin methanol in the presence of trifluoroacetic acid produced the methoxyl derivatives 158b, 159b,and 160b and the unsaturated derivatives 162 and 163 (98,99).

Similarly, both diastereoisomeric alcohols (164 and 165) derived from 8-alkylcycloberbines gave again the C-8-N bond cleavage products. The

166

MIYOJI HANAOKA

\ /

147 :R=Me

c

OMe

Me or d 158:R=Me a:Rl=H

161:RZ.H

162: R2:Me 163: R2=CH=CH2

148:RzEt 157 :RzAI lyl

167 Me 164:R=Me 165: R=Et a R1=OH, R2=H 1 6 6 : ~ = ~ l l ~b:R1:H,R2=0H l

OMe

.

SCHEME 30. Solvolysis of 8-alkyl-8,lCcycloberbines.Reagents:a, HCI; b, CF,CO,H, MeOH; c, NaBH,; d, LiAIH(OBu'),.

preferential C-8-N bond cleavage of 8-alkylcycloberbines is well explained in terms of the stable tertiary carbocation 167 as the intermediate in solvolysis (Scheme 30) (98,99). Irradiation of 8-methoxyberberinephenolbetaine (131) in methanol afforded directly the spirobenzylisoquinoline 136 in 74% yield (Scheme 31) instead of the expected 8,14-cycloberbine 168, which might be so labile that it decomposes immediately to 136 through substitution with methanol. Since 136 possesses a carbonyl and a ketal group on the five-membered ring, it is able to be transformed to any desired type of the various spirobenzylisoquinolines. For example, hydrolysis of 136 with 10% hydrochloric acid provided the diketone 169 (77'73, and on reduction with sodium borohydride 136 gave stereoselectivelythe trans-alcohol 170(lOO%),which was easily hydrolyzed to the hydroxy ketone 171a. The latter was methylated with formaldehydeformic acid to produce N-methylated hydroxy ketone 171b in 87% overall yield (83,93). The reactions described in this section have been applied to synthesis of a variety of spirobenzylisoquinolinealkaloids (Section V,C,5).

3. TRANSFORMATION REACTIONS OF PROTOBERBERINE ALKALOIDS

167

169

SCHEME 3 I . Spirobenzylisoquinolines from 8-methoxyberberinephenolbetaine(131). Reagents: a, hv, N,, MeOH; b, 10% HCl; c, NaBH,; d, HCHO, HCOOH.

2. Indenobenzazepines

Regioselective C- 14-N bond cleavage of an 8,14-cycloberbineleads to the indenobenzazepine skeleton. This transformation was developed by Shamma et al. (100,101) and Hanaoka et al. (102-104) independently. Solvolysis of the cycloberbine 146 in water or methanol in the presence of various acids, such as HCl, H,S04, HC104, CF,COOH, and p-TsOH, afforded smoothly trans-indenobenzazepine 172 or 174 and cis-indenobenzazepine 173 or 175 as kinetically and thermodynamically controlled products, respectively (Scheme 32). There exists an equilibrium among them through the cation 181, and the trans derivative isomerizes to the cis derivative (100- 104). Methylation with methyl iodide gave the N-methyl derivatives (176, ,177, 178, and 154). Treatment of 146 with formaldehyde afforded the bridged oxazolidine 179 through N-hydroxymethylation followed by intramolecular substitution of a hydroxymethyl with an aziridine ring. Reduction of 179 with sodium cyanoborohydride afforded stereoselectively the trans-alcohol 176 (100). Regioselective cleavage to an indenobenzazepine occurred preferentially because the tertiary carbocation 181 is more stable than the secondary carbocation 182, which leads to a spirobenzylisoquinoline.

(78-94%)

(100%)

b (44-96%)

OMe

179

OMe

180 a:RZ=H

181

182

Me

b: RZ- Me SCHEME 32. Indenobenzazepines from the 8,14-cycloberbine 146. Reagents: a, H', H20,or MeOH; b, HCHO; c, NaBH,CN; d, TiCI, or BF, OEt,; e, I,, EtOH; or AcOH; or CF,COOH, benzene; or p-TsOH, benzene.

-

(82%)

HOI'"

-

Me0

Meo

Me0

183

e (67%)

184

/

Meo

-

OMe

I

187 a : R = H b: R E &

OMe b

185

\ (25%) <%d

-

' \

\ /

Me

'%

If

' \

HOM e 0

-

OMe

186 a : R = H b: R = Me

(76%)

SCHEME 33. Indenobenzazepinesfrom the 8,14cycloberbine 184. Reagents:a, hv, N,, MeOH; b, 10% HCI; c, Me,SO,, THF; d, BF, OEt,; e, p-TsOH, benzene; f, Me,SO,, NaH, HMPA.

-

168

3. TRANSFORMATION REACTIONS OF PROTOBERBERINE ALKALOIDS

169

On exposure to a Lewis acid such as TiCI, and BF,, both trans- and cisindenobenzazepines 176 and 177 afforded the vinylogous amide 180b in 2542% yield (Scheme 32) (102,104). The secondary vinylogous amide 180a was obtained directly from the cycloberbine 146 on treatment with iodine in trifluoroacetic acid in benzene ethanol (77%) (lo]),acetic acid (56%)(103,104), (4473, or p-toluenesulfonic acid in benzene (96%)(103,104). N-Methylation of 180a with dimethyl sulfate in hexamethylphosphoramide in the presence of sodium hydride gave 180b in 92% yield (103,104). Analogous results were obtained from the reaction of another cycloberbine (183), as depicted in Scheme 33 (102-104).These reactions were applied to synthesis of indenobenzazepine (Section V,F,5) and rhoeadine alkaloids (Section V,G,2). B. REACTION WITH

CHLOROFORM

1. Dichlorocarbene The reaction of oxyberberine (58) and berberine (15) with dichlorocarbene has been previously reviewed (11). An interesting product was the keto lactam 189, which was obtained from 58 via the adduct 188 (Scheme 34) (105).This product was later isolated from Berberis darwinii and named magallanesine (106); however, this alkaloid has since been shown to be an artifact (107).

O (38%)

58 RO

189

188

/

, OMe ' OMe OMe

190 a : R + R : C H , b : R = Me

191:R+R=CH, 192: R = Me

SCHEME34. Transformation to magallanesine (189), puntarenine (191), and saulatine (192). Reagents: a, CHCI,, 50% NaOH, PhCH,N+MeEt,I-; b, aq py; c, silica gel column chromatography, CHC1,-MeOH.

170

MIYOJI HANAOKA

2. Berberine- and Palmatine- Chloroform Chloroform adducts 190a and 190b of berberine (15)and palmatine (64)are well known. Column chromatography of palmatine-chloroform 190b on silica gel with chloroform-methanol gave saulatine (192) (Scheme 34). This alkaloid and its analog puntarenine (191)had been isolated from Abuta bullata (108)and B. actinacantha (109),respectively, but have now been shown to be artifacts (107).

V. Transformation of Protoberberines to Related Alkaloids A. BENZO[C]PHENANTHRlDINE AND 3-ARYLISOQUINOLINE ALKALOIDS Benzo [c] phenanthridine alkaloids have been reviewed previously (1,2,710,f10) and compiled ( 1 I f ) . Their synthesis has also been reviewed (112). Both fully aromatized and B/C-hexahydro benzo[c] phenanthridine alkaloids have been shown to be biosynthesized from the corresponding protoberberine alkaloids through oxidative C-6-N bond cleavage leading to a hypothetical aldehyde enamine intermediate (193), followed by intramolecular condensation between the C-6 and C-13 positions of the protoberberine (Scheme 35)(113).Along this biosynthetic route, much effort has been directed toward realization of the transformation of protoberberines to benzo[c]phenanthridines. In general the starting materials used for this transformation are the Hofmann degradation products of dihydroprotoberberines, which are obtained from either protopine or protoberberine alkaloids.

K

R-

SCHEME35. Biosynthesis of benzo[c]phenanthridine alkaloids from protoberbines via the enamine aldehydes 193.

3. TRANSFORMATION REACTIONS OF PROTOBERBERINE ALKALOIDS

171

OMe

194: R = Me

c,a

198

199

SCHEME 36. Acid-catalyzed cyclization of the Hofmann degradation products of dihydroprotoberberines. Reagents: a, conc HCI; b, POCI,; c, H2S04;d, 10% HCI.

1. Acid-Catalyzed Cyclization

At first, acid-catalyzed cyclization of Hofmann degradation products was undertaken; however, the cyclization proceeded via the 5-exo-trigonal mode instead of the 6-endo-trigonal mode, resulting in no benzo[c]phenanthridine skeleton. Dyke and Brown (114-117) reinvestigated Perkin’s results (118,119) and established the structure of the cyclized products 1% and 197 derived from the methine base 194 (Scheme 36). Onda et al. (120,121)obtained the fivemembered spiro compounds 198 and 199 by treatment of 195 with dilute hydrochloric acid. 2. Photocyclization The first successful transformation of protoberberines to benzo[c]phenanthridines was reported by Onda el al. (122,123). Irradiation of the enamines 200 and 195, the Hofmann degradation products of the corresponding protoberberines, in benzene afforded the initial photoproducts 201, which immediately rearranged to the tetrahydrobenzo[c]phenanthridines 202 in 70% yield (Scheme 37). Dehydrogenation of 202 afforded dihydrochelerythrine (203) and dihydrosanguinarine (204), which were further oxidized with dichlorodicyanobenzoquinone (DDQ) to yield chelerythrine (205) and sanguinarine (206), respectively. 13-Methylberberine (207) was easily converted to the enamine 208, photolysis of which afforded the two carbinolamines 209a and 209b (124).On exposure to sodium cyanide the mixture was converted to the desired cyanide 210 after separation. Successive oxidation of 210 with potassium ferricyanide

172

MIYOJI HANAOKA

___)

Me

R OR

201

200: R = M e 195: R+R=CH, b

RO OR

(55-70%)

203: R =Me 204: R+R=CH,

OR

(65%)

205 : R=Me 206 :R+R-CH,

SCHEME37. Synthesis of chelerythrine (205) and sanguinarine (206) by photocyclization. Reagents: a, hv, benzene; b, Pd-C, p-cymene; c, DDQ, benzene.

and DDQ furnished the ring-opened keto amide 211, which recyclized stereoselectivelyto the cis-fused tetracyclic compound 212 on treatment with lithium aluminum hydride followed by hydrochloric acid. Introduction of the hydroxyl group at C- 1 1 was accomplished through oxidation-reduction via the ketone 213 as shown in Scheme 38 to give the corynoline analog 214 (125). The same corynoline analog (214) was obtained more conveniently through photolysis in the presence of nitrosobenzene. Addition of nitrosobenzene to 208 from the opposite side of the methyl group resulted in the B/C-trans adduct 215. Reduction of 215 with sodium borohydride followed by acidic treatment gave the B/C-cis product 217 via 216. Hydroxylation of 217 with performic acid and hydrogenolysis of the diol218 completed the synthesis of 214 (126). Another photocyclization to a benzo[c] phenanthridine was reported (127). Oppenauer oxidation of ( )-ophiocarpine (92) with potassium tert-butoxide and benzophenone in dioxane effected C-6-N bond cleavage to afford the hydroxyisoquinoline 219 via berberinephenolbetaine (121) (Scheme 39). Although photolysis of 219 gave only the oxepine 221, that of its methyl ether 220 furnished directly norchelerythrine (222) through electrocyclization followed by spontaneous elimination of methanol.

+

3. Oxidative Cyclization

Lead tetraacetate oxidation was applied to construct a benzo[c]phenanthridine skeleton. The Hofmann degradation product 224 derived from the phenolic protoberberine 59a was oxidized with lead tetraacetate to afford the p-quinol acetate 225, which was cyclized to the benzo[c]-

3. TRANSFORMATION REACTIONSOF PROMBERBERINE ALKALOIDS

%t

a

Me

/

'

,

b

0 ,

c\ -

s

> 0

OMe MeO OMe

\

173

NMe

Me0

OMe

'

'"R2 NMe

0

OMeR'

207

Me

N (29% from

211

208)

210

Ph

212 208

213

N

NHPh

-

(57%)

2 14

Me

Me0 OMe

215

OMe

217

OMe

(43%)

216

dMe

(91%)

218

SCHEME38. Synthesisof corynoline analog 214 by photocyclization.Reagents:a, NaBH,, py; b, Me,SO,; c, KOH, MeOH; d, hv, benzene;e, NaCN; f, K,Fe(CN),; g, DDQ; h, LAH; i, HCI; j, MCPBA; k, CF,COOH; I, PhNO, hv, benzene;m, NaBH,; n, HCI, AcOH; 0, HC0,H; p, 20% aq KOH; q, H,/10% Pd-C.

phenanthridine 226 by treatment with sulfuric acid in acetic anhydride (Scheme 40). Elimination of the acetoxy group and subsequent dehydrogenation gave the dihydro compound 228 (128,129). A similar procedure was successfully applied to a synthesis of dihydronitidine (229) from 223 (229).

174

MIYOJI HANAOKA

HI" HO

'

OMe OMe

OMe

121

92

/

219: 220:

XI

R=H R-Me

221 SCHEME 39. Synthesis of norchelerythrine (222) by photocyclization. Reagents: a, KOBu', benzophenone, dioxane; b, CH,N,, CH,CI,; c, hv, benzene.

227 SCHEME40. Synthesis of dihydronitidine (229) and its analog by lead tetraacetate oxidation. Reagents: a, MeI; b, KOH; c, Pb(OAc),, KOAc; d, HCI; e, CH,N,.

3. TRANSFORMATION REACTIONS OF PROMBERBERINE ALKALOIDS

175

4. Aldehyde Enamide Cyclization

A biomimetic synthesis of benzo[c]phenanthridine alkaloids from a protoberberine via the equivalent of a hypothetical aldehyde enamine intermediate has been developed (130,131). The enamide 230 derived from berberine (15) was subjected to hydroboration-oxidation to give alcohol 231, oxidation of which with pyridinium chlorochromateafforded directly oxychelerythrine (232)instead of the expected aldehyde enamide 233. However, the formation of oxychelerythrine can be rationalized in terms of the intermediacy of 233 as shown in Scheme 41. An alternative and more efficient

OMe

15

Me

230

\

Me

23 1

C

2 03

235

205

SCHEME41. Biomimetic synthesis of chelerythrine (205) and fagaridine (238) via the enamide aldehyde. Reagents: a, B,H,; b, H,O,, NaOH; c, PCC; d, TI(NO,),, MeOH; e, HCI; f, LAH; g, MeOH; h, NaBH,; i, pTsOH, toluene; j, I,, EtOH.

176

MIYOJI HANAOKA

synthesis of 232 was accomplished in excellent yield by treatment of the enamide 230 with thallium trinitrate in methanol followed by exposure of the resulting acetal234 to 10% hydrochloric acid. Lithium aluminum hydride reduction of oxychelerythrine (232) gave 6hydroxydihydrochelerythrine (235), recrystallization of which in methanol afforded 6-methoxydihydrochelerythrine(agoline) (236). Both compounds have been isolated from plants, but they are probably artifacts arising during isolation. On reduction with sodium borohydride or dehydration with 10% hydrochloric acid, 235 was converted to dihydrochelerythrine (203) or chelerythrine (205), respectively (230,231). Heating of 232 with p-toluenesulfonic acid in benzene effected regioselective 0-demethylation to afford 7-0-demethyloxychelerythrine(237), the structure of which was unambiguously established by an alternative synthesis from berberrubine (71). Sequential treatment of 237 with lithium aluminum hydride, sodium borohydride, and iodine gave fagaridine (238) (232). The synthetic fagaridine has not yet been directly identified with the natural one, the structure of which might be 8-hydroxy-7-methoxy instead of 238 (233). The above biomimetic method was successfully applied to synthesis of 2,3,8,9-tetraoxygenated fully aromatized benzo[c]phenanthridine alkaloids such as nitidine (243) (234,235),fagaronine (244) (234,235),and oxyterihanine (242) (136) (Scheme 42). The former two alkaloids attract many synthetic

-

242:R ~ + R ~ = c H ~ R3=H, R4=Me

243: Rl+R2=CH2, R3=R4=Me 244: R15 R3=R4=Me,R2zH

SCHEME 42. Biomimetic synthesis of nitidine (243), fagaronine (244), and oxyterihanine (242) via enamide aldehydes.

3. TRANSFORMATION REACTIONS OF PROTOBERBERINE ALKALOIDS

Me0

177

__f_)

Me Me

245

246

SCHEME 43. Synthesis of sanguilutine (248).

chemists because of their strong antileukemic activities (137). The phenolic hydroxyl group was protected with a conventional benzyl group in these syntheses because all steps proceed under relatively mild conditions. Debenzylation was readily carried out by acidic treatment or hydrogenolysisin the case of fagaronine or oxyterihanine, respectively. The 2,3,7,8,10-pentaoxygenatedbenzo[c]phenanthridine alkaloid sanguilutine (248) was also conveniently synthesized according to the above method (Scheme 43) (138).The presence of the methoxyl group at C-5 peri to the cyclization position (C-4) was at first anticipated to retard cyclization; however, the cyclization of the acetal 246 proceeded smoothly to give oxysanguilutine (247) in high yield.

5 . Aldehyde Enamine Cyclization A biomimetic synthesis of the B/C-cis hexahydrobenzo[c] phenanthridine alkaloids corynoline (254), 11-epicorynoline (257), and their analogs was easily accomplished starting from the 13-methylprotoberberinescorysamine (250), 13-methylberberine(207), and dehydrocorydaline (249) via the aldehyde enamines, the key intermediates in the biogenesis of these alkaloids (Scheme 44). Sequential treatment of the Hofmann degradation products 252,208, and 251 with thallium trinitrate in methanol, sodium borohydride, hydrochloric acid, and sodium cyanoborohydride afforded ( )-corynoline (254) (45%) and its analogs 214 (51%) and 253 (43%) along with ( k ) - l l epicorynoline (257) (13%) and its analogs 255 (8%) and 256 (19%), respectively (139).

178

MIYOJI HANAOKA

f --L

(51%)

(43%) (45%)

214: R1+R2=CH,,R3-R4=Me 253: R1=R2=R3=R'=Me 254: R'+R2=R3+R4=CH2

255 256 257

(8%)

(19%) (13%)

SCHEME44. Biomimeticsynthesis of corynoline (254), 1 lepicorynoline (257), and their analog via enamine aldehydes.Reagents:a, LAH; b, Me,SO,; c, KOH; d, TI(NO,),, MeOH; e, NaBH,; f, HCI; g, NaBH,CN.

6. Cationic Cyclization

Another efficient and convenient method employing cationic cyclization was developed for a synthesis of B/C-cis hexahydro as well as fully aromatized benzo [clphenanthridine alkaloids. The Hofmann degradation product 195 derived from coptisine (65) was oxidized with m-chloroperbenzoic acid to afford the isoquinoline betaine 258, which was reduced with sodium borohydride gave a mixture of the trans- and cis- benzyl alcohols 259 in a ratio 5 : 1 (Scheme 45). On treatment with concentrated sulfuric acid in acetic acid, both alcohols underwent cationic cyclization to give stereoselectivelythe B/Ccis tetrahydrobenzo[c]phenanthridine 260 in high yield. Introduction of the oxygen function at the C-11 and C-12 positions was accomplished by the known performic acid oxidation method to furnish 12-hydroxychelidonine (261), which was identified with chelamine. Hydrogenolysisof the 12-hydroxyl group with triethylsilane in the presence of boron trifluoride etherate proceeded more efficiently than ordinary catalytic hydrogenolysis over Pd-C, resulting in ( f)-chelidonine (263) in excellent yield. Dehydrogenation of the

3. TRANSFORMATION REACTIONS OF

RO

RO

PROTOBERBERINE ALKALOIDS

179

(92-96%)

258

195:R*R=CH,

200: R= Me

204:R+R=CH, ( 6 5 % ) 203:R-Me (70%)

206 :R*R =CH,

263:R*R=CH, ( 8 2 % ) 264:R:Me ( 9 2 % )

(47% )

205:R=Me ( 5 2 % )

SCHEME45. Synthesis of both B/C-cis hexahydro- and fully aromatized be.nzo[c]phenanthridine alkaloids via a common intermdiate. Reagents: a, MCPBA; b, NaBH,; c, conc H,SO,, AcOH; d, HCO,H, HCOOH; e, KOH; f, Et,SiH, BF, OEt,, CHCI,; g, 10% Pd-C.

-

cis-fused compound 260 with Pd-C afforded sanguinarine (206) and dihydosanguinarine (204) (140). Similarly, berberine (15) was readily converted to (&)-homochelidonine (264), ( +)-chelamidine (262), chelerythrine (205), and dihydrochelerythrine (203) (242).According to this method both hexahydro and fully aromatized benzo [c] phenanthridine alkaloids can be readily synthesized via a common intermediate (e.g., 260). 7. 3-Arylisoquinoline Alkaloids

The small group of 3-arylisoquinoline alkaloids are biogenetically related to benzo [c]phenanthridine alkaloids (113). Corydamine (266) was synthesized from ( +)-tetrahydrocoptisine (82) through C-6-N bond cleavage using the von Braun reaction followed by aminolysis and dehydrogenation (Scheme 46) (142).

180

MIYOJI HANAOKA

MeO,

OHC g (77%)

8 SCHEME46. Synthesisof 3-arylisoquinolinealkaloids.Reagents: a, BrCN; b, CH,NH,; c, 10% KOH, EtOH; d, Pd, tetralin;e, NaBH,CN; f,TI(NO,),, MeOH; g, 5% HCI; h, H,CrO,, H,SO,; i, CH,N,.

The Hofmann degradation product 252 used for a synthesis of corynoline (254) was again a useful starting material for (*)-corydalic acid methyl ester (8).It was reduced with sodium cyanoborohydride to the trans derivative 10 as a major product, which was converted to 8 via acetal268 and aldehyde 269 (143). B. SECOBERBINE ALKALOIDS Regioselective C-8-N bond cleavage of protoberberines is a crucial step for synthesis of secoberbine alkaloids (2). I. Cleavage of 8-Benzyltetrahydroprotoberberine Shamma et al. (144-146) utilized Hofmann degradation of 8-benzyltetrahydroprotoberberine for selective C-8-N bond cleavage (Section II,A,l). Benzylidene products 17 and 271, derived from berberine (15) and coptisine (65), were subjected to Lemieux-Johnson- Pappu oxidation to provide ( 2)canadaline (272) and ( )-aobamine (273), respectively, the latter of which was

+

3. TRANSFORMATION REACTIONS OF PROTOBERBERINE ALKALOIDS

18 1

277

276

SCHEME47. Synthesis of secoberbines via 8-benzylprotoberberines.Reagents:a, PhCH,MgCI; b, NaBH,; c, MeI; d, KOH, MeOH; e, Os0,-NaIO,; f, CICO,Et, KOH; g, HC(OMe),, H,SO,; or MeOH, HCI; h, LAH; i, HCI; j, 00,.

reduced to (+)-corydalisol (275) (Scheme 47). On treatment with ethyl chloroformate and aqueous potassium hydroxide, the aldehydes 272 and 273 gave the acetals 276 through S,2 displacement of a transient quaternary urethane with a hydrated aldehyde. The acetals 276 were converted to (+)peshawarine (279) and its analog 278 in good yields. 2. Cleavage with Ethyl Chloroformate Using ethyl chloroformate as a reagent for C-8-N bond cleavage (Section II,A,4), synthesis of ( )-canadaline (272) from tetrahydroberberine (26) was independently achieved by Ronsch (40) and Hanaoka et al. ( 4 1 4 . Bondcleaved iodide 40a or chloride 40b was converted to the acetate 280 or the alcohol 281, both of which were easily derivatized to 272 through reduction of the urethane and oxidation of the alcohol 274 (Scheme 48).

+

182

MIYOJI HANAOKA

26

CHO

____c

(71-80%)

OMe Me

274

OMe

272

SCHEME48. Synthesis of canadaline (272) via cleavage with ethyl chloroformate. Reagents: a, CIC0,Et; b, NaOAc, DMSO; or AgNO,, aq acetone; or A1,0,; c, LAH; d, PCC.

C. SPIROBENZYLISOQUINOLINE ALKALOIDS The spirobenzylisoquinoline alkaloids have been reviewed (1,2,7-10,147) and compiled (148).The exact biosynthetic route to spirobenzylisoquinolines from protoberberine alkaloids has not yet been elucidated (149). 1. Base-Induced Rearrangement via Quinomethides

Biosynthesis of the spirobenzylisoquinoline alkaloid ochotensimine (282) via the quinomethideintermediate(Scheme49) was proposed by Shamma and Jones (150). On the basis of this hypothesis, several biomimetic transformations of phenolic protoberberines to spirobenzylisoquinolineshave been realized by the base-induced rearrangement via the quinomethide. The diphenolic protoberberine methobromide 285 derived from 283 was refluxed in aqueous ethanolic sodium hydroxide for 12 hr to furnish the quinomethide 287 in 92% yield (Scheme 50). Compound 287 was treated with dimethyl sulfoxide to give rise to the desired diphenolic ochotensimine analog 288 through enolization (150,151). The presence of the phenolic hydroxyl group is essential in this rearrangement because the benzyl ether (284) was recovered unchanged under the same alkaline conditions. A similar rearrangement also occurred in the dihydroprotoberberine methobromide 289a possessing two phenolic hydroxyl groups on rings A and D as well as in 289b and 28% having one hydroxyl group on ring D to provide the spirobenzylisoquinolines2Wa,2Wb,and 2% in 50,71, and 32.3% yields,

3. TRANSFORMATION REACTIONS OF PROTOBERBERINE ALKALOIDS

183

Me0 ___)

-

Me0

Me0

282 SCHEME 49. Biogenesis of ochotensimine (282).

-

.Me

d

Me

286

287

288

SCHEME 50. Synthesis of the ochotensimine analog 288 from a phenolic protoberberine by base-induced rearrangement. Reagents: a, LAH; b, MeI; c, HBr; d, NaOH, aq EtOH; e, DMSO.

respectively (Scheme 5 l), under rather prolonged reaction times (4 days, 16 hr, and 4 days) (152,153). In these cases, the intermediate quinomethides corresponding to 287 could not be isolated owing to the lack of hydrogen bonding stabilizing quinoide structure. In contrast to the above examples, the quaternary salt having one phenolic

R'T-R

184

MIYOJI HANAOKA

Me

Me0?Me

\

\ /

OR2

OR,

R30

289

OR2

290 a:RlzRZ=H ,R3=Me ( 5 0 % ) b:Rl: R*=Me,R3=H ( 7 1 % ) C:R1: R3=MetR2=H ( 3 2 . 3 % )

SCHEME 5 1. Base-induced rearrangement to spirobenzylisoquinolines.

hydroxyl group on ring A gave an indenobenzazepine instead of the corresponding spirobenzylisoquinoline (153,154). This result is described in Section V,F,1.The above elegant biomimetic transformation has not yet been applied to a synthesis of spirobenzylisoquinoline alkaloids such as ochotensimine and ochotensine. 2. Photoinduced Rearrangement via Quinodimethides Another biomimetic transformation was reported by Nalliah et al. (155).13Oxotetrahydroberberine (ophiocarpinone) metho salt (291), derived from berberinephenolbetaine (121), was irradiated in methanol in the presence of sodium hydride to afford the spirobenzylisoquinoline 294 in 45% yield

OMe

292

\

293

Me

OMe

Me

294

Me

295

SCHEME 52. Photoinduced rearrangement to the spirobenzylisoquinoline.Reagents: a, LAH then Me,SO,; b, hv, NaH, EtOH.

3. TRANSFORMATION REACTIONS OF PROTOBERBERINEALKALOIDS

185

(Scheme 52). The reaction will proceed via the enolate 292 and the quinodimethide 293 as key intermediates. Basic treatment of 291 did not cause the Stevens rearrangement but gave the Hofmann degradation product 295. Wu et al. (156) found that photolysis of 13-substituted dihydroprotoberberine metho salts 296 in methanol similarly afforded the corresponding spirobenzylisoquinolines 297 in 23-54% yields via the quinodimethides (Scheme 53). On the other hand, 13-unsubstituted metho salts 298 furnished, on irradiation, the imino ketones 299 (Scheme 54) instead of spirobenzylisoquinolines through N-demethylation and oxidation via the quinodimethide

a: R1+RZ= C H,, R3 = R4=OMe1R5=H .R6=Me,R7-C H, ( 3 6 % ) b: R1=R*=R6=Me,RJ=H, R4+R5=OCH20,R7=CHz( 2 6 % ) c: R1=RG=Me. R2z R3=H, R4zR5~ OMe, R7=CH, ( 2 3 % 1 d: R1+R*=CH,,R3~R4:R6=OMe,R5=H,R7=0 ( 5 4 % )

SCHEME 53. Photoinduced rearrangement to spirobenzylisoquinolines. Reagents: a, hv, MeOH.

HOO

298

Me

299

a: R = H

a:R-H

b: R=OMe

b: R-OMe

(27%)

(30%)

SCHEME54. Photolysis of 13-unsubstituted protoberberines. Reagnents: a, hv, air, MeOH.

186

MIYOJI HANAOKA

and the hydroperoxide. Kessar et al. (157)reinvestigated this reaction with Ntrideuterated methyl derivative 298a and proposed the alternative mechanism through a 1,7 hydrogen shift based on the observation that the product 2Wa contains one deuterium in the C-methyl group. 3. Stevens Rearrangement

In contrast to case of phenolic protoberberine metho salts, the nonphenolic ones are rather stable to base, as seen in the previous sections. Several successfulStevens rearrangements of tetrahydroprotoberberine metho salts to spirobenzylisoquinolineshave been reported by three groups. Kondo et al. (158,159) first discovered the rearrangement of tetrahydroberberine metho salt (l),using phenyllithium or lithium aluminum hydride, to the spirobenzylisoquinoline 300 in 25 or 62% yield, respectively (Scheme 55). Similarly, on treatment with dimsylsodium,(+)-thalictricavine metho salt (5) afforded 301, though in 6% yield, in addition to the Hofmann degradation products. The optically active metho salt 1 was converted to the corresponding optically active spiro compound 300 with retention of configuration (159,160).

1 :R=H 5 :R = M e

OMe 300: R = H (25-62%) 301 : R = M e (6%)

SCHEME55. Stevens rearrangement to spirobenzylisoquinolines.Reagents: a, PhLi, LAH, or NaCH,SOCH,.

Kano et al. (161,162) also investigated the Stevens rearrangement of tetrahydroprotoberberine metho salts 302 with dimsylsodium and obtained the spirobenzylisoquinolines 303 in high yield (Scheme 56). Similarly Chomoprotoberberine 304 gave the new spiro compound 305, whereas Bhomoprotoberberine 306 afforded only the Hofmann degradation product 307. Kametani et al. (163-165) studied the Stevens rearrangement using sodium bis(2-methoxyethoxy)aluminum hydride as the base in dioxane. It became clear from studies using deuterium-labeled or optically active compounds that quasi-axially oriented hydrogens at C-8 and C-14 were independently abstracted by the base, leading to a spirobenzylisoquinoline and an 8-

3. TRANSFORMATION REACTIONS OF PROTOBERBERINE ALKALOIDS

187

\

OR2

302

303

Meq

a:Rl:RZ=Me ( 8 0 % ) b:R1+R2=CH2( 8 3 % ) c: Rl=Me,RZ=H( 8 5 % )

Me0

a

'

304

R 2 0 OR1

Me --+

Me0

65%

'

OhoMe

P oMe OMe

(67%)

\ I

Me

Me0

307

OMe

Me

305

306 SCHEME56. Stevens rearrangement of protoberberinesand C- and B-homoprotoberbennes. Reagents: a, NaCH,SOCH,.

methylprotoberberine,respectively. The trans-methiodide 3041 gave the spirobenzylisoquinoline 310 with retention of the stereochemistry at C-8 and (2-14 and the 8-ethyl-8-methylberbine 311 with inversion at C-8 position (Scheme 57). On the other hand, the cis-methiodide 309 gave the spirobenzylisoquinoline 312 with retention at C-8 and inversion at C-14 and the 8-ethyl-8-methylberbine313 with retention at (2-8. In conclusion, although the Stevens rearrangement of a tetrahydroprotoberberine metho salt readily afforded a spirobenzylisoquinoline skeleton, there exist no reports on synthesis of functionalized spirobenzylisoquinolines or related alkaloids using this method. 4. From Indenobenzazepines

The indenobenzazepines 314, obtainable from the corresponding protoberberines (Sections V,F,2 and V,G,2), were converted to the spirobenzylisoquinolinediones 315 in 76% yield through hydrolytic bond cleavage and recyclization by sequential treatment with 4 N hydrochloric acid, bromine in acetic acid, and triethylamine, via the indanediones (Scheme 58) (166).A onestep stereoselectiverearrangement of an indenobenzazepine to a spirobenzylisoquinoline was developed by Blasko et al. (167). 0-Methylfumarofine (316)

188

MIYOJI HANAOKA

M e O m N M e Me0

A E t

+

(3

9) Me0

310

OMe OMe

OMe

311

OMe

SCHEME57. Stereochemistry of the Stevens rearrangement. Reagents: a, Red-Al.

Me

o w R o RO

3 14

315 a: R-Me

b: R+R-CH, SCHEME58. Conversion of indenobenzazepinesto spirobenzylisoquinolinesvia indanediones. Reagents: a, 4 N- HCI; b, Br,, AcOH; c, Et,N.

(Section V,F,3)was treated with trifluoroacetic anhydride in pyridine at room temperature followed by work-up with aqueous ammonia to rearrange to the spirobenzylisoquinoline 317 in 86% yield (Scheme 59). The product was reduced with sodium borohydride to afford ( -k)-raddeanine (318) which was also obtained similarly from the dihydroxyindenobenzazepin 319. Regardless of the stereochemistry at C- 14, both diasteroisomeric indenobenzazepines 176 and 177 afforded the same spiro compound 320. The stereochemistry at C-8 (or C-13) is retained, and the hydroxyl group newly

189

3. TRANSFORMATION REACTIONS OF PROTOBERBERINE ALKALOIDS

Me

HO

H-

a b

-

/ \

Me0

OH

(86%)

OH

-

316

OH

7

320 OMe

6Lb

Meo 319

-Me0

'

OH e

HOP-

-

0

321

322

\ /

323

SCHEME59. One-step conversion of indenobenzazepines to spirobenzylisoquinolines. Reagents: a, (CF,CO),O, py; b, aq NH,; c, NaBH,.

produced at C-13 (or C-8) always has the configuration trans to the nitrogen. The latter trans stereochemistry is well rationalized in terms of an aziridinium intermediate such as 322 as shown in the conversion of the indenobenzazepine 321 to ( -t)-yenhusomine (323)(Scheme 59). The starting indenobenzazepines can be easily obtained from protoberberines via 8,14-cycloberbines (Section V,F,5); therefore, this rearrangement will be a useful method for synthesis of spirobenzylisoquinoline alkaloids. 5. Via 8,14-Cycloberbines

Almost all types of spirobenzylisoquinolinealkaloids have been synthesized from corresponding protoberberines via 8,14-cycloberbineson the basis of the fundamental reactions described in Section IV,A,l. For example, on irradiation in methanol the phenolbetaine 325 derived from the protoberberine 324 afforded the 8,14-cycloberine 326 in excellent yield (Scheme 60).Sequential

MIYOJI HANAOKA

190

Me0

OMe

327

328

328

SCHEME 60. Synthesis of fumaricine (328) via an 8,lCcycloberbine. Reagents: a, LAH; b, MCPBA; c, hv, MeOH; d, CIC0,Et; e, H,/Pd-C.

treatment of 326 with ethyl chloroformate, hydrogen over Pd-C, and lithium aluminum hydride afforded ( )-fumaricine (328) (63,168).With exactly the same procedure, palmatine (64) was converted in 30% overall yield to the corresponding spirobenzylisoquinoline329 (63),which was converted to ( & )alpinigenine, a rhoeadine alkaloid (Section V,G,1). Generally a ketone in a five-membered ring of a spirobenzylisoquinoline (e.g., 327) was stereoselectivelyreduced with metal hydride to a trans-alcohol (e.g., 328) as shown in Scheme 60. In fact, reduction of fumariline(337)afforded dihydrofumariline 2 (338) having a trans-alcohol along with dihydrofumariline 1 (336) having a cis-alcohol as a minor product (Scheme 61) (269).On the other hand, reduction of a ketone in a rigid 8,14-cycloberbinewas found to show completely different stereoselectivity, giving a cis-alcohol. A highly stereoselective synthesis of dihydrofumariline 1 was accomplished by stereoselective reduction and reductive C-8-N bond cleavage of a key 8,14cycloberbine (I70). Reduction of the cycloberbine 332 with sodium borohydride in methanol afforded exclusively the cis-alcohol 333, whereas that with lithium aluminum tri-tert-butoxyhydridein benzene/tetrahydrofuran under reflux produced the trans-alcohol (54%) along with 333 (19%)(Scheme 61). The reverse stereoselectivity with the latter reagent is explained from the intramolecular reduction with the initially formed complex of the reagent with the nitrogen of 332. Regioselective and hydrogenolytic ring opening of 333 to 334 was effectively achieved by treatment with sodium cyanoborohydride in tetrahydrofuran in

+

3. TRANSFORMATION REACTIONS OF PROTOBERBERINE ALKALOIDS

330: R = H

>

arb

334 0

33 2

333

335

336

d

0

Lo

337

\ /

% ‘M e

+

19 1

336

0 \ I

338

SCHEME61. Stereoselective synthesis of dihydrofumariline 1 (336). Reagents: a, LAH; b, MCPBA; c, hv, MeOH; d, NaBH,; e, NaBH,CN, pTsOH, THF; f, HCHO; g, NaBH,CN.

the presence of p-toluenesulfonic acid. The amino alcohol 334 was converted to (&)-dihydrofumariline 1 (336)via the oxazolidine 335 in excellent yield. The cycloberbine 339 derived from coptisine (65)was reduced with lithium aluminum tri-tert-butoxyhydride to afford the trans-alcohol 340 along with a small amount of the cis-alcohol (Scheme 62). Treatment of 340 with ethyl chloroformate effected C-8-N bond cleavage and simultaneous oxyfunctionalization at C-8 with the desired stereochemistry to produce the oxazolidinone 341. This was hydrolyzed with potassium hydroxide and then underwent N-methylation to give ( f )-ochrobirine (343). Similarly, the ochrobirine analog 344 was also obtained from berberine (15)(171). Concomitant protection of the amino group and the cis-hydroxyl group of the diol 342 was realized by treatment with formaldehyde to afford the oxazolidine 345, oxidation of which with silver carbonate on Celite gave the

192

MIYOJI HANAOKA

65: R+R=CH, 15: R = M e

OR

339: R + R = C H ,

OR

340

146:RzMe

0 HO

.IIIO-

-

(67-75%)

\ / OR

341

345

OR

h

/

OR

OR

342

P4-98%) 346

347 : R + R - C H , 348 : R = Me

SCHEME62. Stereoselective synthesis of ochrobirine (343) and corydaine (347). Reagents: a, LAH; b, MCPBA; c, hv, MeOH; d, LiAIH(OBu'),; e, CIC0,Et; f, KOH; g, MeI; h, HCHO; i, Ag,CO,; j, NaBH,CN; k, NaBH,.

ketone 346 (Scheme 62). On reduction with sodium cyanoborohydride, 346 underwent both N-methylation and deprotection of the cis-alcohol to furnish (+)-corydaine (347)and its analog 348 in high yield (172). Corydaine was reduced stereoselectivelyto ochrobirine (343). ( +)-Sibiricine (352)was stereoselectivelysynthesized from the corresponding protoberberine 330 in four steps (Scheme 63) (173). Photooxygenation of 330 in methanol in the presence of sodium methoxide and Rose Bengal produced 8-methoxyphenolbetaine 349, which was irradiated in methanol to give the spirobenzylisoquinoline 350. Reduction of 350 with sodium borohydride followed by concomitant N-methylation and deketalization

3. TRANSFORMATION REACTIONS OF PROTOBERBERINE ALKALOIDS

330: R*R=CH, 324 ' R: Me

349

350

(90-91%)

OMe

351

193

352: R+R=CH,

353 :R+R=CH, 318 :R = Me

Me

OH

OMe

355

OH

358

359

323

SCHEME63. Stereoselectivesynthesis of sibiricine (352), sewercinine (353), raddeanone (354), raddeanine (318), raddeanidine (355), yenhusomidine (359), and yenhusomine (323). Reagents: a, hv, O , , Rose Bengal, NaOMe, MeOH; b, hv, MeOH; c, NaBH,; d, HCHO, HCOOH; e, Ac,O, py; f, CIC0,Et; g, MsCI; h, KOH, aq EtOH; i, HCHO;j, NaBH,CN; k, 10% HCI.

194

MIYOJI HANAOKA

under Eschweiler-Clarke reaction conditions provided ( f)-sibiricine (352), reduction of which gave ( f )-sewercinine (353). Analogously, ( f)-raddeanone (354) and (+)-raddeanine (318) were stereoselectively synthesized from the protoberberine 324 (Scheme 63). The former alkaloid 354 was converted to (fbraddeanidine (355)(174). (2)Yenhusomidine (359),a diastereoisomer of 354, was also prepared from the same synthetic intermediate 351 through inversion of the hydroxyl group using neighboring group participation of the urethane (Scheme 63). On treatment with mesyl chloride, the urethane 356 derived from 351 afforded the oxazolidinone 357 through intramolecular substitution of a transient,mesyloxyl group with the urethane group. Alkaline hydrolysis of the product gave the inverted amino alcohol 358, which was transformed to (f)-yenhusomidine (359)and ( f)-yenhusomine (323)(174). Raddeanamine (360)is an unusual spirobenzylisoquinolinealkaloid having a tertiary methyl group in five-membered ring. Methylation of the corresponding ketone gave the methyl carbinol with the reverse stereochemistry, namely, the methyl carbinol361 was obtained from the reaction of the ketone 294 with methyllithium (Scheme 64). Stereoselective synthesis of (+)raddeanamine was accomplished by an intramolecular oxyfunctionalization 364 (I75). via the 8-methyl-8,14-cycloberbine The 8-methyl-8,14-cycloberbine 364, derived from the protoberberine 324 via the betaine 363, was reduced with sodium borohydride or lithium aluminum tri-tert-butoxyhydride to give a diastereoisomeric mixture of cisand trans-alcohols (7.8:1 or 1 :7.8,respectively) (Scheme 64).b n exposure to formaldehyde the mixture underwent N-hydroxymethylation and subsequent intramolecular substitution on the aziridine ring to give the oxazolidine 365. Removal of the hydroxyl group in 365 was accomplished by chlorination followed by hydrogenolysiswith tributyltin hydride. Reductive opening of the oxazolidine 366 with sodium cyanoborohydride afforded ( f)-raddeanamine (360), which has already been converted to ochotensimine (282) by dehydration. Transformation of phthalideisoquinolines to spirobenzylisoquinolinealkaloids is described in Section V,D,6. D.

PHTHALIDEISOQUINOLINE

ALKALOIDS

Phthalideisoquinoline alkaloids have been reviewed (1,2,I 76-179) and compiled (180). Because of the potential usefulness of phthalideisoquinoline alakloids such as bicuculline, a competitive antagonist of y-aminobutyric acid, many synthetic methods for these alkaloids have been developed. Several attractive transformations from protoberberines have also been reported.

3. TRANSFORMATION REACTIONS OF PROTOBERBERINE ALKALOIDS

Me0

195

Me0

'

(91%)

\

0 L O

324

362

b'

363

LO'

364

O

365

P

36 6

Me

360

282

294

36 1

SCHEME 64. Synthesis of raddeanamine (360).Reagents: a, MeMgI; b, MCPBA; c, hv, MeOH; d, NaBH, or LiAI(OBu'),; e, HCHO; f, SOCl,;g, n-Bu,SnH; h, NaBH,CN; i, A; j, MeLi.

1. From 8-Methoxyberberinephenolbetaine

The first conversion of protoberberines to phthalideisoquinoline alkaloids was achieved by Moniot and Shamma (88,89). 8-Methoxyberberinephenolbetaine (131), derived from berberine (15) (Section III,B,2), is an attractive compound having a carboxyl group masked as an imino ether in ring B. The masking was uncovered by hydration with water-saturated ether to furnish dehydronorhydrastine methyl ester (367) (Scheme 65). On Nmethylation (68%)and subsequent sodium borohydride reduction (90%),367 provided ( f)-B-hydrastine (368)and (i- )-a-hydrastine (369) in a 2 : 1 ratio. Compound 367 was 'converted to dehydrohydrastine (370), which also afforded 368 and 369 by catalytic hydrogenation. 2. Photooxygenation of Oxyberberine Irradiation of oxyberberine (58)in benzene in a stream of oxygen afforded directly the y-lacto1371 in 42% yield (Scheme 66). On treatment with methyl

196

MIYOJI HANAOKA

(96%)

\

367

131

OMe OMe

370

\

368

369

OMe

OMe

SCHEME 65. Conversion of 8-methoxyberberinephenolbetaineto a- and J-hydrastine (369and 368).Reagents: a, H,O, Et,O; b, MeI; c, NaBH,; d, HCI, MeOH.

(%-g"T .

0

COz H OMe

0.

'

\ 0

58

OMe

Me

OMe

368 (95%)

371

,

37 2

3 73 P

ic

SCHEME 66. Stereoselective synthesis of 8-hydrastine (368)from oxyberberine by photooxygenation. Reagents: a, hv, 0 , ,benzene; b, MeI; c, NaBH,.

197

3. TRANSFORMATION REACTIONS OF PROTOBERBERINEALKALOIDS

iodide at room temperature or under reflux, 371 gave the imminium lactone 372 or the keto ester 373, respectively, both of which were reduced with sodium borohydride to furnish stereoselectively( f)-8-hydrastine (368)in 95% overall yield from 371 along with a trace of (&)-a-hydrastine. Alternatively, reduction of 371 with sodium borohydride followed by N-methylation afforded 368 in 35% overall yield (181).

3. Photooxygenation of Phenolbetaines Kondo et al. (282,283) reported a conversion of a fully aromatized phenolbetaine to a phthalide skeleton through photooxygenation. Reduction of norcoralyne (54)with zinc in acetic acid afforded dihydronorcoralyne (374), which was oxidized with rn-chloroperbenzoic acid to the fully aromatized phenolbetaine 375 (Scheme 67). Photooxygenation of 375 in the presence of Rose Bengal, followed by reduction with sodium borohydride, gave rise directly to the phthalideisoquinoline 376 in 70% yield. The same phthalide (376) was also obtained from 2'-acetylpapaveraldine (129) (Section III,B,l).

'6 '

54

OMe

OMe

374

Me0

OMe

]

375

'

-Me0 d

'

OMe

(70%)

:%--"";g' I

'

OMe

Me 0

OMe

#

'

OMe OMe

127

0

\ I Me0 OMe

(92%)

\

-

376

Me

OMe

129

SCHEME 67. Conversion to phthalideisoquinolines by photooxygenation. Reagents: a, Zn, AcOH; b, MCPBA; c, hv, 02,Rose Bengal, MeOH; d, NaBH,; e, NaOBr.

198

’

MIYOJI HANAOKA

SCHEME68. Synthesis of phthalideisoquinolinesfrom prechilenine (139) and the epidioxide. Reagents: a, 25% H,SO,; b, KOH then conc H,SO,; c, py-HCI, py; d, Me,SO,; e, CHJ.

4. From Prechilenine

Acidic treatment of prechilenine (139) (Section III,C) afforded the imino keto acid 377 via the imminium salt 140 (Scheme 68). Neutralization and work-up furnished the known y-lacto1371 in 90% overall yield from 139 (96, 181). Kondo et al. (183) obtained 139 from the epidioxide 122 by treatment with pyridine hydrochloride in pyridine along with 377 and norhydrastine. The acid 377 was converted to the known imino ester 373 through N,Odimethylation. 0-Methylprechilenine (117) (Section III,C) was heated at 175°Cfor 20 min at reduced pressure to yield the keto ester 378, the phthalide 379, and (2)chilenine (380)(Scheme 69). Reduction of 378 gave quantitatively 379. Hydrogenation of 379 over Adams’ catalyst gave ( +)-nor-b-hydrastine and ( f)-nor-a-hydrastine in 35 and 31% yield, N-methylation of which afforded (5)-8-and (&)-a-hydrastine(368and 369), respectively (184). 5. From Ophiocarpine

Phthalideisoquinoline alkaloids have been suggested to be biosynthesized from 13-oxyberbines with retention of the configuration at C-13 and (2-14 through regioselective C-8-N bond cleavage (185).Based on this biogenetic viewpoint, ( +)-ophiocarpine and ( f )-epiophiocarpine were converted to (&)-a- and (+)-p-hydrastine, respectively (Scheme 70) (186). Treatment of

Me0

/

'

OMe OMe

(35%)

117

(7%)

OMe

380

OMe

368: R Z ..IIH 369:Rz - H SCHEME69. Pyrolytic conversion of 0-methylprechilenine (117) to a- and 1-hydrastine (369 and 368).Reagents: a, A; b, NaBH,; c, H,/Pt,O; d, HCHO.

H

384

OH

OEt

OMe

385

OMe

36 9

OMe

OMe (39%)

386

387

(47%)

388

SCHEME 70. Synthesis of a- and 8-hydrastine (369 and 368) from ophiocarpine and epiophiocarpine. Reagents: a, C1C02Et;b, AgNO,; c,'PCC; d, 10% NaOH, MeOH; e,p-TsOH, EtOH; f, LAH; g, 10% HCI.

200

MIYOJI HANAOKA

0-acetylophiocarpine (381) with ethyl chloroformate afforded the C-8-N cleaved urethane 382 in quantitative yield. Sequential treatment of 382 with silver nitrate, PCC, sodium hydroxide, and p-toluenesulfonic acid in ethanol furnished acetal 384, which was reduced with lithium aluminum hydride followed by hydrolysis to afford the hemiacetal 385. Oxidation of 385 with PCC provided ( f)-a-hydrastine (369).Similar treatment of O-acetylepiophiocarpine (386)afforded ( f)-j?-hydrastine (368);however, in this case, C-N bond cleavage of 386 with ethyl chloroformate proceeded without regioselectivity. 6 . From Spirohenzylisoquinolines

The spirobenzylisoquinoline 171b derived from berberine (15)(Section IV,A,l) was oxidized with rn-chloroperbenzoic acid to the N-oxide 389,which was treated with trifluoroacetic anhydride to afford dehydrohydrastine (370) in 56”/, overall yield (Scheme 71) through the Polonovski reaction (187). Holland et al. (188,189) reported the reverse reaction from dehydrophthalides to spirobenzylisoquinolines, namely, 370 was reduced with diisobutylaluminum hydride to give a mixture of two diastereoisomeric spirobenzylisoquinolines 320 and 348 via the enol aldehyde. This reaction was applied to synthesis of various spirobenzylisoquinoline alkaloids such as ( f)-sibiricine (352),( +)-corydaine (347),( f)-raddeanone (354),( )-yenhusomidine (359), ( )-ochrobirine (343),and ( f)-yenhusomine (323).

+

+

I ( 5 6 % from 171b)

370 SCHEME 71. Interconversion of spirobenzylisoquinolines and dehydrohydastine (370). Reagents: a, MCPBA; b, (CF,C0)20, CH,Cl,; c, DIBAL.

3. TRANSFORMATION REACTIONS OF PROTOBERBERINE ALKALOIDS

20 1

E. PROTOPINE ALKALOIDS The protopine alkaloids have been reviewed (1,2,7-10,190)and compiled (191). Although conversion of protoberberines to protopine alkaloids was achieved relatively early, only a few methods have since been developed. 1. Rearrangement of the N-Oxides of the Methine Base A

Some protopine alkaloids such as allocryptopine (392)(192), protopine (393)(193), cryptopine (394)(193, and cryptopalmatine (muramine) (395) (194)were obtained from the corresponding protoberberine alkaloids via the N-oxides of the Hofmann degradation products, anhydrobase A having a 10-membered ring, through acid-catalyzed transannular rearrangements (Scheme 72). The mechanism was reported by Russell (Z95). This classic method was applied to a synthesis of fagarine I1 (396)(196),muramine (395) (197),munnenamine (397)(198),and pseudoprotopine (398)(199)as well as its skeleton (399)(200) having no oxygenated substituents on the aromatic rings.

R3 R5

R5

R5

39 2 :R1+R2=0C H,O ,R3=R4=0Me,R5= H 3 9 3 :R1+R2 = R3+R4=OC H,O, R5=H 394 :R1-R2=0Me,RJ+R4=OCH20,R5=H 395: Rf=RZ-RJ=R4=OMe,RkH 396 :R1+R2-OCH2O,R3=H,RkR5=OMe 397 :R'~R2=OCH,O,RJ=OH,R4=o~,R5--H 39 8 :R' +R2- R4 +R5= OC H,O,RJ= H 399 :Rl=RZ=R3zR4=RS-H SCHEME72. Synthesisof protopine alkaloids through transannular oxygen transfer. Reagents: a, peracid:b, HCI.

202

MIYOJI HANAOKA

-RO

"%a RO

, OMe \

OMe

'%b

' R'O

-

, OMe '

Ro% RO 0

OMe

35a: R+R=CH, 4OO:R=Me

\

OMe OMe

392: R+R:CH; 395:R-Me

SCHEME 73. Synthesis of protopine alkaloids from tetrahydroprotoberberine N-oxides. Reagents: a, K,CrO,; b, MeI.

2. Rearrangement of the N-Oxides of Tetrahydroprotoberberines

Bentley and Murray (201) reported another method for synthesis of protopine alkaloids allocryptopine (392) and cryptopalmatine (395) from tetrahydroprotoberberine N-oxides (35a and 400) through oxidative rearrangement with potassium chromate (Scheme 73). 3. Oxidation and Reduction of Ophiocarpinone Metho Salt

Nalliah et al. (202,203)developed a novel entry to protopine alkaloids from a protoberberine. 13-Oxotetrahydroberberine (ophiocarpinone) metho salt (291) was reduced with zinc in 30% acetic acid to afford a new type of the protopine analog 401 (Scheme 74) (202). On the other hand, 291 gave 13oxoallocryptopine (402) via the hydroperoxide on exposure to air in the presence of sodium hydride and potassium iodide in dimethoxyethane (203).

29 1

SCHEME 74. Synthesis of 13-oxoallocryptopine (402)from ophiocarpinone metho salt (291)by oxidation. Reagents: a, air, NaH, KI, (MeOCH,),; b, Zn, AcOH.

4. Photooxygenation of Tetrahydroberberine Methiodide

Irradiation of tetrahydroberberine methiodide (1) in aqueous methanol in a stream of oxygen in the presence of Rose Bengal afforded in one step

3. TRANSFORMATION REACTIONS OF PROTOBERBERINE ALKALOIDS

203

Me

392

1

SCHEME 75. One-step synthesis of allocryptopine (392)from tetrahydroberberinemethiodide (1) by photooxygenation. Reagents: a, hv, 0,,Rose Bengal, MeOH.

allocryptopine (392) in 16% yield (Scheme 75) (204).The reaction did not depend on the stereochemistry of the starting methiodides and probably proceeded via the hydroperoxide (204,205). 5. von Braun Reaction and Osmium Tetroxide Oxidation

Labeled muramine (395) was synthesized for biosynthetic studies from tetrahydropalmatine (27) in 35% overall yield via the von Braun reaction product 3Oc (Section II,A,2) and the alcohol 403 (Scheme 76) (42). Labeled 13-oxygenated muramines 405a and 405b were obtained by oxidation of dihydropalmatine metho salt (404)with osmium tetroxide (42). 6 . From Indenobenzazepines

Orito et al. (206-208) developed an attractive conversion of indenobenzazepines to protopines through photosensitized oxygenation of the

30c

403

Me0 MeOQ

OMe

404

'

OMe

395

-"% \

405

OMe

OH a: R = < H

b: R = O SCHEME 76. Reagents: a, LAH; b, HCHO then NaBH,; c, PCC; d, OsO,.

204

MIYOJI HANAOKA

UK

406

a:R=Me b:R+R=CH,

UP(

OR

396:R=Me (64%) 398:R+R=CH, (67%)

SCHEME77. Synthesis of protopine alkaloids by photooxygenation of indenobenzazepines. Reagents: a, hv, O , , Methylene Blue; b, LAH; c, MnO,.

enamine grouping. Though the starting indenobenzazepines were not prepared from protoberberines, the conversion is worthy of description here because indenobenzazepines can be readily obtained from protoberberines via 8,14-cycloberbines (Section IV,A,2). Photooxygenation of indenobenzazepines 406a,b in the presence of methylene blue afforded 10-membered keto amides, which were reduced with lithium aluminum hydride followed by oxidation with manganese dioxide to provide the desired protopine alkaloids, fagarine I1 (396)and pseudoprotopine (398),in good overall yield (Scheme 77).

F. INDENOBENZAZEPINE ALKALOIDS Indenobenzazepines have been used as key intermediates for synthesis of rhoeadine, protopine, phthalideisoquinoline, and spirobenzylisoquinoline alkaloids. Several new alkaloids possessing an indenobenzazepine skeleton have been isolated, and they are presumably biosynthesized from protoberberine alkaloids. I . Skeletal Rearrangement of Phenolic Dihydroprotoberberines

Base-induced rearrangement of the dihydroprotoberberine metho salt 407 having a phenolic hydroxyl group in ring A proceeded in a different way to affordthe indenobenzazepine 408 (153,154)instead of a usual spirobenzylisoquinoline (Scheme 78) (Section V,C,l). The key difference is that the intermediate bears a full positive charge distributed between rings C and D, which is not the case in any of the previous quinomethides leading to spirobenzylisoquinolines. Therefore, the nitrogen attacks intramolecularly at C-13 to provide the indenobenzazepine via the aziridinium ion. 2. From Protopines

An indenobenzazepine skeleton was constructed from a protoberberine through C-8-N and C-14-N bond cleavage followed by formation of C-13-N and C-8-C-14 bonds via a protopine analog according to a bio-

205

3. TRANSFORMATION REACTIONS OF PROTOBERBERINE ALKALOIDS

OMe

I

w

Me0

OMe

M e 6 @Me

.

%e

OMe

OMe

408

c

bMe

SCHEME 78. Base-induced rearrangement to indenobenzazepines.Reagents: a, NaOH.

'%

RO

'

401 :R+R=CH,

Me

, OMe

OMe

'

409: R =Me

Br

::%

-

a -Ro% RO OMe ( 4 7 % )

OMe

b

' \

\

OMe

410: R+R=CH, 41 1 : R - M e

SCHEME 79. Conversion of protopines to indenobenzazepines. Reagents: a, BrCN, THF; b, KOH, EtOH.

genetic route. von Braun reaction of the protopine-type compounds 401 and 409,derived from 13-oxoprotoberberine metho salts (Section V,E,3), effected further C-N bond cleavage to the bromide, cyclization of which with base provided the indenobenzazepines 410 and 411, respectively (Scheme 79) (202). Blasko et al. (101) reported a direct conversion of the 13-oxoallocryptopine (402) to the indenobenzazepine 177 on exposure to sunlight in tert-butyl alcohol in the presence of potassium tert-butoxide (Scheme 80). 3. From Spirobenzylisoquinolines

Rearrangement of spirobenzylisoquinolines, having a hydroxyl group on ring C trans to the nitrogen, to indenobenzazepines was first reported by Irie et al. (209,210)in their synthesis of rhoeadine alkaloids (Section V,G,l). This

206

MIYOJI HANAOKA

(40%)

Me

402

177

"3 "To) 'x0 SCHEME 80. One-step conversion of 13-oxoallocryptopine (402) to indenobenzazepines. Reagents: a, hv, f-BuOK, 1-BuOH.

RO

a

HO

-

\ / 328:R=Me 338: R+R=CH,

-

RO

(75%)

b

L'

RO

(20%)

0

i' 0

412: R = M e 4 13: R+R=CH,

SCHEME 81. Synthesis of lahoramine (412)and lahorine (413).Reagents: a, MsCI, Et,N, THF; b, I,, EtOH.

rearrangement was applied to a synthesis of indenobenzazepine alkaloids. Dihydroparfumidine (328) was treated with methanesulfonyl chloride and triethylamine in tetrahydrofuran to afford the indenobenzazepine, dehydrogenation of which with iodine in ethanol provided lahoramine (412) (Scheme 81) (221).In a similar fashion, dihydrofumariline 2 (338) was converted to lahorine (413) (222). Similarly, the spirobenzylisoquinoline 414 was converted to O-methylfumarofine (316) (Scheme 82). Reduction of 414 with sodium borohydride afforded the trans-alcohol 415 (52%)along with the cis-alcohol (14%).The former gave the indenobenzazepine 416, which was oxidized with osmium tetroxide and then with PCC to give 0-methylfumarofine (316) (212). This synthesis unequivocally confirmed the revised structures of fumarofine (417) and 0methylfumarofine (316), which were previously assigned spirobenzylisoquinoline structures (418 and 419, respectively). The spirobenzylisoquinoline structures 423 and 424 for fumaritrine and fumaritridine were also revised to indenobenzazepine structures 421 and 422, respectively, by their synthesis from the trans-alcohols 328 and 420, using the rearrangement reaction caused by treatment with trifluoroacetic anhydride and then with methanol (Scheme 83), presumably via 8,14-cycloberbines (213).

3. TRANSFORMATION REACTIONS OF PROTOBERBERINE ALKALOIDS

319

417: R - H 316: RZMe

207

418: R = H 4 19 :R Me

SCHEME82. Synthesis of 0-methylfumarofine (316). Reagents: a, NaBH,; b, MsCI, Et,N, THF; c, OsO,; d, PCC.

421:R=Me 422: R = H

423: R =Me 424: R= H

SCHEME 83. Synthesis of fumaritrine (421) and fumaritridine (422). Reagents: a, (CF,CO),O; b, MeOH.

4. From Phthalideisoquinolines

Holland et al. (214) reported a conversion of /?-hydrastine to the corresponding indenobenzazepines. On treatment with p-nitrophenyl chloroformate, /I-hydrastine (368)was converted to the ene lactone 425 through C-N bond cleavage (Scheme 84). Treatment of 425 with sodium methoxide in methanol afforded the indanedione 426a. Basic hydrolysis of 426a and

MIYOJI HANAOKA

208

Me

+ Y

180b

OMe

426 a : R : C O O e N 0 2 b:R=H

-2. (95%)

(98%)

SCHEME 84. Conversion of 8-hydrastine (368) to indenobenzazepines. Reagents: a, pnitrophenol chloroformate; b, NaOMc, MeOH; c, NaOH, DMSO; d, p-TsOH, toluene.

cyclization with p-toluenesulfonic acid gave the two regioisomeric indenobenzazepines 180b and 187b in 14 and 32% yield, respectively.

5. Via 8.14-Cycloberbines On the basis of fundamental experiments (see Section IV,A,2) some indenobenzazepine alkaloids have been efficiently synthesized from the corresponding protoberberines via 8,14-cycloberbines. For example, the cycloberbine 428 derived from the protoberberine 427 was heated with methanesulfonic acid in aqueous tetrahydrofuran to afford a 2 : 1 mixture of cis- and trans-indenobenzazepines 429 in 92% yield (Scheme 85). The mixture was methylated with methyl iodide to give the cis-N-methyl derivative 430and the unchanged trans secondary amine (2179, which was very difficult to methylate and which gave the N-methyl derivative only in 6% yield even on treatment with dimethyl sulfate for 43 hr. Contrary to the ordinary cases (Section IV,A,2), the trans derivative did not isomerize to the cis isomer 430 under various acidic conditions. Debenzylation of 430 by hydrogenolysis afforded fumarofine (417),which was converted to 0-methylfumarofine (316) by methylation with diazomethane (215).

3. TRANSFORMATION REACTIONS OF PROTOBERBERINE ALKALOIDS

*L I

428

209

~

429 316: RZMe (82%)

SCHEME85. Synthesis of fumarofine (417) and 0-methylfumarofine(316) via 8.14-cycloberbines. Reagents: a, MCPBA; b, hv, MeOH; c, MsOH, aq THF; d, MeI; e, HJPd-C, MeOH; f, CH,N,.

Epiberberine and berberine were stereoselectively converted to fumaritrine (421) and its analog via 8,14-cycloberbines (216). The cycloberbine 432, derived from epiberberine (431) in the established way, was treated with p-

toluenesulfonic acid in methanol and then with methyl iodide to give stereoselectively the cis-fused indenobenzazepine 433 in excellent yield (Scheme 86). Deoxygenation of the hydroxyl group in 433 was accomplished by treatment with methanesulfonyl chloride and subsequent reduction with sodium borohydride in dimethoxyethane to give ( )-fumaritrine (421) (216).

+

G. RHOEADINE ALKALOIDS

Rhoeadine alkaloids have been reviewed (1,2,7-10,217)and compiled (218). Only a few transformations have been developed despite the interesting structural features of these alkaloids. 1. From Spirobenzylisoquinolines

The first synthesis of a rhoeadine alkaloid was achieved by Irie et al. (209,210) through skeletal rearrangement of a spirobenzylisoquinoline to an indenobenzazepine. The trans-alcohols 434 and 329 were treated with methanesulfonyl chloride and rearranged to the indenobenzazepine 435,

210

MIYOJI HANAOKA

432

433

42 1

SCHEME86. Synthesis of fumaritrine (421) via 8,14-~ycloberbines.Reagents: a, LAH; b, MCPBA; c, hv, MeOH; d, NaBH,, MeOH; e, p-TsOH, MeOH; f, MeI; g, MsCI, CH2Cl,; h,NaBH,,(MeOCH,),.

probably through the aziridinium ion (Scheme 87). The allylamines 435 initially obtained are rather unstable and tend to isomerize to the enamines 436 and 411. The allylamine was converted to the diol 437a with osmium tetroxide oxidation, which was successively treated with sodium periodate and sodium borohydride to afford ( +)-rhoeagenine diol (438). The diol 4371, similarly afforded (+)-alpinigenine diol(440) and its diastereoisomer 439 in 10 and 50% yield, respectively. The former was obtained in 40% yield when reduced with lithium perhydro-9bboraphenalenyl hydride. Oxidation of 440 with manganese dioxide furnished (+)-alpinigenine (441), though only in 10% yield. The starting spirobenzylisoquinolines were originally synthesized from the corresponding phenethylamines and indanediones. Compound 329 was prepared from palmatine (64)via the 8,14-cycloberbine 442 (Scheme 88). Thus, a formal transformation of palmatine to ( )-alpinigenine (441) was accomplished (63).

+

2. Through Photooxygenation The indenobenzazepine 411 (202), derived from 13-oxotetrahydropalmatine metho salt, was oxidized to the vinylogous amide 314a, photooxygenation of which in the presence of Rose Bengal afforded the keto lactone 443 through an interesting rearrangement via the dioxetanes (Scheme 89). Reduction of 443 followed by acidification gave the cis-b-lactone 444, which was reduced with diisobutylaluminum hydride to provide (+)-cisalpinigenine (445) (219).

211

3. TRANSFORMATION REACTIONS OF PROTOBERBERINE ALKALOIDS

b

R 0' 434: R*R=CH, 329:R.rMe

RO

437

RO

a : R+R=CH,

441

440

438:R+R=CH, 439: R = Me

SCHEME 87. Synthesis of rhoeagenine diol(438) and alpinigenine (441) from spirobenzylisoquinolines. Reagents: a, MsCl, Et,N; b, OsO,; c, HIO,; d, NaBH,; e, lithium perhydro-9bboraphenalenyl hydride, THF; f, MnO,.

64

OMe

OMe

442

SCHEME 88. Synthesis of the alpinigenine intermediate 329. Reagents: a, LAH; b, MCPBA; c, hv, MeOH; d, CIC0,Et; e, H,/Pd-C.

212

MIYOJI HANAOKA

411

314a

443

444

445

SCHEME 89. Synthesis of cis-alpinigenine (445) by photooxygenation. Reagents: a, 0,,Triton B, py; b, hv, 0 , ,Rose Bengal; c, NaBH,; d, HCI; e, DIBAL.

e

,iNH

Me

HO (100%)

\ / OMe

b

Me0 (100%)0

Me0

OMe

448

'

' OMe

449

=

Me0 (78%)

Me0 \-I MeO

450

SCHEME 90. Synthesis of the cis-alpinigenine intermediate 314a. Reagents: a, hv, 0,, Rose Bengal, NaOMe, MeOH; b, hv, MeOH; c, NaBH,; d, HCI; e, 10% NaOH, EtOH; f, p-TsOH, benzene; g, Me,SO,, NaH, HMPA.

3. TRANSFORMATION REACTIONS OF PROTOBERBERINE ALKALOIDS

2 13

The intermediate vinylogous amide 314a was alternatively synthesized from palmatine (64) through D ring inversion (Section V,I,4). According to the established method (Section IV,A,l), 64 led to the spirobenzylisoquinoline 448,treatment of which with 10%sodium hydroxide effected ring D inversion to give the betaine 449 (Scheme 90). Sequential treatment of 449 with irradiation, p-toluenesulfonic acid, and dimethyl sulfate afforded the indenobenzazepine 314a (103,220). Another interesting conversion of a protoberberine to a rhoeadine skeleton was developed by Murugesan et al. (100).The ketoll76 obtained easily from berberine (15) (Section IV,A,2) was oxidized with sodium periodate to the keto lactone 451, which was transformed to the rhoeadine analogs 452 and 453 by known methods (Scheme 91). Their stereochemistry at the anomeric carbon was not fully clarified.

176

451 (90%)

SCHEME91. Synthesis of rhoeadine analogs via indenobenzazepines. Reagents: a, NaIO,; b, NaBH,; c, HCI; d, DIBAL; e, HC(OMe),. .

3. Through Photochemical Double Cyclization

Hofmann degradation of the nonnatural protoberberine 454 afforded the 10-membered ring base 455 (65%) in addition to the styrene-type compound (13%) (Scheme 92). Dihydroxylation of the former with N-bromosuccinimide in the presence of a large excess of hydrochloric acid and subsequent oxidation of the product diol456 with periodic acid afforded the dialdehyde 457. On irradiation in tert-butyl alcohol 457 provided ( f)-cis-alpinigenine (445)along with (f)-alpinigenine (441) as a result of endo and exo intramolecular cycloaddition, respectively, of the intermediate photodienol (221,222). H. ISOINDOLOBENZAZEPINE ALKALOIDS

Several isoindolobenzazepine alkaloids have been isolated recently (223). Some of them had already been synthesized prior to their isolation.

214

MIYOJI HANAOKA

,b,c_

Me0

NMe-

Me

d

’ Me0 ‘

/

(60-70%)

(65%)

Me0

\

OMe

Me0

HO HO

’

Me0

\

OMe

OMe

455

454

456

457 SCHEME 92. Synthesis of cis-alpinigenine (445) and alpinigenine (441) by photochemical double cyclization. Reagents: a, MeI; b, IRA-400; c, A; d, NBS, 1 N HCl; e, HIO,, H,SO,; f, hv, t-BuOH.

1. Schopys Base VI (Chilenamine)

Reduction of berberinephenolbetaine(121)with zinc in acetic acid afforded tetrahydroberberine(26)and its isomer. The structure of the latter was shown to be the isoindolobenzazepine 458, commonly referred to as Schopf‘s base VI, and its formation mechanism was also postulated (Scheme 93) (224).Recently 458 was isolated and named as chilenamine.

OMe

HO

’

O

H

/

HO

SCHEME93. Synthesis of chilenamine(458). Reagents: a, Zn,AcOH.

’

2 15

3. TRANSFORMATION REACTIONS OF PROTOBERBERINE ALKALOIDS

2. Chilenine and Its Conversion The isoindolobenzazepine 380 obtained readily from prechilenine (139), 13-hydroxyoxyberberine (134), or oxybisberberine (130) (223), was recently isolated and named as chilenine (225).On reduction with zinc in hydrochloric acid-acetic acid 380 gave chilenamine (458) along with the hydroxylated product 459 (Scheme 94). Reduction of 380 followed by methylation and elimination of methanol gave pictonamine (460).On treatment with sodium hydroxide in aqueous methanol, 380 was converted to the isoindole 461, exposure of which to trifluoroacetic acid promoted cyclization and decarboxylation to afford the isoindoloisoquinoline neuvanine (462) (226).Its structure was revised (227)from the one originally proposed 463 (228).

OMe OMe

139

460

134

Oxybis be rber ine

130

\b

OH

OMe (35%)

458

380

461

/ <%Me

HO

-.

I

c%

Me

(7%)

459

'

'(91%)

OMe

463

462

SCHEME94. Synthesis of chilenine (380)and its conversion to related alkaloids. Reagents: a, aq NH,; b, py.HC1, py; c, Zn, HCI-AcOH; d, NaBH,; e, MeI, MeOH; f, AcOH; g, NaOH, aq MeOH; h, CF,COOH.

216

MIYOJI HANAOKA

468 469 4 70 47 1

90: R+R = CH, 472: R=Me SCHEME95. Synthesis of 13-methylprotoberberines.Reagents: a, MeI; b, NaBH,; c, HCHO, AcOH.

I. PROTOBERBERINE AND RETROPROTOBERBERINE ALKALOIDS Many methods have been developed so far for synthesis of protoberberine alkaloids (229).In this section interconversions of these alkaloids as well as transformations to nonnatural alkaloids are described.

I . 13-Methylprotoberberine Introduction of an alkyl group to the C-13 position of protoberberine was simply accomplished by the reaction of dihydroprotoberberines (230-232) or their 8-acetonyl derivatives (233,234)with alkyl halides, though yields are not always satisfactory. In some cases, oxidized products, protoberberines, and/or N-alkyl quaternary bases were concomitantly produced. These methods were applied to a synthesis of corydaline (469) (231), tetrahydrocorysamine (470) (235),and corybulbine (471) (236) (Scheme 95). Rather mild 13-methylationwas developed by treatment of dihydroberberine (90) with 30% formaldehyde in 10% acetic acid (237,238). However, this method cannot be applied to an introduction of other C-13 substituents because aldehydes other than formaldehyde do no react. A different method using 8,14-cycloberbineswas developed for synthesis of 13-methylprotoberberines (239). The Wittig reaction of the 8,14-cycloberbines 146,442, and 339 derived from protoberberines 15,64, and 65 afforded

3. TRANSFORMATION REACTIONS OF PROTOBERBERINE ALKALOIDS

(80-868)

Me

2 17

250

SCHEME96. Synthesis of 13-methylprotoberberinesvia 8,14-cycloberbines. Reagents; a, LAH; b, hv, MeOH; c, Ph,P=CH,.

almost quantitatively the methylidene derivatives 473, which on irradiation in aqueous ethanol underwent photochemical electrocyclization to yield 13methylprotoberberines 207, 249, and 250 in excellent yields, respectively, without formation of the starting protoberberines (Scheme 96). Sodium borohydride reduction of the products produced ( +)-thalictricavine (9579 ( )-corydaline (97%), and ( +)-tetrahydrocorysamine (94%). Other alkyl groups such as ethyl and propyl groups were also introduced efficiently by this method.

+

2. 8-Methylprotoberberine The Grignard reaction of protoberberines is a well-known method for preparation of 8-alkylprotoberberines. For example, treatment of berberine with methylmagnesium iodide followed by reduction with sodium borohydride gave a 5.5 : 1 mixture of (*)-cis- and (f)-trans-8-methylcanadine (27). Optically active (- )-(8R)-methylcanadine was stereoselectively synthesized through selective monocomplexation of ( -)-canadine (26) to chromium tricarbonyl (240). Heating of chromium hexacarbonyl with 26 effected regioselective complexation of the D ring to give the diastereomeric complexes, which were treated with n-butyllithium and trimethylsilyl chloride to give the 11-trimethylsilyl derivative 475 (Scheme 97). Methylation of this complex with methyl iodide gave stereoselectively the 8-methyl derivative 476 by preferential alkylation from the opposite face to the bulky chromium

218

MIYOJI HANAOKA

(20%)

26

/

Me

(15%)

474

HI'' /

(78%)

OMe

OMe iMe,

Cr(CO)3

475

(64%)

\

Me Me

477

476

SCHEME97. Synthesis of optically active 8-methylcanadine (477) via the chromium complex. Reagents: a, Cr(CO),; b, n-BuLi, Me,SiCl; c, n-BuLi, MeI; d, n-Bu,NF; e, 0,.

tricarbonyl moiety. Desilylation and decomplexation gave ( - )-(8R)-methylcanadine (477) in 64% yield.

3. 13-Hydroxyprotoberberines Synthesis of ophiocarpine and its analogs was described in Sections II1,A and II1,B. 4. Ring D Inversion via Spirobenzylisoquinolines

Ring D inversion seems to be a crucial step in biogenetic transformations of protoberberines to related alkaloids such as rhoeadine, retroprotoberberine, spirobenzylisoquinoline, and indenobenzazepine alkaloids. 8,lCCycloberbin-13-01478 derived from berberine (15) was successively treated with ethyl chloroformate, silver nitrate, and pyridinium dichromate (PDC) in dimethylformamide to give the keto oxazolidinone 479 (Scheme 98). Heating of 479 with 10% aqueous sodium hydroxide in ethanol effected hydrolysis, retroaldol reaction, cyclization, and dehydration to provide successfully the 11,lZoxygenated phenolbetaine 183 via the hydroxy ketone and the keto aldehyde (241,242). An alternative and more convenient method was accomplished from 8methoxyberberinephenolbetaine(131) via the ketol 171a (Scheme 99). Treatment of 171a with 10% aqueous sodium hydroxide furnished the expected 11,12-dioxygenatedphenolbetaine (183) in 95% yield (241,242).This method

2 19

3. TRANSFORMATION REACTIONS OF PROTOBERBERINE ALKALOIDS

“To -

-

0

e

(100%) \

Me0

Me0

OMe

OMe

183

SCHEME 98. Ring D inversion of berberine. Reagents: a, NaBH,; b, CIC0,Et; c, AgNO,, aq THF; d, PDC; e, 10% NaOH, EtOH.

Me

‘3p% Me0

131

171a

”OzEt 0

CI

-

\ /

OMe OMe

149

OMe

b,c

183

Meo

- 0d

(64%)

\-/ OMe

(43%)

Me0

0 Me

480

’ \

OMe

481

SCHEME 99. Ring D inversion of protoberberines. Reagents:a, 10% NaOH, EtOH; b, HJPdC; c, 20% KOH; d, hv, THF.

was successfully applied to conversion of palmatine to 2,3,11,12-tetramethoxyprotoberberinephenolbetaine(449), which was used for synthesis of ( +)-cis-alpinigenine (Section V,G,2). A third conversion was achieved by application of photochemical transformation of a spirobenzylisoquinoline to a protoberberine (243,244).Hydrogenolysis of the urethane 149 followed by hydrolysis gave the amino ketone

MIYOJI HANAOKA

220

480, irradiation of which in tetrahydrofuran provided the 11,12-0xygenated

oxyprotoberberine 481 (Scheme 99) (241,242). Another photochemical method was reported by Kessar et al. (257). l-o-Toluyl-3,4-dihydroisoquinoline2Wa, derived from dihydroberberine metho salt (298a), was irradiated and then reduced with sodium borohydride to provide the ring D-inverted 11,12-0xygenated protoberberine 482 (Scheme 100).

298 a

299 a

Me0

482

SCHEME 100. Photolytic ring D inversion. Reagents:a, hv; b, NaBH,.

5 . 2,3,10,11-TetraoxygenatedProtoberberines from 2,3,9,10-Tetraoxygenated Protoberberines

Another type of D ring inversion achieved via polycarpines. Enamide photocyclization of polycarpines derived from protoberberines (Section II,B) followed by reduction with sodium borohydride afforded 2,3,10,11,12-pentaoxygenated protoberberines 483 (Scheme 101). Reductive removal of the hydroxyl group at C- 12 was realized via the phosphates to give tetrahydropseudoberberine ( M a ) , ( k)-xylopinine ( M b ) , and tetrahydropseudocoptisine (4844 (56,245).

R10

OH (44-62%)

HO

66:R1+R2-CH2,R3= R4= Me 67:Rl=RZ=R3=R4=Me 68: R1*R2=R3+R'=CH2

483 a b C

OR^

484

0 ~3

a

b C

SCHEME 101. Synthesis of nonnatural 2,3,10,11-tetraoxygenatedprotoberberines. Reagents: a, hv, EtOH; b, NaBH,; c, CIPO(OEt),; d, Na, liq NH,.

““i;l‘*<%

3. TRANSFORMATION REACTIONS OF PROTOBERBERINE ALKALOIDS

?%a

OMe

, OMe

\

485

OMe

\

(74%)

OH

,

HO

OMe

486 O H Adoe

<%t /

OMe

‘

OMe

28 1

f %

\c

HO

,

OMe OMe

‘<% HO

/

(60%)

/

\

OMe

OH

OMe OMe

22 1

487

OMe

(58%)

489

, \

OMe

0-0

488

SCHEME 102. Synthesisof retroprotoberberines,mecharnbridine(487), orientalidine (488).and analogs. Reagents: a, HCHO, NaOH; b, CH,N2; c, CH,Cl,, NaH, DMF; d, KOH; e, HCHO, AcOH.

6 . Retroprotoberberines from Protoberberines

The Mannich reaction of the protoberberine 485 with formaldehyde in the presence of sodium hydroxide afforded the 12-hydroxymethyl product 486, whereas the reaction with formaldehyde and formic acid furnished the 4-hydroxymethylderivative as a major product along with 486 (Scheme 102). Methylation or methylenation of 486 gave ( +)-mechambridine (487) (246,247) or ( )-orientalidine (488)(248,249), respectively. Hydrolysis of the urethane 281 derived from tetrahydroberberine (26) gave the secondary amine, the Mannich reaction of which afforded the retroprotoberberine 489 in good yield (45,250).Although this retroprotoberberine (489) is not natural product, this transformation is interesting from a biogenetic viewpoint.

+

J. MISCELLANEOUS ALKALOIDS 1. Pavine Alkaloids

0,O-Dimethylmunitagine (494) was synthesized from tetrahydroberberine (26), utilizing the Stevens rearrangement as a crucial step (251).The Hofmann degradation product 3 of 26 was converted to the B-nor derivative 491 through oxidative cleavage of the double bond, reduction to the alcohol 490, and then recyclization via the methanesulfonate (Scheme 103). On treatment with phenyllithium, 491 afforded two rearranged products 492 and 493, the

222

MIYOJI HANAOKA

-

-

, OMe 3

'

OMe

Me

490

49 1

Me

OMe M e- : : -

+

d

492: R*R=CH, 494: R=Me

493

SCHEME103. Synthesis of 0,O-dimethylmunitagine (494). Reagents: a, Os0,-NaIO,; b, NaBH,; c, MsCI, py; d, PhLi.

former of which led to 0.0-dimethylmunitagine (494) through demethylenation with boron trichloride followed by methylation with diazomethane. 2. Emetine The protoberberine 495 was converted to the protoemetine derivative 500 through cleavage of the D ring (252).The Birch reduction of 495 followed by dehydrogenation with N-chlorosuccinimide afforded the a,p-unsaturated ketone 496, catalytic hydrogenation of which gave stereoselectivelythe C/Dtrans ketone 4W (Scheme 104).The thioketal498, prepared from 497 via the enamine, was exposed to potassium hydroxide to furnish the ring-cleaved product 499 after esterification. Desulfurizationof 499 with Raney nickel gave rise to the protoemetine derivative 500, which was converted to ( f)-emetine.

3. Aporphine Alkaloids Oxidativeconversion of palmatine, berberine, and coptisine to polycarpine, polyberbine, and its analog was described in Section I1,B. These products were further transformed to aporphine alkaloids having a phenolic hydroxyl group at (2-2' in the bottom ring (55). Hydrolysis with concomitant air oxidation of polyberbine (66)furnished 3,4-dihydrorugosinone,which was further airoxidized in ethanolic sodium hydroxide to give rise to rugosinone (501) (Scheme 105).Successivereduction of the enamide 68 with lithium aluminum hydride and sodium borohydride afforded a mixture of ( _+ )-norledecorineand ( f)-ledecorine (502). N-Methylation of the former with formaldehyde and sodium borohydride led to the latter.

3. TRANSFORMATION REACTIONSOF PROTOBERBERINE ALKALOIDS

223

SCHEME 104. Synthesisof the protoemetine derivative 500. Reagents: a, Li, liq NH,, I-BuOH; b, NCS, CH,CI,; c, H,/Pd-C, MeOH; d, pyrrolidine, benzene; e, (TsSCH,),CH,; f, KOH, t-BuOH, THF; g, CH,N,; h, Ra-Ni, MeOH.

66:R=Me 68:R+R=CH,

\

501 c,d,e

SCHEME 105. Synthesis of the aporphine alkaloids rugosinone (501) and ledecorine (502). Reagents: a, MeOH; b, NaOH, EtOH; c, LAH; d, NaBH,; e, HCHO then NaBH,.

op

224

MIYOJI HANAOKA

e

/

iMe,

503

. OJ

(66%)

‘4 0 4

504

505

SCHEME 106. Synthesis of karachine (505).

4. Karachine

Karachine (505) (253), the first natural protoberberine incorporating an acetone unit, was synthesized from berberine (15) (254). Heating of 15 with siloxydiene 503 in dimethyl sulfoxide afforded karachine (505) in 66% yield through Mannich condensation, intramolecular Michael addition, and then further Mannich condensation via 504 (Scheme 106).

References

1. M. Shamma, “The Isoquinoline Alkaloids: Chemistry and Pharmacology”, Academic Press, New York, 1972. 2. M. Shamma and J. L. Moniot,“Isoquinoline Alkaloids Research 1972-1977.” Plenum Press, New York, 1978. 3. T. Kametani, “The Chemistry of the Isoquinoline Alkaloids.” Hirokawa, Tokyo, 1968. 4. T. Kametani, “The Chemistry of the Isoquinoline Alkaloids,” Vol. 2. Kinkodo, Sendai, Japan, 1974. 5. R. H. F. Manske and W. R. Ashford, Alkaloids ( N . Y . ) 4, Chapter 29 (1954). 6. P.W. Jeffs, Alkaloids ( N . Y . ) 9, Chapter 2 (1967). 7. R. H. F. Manske, Alkaloids ( N . Y . ) 10, Chapter 8 (1968). 8. F. Santavj, Alkaloids ( N . Y.) 12, Chapter 5 (1970). 9. V. Preininger, Alkaloids ( N . Y.) 15, Chapter 5 (1975). 10. F. Santavy, Alkaloids ( N . Y.) 17, Chapter 4 (1979). 11. D. S. Bhakuni and S. Jain, Alkaloids ( N . Y . ) 28, Chapter 2 (1986). 12. Y. Kondo, Heterocycles 4, 197 (1976). 13. T. Kametani, M. Ihara, and T. Honda, Heterocycles 4,483 (1976). 14. T. R. Govindachari, J. Indian Chem. SOC.57, 353 (1980). 15. G. D. Pandey and K. P. Tiwari, Heterocycles 14,59 (1980). 16. A. C. Cope and E. R. Trumbull, “Organic Reactions,” Vol. 11, p. 317, John Wiley & Sons, New York.

3. TRANSFORMATION REACTIONS OF PROTOBERBERINE ALKALOIDS

225

F. L. Pyman and H. A. D. Jowett, J. Chem. SOC.103,290(1913). F. L. Pyman, J. Chem. Soc. 103,817(1913). A. J. Kirby and C. J. Logan, J. Chem. SOC.,Perkin Trans. 2,642 (1978). P. W. Jeffs and J. D. Scharver, J. Am. Chem. SOC.98,4301 (1976). 21. H.-W. Bersch, Arch. Pharm. (Weinheim, Ger.) 283,36(1950). 22. H.-W. Bersch, Arch. Pharm. ( Weinheirn,Ger.) 291, 595 (1958). 23. C. Tani, N. Takao, S. Takao, and K. Tagahara, Yakuguku Zmshi 82,751 (1962). 24. G. Nonaka, Y. Kodera, and I. Nishioka, Chem. Pharm. Bull. 21,1020 (1973). 25. K. L. Wert, S. Chackalamannil, E. Miller, D. R. Dalton, D.E. Zacharias, and J. P.Glusker, J. Org. Chem. 47, 5141 (1982). 26. M. Freund and K. Fleischer, Ann. 397,30 (1913). 27. J. R. Gear and I. D. Spenser, Can. J. Chem. 41,783 (1963). 28. T. Kametani, M. Takemura, K. Fukumoto, T. Terui, and A. Kozuka, Heterocycles 2,433 (1974). 29. T. Kametani, M. Takemura, K. Fukumoto, T. Terui, and A. Kozuka, J. Chem. Soc., Perkin Trans. 1 2678 (1974). 30. T. Kametani, M. Takemura, K. Takahashi, M. Takeshita, M.Ihara, and K. Fukumoto, Heterocycles 2,653 (1974). 31. T. Kametani, M. Takemura, K. Takahashi, M. Takeshita, M.Ihara, and K. Fukumoto, J . Chem. Soc., Perkin Trans. 1. 1012 (1975). 32. H. A. Hageman, “Organic Reactions,” Vol. 7, p. 198, John Wiley & Sons, New York, 1953. 33. I. Sallay and R. H. Ayers, Tetrahedron 19, 1397 (1963). 34. J. D. Albright and L. Goldman, J. Am. Chem. Soc. 91,4317 (1969). 35. H. Ronsch, J. Prakr. Chem. 314,382 (1972). 36. W. Nagata, K. Okada, H. Itazaki, and S . Uyeo, Chem. Pharm. Bull. 23,2878 (1975). 37. K. Iwasa, P. Chinnasamy, and M. Shamma, J. Org. Chem. 46,1378 (1981). 38. P. Chinnasamy, R. D. Minard, and M. Shamma, Tetrahedron 36,1515 (1980). 39. J. Knabe, Arch. Pharm. ( Weinheim, Ger.) 289,479 (1956); J. Knabe. and U. R. Shukla, Arch. Pharm. (Weinheim, Ger.) 295, 690 (1962); J. Knabe and U. R. Shukla, Arch. Pharm. (Weinheim Ger.) 295, 871 (1962); J. Knabe and U. R. Shukla, Arch. Pharm. (Weinheim, Ger.) 298, 257 (1965). 40. H. Ronsch, Z. Chem. 19,447 (1979). 41. M. Hanaoka, K. Nagami, and T. Imanishi, Heterocycles 12,497 (1979). 42. H.Ronsch, Phytochemistry 16,691 (1977). 43. M. Hanaoka, K. Nagami, S. Horima, and T. Imanishi, Heterocycles 15,297 (1981). 44. S. Prior, W. Wiegrebe, and G. Nariyar, Arch. Pharm. (Weinheim. Ger.) 315,273 (1982). 45. M. Hanaoka, K. Nagami, M. Inoue, and S . Yasuda, Chem. Pharm. Bull. 31,2685 (1983). 46. P. N. Sharma, K. C. Rice, and A. Brossi, Heterocycles 19, 1895 (1982). 47. P. N. Sharma, K. C. Rice, and A. Brossi, Heterocycles 20,2417 (1983). 48. S.-I. Murahashi and T. Yano, J. Chem. Soc., Chem. Commun., 270 (1979). 49. S.-I. Murahashi and T. Yano, J. Am. Chem. SOC.102,2456 (1980). 50. M. Shamma and L. A. Smeltz, Tetrahedron Lett., 1415 (1976). 51. T. Kametani, S. Shibuya, S. Hirata, and K. Fukumoto, Chem. Phurm. Bull. 20,2570 (1972). 52. M. Shamma, L. A. Smeltz, J. L. Moniot, and L. Toke, Tetrahedron Lett., 3803 (1975). 53. M. Shamma, J. L. Moniot, L. A. Smeltz, W. A. Shores, and L.Toke, Tetrahedron 33,2907 (1977). 54. N. Murugesan and M. Shamma, Tetrahedron Lett., 4521, (1979). 55. N. Murugesan and M. Shamma, Heterocycles 14,585 (1980). 56. M. Hanaoka, M. Marutani, K. Saitoh, and C. Mukai, Heterocycles 23,2927 (1985). 57. M. Oberlin, Arch. Pharm. ( Weinheim. Ger.) 265,256 (1927). 58. E. Spath and G. Burger, Ber. Deutsch. Chem. Ges. 59, 1486 (1926). 17. 18. 19. 20.

I

226

MIYOJI HANAOKA

59. H. L. Holland, P. W. Jeffs, T. M. Capps, and D. B. MacLean, Can. J. Chem. 57,1588 (1979). 60. S.Teitel, J. OBrien, and A. Brossi, J. Org. Chem. 37,3368 (1972). 61. S.Teitel and J. P. OBrien, J. Org. Chem. 41, 1657 (1976). 62. S.Teitel and J. P. OBrien, Heterocycles 5,85 (1976). 63. M. Hanaoka, K. Nagami, Y. Hirai, S.Sakurai, and S . Yasuda, Chem. Pharm. Bull. 33,2273 (1985). J. P. OBrien and S. Teitel, Heterocycles 11, 347 (1978). S.Teitel and J. P. O’Brien, Heterocycles 2,625 (1974). Cf. S.Teitel, J. OBrien, and A. Brossi, J . Org. Chem. 37, 1879 (1972). M. Hanaoka, unpublished work. M. Tomita, M. Kozuka, H. Ohyabu, and K. Fujitani, Yakugaku Zusshi 90, 82 (1970); M. Tomita, S. Matsumura, Y. Sasaki, and E. Kinoshita, Yakugaku Zusshi 79, 329 (1959); M. Tomita and S . Matsumura, Yakugaku Zasshi 79,690 (1959). 69. S. Naruto, H. Mizuta, J. Nakano, and H. Nishimura, Tetrahedron Lett., 1595 (1976). 70. S. Naruto, H. Mizuta, and H.Nishimura, Tetrahedron Lett., 1597 (1976). 71. I. W.Elliott, Jr., J. Heterocycl. Chem. 4,639 (1967). 72. T. Kametani, M. Takeshita, F. Satoh, and K. Nyu, Yakugaku Zusshi 94,478 (1974). 73. H. Hara, M. Hosaka, 0.Hoshino, and B. Umezawa, Heterocycles 8,269 (1977). 74. H. Hara, M. Hosaka, 0.Hoshino, and B. Umezawa, Tetrahedron Lett., 3809 (1978). 75. H. Hara, M. Hosaka, 0. Hoshino, and B. Umezawa, J . Chem. Soc., Perkin Trans. 1. 1169 ( 1980). 76. H. Hara, A. Tsunashima, H. Shinoki, T. Akiba, 0.Hoshino, and B. Umezawa, Chem. Pharm. Bull. 34,66 (1986). 77. M. H. Abu Zarga and M. Shamma, Tetrahedron Lett. 21,3739 (1980). 78. C. R. Dorn, F. J. Koszyk, and G. R. Lenz, J. Org. Chem. 49,2642 (1984). 79. F. L. Pyman,J. Chem. SOC.99,1690(1911). 80. J. Iwasa and S.Naruto, Yakugaku Zasshi 86,534 (1966). 81. T. Takemoto and Y. Kondo, Yukugaku Zusshi 82, 1413 (1962). 82. P. W. Jeffs and J. D. Scharver, J . Org. Chem. 40,644 (1975). 83. M. Hanaoka, C. Mukai, K. Nagami, K. Okajima, and S.Yasuda, Chem. Pharm. Bull. 32, 2230 ( 1984). 84. Y. Kondo, H. Inoue, and J. Imai, Heterocycles 6,953 (1977). 85. Y. Kondo, J. Imai, and H. Inoue, J. Chem. Soc., Perkin Trans. 1.91 1 (1980). 86. D. S.Bhakuni, P. K. Gupta, P. P. Joshi, and S. Gupta, Indian J. Chem. 21B, 389 (1982). 87. J. Imai and Y. Kondo, Heterocycles 5,153 (1976). 88. J. L. Moniot and M. Shamma, J. Am. Chem. SOC.98,6714 (1976). 89. J. L. Moniot and M. Shamma, J. Org. Chem. 44,4337 (1979). 90. M. Hanaoka, C. Mukai, and Y. Arata, Heterocycles 6,895 (1977). 91. M. Hanaoka, C. Mukai, and Y. Arata, Chem. Pharm. Bull. 31,947 (1983). 92. J. L. Moniot, A. el Rahman H. A. el Rahman, and M. Shamma, Tetrahedron Lett., 3787 (1977). 93. M. Hanaoka and C. Mukai, Heferocycles6, 1981 (1977). 94. M. Shamma, J. L. Moniot, and D. M. Hindenlang, Tetrahedron Len., 4273 (1977). 95. G. Manikumar and M. Shamma, Heterocycles 14, 827 (1980). 96. J. L. Moniot, D. M. Hindenlang, and M. Shamma, J . Org. Chem. 44,4343 (1979). 97. M. Hanaoka, S.Yasuda, K. Nagami, K. Okajima, and T. Imanishi, Tetrahedron Lett., 3749 (1979). 98. M. Hanaoka, S.Sakurai, Y. Sato, and C. Mukai, Heterocycles 19,2263 (1982). 99. M. Hanaoka, S. K. Kim, S. Sakurai, Y. Sato, and C. Mukai, Chem. Pharm. Bull. 35,3155 (1987).

64. 65. 66. 67. 68.

3. TRANSFORMATION REACTIONS OF PROTOBERBERINE ALKALOIDS

227

100. N. Murugesan, G. Blask6, R. D. Minard, and M. Shamma, Tetrahedron Lprt. 22,3131 (1981). 101. G. Blasko, V. Elango, N. Murugesan, and M. Shamma,J. Chem. SOC.Chem. Commwt., 1246 (1981). 102. M. Hanaoka, M. Inoue, K. Nagami, Y. Shimada, and S . Yasuda, Heterocycles 19, 313 (1982). 103. M. Hanaoka, M. Inoue, S.Sakurai, Y. Shimada, and S . Yasuda, Chem. Pharm. Bull. 30,1110 (1982). 104. M. Hanaoka, S. K. Kim, M. Inoue, K. Nagami, Y. Shimada, and S . Yasuda, Chem. Pharm. Bull. 33, 1434 (1985). 105. G . Manikumar and M. Shamma, J. Org. Chem. 46,386 (1981). 106. F. Valencia, V. Fajardo, A. J. Freyer, and M. Shamma, Tetrahedron Lett. 26, 993 (1985). 107. M. Shamma and M. Rahimizadeh, J. Nat. Prod. 49,398 (1986). 108. R. Hocquemiller, A. Cave, and A. Fourner, J. Nat. Prod. 47,539 (1984). 109. S. Sepulveda-Boza, E. Friedrichs, H. Puff, and E. Breitmaier, Planta Med. 43, 32 (1983); V. Fajardo, V. Elango, S.Chattopadhyay, L. M. Jackman, and M. Shamma, Tetrahedron Lett. 24, 155 (1983). 110. V. Simanek, Alkaloids ( N . Y.) 26, Chapter 4 (1985). 111. B. D. Krane, M. 0. Fagbule, and M. Shamma, J. Nat. Prod. 47, l(1984). 112. I. Ninomiya and T. Naito, Recent Deu. Chem. Nor. Carbon Compd. 10,11(1984). 113. E. Leete and S. J. B. Murrill, Phytochemistry 6, 231 (1967); A. Yagi, G. Nonaka, S.Nakayama, and 1. Nishioka, Phytochemistry 16,1197 (1977);A. R. Battersby, J. Staunton, H. C. Summers, and R. Southgate, J. Chem. SOC.,Perkin Trans. 1, 45 (1979); N. Takao, M. Kamigauchi, and M. Okada, Helu. Chim. Acra 66,473 (1983). 114. D. W. Brown and S . F. Dyke, TetrahedronLetr., 3975 (1966). 115. S. F. Dyke and D. W. Brown, Terrahedron 24, 1455 (1968). 116. D. W. Brown and S . F. Dyke, Tetrahedron Lerr., 2605 (1968). 117. S. F. Dyke and D. W. Brown, Terrahedron 25,5375 (1969). 118. W. H. Perkin, Jr., J. Chem. SOC.109,815 (1916). 119. W. H. Perkin, Jr., J. Chem. SOC.115,713 (1919). 120. M. Onda, K. Abe, and K. Yonezawa, Chem. Pharm. Bull. 16,2005 (1968). 121. M. Onda, K. Yonezawa, and K. Abe, Chem. Pharm. Bull. 17,2565 (1969). 122. M. Onda, K. Yonezawa, and K. Abe, Chem. Pharm. Bull. 17,404(1969). 123. M. Onda, K. Yonezawa, and K. Abe, Chem. Pharm. Bull. 19,31(1971). 124. M. Onda, K. Yuasa, J. Okada, K. Kataoka, and K. Abe, Chem. Pharm. Bull. 21,1333 (1973). 125. M. Onda, K. Yuasa, and J. Okada, Chem. Pharm. Bull. 22,2365 (1974). 126. M. Onda, H. Yamaguchi, and Y. Harigaya, Chem. Pharm. Bull. 28,866 (1980). 127. V. Smula, R. H. F. Manske, and R. Rodrigo, Can.J. Chem. 50,1544 (1972). 128. T. Kametani, M. Takemura, M. Ihara, K. Fukumoto, and K. Takahashi, Hererocycles6,99 (1977). 129. T. Kametani, M. Takemura, M. Ihara, K. Fukumoto, and K. Takahashi, Israel J. Chem. 16,4 (1977). 130. M. Hanaoka, T. Motonishi, and C. Mukai, J. Chem. Soc.. Chem. Commun.. 718 (1984). 131. M. Hanaoka, T. Motonishi, and C. Mukai, J. Chem. SOC.,Perkin Trans. 1.2253 (1986). 132. M. Hanaoka, H. Yamagishi, and C. Mukai, Chem. Pharm. Bull. 33,1763 (1985). 133. Private communications from Prof. N. Takao and Prof. H. Ishii. 134. M. Hanaoka, H. Yamagishi, M. Marutani, and C. Mukai, Tetrahedron Lett. 25,5169(1984). 135. M. Hanaoka, H. Yamagishi, M. Marutani, and C. Mukai, Chem. Pharm. Bull. 35, 2348 (1987). 136. M. Hanaoka, N. Kobayashi, and C. Mukai, Heterocycles 26, 1499 (1987). 137. M. Suffness and G. A. Cordell, Alkaloids ( N . Y.) 25,178 (1985).

228

MIYOJI HANAOKA

138. M. Hanaoka, N. Kobayashi, K. Shimada, and C. Mukai, J . Chem. Soc., Perkin Trans. I , 677 (1987). 139. M. Hanaoka, S.Yoshida, and C. Mukai, unpublished work. 140. M. Hanaoka, S. Yoshida, M. Annen, and C. Mukai, Chem. Lett., 739(1986). 141. M. Hanaoka, S. Yoshida, and C. Mukai, Tetrahedron Lett. 26,5163(1985). 142. N. Takao and K. Iwasa, Chem. Pharm. Bull. 21,1587 (1973). 143. M. Hanaoka, S.Yoshida, and C. Mukai, J. Chem. Soc., Chem. Commun.. 1703 (1984). 144. M. Shamma, A. S. Rothenberg, and S. F. Hussain, He/erucyc/e.r6,707 (1977). 145. M. Shamma, A. S. Rothenberg, G. S. Jayatilake, and S. F. Hussain, Heterocycles 5,41(1976). 146. M. Shamma, A. S. Rothenberg, G. S. Jayatilake, and S. F. Hussain, Tetrahedron 34, 635 (1978). 147. M. Shamma, Alkaloids ( N . Y . ) 13,Chapter 2(1971). 148. R. M. Preisner and M. Shamma, J. Nut. Prod. 43,305 (1980). 149. H. L.Holland, M. Castillo, D. B. MacLean, and I. D. Spenser, Can. J. Chem. 52,2818(1974). 150. M. Shamma and C. D. Jones, J. Am. Chem. Soc. 91,4009(1969). 151. M. Shamma and C. D. Jones, J. Am. Chem. Soc. 92,4943 (1970). 152. M. Shamma and J. F. Nugent, Terrahedron Lett.. 2625 (1970). 153. M. Shamma and J. F. Nugent, Tetrahedron 29, 1265 (1973). 154. M.Shamma and J. F. Nugent, J. Chem. Soc., Chem. Commun., 1642 (1971). 155. B.Nalliah, R. H. F. Manske, R. Rodrigo, and D. B. MacLean, Tetrahedron Lett., 2795 (1973). 156. T.-T. Wu,J. L. Moniot, and M. Shamma, Tetrahedron Lett.. 3419 (1978). 157. S. V. Kessar, Y. P. Gupta, T. V. Singh, A. Sood, A. K. Nanda, and K. R. Agnihotri, Tetruhedron Lett. 23, 3619 (1982). 158. Y. Kondo, T.Takemoto, and K. Kondo, Heterocycles 2,659 (1974). 159. J. Imai, Y. Kondo, and T. Takemoto, Tefrahedron32, 1973 (1976). 160. J. Imai, Y. Kondo, and T. Takemoto, Heterocycles 3,467 (1975). 161. S. Kano, T. Yokomatsu, E. Komiyama, S. Tokita, Y. Takahagi, and S. Shibuya, Chem. Pharm. Bull. 23, 1171 (1975). 162. S.Kano, T. Yokomatsu, T. Ono, Y. Takahagi, and S. Shibuya, Chem. Pharm. Bull. 25,2510 (1977). 163. T.Kametani. S.-P. Huang, A. Ujiie, M. Ihara, and K. Fukumoto, Heterocycles4,1223(1976). 164. T. Kametani, A. Ujiie, S.-P. Huang, M. Ihara, and K. Fukumoto,J. Chem. Soc. Perkin Trans. I . 394(1977). 165. T.Kametani, S.-P. Huang, C. Koseki, M. Ihara, and K. Fukumoto, J. Org. Chem. 42,3040 (1977). 166. S. 0. de Silva, K. Orito, R. H. Manske, and R. Rodrigo, Tetrahedron Lett, 3243 (1974). 167. G. Blasko, N. Murugesan, A. J. Freyer, D. J. Gula, B. Sener, and M. Shamma, Tetrahedron Lett. 22,3139 (1981). 168. M. Hanaoka, S.Yasuda, Y. Hirai, K. Nagami, and T. Imanishi, Heferocycles 14,1455(1980). 169. Z.H. Hardirossian, H. G. Kiryakov, J. P. Ruder, and D. B. MacLean, Phytorhemistry 22,759 (1983). 170. M. Hanaoka, M. Iwasaki, and C. Mukai, Tetrahedron Lett.26,917 (1985). 171. M. Hanaoka, S.Sakurai,T. Ohshima, S. Yasuda, and C. Mukai, Chem. Pharm. Bull. 30,3446 (1982). 172. M. Hanaoka, A. Ashimori, and S. Yasuda, Heterocycles 22,2263(1984). 173. M. Hanaoka, M. Kohzu, and S. Yasuda, Chem. Pharm. Bull. 33,2621 (1985). 174. M. Hanaoka, M.Kohzu, and S. Yasuda, unpublished work. 175. M. Hanaoka, M. Kohzu, and S. Yasuda, Chem. Pharm. Bull. 33,4113 (1985). 176. J. Stanek and R. H. F. Manske, Alkaloids ( N . Y . ) 4 , Chapter 32 (1954). 177. J. StanEk, Alkaloids (N. Y . ) 7 , Chapter 20 (1960).

3. TRANSFORMATION REACTIONS OF PROTOBERBERINE ALKALOIDS

229

178. J. Stantk, AIkaloids (N.Y.) 9, Chapter 3 (1967). 179. D. B. MacLean, Alkaloids ( N . Y.) 24, Chapter 5 (1985). 180. G. Blasko, D. J. Gula, and M. Shamma, J . Naf. Prod. 45, 105 (1982). 181. M. Shamma, D. M. Hindenlang, T.-T. Wu, and J. L. Moniot, Tetrahedron Leff.,4285 (1977). 182. J. Imai and Y. Kondo, Heterocycles 6,959 (1977). 183. Y. Kondo, J. Imai, and S. Nozoe, J. Chem. SOC.,Perkin Trans. 1,919 (1980). 184. V. Elango and M. Shamma, J. Urg. Chem. 48,4879 (1983). 185. A. R. Battersby, J. Staunton, H. R. Wiltshire, R. J. Francis, and R.Southgate,J. Chem. SOC., Perkin Trans. I , 1147 (1975); A. R. Battersby, J. Staunton, H.R.Wiltshire, B. J. Bircher, and C. Fuganti,J. Chem. Soc., Perkin Trans. 1, 1162(1975). 186. M. Hanaoka, K. Nagami, and T. Imanishi, Chem. Pharm. Bull. 27,1947 (1979). 187. M. Hanaoka, S. K. Kim, T. Mitsuoka, and S. Yasuda, unpublished work. 188. H. L. Holland, D. B. MacLean, R. G. A. Rodrigo, and R. H. F. Manske, Tefrahedron Left.. 4323 (1975). 189. B.C. Nalliah, D. B. MacLean, H. L. Holland,and R. Rodrigo, Can. J . Chem. 57,1545(1979). 190. R. H. F. Manske, Alkaloids (N.Y.) 4, Chapter 31 (1954). 191. H. Guinaudeau and M. Shamma, J. Naf. Prod. 45,237 (1982). 192. R. D. Haworth and W. H. Perkin, Jr., J. Chem. SOC.,445 (1926). 193. R. D. Haworth and W. H. Perkin, Jr., J. Chem. Soc., 1769 (1926). 194. R. D. Haworth, J. B. Koepfli, and W. H. Perkin, Jr., J. Chem. Soc.. 2261 (1927). 195. P. B. Russell, J. Am. Chem. SOC.78,3115 (1956). 196. D. Giacopello, V. Deulofeu, and J. Comin, Tefrahedron20,2971 (1964). 197. D. Giacopello and V. Deulofeu, Tetrahedron Left.,2859 (1966). 198. D. Giacopello and V. Deulofeu, Tetrahedron 23,3265 (1967). 199. R. M. Sotelo and D. Giacopello, Aust. J. Chem. 25,385 (1972). 200. A. L. Margni, D. Giacopello, and V. Deulofeu, J. Chem. SOC.C, 2578 (1970). 201. K. W. Bentley and A. W. Murray, J. Chem. Soc.. 2497 (1963). 202. B. Nalliah, R. H. Manske, and R. Rodrigo, Tetrahedron Leff., 2853 (1974). 203. B. Nalliah, R. H. F. Manske, and R. Rodrigo, Tetrahedron Lett.. 1765 (1974). 204. M. Hanaoka, C. Mukai, and Y. Arata, Hekrocycles 4,1685 (1976). 205. M. Hanaoka, C. Mukai, H. Nagayama, and Y. Arata, Pol. J . Chem. 53,79 (1979). 206. K. Orito and M. Itoh, J. Chem. SOC.. Chem. Commun., 812 (1978). 207. K. Orito, S. Kudoh, K. Yamada, and M. Itoh, Heterocycles 14, 11 (1980). 208. K. Orito, Y.Kurokawa, and M. Itoh, Tefrahedron36,617 (1980). 209. H. Irie, S. Tani, and H. Yamane, J. Chem. SOC.,Chem. Commun.,1713 (1970). 210. H. Irie, S. Tani, and H. Yamane, J . Chem. SOC..Perkin Trans. I , 2986(1972). 21 1. G. Blasko, S. F. Hussain, A. J. Freyer, and M. Shamma, Tetrahedron Lett. 22,3127 (1981). 212. G. Blasko, N. Murugesan, S. F. Hussain, R. D. Minard, and M. Shamma, Tetrahedron Left. 22, 3135 (1981). 213. G. Blasko, N. Murugesan, A. J. Freyer, R. D. Minard, and M. Shamma, TetrahedronLett. 22, 3143 (1981). 214. H. L. Holland, M. Curcumelli-Rodostamo, and D. B. MacLean, Can. J. Chem. 54, 1472 (1976). 215. M. Hanaoka, A. Ashimori, H. Yamagishi, and S. Yasuda, Chem. Pharm. Bull. 31,2172 (1983). 216. M. Hanaoka, M. Iwasaki, S. Sakurai, and C. Mukai, Tetrahedron Left. 24,3845 (1983). 217. H. Ronsch, A1kaloid.s ( N . Y . ) 28, Chapter 1 (1986). 218. C. T. Montgomery, B. K. Cassels, and M. Shamma, J. Nut. Prod. 4,441 (1983). 219. K. Orito, R. H. Manske, and R. Rodrigo, J. Am. Chem. SOC.%,1944(1974). 220. M. Hanaoka, M. Inoue, N. Kobayashi, and S. Yasuda, Chem. Pharm. Bull. 35,980 (1987). 221. S. Prabhakar, A. M. Lobo, and I. M. C. OliveiraJ. Chem. SOC.,Chem. Commun.,419(1977).

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222. S. Prabhakar, A. M. Lobo, M. R. Tavares, and I. M. C. Oliveira, J . Chem. SOC.,Perkin Trans. 1 . 1273 (1981). 223. E. Valencia, 1. Weiss, S. Firdous, A. J. Freyer, M. Shamma, A. Urzua, and V. Fajardo, Tetrahedron 40,3957 (1984). 224. C. Schopf and M. Schweickert, Chem. Ber. 98,2566 (1965). 225. V. Fajardo, V. Elango, B. K. Cassels, and M. Shamma, Tetrahedron Left.23,39 (1982). 226. J. L. Moniot, D. M. Hindenlang, and M. Shamma, J. Org. Chem. 44,4347 (1979). 227. R. Alonso, L. Castedo, and D. Dominguez, Tetrahedron Lett. 26,2925 (1985). 228. E. Valencia, A. J. Freyer, M. Shamma, and V. Fajardo, Tetrahedron Len. 25, 599 (1984). 229. T. Kametani, in ‘The Total Synthesis of Natural Products” (J. ApSimon, ed.), Vol. 3, p. 1. Wiley, New York, 1977. 230. M. Freund and K. Fleischer, Ann. 409,229 (1915). 231. F. von Bruchhausen, Arch. Pharm. ( Weinheim. Cer.) M1,28 (1923). 232. T. Takemoto and Y. Kondo, Yakugaku Zusshi 82, 1408 (1962). 233. M. Freund and P. Walbaum, Ann. 409,266 (1915). 234. S. Naruto and H. Kaneko, Yakugaku Zusshi 92,1017 (1972). 235. C. Tani, N. Takao, and S. Takao, Yakugaku Zusshi 82,748 (1962). 236. C. Tani, 1. Imanishi, and J. Nishijo, Yakugaku Zusshi 90,407 (1970). 237. H. W. Bersch, Arch. Pharm. ( Weinheim, Ger.) 238, 192 (1950). 238. 2. Kiparissides, R. H. Fichtner, J. Poplawski, B. C. Nalliah, and D. B. MacLean, Can. J. Chem. 58,2770 (1980). 239. M. Hanaoka, S. Yoshida, and C. Mukai, J. Chem. Soc.. Chem. Commun., 1257 (1985). 240. J. Blagg and S. G. Davies, J. Chem. Soc.. Chem. Commun..492 (1986). 241. M. Hanaoka, M. Inoue, M. Takahashi, and S. Yasuda, Heferocycles 19,31(1982). 242. M. Hanaoka, M. Inoue, M. Takahashi, and S. Yasuda, Chem. Pharm. Bull. 32,4431 (1984). 243. H. Irie, K. Akagi, S. Tani, K. Yabusaki, and H. Yamane, Chem. Pharm. Bull. 21,855 (1973). 244. D. Greenslade and R. Ramage, Tetrahedron 33,927 (1977). 245. M. Hanaoka, W.J. Cho, M. Marutani, and C. Mukai, Chem. Pharm. Bull. 35, 195 (1987). 246. T. Kametani, A. Ujiie, and K.Fukumoto, Heferocyc/es2,55 (1974). 247. T. Kametani, A. Ujiie, aand K. Fukumoto, J. Chem. Soc., Perkin Trans. I, 1954 (1974). 248. T. Kametani, A. Ujiie, M. Ihara, and K. Fukumoto, Heterocycles 3, 143 (1975). 249. T. Kametani, A. Ujiie, M. Ihara, and K.Fukumoto, J . Chem. Soc., Perkin Trans. I , 1822 (1975). 250. M. Hanaoka, M. Inoue, S. Yasuda, and T. Imanishi, Heterocycles 14, 1791 (1980). 251. K. Ito, H. Furukawa, T. Iida, K.-H. Lee, and T. 0.Soine, J. Chem. Soc., Chem. Commun., 1037 (1974). 252. S. Takano, M. Sasaki, H. Kanno, K. Shishido, and K. Ogasawara, Heterocycles7,143 (1977). 253. G. Blask6, N. Murgesan, A. J. Freyer, and M. Shamma, J. Am. Chem. SOC.104,2039 (1982). 254. R. V. Stevens and J. R. Pruitt, J. Chem. Soc., Chem. Commun., 1425 (1983).

-CHAPTER 4-

SECOISOQUINOLINE ALKALOIDS MARIAD. ROZWAD~WSKA Faculty of Chemistry A. Mickiewicz University P O Z M IPoland ~, 1. Introduction.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . ... . .. . .. . . . . , 23 1 11. Secoberbine Alkaloids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233

.. .

. . .. .

A. 7,s-Secoberbine Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . .. . . .. . . . B. Peshawarine, a 7,8-14,7-Bissecoberbine Alkaloid . . . . . . . . . . .. . . . .. . . . . . . C. 6,7-Secoberbine Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . .. .. . . . D. 8,Sa-Secoberbine Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . ... 111. SecophthalideisoquinolineAlkaloids . . . . . . . . . . . . . . . . . . . . . . .. . . .. . . . .. . . . . A. Secophthalideisoquinoline Enol Lactones . . . . . . . . . . . . . . . . . . . . .. . . . B. SecophthalideisoquinolineKeto Acids. . . . . . . . . . . . . . ... . . . . .. .. . . . . . C. Secophthalideisoquinoline Diketo Acids . . . . . . . . . . . . . . . . . . . . . . .. .. . . . . . D. Secophthalideisoquinoline Ene Lactams and Hydroxy Lactams . . . . . . . . .. IV. Secobenzylisoquinoline Alkaloids . . . . . . . . . . . . . . . . . . . . . .. .. . . . . .. . . .. . . . . V. Secobisbenzylisoquinolineand Secodimeric Isoquinoline Alkaloids . . .. . . . . . . . A. SecobisbenzylisoquinolineAlkaloids. . . . . . . . . . . . . . . . . .. . . . . . . . . .. B. Secodimeric Isoquinoline Alkaloids . . . . . . . . . . . . . . . . . . . . . . .. . . .. . . .. . . . VI. Secobenzophenanthridine Alkaloids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VII. Secocularine and Secoquettamine Alkaloids . . . . . . . . . .. . . .. . . . . .. . . . A. Secocularine Alkaloids . . . . . . . . . . . . .. . . . . . . . . . ..... .. . ... . . . . . . . .. .. B. Secoquettamine Alkaloids . . . . . . . . . . . . . . . . . . ... . . . . . . . . . . . . . . . . . .. . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . .. . . .

...

.. . . . .

..

.. .

.. . .

. . .. .

. .

.

... . ..

.

. .. ..

233 246 250 256 262 265 268 27 1 274 279 285 285 292 294 297 297 299 301

I. Introduction In recent years a number of new isoquinoline alkaloids of untypical structures, i.e., structures with open heterocyclic rings, have been isolated from natural sources. These bases were named secoisoquinoline alkaloids because they were believed to be produced in uiuo from classic isoquinoline alkaloids as a result of various degradation processes causing oxidative cleavage of some bonds. From a historical standpoint, the first secoisoquinoline alkaloid was narceine, isolated from opium by Pelletier as early as 1832 ( I ) . Up to 1986, over 70 secoisoquinolinealkaloids had been discovered. Most of them were found 23 1

THE ALKALOIDS, VOL. 33 Copyright 0 1988 by Academic Press. Inc. All rights of reproduction in any form reserved.

232

MARIA D. ROZWADOWSKA

in plants in scant amounts, and they often accompany their cyclic precursors. Many classic alkaloids turned out to have seco analogs. On the grounds of structural features and biogenetic reasons, the seco bases isolated so far can be divided into the following groups: secoberbines, secophthalideisoquinolines, secobenzylisoquinolines, secobisbenzylisoquinolines, secobenzophenanthridines, secocularines, and secoquettamines. No collective comprehensive review on this subject has yet been published in the chemical literature, although some of these groups were occasionally reviewed (2-8). The intent of this chapter is to collect these alkaloids in one group and in this way introduce a new type of alkaloids to the big isoquinoline family and term them the secoisoquinoline alkaloids. In this chapter two criteria of classifying alkaloids as secoisoquinolines have been assumed: chemical and biogenetic. The chemical criterion requires a structural relationship to the classic isoquinoline alkaloids clearly indicating that the seco bases were formed as a result of oxidative degradation of the latter. Since not enough bisosynthetic investigations in uiuo have been carried out, the fact that these bases occur in the same plants as their cyclic precursors is assumed to meet the biogenetic criterion. The alkaloids described here are organized into six groups beginning with the most numerous secoberbines and secophthalideisoquinolines and ending with secoquettamines. For each group a concise compilation of their structural, physical, and spectral data as well as their synthesis and transformations are provided, the literature being covered until mid- 1986. The numbering system of each group of the seco bases follows the one accepted for the isoquinoline alkaloids (2,9).No significant biological and physiological effects have been reported for this type of compound. When discussing seco alkaloids the question of their genesis should not be disregarded. Are they true alkaloids or artifacts of isolation? It is difficult to answer this question with certainty. Some of them, e.g., secophthalideisoquinoline ene lactams, are postulated to be formed during the extraction process; however, most of them are believed to be metabolites produced naturally. This may be evidenced by the fact that some of these alkaloids retain optical activity, and in addition many of them can be synthesized in biomimetic syntheses in the laboratory. Thus, one can generalize the opinion of Shamma (ZO), whose significant contribution to the field of secoisoquinoline alkaloids should be acknowledged, that “[a process] . . . could presumably occur in uiuo at least as readily as it could in uitro.”

4. SECOISOQUINOLINE ALKALOIDS

233

11. Secoberbine Alkaloids

A number of secoisoquinoline alkaloids turned out to originate from the protoberberine type to bases. The variety of structures of secoberbines shows that the quinolizidine ring in the cyclic base can be opended in various places. Thus, secoberbines can be divided into the following subgroups: (A) 7,8-secoberbines, tricyclic and tetracyclic; (B) peshawarine, a 7,8- 14,7bissecoberbine; (C) 6,7-secoberbines (3-arylisoquinolines); and (D) 8,8asecoberbines (pseudobenzylisoquinolines). Some of these alkaloids, often termed differently, have already been reviewed by Shamma et al. (2.3)and Santavy (7). The secoberbine alkaloids are mainly found in the families Papaveraceae, Fumariaceae, and Berberidaceae and also in the families Annonaceae and Ranunculaceae, families, though much less frequently.

A. 7,8-SECOBERBINE ALKALOIDS Apart from the alkaloids mentioned in the previous reviews (2,3,7),two other alkaloids of the 7,8-secoberbine subgroup, i.e., macrantaline (6) and mactantoridine (7) are known. They were both isolated from Papauer pseudoorientale ( 11.12, Addendum) and macrantaline from Papaver lisea (13). In all, eight natural 7,8-secoberbines, aobamine (I), (+)-canadaline (2), (+)corydalisol(4), ( -)-corydalisol(5), ( + )-macrantaline (6),macrantoridine (7), hypecorine (8), hypecorinine (corydalispirone 9), and one unnatural alkaloid, canadalisol (3), have been discovered. These alkaloids are listed in Table I along with plant species in which they were found. All the 7,8-secoberbines incorporate an N-methyltetrahydroisoquinoline moiety with two or three oxygenated substituents at C-1, C-2, and C-3. The lower aromatic ring possesses four substituents in a vicinal arrangement of which two are alkoxyls and the third the “berbine bridge” carbon. The latter may occur in different oxidation states: as an aldehyde (in 1 and 2), an alcohol (3-6,8,9), or a carboxylic acid (7). The 7,8-secoberbine alkaloids are found mainly in genera of the family Papaveraceae. The most wide spread alkaloid seems to be hypecorinine (9), present in four species, whereas the remaining ones, except for macrantaline (6),have so far been discovered in only one plant. It is postulated that the 7,8seco bases are formed in nature as a result of oxidative degradation of either protoberberinium or tetrahydroprotoberberinium salts, due to the cleavage of C-8-N bond. Various speculations concerning the biosynthesis of these alkaloids have been put forward (3,21-23); however, no biogenetic investigations in uiuo have been carried out. As the key biosynthetic

234

MARIA D. ROZWADOWSKA

TABLE I 7,8-SECOBERBINE ALKALOIDS AND WURCES OF OCCURRENCE

Compound

R

Aobamine (1) (+)-Canadaline (2) Canadalisol(3) (+)-Corydalisol(4) (-)-Corydalisol (5) ( +)-Macrantaline (6)

H H H H H OCH,

CH2 CHO CHO CH, CH, CHZOH CH, CH3 CH2 CH,OH CH2 CH,OH CH,OH CH, CH,

Macrantoridine (7)

OCH,

COOH

Hypecorine (8) (X = H) Hypecorinine (Corydalispirone, 9) (X + x = 0)

R'

R2

CH,

R3

CH,

Source (%)

Ref.

Corydalis ochotensis var. raddeana Hydrastis canadensis L.

14.15 16 16 17 18 11,12

Corydalis incisa Pers. (0.00004) Hypecoum procumbens L. (O.OOO4) Papaver pseudoorientale Fedde Medw. (0.08) Papaver lisea N. Busch Papaver pseudoorientale Fedde Medw. (0.004)

Hypecoum erectum L. (0.086) Hypecoum erectum L. (0.006) Corydalis incisa Pers. (0.0006) Hypecoum procumbens L. (0.0002) Pteridophyllum racernosum Sieb. et Zucc (0.0006)

13 I!

19 19 17 18

20

intermediates, immonium compounds of type 10 and/or 11 have been postulated. The immonium system 11 has been examined by Czech authors (22,24,25), who claimed that it reacts with hydroxide ions in aqueous media to form pseudobases. This implies that hypecorine (8) and hypecorinine (9) may be artifacts of isolation. In all probability, the quaternary immonium system

4.

235

SECOISOQUINOLINE ALKALOIDS

OR’ OR’ 10

11

exists in the plant which during the isolation process in alkaline so1u:ion cyclizes to the spirocyclic 0,N-acetal. The structures of these bases have been established mainly on the grounds of their physicochemical data and have been confirmed by synthesis. In Table I1 the melting points, specific rotations, absolute configurations, and IR and UV spectral features are collected. The absolute configuration of two alkaloids from the 7,8-seco subgroup has been established by chemical correlation with compounds of known stereochemistry. ( )-Corydalisol (4) was transformed to (14R)-(+)-stylopine (39) (26)(see Scheme 9 in Section II,A,2,d), and macrantaline (6)was transformed to the methyl derivative 12, identical to that obtained from (-)-a-narcotine (13)(ZZ) (Scheme 1). In this way that (14s) configuration of macrantaline (6) has been determined. By analogy to (+)-corydalisol (4), (+)-canadahsol (3) has been assigned the identical configuration (3);since 3 has been prepared by hydride reduction of ( + )-canadaline (2), consequently the latter must belong to the same configurational series (3).In contrast, (-)-corydalisol (5) must possess the opposite stereochemistry around C-14, with its C D spectrum being the mirror image of that of the (+) enantiomer (4) (18). However, though macrantoridine (7) shows a C D curve of opposite sign to that of macrantaline (6)(11), one cannot infer that it differs in configuration at C-14 because of the presence of the C-8 carboxylic function. Exact ‘H-NMR data of these alkaloids can be found in Shamma’s book (2); data for macrantaline (6) and macrantoridine (7) are in Refs. 11-13. The absorption of the H-14 proton was found to be a characteristic feature of the spectra and appears in the region arounds 63.6. However, it was not clear whether it forms a triplet (3,21,26),a doublet of doublets (23,27),or a quartet (ZZ). Methylene protons from the ArCH,O group (64.48-4.74) are nonequivalent, and in the spectra of both alcohols (3-6) and tetracyclic bases (8,9)they form an AB quartet with the coupling constants equal to 10-12 and 15- 16 Hz, respectively. The AB quartet originating from the H-11 and H-12 ortho protons (J = 7-8 Hz) is a characteristic spectral pattern of the aromatic region in spectra of compounds with the benzyloxy substituent. As might be expected, the I3C-NMR spectra of 7,8-secoberbines, recorded

+

236

MARIA D. ROZWADOWSKA

SOME PHYSICAL AND

Compound Aobamine (1)

(+)-Aobamine (1) (+)-Canadaline (2) (+)-Canadaline (2)

(+)-Canadahsol (3) (f)-Canadalisol(3)

Melting point ("C) Oil

164-165.5 168- 168.5 117-118 139-140 140-141 143-143.5

TABLE I1 SPECTRAL DATAOF 7,8-SECOBERBINE ALKALOIDS CHCli V,,"

[ a ] ~ " c ' 3 Configuration

-

1680

-

I685 1680 (KBr) 1680 1685 1680 1693(CCI,)

+43" -

-

(+ )-Corydalisol(4)

Oil 105-107 107-108 160-161

+21.4"

(-)-Corydalisol(5)

-

- 18"

(+)-Corydalisol(4)

127- I28 145-146 145.5- 147 147-148 140-141

-

(+)-Macrantaline (6)

-

3150(KBr) 3460 1660 (KBr) -

1I4

-

(+)-Hypecorine (8)

154-156 160- 162

-

( f )-Hypecorinine

196-198 197- 198 197-199 200-201

-

~CHJOH

max , nm (log E )

212 (4.24) 234 (4.06) 291 (3.80) 348 (3.31) 288 (4.89) 226 (4.39) 262 (3.82) 288 (3.90) 331 (3.42) -

3400-3100 3175 (Nujol) 3120 240 (3.75) 294 (3.83) 210 (4.45) 3 100 235 sh (3.83) 293 (3.87) 210 (4.51) 3160 239 sh (3.87) 3340 3150 (Nujol) 293 (3.91)

+30.2"

Macrantoridine (7)

(Corydalispirone, 9)

(cm-')

1690 1692 1685 (KBr)

238 (4.04) 285 (3.64) 236(3.91) 284 (3.45) 208 (4.55) 248 (4.15) 294 (3.85) 369 (3.89) 240(4.38) 292 (4.08) 320 (3.93)

Ref. 14,15

3.30.46 16 3.29 31-33

3,16 23.27 29.33 17.26 18

3.23.27, 30,42, 46 11.13

I1 19.23, 27.42

17,19, 20.26, 41.46

for 3, 4, 8 ( 2 3 , and 9 (28),are very similar to those of benzylisoquinoline alkaloids (28).The "berbine bridge" C-8 carbon, found in the region between 654.9 and 59.2, causes a clear deshielding effect on the neighboring C-8a atom. The upfield shift of C-13 in the spectrum of hypecorine (8)(636.0) may reflect conformational changes in the spirocyclic system compared to the tricyclic system (641.0). In the spectrum of hypecorinine (9), a marked

237

4. SECOISOQUINOLINE ALKALOIDS

6

I

12 1.Ac20 2.H2/W-C

13 SCHEME 1

influence of the carbonyl group on the chemical shifts of (2-10, C-1 1, and C12a is observed. The mass fragmentation of tricyclic bases (1-7) is analogous to that of benzylisoquinoline alkaloids as well. The fragmentation pattern is consistent with fission of the central and double benzylic C-C bond forming Nmethyltetrahydroisoquinolinium ions, being at the same time the base peaks. In some spectra ions representing the “lower” benzylic fragments of molecules (11,18,26)are present, but only as minor peaks. The mass fragmentation of tetracyclic alkaloids (8,9) procedes in a different way. The cleavage starts with a retro-Diels- Alder process (23,26,27)and leads to the base peak originating from the “lower” ring. Molecular ions are found in the spectra of all alkaloids, although they are sometimes of low intensity and are detected by means of CI or FD techniques. Frequently the derivatives containing a hydroxymethyl function show the presence of M - 1 ions (18.29).

I . Synthesis of 7,8-SecoberbineAlkaloids In many syntheses of 7,8-secoberbines other isoquinoline alkaloids have been used as substrates.

238

TR MARIA D. ROZWADOWSKA

'

OR

16

14 R + R = C H 2 15 R=CH3

17 SCHEME 2

AcONa

SCHEME

3

4.

SECOISOQUINOLINE ALKALOIDS

239

a. Synthesis from Protoberberine Alkaloids. Both quaternary protoberberinium salts and tetrahydroprotoberberine bases have been employed for syntheses. ( +)-Aobamine (I), (+)-canadaline (2), and (+)-corydalisol(4) were synthesizedfrom the quaternary compounds coptisine(14)and berberine (15), respectively, by means of the method worked out by Shamma et al. (3,30,31)(Scheme 2). The key step of this synthesis was the regioselective Hofmann degradation of the methiodides of 8-benzyl derivatives 16, prepared from the quaternary bases. OsO,/NaIO, oxidation of degradation products 17 gave rise to alkaloids 1 or 2. Reduction of 2 led to alcohol 4. Chloroformates have been used for regioselective C-8-N bond cleavage of tetrahydroprotoberbine bases to produce secoberbines (29,32-36). Although under traditional Schotten-Baumann conditions these alkaloids are known to be resistant to the action of these reagents, reactions carried out in homogeneous systems, such as C1COOC2H,/NaI/acetone at room temperature (29)or neat chloroformate at reflux for a prolonged time (32-36), proved to be successful. Ronsch (29) and Hanaoka et al. (33) obtained ( +)-canadalisol (3) and ( + )-canadaline (2) from tetrahydroberberine (18, canadine) in this way (Scheme 3). Kametani et al. (37-40) reported an abnormal Hofmann degradation of tetrahydroprotoberberine metho salts which resulted in secoberbines.From a synthetic point of view, however, this method appeared to be of little importance since other degradation products were formed as well. Furthermore, it was applicable only to derivatives with phenolic hydroxy groups at C-9 and/or C-1. b. Synthesis from Phthalideisoquinoline Alkaloids. An elegant method of synthesis of hypecorinine (9) from dehydrobicuculline (19) was performed by Nalliah and MacLean (41) (Scheme 4). Lithium aluminum hydride reduction of the dehydrobase 19 resulted in hydroxymethyl derivative 20, which spontaneously underwent oxidation in air to the desired product 9.

c. Synthesis from Protopine Alkaloids. Gozler and Shamma (42)as well as Iwasa et al. (23.27) applied the pyrolytic Meisenheimer rearrangement of protopine N-oxide (21) for the synthesis of ( +)-corydalisol(4) and hypecorine (8) (Scheme 5). The ring-enlarged rearrangement product 22 when reduced with zinc in acetic acid produced both 4 and 8, while catalytic hydrogenation resulted in 4 as the sole product. d. Synthesis from Spirobenzylisoquinoline Alkaloids. The oxidative photolysis of fumaricine conducted by Gozler et al. (43,44),as a result of which a derivative structurally related to hypecorinine (9)was formed, demonstrates the possibility of obtaining secoberbine alkaloids from spirobenzylisoquinolines.

240

MARIA D. ROZWADOWSKA

19

air

L

9 SCHEME 4

22

21

4

8 SCHEME 5

4. SECOISOQUXNOLINE ALKALOIDS

24 1

23

CH2O

24 SCHEME 6

e. Synthesis from Benzylisoquinoline Alkaloids. It is well known that electrophilic substitution of l-benzylisoquinoline derivatives occurs at C-6; yet Narasimhan et al. (45), making use of the heteroatom-directed ortho lithiation of aromatic compounds, were able to introduce substituents at C-2. Thus, laudanosine (23)when treated first with butyllithium and then with paraformaldehyde yielded the canadaline analog 24 having the desired sequence of substituents in “lower” aromatic ring (Scheme 6). f. Total Synthesis. In a total synthesis of (+)-aobamine (I), (*)corydalisol (4), and ( f)-hypecorinine (9), Rozwadowska and Metecka (46) applied hydrastinine hydrochloride (25) and 1,3-dithian (26) as basic building blocks (Scheme 7). The addition product 27 was desulfurized with Raney nickel to give 28, which when reduced afforded (+)-corydalisol(4). Oxidation of the latter resulted in aldehyde 1. Alternatively, reduction and hydrolysis of the masking group in 27 led to keto alcohol 29, which was used for synthesis of hypecorinine (9). 2. Reactions of 7,s-Secoberbine Alkaloids a. Degradation and Ring-Opening Processes. The structures of the seco alkaloids were determined on the basis of their spectral properties. In the case

242

MARIA D. ROZWADOWSKA

25

+

27

I

26

1. LAH

2. H ~ O / B F ~

29

20

(?)-I SCHEME 7

of hypecorine (8),however, a classic degradation method using potassium permanganate, resulting in 3.4-methylenedioxyphthalide,was applied for this purpose (19). Reactions with acid halides and anhydrides were sometimes applied for partial degradation. They caused cleavage of the C-14-N bond in the tetrahydroisoquinoline ring. Hypecorine (8) when heated with acetic

4. SECOISOQUINOLINE ALKALOIDS

243

anhydride formed 0,N-diacetyl derivative 30 (19), while hypecorinine (9) proved to be resistant to the action of this reagent. On the other hand, corydalisol (4) formed diacetyl derivative 31 of stilbene type (21). A monoacetyl ester of macrantaline (6) was also obtained (11). Wiegrebe et al. (47-50) studied the action of chloroformates on 7,8secoberbines. These reagents caused cleavage of the tetrahydroisoquinoline ring with simultaneous formation of isochroman 32 or isochromanon 33 systems. The mechanism of this process is the S,Ztype attack of a carboxylate or hydroxyl ion on C-14 causing the inversion of configuration at this center (50).This type of degradation was employed by Shamma et al. (3,30,31)in the synthesis of pashawarine (43) and by Wiegrebe et al. (48-50) in the synthesis of its analogs. Macrantaline (6) when treated with ethyl chloroformate produced stilbene 34 (52) instead of the expected isochroman derivative, possibly because of the steric interactions. Prior and Wiegrebe ( 5 2 3 ) examined the von Braun degradation of 7,8secoberbines. It proceeded analogously to the reaction with chloroformates

30

OCH3

32 33 35 36

R=COOC2H5 i X = H R=COOC2Hsi X+X=O R = C N i X=H R =CN i X+X=O

244

MARIA D. ROZWADOWSKA

and led to the ring-opened cyanamine with concomitant formation of either isochroman 35 or isochromanon 36 derivatives.

b. Oxidation and Reduction. Many of the 7,8-secoberbine alkaloids were transformed to one another as a result of reduction or oxidation processes. Sodium borohydride was most often applied for transformations of the aldehydic alkaloids to alcohols (3,16,30). The carboxylic group in macrantoridine (7)was reduced to a hydroxymethylfunction by lithium aluminum hydride (11).The same reducing agent converted hypecorinine(9)to a mixture of diastereomeric diols: bicucullinodiol and adluminodiol (26).Pseudohypecorine (37) was reduced to corydalisol (4) by means of both sodium borohydride and zinc in hydrochloric acid (22).The oxidation of hydroxymethyl derivatives to aldehydes was carried out with pyridinium chlorochromate ( 2 9 3 )or pyridine XrO, (46). c. Action of Acids and Bases. Tetracyclic 7,8-secoberbine alkaloids (21.26)and their analogs (22,24)underwent acid-catalyzed transformation to tricyclic derivatives of the pseudohypecorine (37) type due to opening of the spirocyclic ring (Scheme 8). Strong bases caused recyclization to the parent tetracyclic system. The ease with which the transformation took place seems to explain the reason why hypecorine (8)and hypecorinine (9)occur in the form of racemates (21).A similar type of conversion was reported for canadaline (2); a tetracyclic carbinolamine type of salt 38was isolated in crystallineform (29).

0-J 37

8

38 SCHEME^

245

4. SECOISOQUINOLME ALKALOIDS

4 R+R=CH2 3 R=CH3

I

40 R=CH3

39 SCHEME 9

d. Transformations of 7,&Secoberbines to Other Alkaloids. Two “retro” reactions were carried out in which the parent tetrahydroprotoberberine alkaloids were obtained from secoberbines. Nanaoka and Nishioka (26) converted ( + )-corydalisol (4) to ( +)-tetrahydrocoptisine (39) (stylopine), while Ronsch (54), under Pfitzner-Moffat reaction conditions, transformed ( f)-canadalisol(3) to a-canadine methochloride (40)(Scheme 9). Secoberbine 41 was an intermediate in a biomimetic transformation of (Scheme 10). tetrahydroberberine (18) to retroprotoberberine (42) (33,55,56)

SCHEME

10

246

MARIA D. ROZWADOWSKA

The following section shows the synthesis of peshawarine (43) from aobamine (1). B.

PESHAWARINE, A 7,8-14,7-BISSECOBERBINE

ALKALOID

(-)-Peshawarine (43) was isolated by Shamma et al. (31) from Hypecoum paruiJlorum Kar & Kir (0.00066%)and was classified as a secoberbine. It was postulated (3) that it could be biosynthesized from protoberberine by a process in which a macrantoridine (7) type of base was one of the

(-1 43

(+I44

Ill 3Emde

1

51 SCHEME 11

Emde

247

4. SECOISOQUINOLINE ALKALOIDS

intermediates; after N-methylation it could undergo intramolecular SN2displacement of the quaternary nitrogen by the carboxylate ion to produce a bissecoberbine. Such a process would account for the absolute configuration of (-)-peshawarine (43), which is opposite to the configuration of most of the other 7,s-secoberbines. The absolute configuration of (-)-peshawarine (43) was determined by chemical correlation of (+)-peshawarinediol (44), obtained by LiAlH, reduction of the natural base 43, with the diol prepared by Emde degradation of ( + )-rhoeagenine methiodide (4S), whose stereochemistry was known as (14s) (30,57,58) (Scheme 11). Both diols were identical in terms of spectral and physical data as well as CD curves. In Table I11 some physical constants and characteristic spectral data of natural and synthetic peshawarine (43) and peshawarinediol (44) are presented. In the 'H-NMR spectra the signal coming from H-14 deserves attention. It occurs as a doublet of doublets in spectra of both peshawarine (43) and diols (44). Another doublet of doublets in the aromatic region in spectra of peshawarine (43) can be attributed to C-1 1and C-12 ortho protons. In the case of the peshawarinediols(44), these protons appear as two singlets. In the mass spectra of these compounds the base peak at m/z 58, [CH,=N(CH,)J+, characteristic of the N,N-dimethylaminoethyl side chain, dominates; the remaining peaks are of low intensity. They may be consistent with the following fragment ions:

mlz 163

rnlz 190

mlz 135

( HH.M.S.190.08621)

CH=OH rnlz 222

mlz 165

Three independent syntheses of ( f )-peshawarine (43) have been carried out. Shamma et al. ( 3 3 4 ,in a biogenetictype transformation, prepared it from ( f)-aobamine (1) which had been obtained from coptisine (14) (see Scheme 2, Section II,A,l,a). Under the action of ethyl chloroformate, 1was converted to cyclic hemiacetal46, whose methyl acetal was reduced to the tertiary base 47.

TABLE 111

soME~ H Y S I C A LDATAAND SPECTRAL CHARACTERISTICS OF PESHAWARINE (43) AND PESHAWARINEDIOL(44) 'H NMR (6, CDCI,) Compound (-)-Peshawarine (43)

(+)-Peshawarine (43)

(+)-Peshawarinediol (44)

L

McOH

Melting point ("C)

[alD

(ern-')

nm (log P)

(m/4

N-CH,

H-14

H-11, H-12

190-191 (CH,OH)

- 109" (CH,OH)

1725 (CHCI,)

385 (M'), 190, 163, 150, 135,58 (100%)

2.26

5.55 d 5.73 d J = 4.5 Hz

6.65 d 6.93 d J = 8 Hz

3

182-183

-

385 (M'), 190, 163, 165, 134,58, (100%)

2.27

5.59 d 5.72 d J = 3.5 Hz

6.68 d 6.97 d J = 8 HZ

3.59.60

(CH3OH) 196-198 (CH3OH) 201- 203 (CH3OH) 133-136 (CH,OH) 135-136 (AcOEt)

1725 (CHCIJ 1705 (KBr)

228 (4.96) 245 (4.32) 293 (3.78) 333 (3.69) -

+11T (CH,OH) + 63" (CHCI,)

225 (4.21) 288 (3.63) or 237 (3.92) 292 (3.91) -

387.4183 (M+)

2.10

4.92 q J = 13.5 Hz

6.67 s

3,57,58

-

-

-

-

387 (M+), 369 (M - H,O), 222, 177, 163, 58 (100%)

2.10

4.79 d 4.90 d J = 3.5 Hz

6.69 s

(-)-Peshawarinediol (44)

135-136 (AcOEt)

(+)-Peshawarinediol (44)

138-140 (CH3OH)

-110" (CH3OH) -61" (CHCI,) -

vmax

3320 (KBr)

I

Mass spectrum

-

Ref.

58.61

62

249

4. SECOISOQUINOLINE ALKALOIDS

1

46

SCHEME 12

Acid-catalyzed hydrolysis of the latter followed by Jones oxidation furnished racemic peshawarine (43)(Scheme 12).Simanek et al. (59)transformed the same amino acetal47, obtained in optically active form from the Emde degradation to (+)-43, also by hydrolysis and oxidation. of rhoeadine methiodide (a), However, the optical activity was lost during hydrolysis (Scheme 12). Chrzanowska and Rozwadowska (60) performed a total synthesis of (+)43, using amine 49 and the thioacetal of methoxycarbonylpiperonal (26) as substrates (Scheme 13). These two synthons were joined together under the influence of LDA, and the resulting addition product 50 was subjected to reductive desulfurization with Raney nickel to give racemic peshawarine (43). Several syntheses of peshawarinediol (44) were carried out. The dextrarotatory enantiomer was synthesized by a Czech group (57-59) from both rhoeagenine methiodide (45) and rhoeageninediol methiodide (51) by Emde degradation (Scheme 11). The same reaction performed on isorhoeageninediol resulted in (-)a (58,61). Racemic peshawarinediol (44) was synthesized (52) in way similar to that of (f)-43 by using urethane 52 and dithian 26

250

MARIA D. ROZWADOWSKA

1

26

(2)-

LAH

44

Ra-Ni

54 SCHEME 13

(Scheme 13).The addition product 53 was reduced to diol54, and Raney nickel was used for the removal of the masking group.

c. 6,7-SECOBERBINE ALKALOIDS (3-ARYLISOQUINOLINE ALKALOIDS) The 6,7-secoberbinealkaloids contain the four following natural products: corydalic acid methyl ester (55), corydamine (S),N-formylcorydamine (57), and hypecumine (58). These bases, called 3-arylisoquinolines, were described by Shamma and Moniot (2) as a separate class of isoquinoline alkaloids. Santavy (7) classified them among benzophenanthridines. It seems,however, that they may be considered as biosynthetic intermediates between the protoberberines on the one hand and the benzophenanthridines on the other.

25 1

4. SECOISOQUINOLINE ALKALOIDS

56 R = H 57 R = CHO 58 R =COOC2H5

55

Three of the alkaloids (55-57) were isolated from Corydalis i n c h (63-65) and two (57, 58) from Hypecoum procumbens (66),where they coexist with the parent protoberberines. They are formed in plants by an oxidative C-6--N bond cleavage, possibly through an aldehyde intermediate 61. This assumption was supported by in uiuo experiments in which (&)tetrahydrocorysamine-8,Z4-f2(59) and ( & )-tetrahydrocoptisine-8.Z4-t2(60) were fed to Coryduh incisu (67)to produce corydalic acid methyl ester-8-1(55) along with corydamine-8-t (58) and corydalic acid methyl ester-8-t (55) with corynoline-8-t (62), a benzophenantridine alkaloid, respectively (Scheme 14).

55

--

56

- [8-q

__c

+

-3H]

+ 62 SCHEME14

SOME

TABLE IV PHYSICAL DATAAND SPECTRAL CHARACTERISTICSOF 6.7-SECOBERBINE ALKALOLLX

Compound (+)-Corydalic acid methyl ester (55)

140-141

+85.4"

1738

240(4.07) 289 (3.96)

Corydamine hydrochloride (56)

235-239 255-257

-

3420

N-Formylcorydamine (57)

159- 160.5

-

1670

Amorphous

-

1680

245 (4.51) 312 (4.18) 380 (3.59) 244(4.60) 309 (4.14) 376 (3.53) 241 (3.41) 306 (3.00) 375 (2.48)

Hypecumine (58)

a

In DMSO.

397 (M') 382 (89) 366 (81) 204 (50) 162 (100) 350 (M - HCI) 306 (100)

2.1

5.9

6.82 q (65) J = 10.5 Hz or 6.70 s, 6.88 s (69)

65.69

2.63"

6.10" 6.38"

7.56 d, 7.71 d" J=9Hz

63.64

2.68 2.72

6.00 6.24

7.41 s

64

2.67

5.99 6.27

1.42 s

66

44 378 (M+) 318 (100) 306 422 (M+) 320 (28) 319 (78) 318 (100) 306 (36) 116(19)

4. SECOISOQUINOLINE ALKALOIDS

253

In Table IV some physical data and spectral characteristics of 6,7secoberbines are listed. Only methyl corydalate (55) is optically active. Formula 55 presents the spatial structure of this compound, deduced by Nonaka et al. (65)and confirmed by Cushman et al. by both correlation with ( +)-mesotetrahydrocorysamine (72) (68)and total synthesis (69).It is difficult to find common characteristic features in both the mass and 'H-NMR spectra of these alkaloids because they differ significantly from each other in their structures. On one hand, corydalic acid methyl ester (55) incorporates a saturated nitrogen heterocycle, while the three aromatic bases (56-58) differ in the character of the side chain nitrogen. For example, in mass fragmentation, ions of the following structures may be ascribed to the most intensive bands in the spectrum of 55:

+

miz 366

1+

miz 162 (lOOo/o 1

m i z 204

In the case of secondary amine 56 the base peak is due to cleavage of fl bond with respect to the side chain nitrogen, while in both amide 57 and urethane 58 the a bond is broken along with elimination of H,.

I. Synthesis and Transformations of 6,7-Secoberbines Three syntheses of 6,7-secoberbines have been carried out. Two of them and the third involved degradation of the protoberberine alkaloids (63,65), was a total synthesis (69).Takao and Iwasa (63)applied the von Braun reaction to tetrahydrocoptisine (39) to obtain the 6,7-seco bromide 63, which on treatment with dimethylamine, followed by hydrolysis, gave tetrahydrocorydamine (64).This tetrahydrobase 64, which was also produced from 56 by zinc in hydrochloric acid (63),was dehydrogenated to corydamine (56) (Scheme 15). In the synthesis of methyl corydalate (55) Nonaka et al. (65)used the methiodide of ( +)-tetrahydrocorysamine (65) as substrate and the Hofmann degradation method for ring opening (Scheme 16). The methine base (66)on hydroboration afforded alcohol 67, identical with a product obtained from 55 by lithium aluminium hydride reduction.

,254

MARIA D. ROZWADOWSKA

64 SCHEME 15

Hofmann

65

66

67 SCHEME 16

A total synthesis of (+)-55 was performed by Cushman et al. (69) (Scheme 17). It. was based on cycloaddition of Schiff base 68 to anhydride 69. The addition product 70, received in the form of a mixture of diastereomers, was then subjected to thermal decarboxylation to give rise to diastereomer 71 with the desired trans configuration as the major product. The latter upon methanolysis and selective reduction furnished ( +)-55. Several transformations of 6,7-secoberbine alkaloids to their parent congeners were conducted. Corydalic acid methyl ester (55) was converted to ( +)-mesotetrahydrocorysamine (72)(65) (Scheme 18), and corydamine (56) was transformed to tetrahydrocoptisine (39)(64)(Scheme 19).

CN N-CH3

68

CH3CN

+

70

0

OJ

69

(:%: CN

A

CH3

1 2.POC13/NaBHb . CH30H/H*

:I )

71 SCHEME 17

72 SCHEME 18

(+)

- 55

256

MARIA D. ROZWADOWSKA

SCHEME 19

D. 8,8a-SECOBERBINE ALKALOIDS

(PSEUDOBENZYLISOQUINOLINE ALKALOIDS) The following natural products can be assigned to the subgroup of 8,8asecoberbine alkaloids: polycarpine (73),polyberbine (74), ledecorine (75), rugosinone (76),taxilamine (77), berbithine (78), dihydrorugosinone (79), dihydrotaxilamine (80). The 8,8a-secoberbines incorporate a benzylisoquinoline skeleton in which the “lower” aromatic ring is oxygenated at C-8a,

73 R = CH3 74 R + R = CH2

75

79 R + R = C H 2 80 R = C H 3

4. SECOISOQUINOLINE ALKALOIDS

257

C-9, and C-10, always with a phenolic hydroxy group at the 8a position. Moreover, they differ from one another by the oxidation state of the benzylic C-13 as well as by substitution and degree of saturation of the isoquinoline fragment. These alkaloids, classified as benzylisoquinoline alkaloids (2,7074), have recently been called by Shamma et al. (75-77) pseudobenzylisoquinolines originating from protoberberine alkaloids. In Table V a list of 8,8a-secoberbine alkaloids, sources, and spectral data are presented. The pseudobenzylisoquinoline alkaloids are fairly widespread in nature, being found among members of Berberidaceae, Annonaceae, Fumariaceae, and Ranunculaceae. The biogenesis of the pseudobenzylisoquinoline alkaloids assumes their formation from protoberberinium salts by C-8-C-8a bond scission in a Baeyer-Villiger-type oxidative rearrangement to produce the enamides of type 73 and 74. These amides may be further biotransformed either to rugosinone (76) type alkaloids by hydrolytic Ndeformylation followed by oxidation or to ledecorine (75) by enzymatic reduction. These transformations were corroborated by in uitro studies (8082). It is suggested that enamide seco alkaloids may be precursors of aporphine alkaloids (80), on one hand, and of cularine alkaloids (77), on the other. Only one of these alkaloids, ledecorine (75), exhibits optical activity. Its absolute configuration was determined by Shamma et al. (80)as (14s) on the finding that levorotatory N-methyltetrahydroisoquinolinesincorporating a hydroxy function in ring C at C-2 belong to the (S)configurational series. The 2 configuration of polycarpine (73) was assigned by X-ray structural analysis (72),whereas its O-methyl derivative,.also 2, was determined on the grounds of spectral data (71). The UV spectra of these alkaloids exhibit a bathochromic shift in alkaline solution indicating the presence of a phenolic hydroxy group. In the IR spectra of ketonic alkaloids (76, 79, 80) the carbonyl group absorption is clearly shifted toward lower frequencies (1620-1630 cm-I), obviously due to intramolecular hydrogen bonding. The amide band in the spectra of 73 and 74 is located between 1660 and 1670 cm-'. In the mass spectra of amides 73 and 74 the molecular ion is at the same time the base peak, reflecting the high stability caused by the presence of a benzylidenesubstituent in the postion a to nitrogen. In spectra of the other alkaloids, the dominating fragmentation seems to be cleavage of the C-14-C-15 bond. This is evidenced by the presence of base peaks corresponding to isoquinolinium ions. 1 . Synthesis and Transformations of 8,8a-Secoberbine Alkaloids Polycarpine (73) and polyberbine (74) were synthesized by Shamma and Murugesan (80) and Hanaoka et al. (82)from appropriate protoberberinium

TABLE V 8,8a-SECOBERBINE ALKALOIDS, SOURCFS OF OCCURRENCE, AND

Compound

Source (%)

Melting point (“C)

,”’;:A nm (log E)

PHYSICAL AND

v;::

(cm-’)

Polycarpine (73)

Enantia polycarpa End. et Diels (Annonaceae, 0.014)

176- 177 178- 180 179- 180

222 (4.47) 262 (4.02) 332 (4.23) (C,H,OH)

3260 1670 1620

Polyberbine (74)

Berberis valdiviana Phil. (Berberidaceae, 0.00013)

165-166

216 (4.51) 332 (4.17)

3500 1660 1610 (CHW

Ledecorine (75)

Corydalis ledebouriana K. et K. (Fumariaceae)

199-200

240 sh (3.88) 295 (3.74)

3430 1620 1590

Rugosinone (76)

Thalictrum rugosum Ait., Thalictrum foliolosum DC. (Ranunculaceae, 0.000008), Berberis darwinii (Berberidaceae, O.ooOo3)

212-214 220- 22 1 223-224

234 (4.49) 299 (4.06) 336 sh (3.90)

1630 1590 or 1627 (CHCI,)

h)

00 VI

SPECTRAL CHARACTERISTICS

Mass spectrum, mlz (%I 385 (M+, 100) 368 (47) 357 (35) 340 (26) 192 (8) 369 (M+, 100) 352 (33) 341 (34) 324 (37) 176 341 (M+) 190 (loo) 176 149 353 (M’, 29) 294 (71) 181 (16) 174 (43) 172 (100)

‘HNMR(6,CDC13) C-5, C-6

C-1 1, C-12

Ref.

2.81 t 3.97 t J=6Hz

6.46 d 7.02 d J=9Hz

71,72. 73. 80. 82

2.83 t 3.83 t J=6Hz

6.38 d 6.95 d J=9Hz

77.80, 82

260-3.20 m

6.27 d 6.58 d J=8Hz

70,81

7.61 d 8.43 d J=5Hz

6.41 d 7.20 d J=9Hz

74.75,

78

I

81

Taxilamine (77)

Berberis aristata DC. (Berberidaceae, 0.00015)

-

238 (4.48) 299 (4.02) 330 sh (3.85)

-

Berbithine (78)

Berberis actinacantha Mart. ex Schult. (Berberidaceae, 0.0000023)

-

236 (4.04) 316 (3.01) 330 (3.01)

-

Dihydrorugosinone

Berberis darwinii Hook. (O.ooo02h Berberis actinacantha Mart. ex Schult. (O.ooo0l) (Berberidaceae) Berberis actinacantha Mart. ex Schult. (Berberidaceae, O.oooO13)

172-174 220-223

(79)

Dihydrotaxilamine (80)

-

228 sh (4.71) 299 (4.50)

1620 (CHCI,)

230 (4.14) 296 (4.00)

1620 1602 (CHCI,)

369 (M', 32) 310 (68) 296 (33) 188 (57) 181 (13) 339 (M', 100) 324 (36) 306 (47) 224 (23) 187 (11) 174 (18) 355 (M', 42) 353 (53) 296 (93) 174 (53) 172 (100) 371 (M', 45) 312(100) 190 (6) 181 (10)

7.66 d 8.46 d J = 5.5 HZ

6.44 d 7.28 d J = 9.1 Hz

76

7.40 d 8.22 d J = 5.7 Hz

6.39 d 6.95 d J = 8.5 Hz

79

2.8 t 3.8 t J = 6 HZ

6.48 d 7.45 d J = 9.1 HZ

75.8I

2.83 d 3.87 d J = 7.1 HZ

6.50d 7.51 d J = 9 HZ

79

260

MARIA D. ROZWADOWSKA

mC P B A

81 R = CH3 IS R+R=CH2

73 R

= CH3

74 R + R = CH2 SCHEME 20

salts in biogenetically patterned reactions (Scheme 20). Thus, palmatine chloride (81) or berberine chloride (15), when treated with m-chloroperbenzoic acid in the presence of sodium bicarbonate or sodium hydroxide, yielded polycarpine (73) and polyberbine (74), respectively. A Baeyer-Villiger-type oxidative rearrangement mechanism was proposed for this transformation. Small yields of 74 were also obtained from a berberine-chloroform adduct when left on a silica gel chromatography column for a prolonged period of time. (10). Total synthesis of polycarpine (73) from commercially available materials was performed by Lenz end Woo (73)(Scheme 21).The key intermediate in this synthesis was dihydroisoquinoline 82, which on treatment with mixed formicacetic anhydride and removal of the blocking group was converted to 73. In a similar way polycarpine methyl ether was synthesized and used as intermediate in photosynthesis of protoberbine derivatives (83). '

82 SCHEME21

Shamma et a!. (81) carried out a synthesis of ledecorine (75) starting with coptisine chloride (14) (Scheme 22). Compound 14 was first oxidized to enamide 83 (an analog of polycarpine) and then successively reduced to supply a mixture of norledecorine (84) and ledecorine (75).

261

4. SECOISOQUINOLINE ALKALOIDS

83

86 R = H

75 R=CH3 SCHEME 22

In intragroup transformations, dihydrorugosinone (79) and rugosinone (76) were prepared from polyberbine (74) (81),which when kept for about 2 weeks in methanolic solution underwent hydrolysis along with autoxidation to give 79. Air oxidation of the latter in hot ethanolic sodium hydroxide provided 76. A total synthesis of rugosinone (76) utilizing Reissert compound 85 and 2-benzyloxy-3,4-dimethoxybenzaldehyde(or 2,3,4-trimethoxybenzaldehyde) was performed by Cheng and Doskotch (84) (Scheme 23). The addition product 86 was converted to 76 by chromic acid oxidation followed by 0debenzylation (or 0-demethylation). In a final reaction of this group of alkaloids, enamide 8,8a-secoberbines 73 and 74 were transformed by photocyclization and deoxygenation to corresponding isomeric protoberberines with oxygenated substituents at C-10 and C-11 (82).

’‘

85

2. NaOH NaH

+

C

I

~

OR

N

1. Na2Crfl7

2. BCL3orMqSiJ

qCHO

CH3O

OR

86

OCH3

SCHEME 23

76

262

MARIA D. ROZWADOWSKA

111. Secophthalideisoquinoline Alkaloids

The first secoisoquinoline alkaloid discovered was the secophthalideisoquinoline, narceine (106), isolated from opium by J. Pelletier in 1832(I). Up ti1 now 19 natural bases belonging to this group have been isolated, and 6 others have been synthesized. Secophthalideisoquinoline alkaloids have been described in several reviews papers by Shamma et al. (2,4,5),by Santavjr (7), and most recently, in 1985, by MacLean (8). All these alkaloids are 1,2-secoisoquinolinesand have a characteristic N,Ndimethylaminoethyl chain in ring A [except for nornarceine (107)] and a 1',4',5',6'-tetrasubstituted lower aromatic ring. They differ, however, in the structure of the central ethylene bridge, which forms either benzil or deoxybenzoin systems (or enol lactone or ene lactam derived from the latter). The only exception is narlumidine (119) in which a benzoin system can be recognized. On the basis of structural differences it was proposed (5) to subdivide these alkaloids into the following four subgroups: (1) secophthalideisoquinoline enol lactones, (2) secophthalideisoquinoline keto acids, (3) secophthalideisoquinolinediketo acids, and (4) secophthalideisoquinoline ene lactams. This arrangement of subgroups is due to the hypothetical biosynthetic sequence. It assumes that precursors for these alkaloids are the N-methylphthalideisoquinoliniumsalts, whose presence in plants is well documented. Enol lactones may be the initial degradation products formed in a Hofmann-type /?elimination process. They could be hydrated to the keto acids and in the next step oxidated in air to the diketo acids. Diketo acids may undergo further oxidative cleavage to yield simple alkaloids of the fumariflorine (87) type (85,86),which seem to be the final products of the metabolism of phthalideisoquinoline alkaloids. /CH3 R o \ T N \ C H 3 RO

COOH

87

R+R=CH2

In Table VI secophthalideisoquinoline alkaloids and their precursors are presented. They form four series of seco bases from enol lactones to diketo acids ending with ene lactams, which in all probability are not true alkaloids but products arising during the extraction process. The classic precursors of

TABLE VI

SECOPHTHALIDEISOQUINOLINE ALKALOIDS Parent phthalideisoquinoline alkaloid Bicuculline (88)

Configuration Erythro

Enol lactone Aobamidine (W)

Configuration

Z

Keto acid Adlumidiceine (103)

Diketo acid Bicucullinine (108)

Ene lactam Fumaramine

Configuration

Z

(111)

(narceimine) Adlumidine (89) Capnoidine (90) B-Hydrastine (91)

Threo Threo Erythro

a-Hydrastine (92)

Threo

Adlumidiceine enol lactone (97) N-Methylhydrastine (98) (E)-N-Methylhydras-' tine" (99)

(E)-Fumaramine

E

E

(112)

Z E

N-Methylhydras- N-Methyloxohydrasteine teine (104)

Fumaridine (113) (hydrastineimide) (E)-Fumaridine" (114)

Z E

(109)

Corlumine (93)

Erythro

a-Narcotine (94)

Erythro

B-Narcotine (95)

Threo

Adlumiceine enol lactone (100) (Z)-Narceine enol lactone' (101) (aponarceine) (E)-Narceine enol lactone' (102)

Unnatural. Lacks one methyl group in the aminoethyl chain.

Z

Adlumiceine ( W

Z E

Narceine (106)

Bicucullinidine (110)

-

Fumaramidine

Z

(115)

Narceine h i d e (116)

Z

(EFNarceine h i d e " (117)

E

264

MARIA D. ROZWADOWSKA

RRO O%

/ \

OR1 OR1

these seco series are the following alkaloids: bicuculline (88) or its diastereomers adlumidine (89) and capnoidine (90) for the first series, fl- (91) and a-hydrastine (92) for the second, then corlumine (93), and finally a- (94) and B-narcotine (95). Coryrutine (118), narlumidine (119), and fumschleicherine (120) do not fit into this pattern. However, 118 and 120 can be logically connected to it; fumschleicherine (120), which is easily dehydrated, may be an intermediate leading to fumaramine ( I l l ) , while coryrutine (118) is isomeric with Nmethylhydrasteine (104). Yet, the biogenesis of narlumidine (119) may be of different type.

118

119

120

In this chapter the proposed (5)division of secophthalideisoquinolinesinto the four subgroups and the nomenclature have been preserved. Since the publication of the most recent review (8),information about the synthesis of the missing (E)-narceine enol lactone (102) (87),the isolation of ( E ) fumaramine (112) from Fumurh vailunti (88),and the discovery of a new seco alkaloid, coryrutine (118), from Corydulis rutifolia (89) has appeared. In the former plant fumaramine (111) (88) and in the latter N-methylhydrasteine

4.

SECOISOQUINOLINE ALKALOIDS

265

(104) were found as well (89).The secophthalideisoquinoline alkaloids are less widely distributed in nature than their cyclic precursors, and their occurrence is limited to species in the families Fumariaceae and Papaveraceae.

A. SECOPHTHALIDEISOQUINOLINE ENOLLACTONES

The secophthalideisoquinoline enol lactones may exist as 2 or E geometric isomers. Three pairs of such isomers are known: aobamidine (%) (2)and adlumidiceine enol lactone (97)(E), N-methylhydrastine (98) (2)and (E)-Nmethylhydrastine (99) (E), (2)-narceine enol lactone (101) and (E)-narceine enol lactone (102). Three of these enol lactones (99, 101, 102) are synthetic products. Lists of these alkaloids, the plant species in which they occur, as well as their spectral data and other references are provided in the review papers (4,5,8).Narceine enol lactones (101 and 102) are described in Refs. 87 and 90.

Enol lactones are assumed to form from N-methylisoquinolinium salts as a result of a Hofmann-type degradation process. This /3 elimination is a highly stereospecific reaction in which 2 isomers are produced from precursors of erythro configuration and E isomers from threo diastereomers (5.91).This fact seems to suggest that syn rather than the more usual anti elimination takes place. Examination of models indicates, however, that there is a preferred conformation in which the C-8 hydrogen is in the syn and coplanar position to the quaternary nitrogen. This hypothesis was proved correct in experiments carried out in uitro (5,14,15,92-94). The stereochemistry of the enol lactones was established by correlation whose with the structure of derivative 121, prepared from bicuculline (a), configuration as 2 was determined by X-ray analysis (95).In this correlation

266

MARIA D. ROZWADOWSKA

121

the UV spectra are compared with UV spectrum of 121. There is a difference in that makes differentiationbetween 2 and E forms possible. As a rule, the UV absorption bands of 2 isomers appear at longer wavelengths than those of E isomers (4,5,8,87).For example, the absorption maxima at the longest wavelengths in spectra of %,98, and 101 (2form) are 390,385, and 357 nm, while those of 97,99, and 102 (E form) are 388,353, and 348 nm, respectively. This seems to be caused by steric hindrances which prevent the E form from assuming planar conformation. Another spectral method useful in defining the stereochemistry of enol lactones is the comparative analysis of their 'H-NMR spectra, particularly the aromatic proton signals. The olefinic H-1 protons in spectra of E isomers is shifted downfield (66.62-6.65) relative to that of Z isomers (66.28-6.47) because it assumes that syn position with respect to the y-lactone ring oxygen and falls within its deshielding zone. In the 2 isomers it lies anti to the oxygen. Attention should be paid to the diagnostic value of absorption signals arising from H-8 and H-2. In spectra of 2 isomers they appear at a lower field (H-8, 67.61-7.71; and H-2, 67.21-7.49) compared with their E counterparts (H-8, 66.83-6.85; H-2,66.70-6.90). In the latter case each of the protons mentioned gets into the shielding sphere of the aromatic ring of its partner. The above observations come true for the three known pairs of geometric isomers (8,87) and may also be of diagnostic value if the spectrum of only one isomer is available. In the mass spectra of all these substances (4,5,14,15,87,92,94),the molecular ions peaks are present. The base peak at m / z 58, typical for all the seco alkaloids with the N,N-dimethylaminoethyl chain, corresponding to the CH2=N(CH3)2+ ion is observed. The main mass fragmentation under electron impact seems to involve bond cleavage between C-1 and C-9. This can be evidenced by the presence of ions of the 122 and 123 type found in spectra of all compounds except for N-methylhydrastines (98, 99), where the 123 - C 0 2 ion is formed instead. Finally, the carbonyl group absorption

I,

4. SECOISOQUINOLINE ALKALOIDS

RO

\ N +

yCH3

p

267

OR

\CH3

OR

122

123

in IR spectra lies between 1760 and 1785 cm-' and corresponds to the carbony1 frequencies in a y-lactone system. 1. Synthesis of Secophthalideisoquinoline En01 Lactones

The enol lactones were synthesized by Hofmann degradation of metho salts of classic phthalideisoquinoline alkaloids. The biogenetically relevant transformations were highly stereospecific. In this way aobamidine (%) was obtained from the methiodide of (erythro) bicuculline (88) (2), and adlumidiceine enol lactone (97)was produced from both (threo) isomeric adlumidiceine (89) and capnoidine (90) methiodides (14,15,91-93). (2)-(98) and (E)-N-methylhydrastine(99)were obtained from fl- (91, erythro) and a-Nmethylhydrastinium (92, threo) iodides (5,87,91,96-98), respectively, as were (2)-(101)and (E)-narceine enol lactones (102) synthesized from a- (94, erythro) and B-narcotine (95, threo) quaternary N-metho salts (87,90),respectively. In a similar process 8-hydrastine (91) N-oxide heated in chloroform yielded enol lactone 124 of 2 configuration (99);however, a-narcotine (94) N-oxide was transformed to benzoxazocine 125 (99):

124

125

126

Enol lactones can also be obtained from keto acids by enolizationdehydration. Adlumidiceine (103) as well as N-methylhydrasteine (104) when heated in toluene with acetic anhydride or p-toluenosulfonic acid were transformed to enol lactones 97 (91) and 98 (5,102), respectively. Narceine (106) under the influence of PCI, yielded 101 (87,100).

268

MARIA D. ROZWADOWSKA

2. Reactivity of Secophthalideisoquinoline Enol Lactones Both 2 and E isomeric enol lactones undergo photoisomerization to yield mixtures of isomers (5,14,87)in which the thermodynamically more stable one prevails. It is the Z form in hydrastine series (5) and the E isomer in the more hindered narcotine series (87). Relative stabilities of isomeric enol lactones (98 versus 99 and 101 versus 102) were determined by comparing their rates of methanolysis. Keto esters of type 126 were formed (87).It turned out that both (E)-N-methylhydrastine enol lactone (99)and (Z)-narceine enol lactone (101) solvolyzed faster than their geometric partners. In a hydrolytic environment enol lactones can be easily hydrolyzed to the corresponding keto acids. Both N-methylhydrastines (98 and 99) when allowed to stand in aqueous acetone gave rise to N-methylhydrasteine (104) (5).

A series of N-substituted narceine amides (Section III,D,l) was prepared from 101 under the action of primary amines (100). Acid-catalyzed dehydration transformed these amides to corresponding imides (ene lactams) of the (E)-narceine imide (117) type (100).Similar transformations were performed in the hydrastine series (101). N-Methylhydrastine (98) when treated with dilute ammonium hydroxide gave hydroxy lactam 127, which was dehydrated to (2)-fumaridine (113) (5). Sodium borohydride was able to reduce the stilbene double bond in 98 to produce saturated lactone 132 (5).

127

128

129

Secophthalideisoquinoline enol lactones of type 128 were used by Klotzer et al. (95,103-105) for the synthesis of benzazepine system 129 which was further transformed to alkaloids of rhoeadine type. KETOACIDS B. SECOPHTHALIDEISOQUINOLINE

Secophthalideisoquinoline keto acids are postulated to be biosynthesized from phthalideisoquinoline metho salts via enol lactones. Such transformations occur easily in laboratory experiments (Section III,B,l). There are

4. SECOISOQUINOLINE ALKALOIDS

RO

OR1

269

103 104 105 106 107

five naturally occurring secophthalideisoquinolineketo acids: adlumidiceine (103), N-methylhydrasteine (104), adlumiceine (105), narceine (106), and nornarceine (107). Coryrutine (118) has also been included in this group because it is isomeric with N-methylhydrasteine(104). There are doubts about whether 107 is a natural product (5).

Information on the UV, 'H-NMR, and IR spectra of the keto acids is given in the previous reviews (4,8); adlumiceine (105) is covered by Kiryakov et al. (106) and coryrutine (118) by Sener (89).It should be noted that the absorption of the carbonyl groups in the IR spectra can be found as a single band in the region between 1680 and 1700 cm-' (4,92,102,106-109). Esterification of these compounds causes the appearance of the second carbonyl absorption band in the region around 1730 cm-' (5,87).In the 'HNMR spectra the C-1 methylene group protons are characteristic for these keto acids. They absorb around 64.0-4.3 and usually form a broad singlet (4,5,92,93,102,106,108,109). Mass spectra of these alkaloids are almost identical with the mass spectra of their enol lactone precursors. It may tie assumed that the molecular ions, recorded only in spectra of 104 and 106, can be easily dehydrated under electron impact (4,107,108). 1. Synthesis of Secophthalideisoquinoline Keto Acids

Like the secophthalideisoquinoline enol lactones, the keto acids can be obtained by Hofmann degradation of metho salts of classic phthalideisoquinoline alkaloids; however, strong alkaline media and polar solvents are required. For example, under such conditions N-methylhydrasteine (104) was produced as a result of degradation of hydrastine (91)methiodide (97),and also on alkalization of the chloroform solution of the quaternary salt (91.CH31) by sodium methoxide (91).In the case of the methiodides of the threo isomers adlumidine (89)and capnoidine (90), because of steric reasons a prolonged reaction time was obviously needed for the conversion of the initially formed enol lactone (97)to the keto acid 103 (91).Because of even greater steric hindrances in narcotines (91 and 92), narceine (106) was for a long time the only product isolated following Hofmann degradation of their methiodides (110). It was assumed that the primary degradation products,

270

MARIA D. ROZWADOWSKA

I .

I

0 '

COOH

enol lactones, were too readily hydrolyzed to be isolated. Indeed, when this reaction was run in a nonsolvolytic medium (dichloromethane-Fetizon reagent) narceine enol lactones (101 and 102) were isolated in high yield (87). Steric hindrances may also be the reason why quaternary salts of 8alkylnarcotoline (130)were transformed during Hofmann degradation to analogous keto acids (131) (111,112)and not to the enol lactones (Scheme 24). In some cases (5,87) the keto acids and their esters have been synthesized from the corresponding enol lactones by hydration (Section 11I,A,2). Nornarceine (107) was prepared from N-benzyl-(-)-a-narcotinium bromide (139, X = Br) by Hofmann degradation followed by N-debenzylation and ester hydrolysis (109).

2. Transformations of Secophthalideisoquinoline Keto A c i h Keto acids can be dehydrated to enol lactones (Section III,A,l). They may also undergo esterification with alcohols; e.g., N-methylhydrasteine (104) in methanol at room temperature gave the expected keto ester 126 (R + R = CH,, R' = CH,) (5,87). Sodium borohydride reduction of keto acid 104 supplies the saturated y-lactone 132 identical with that obtained from enol lactone 98 (5). Potassium permanganate oxidizes both adlumidiceine (103) and adlumiceine (105) to the corresponding diketo acids bicucullinine (108) and bicucullinidine(1lo),respectively(113).Air oxidation of N-methylhydrasteine (104) leads to the expected N-methyloxohydrasteine (109) as well (5). Another way of transforming the keto acids (e.g., 104)to diketo acids (e.g., 109)utilizes the isonitroso derivatives (e.g., 133), which on hydrolysis gives the diketone (102).

Several norsecophthalideisoquinoline keto acids of type 134 were used as

27 1

4. SECOISOQUINOLINE ALKALOIDS

132

133

OR1 OR1 134

key intermediates in the transformation of phthalideisoquinolinesto alkaloids of the rhoeadine type. They were prepared in two different ways: by hydrolysis of urethanes 135 or 136, prepared from bicuculline (88) or hydrastine (91) (114), respectively, or by hydrogenolysis of the Hofmann degradation products 137, or 138 derived from the N-benzyl salts of narcotine (139) (114,109) or 8-ethylnarcotoline (140) (115), respectively. Air oxidation of the norseco alkaloids (135-138), gave the benzoazepinone 129 type of compounds, which were further transformed to rhoeadine alkaloids (95,103105,109,114,115).

C. SECOPHTHALIDEISOQUINOLINE DIKETO ACIDS

Alkaloids belonging to the secophthalideisoquinolinediketo acids, bicucullinine (IOS), N-methyloxohydrasteine (109), and bicucullinidine (IlO), are naturally occurring benzils. They are characterized by a yellow color and are sparingly soluble in most organic solvents as well as in water. It is assumed that their direct precursors in plants are monoketo acids. This hypothesis was confirmed by biomimetic synthesis (5,113). However, other biogenetic routes to these alkaloids, e.g., involving narlumidine-type (119) bases as

272

MARIA D. ROZWADOWSKA

108

R+R=R~+R~=cH~

intermediates, cannot be excluded. For this reason, narlumidine (119) is included in this section. Spectral data of these alkaloids are presented in the review works (4,8) but do not include data for bicucullinidine (IIO), which was discovered in 1981 (223-226). In the IR spectra of these compounds the carbonyl region generally consists of three bands. The first one is placed at 1675-1670 cm-’ and the latter two around 1625-1590 cm-’. The amino acid nature of these compounds is demonstrated by the presence of an &H band (2350 cm-’) found in the IR spectrum of bicucullinine (108) (227), as well as by the solventdependent position of the N(CH,), group in the’H-NMR spectra. For instance, in the spectrum of bicucullinine (108) run in basic aqueous solution it can be found at 62.08 (228), in DMSO-d6 at 62.69 (213,226), and in CF,COOD at 63.13 (227,229).Moreover, in ’H-NMR spectra the influence of the C-1 carbonyl group on the chemical shift of H-8 can be observed. This proton falls in its deshielding zone and is shifted downfield around 1 ppm compared to the absorption of H-8 in spectra of monoketo acids. In the I3C-NMR spectra of bicucullinine (108) (4,126,228)and bicucullinidine (110)(4,226),the carbonyl signals are of informativevalue. The ones of the benzil fragment absorb at 6190 and 190.4 in spectra of 108 and at 6187.1 and 190.7 in spectra of 110. Carboxylic carbonyls can be assigned to signals at 6168.0 and 167.7, respectively, in spectra of both bases. In the mass spectra (4,5,206,226-229) of diketo acids peaks derived from molecular ions and M - 18 ions are present. The characteristic of N,Ndimethylaminoethylside chain base peak at m / z is present as well. The rupture of the C-C bond between the two central carbonyls is represented by peaks due to ions formed from “upper” and “lower” fragments of the molecules. The respective structures 141 and 142 can be ascribed to them. 1

141

+

+

142

4. SECOISOQUINOLINE ALKALOIDS

213

H20 Triton B

143

air

__c

SCHEME 25

1. Synthesis of Secophthalideisoquinoline Diketo Acids Bicucullinine (108) was synthesized by Nalliah and MacLean (41) from Nmethyldehydrobicucullinium salt (143) by Hofmann degradation preceded by hydrolysis and air oxidation (Scheme 25). Bicucullinine (IOS),bicucullinidine (1lo), and N-methyloxohydrasteine(109) were prepared from the corresponding keto acids, adlumidiceine (103), adlumiceine (105), and N-methylhydrasteine (104), respectively, by oxidation with potassium permanganate (108 and 110) (113)or by air oxidation (109) (5). In another partial synthesis Nmethyloxohydrasteine (109) was obtained from monoketo acid 104 by isonitrosation followed by hydrolysis (102). 2. Reactivity of Secophthalideisoquinoline Diketo Acids Independently of spectral evidence the structure of bicucullinine (108) was established on the grounds of classic degradation methods by Dasgupta et al. (117).Hofmann degradation of thhe methiodide of 108 gave a nitrogen-free base (144). Sodium borohydride reduction of 108 resulted in a hydroxy ylactone (145), which when subjected to periodic acid degradation gave amine 50 and phthalaldehydic acid 146 (5,117JZ9). The diketo acids were transformed to their methyl esters under the action of diazomethane (5), SOCI,/CH,OH (102), or methanolic hydrogen chloride (117). Like other bends, N-methyloxohydrasteine (109) when

274

MARIA D. ROZWADOWSKA

COOH

144

145

CH3

CHO

146

147

treated with o-phenylenediamine ‘was transformed to the quinoxaline derivative (102).

3. Narlumidine (119) The structure of narlumidine (119) was established by Dasgupta et al. (117,119) on the basis of spectral data, particularly by comparison with spectra of bicucullinine (108), and also on chemical grounds. On hydrolysis followed by oxidation-methylation, narlumidine (119)was converted to ester 147, which was also obtained from 108 by N,O-methylation. Sodium borohydride reduction gave lactone 145, identical to the lactone obtained from 108.

D. SECOPHTHALIDEISOQUINOLINE ENE LACTAMSAND HYDROXY LACTAMS It has been postulated that secophthalideisoquinoline ene lactams and hydroxy lactams are most probably artifacts of isolation resulting from the reaction of enol lactones or keto acids with ammonia during the extraction process. The hydroxy lactams are probably formed initially and then undergo dehydration to give ene lactams (5,8). For this reason, this section covers the hydroxy lactams in addition to the ene lactams. The hydroxy lactams are

4. SECOISOQUINOLINE ALKALOIDS

275

represented by natural fumschleicherine (120) (120,122) and synthetic Nmethylhydrasteine hydroxy lactam (148) (5) and narceine amide (149) (ZOO,122). Since the review of MacLean (8),Sener et al. (88)have reported the isolation of (E)-fumaramine(112) from Fumaria vaillantii. Only one alkaloid, fumschleicherine (la), is optically active, but no suggestion as to the absolute configuration has been made so far. Six of the ene lactams form pairs of geometric isomers: (2)-(111) and (E)-fumaramine(112), (2)-(113) and (E)-fumaridine (114), and (2)-(116) and (E)-narceine imide (117). The E partner of fumaramidine (115) has not yet been discovered. As in the case of enol lactones, the stereochemistry of the ene lactams may be deduced from the UV and ‘H-NMR spectral data. Details about the

276

MARIA D. ROZWADOWSKA

spectra of these bases or references to them can be found in the other reviews (4,5,8); data concerning (E)-fumaramine (112) may be found in Ref. 88, (E)-narceine imide (117)in Ref. 123,compound 148 in Ref. 5 , and narceine amide (149) in Ref. 100.Also like enol lactones, the absorption bands in the UV spectra of the E isomers appear at shorter wavelengths than those of the Z isomers. For example, the absorption maxima at the longest wavelength in spectra of 112,114, and 117 (E form) are 357,345, and 345 nm, and those of 111,113, and 116 (2 form) at 365,368, and 352 nm, respectively. The diagnostic value of the ‘H-NMR spectra is practically reduced to determination of the chemical shifts of the aromatic H-2’ and H-3‘ ortho protons, which can easily be found in the form of two doublets (J = 8 Hz). In spectra of the E isomers they appear at relatively higher field (H-2’, 66.556.80; H-3’, 66.82-6.98) than those of the corresponding Z partners (H-2’, 67.07-7.18; H-3’, 67.30-7.48), probably because of the lack of coplanarity and the possibility of free rotation around the C-8a-C-1 bond, which brings them into the shielding zone of ring A (5). A meaningful feature of the ‘HNMR spectra of hydroxy lactams 120 and 148 is the presence of two doublets (AB quartet) in the region 62.99-3.54 (J = 14 Hz) arising from the C-1 methylene protons. In the case of compound 149 a singlet corresponding to these protons is found instead. In comparing the mass spectra of ene lactams, a conclusion can be reached that they all undergo a similar major fragmentation under electron impact. The spectra show the presence of peaks of molecular ions and peaks formed by the loss of a molecule of dimethylamine from M’. The base peak at m/z 58 is present in spectra of all these alkaloids as are the peaks representing ions of type 122 arising from the “upper” part of the molecules. The mass spectrum of fumschleicherine(120)(120,121)is very similar to that of fumaramine(lll), yet a weak peak at m/z 398 represents the molecular ion, which loses a molecule of water prior to the major fragmentation.

1. Synthesis of Secophthalideisoquinoline Ene Lactams and Hydroxy Lactams The hydroxy lactams are postulated to be intermediates in transformations of enol lactones to ene lactams. This hypothesis was proved by synthesis. For example, treatment of N-methylhydrastine (98) with dilute ammonium hydroxide resulted in hydroxy lactam 148, which by the action of hydrochloric acid underwent dehydration to produce fumaridine (113)(5). Similarily, fumschleicherine (120) in reaction with trifluoroacetic acid gave fumaramine (111)(121).Narceine amide (149) was prepared from (Z)-narceine enol lactone and dehydrated to narceine imide (116). (101) in likewise fashion (100,122) A large number of N-alkylated narceine amides was synthesized from (Z)narceine enol lactone (101) and primary amines by Czech investigators for

277

4. SECOISOQUINOLINE ALKALOIDS

biological evaluation (100). All the intermediate hydroxy lactams were isolated and characterized. It is worth mentioning that on the grounds of spectral data the N-alkylated narceine imides were found to be the E stereoisomers. Ene lactams can be obtained directly from quaternary phthalideisoquinolinium salts by treating them with concentrated ammonium hydroxide. In this way fumaramine (111) was synthesized from bicuculline (88) methiodide (121,124, fumaridine (113) from methiodides of both diastereomeric 8- (91) and a-hydrastines (92) (5,124-126), and narceine imide (116) from narcotine (94) methiodide (122,127,128).In the case of the hydrastines (91 and 92) the Hofmann degradation of their methiodides in ammonia was not stereospecific but yielded the thermodynamically more stable Z isomer (113) (5). It seems, however, that from narcotine (94) a mixture of the Z and E forms was produced rather than a single isomer (123,127). Ronsch (129,130) described the synthesis of ene lactam 152, formally belonging to cordrastine series, from the rhoeadine alkaloid, alpinigenine (150), by Hofmann degradation of its derivative 151 (Scheme 26). Treatment of the nitrile 151 with methyl iodide and then with potassium hydroxide gave ene lactam 152, for which the Z configuration could be deduced on the grounds of UV (365 nm) and 'H-NMR (67.09 and 7.39, J = 8 Hz)spectral data.

150

151

1. CH3J 2. Hofmann

152 SCHEME26

278

MARIA D. ROZWADOWSKA

The less stable isomers were obtained from the more stable ones by photoisomerization. (2)-Fumaridine (113) when exposed to sunlight was isomerized to a separable 3:2 mixture of geometric isomers (5).The 2 form of narceine imide (116) is unstable and in daylight equilibrates easily to a mixture of Z and E forms (123). 2. Transformations of Secophthalideisoquinoline Ene Lactams Several degradation reactions were performed with ene lactams. The Hofmann degradation of fumaridine (113) methiodide led to des base 153 (131),the correct structure of which and consequently of fumaridine (113) was

\

0ch3

153

155

157

154

156

158

4. SECOISOQUINOLINE ALKALOIDS

279

established by Shamma and Moniot (124).Narceine imide (117) methiodide was subjected to this degradation as early as 1895(122),but only recently has it been shown that this process is more complex than suggested (128,132). Depending on reaction conditions, two minor products were isolated in addition to the Z and E des bases; these were isoindolobenzazepinone 154 or isoindoloquinoline 155. The two minor components could also be formed by cyclization of the des bases in alkaline or acidic media, respectively (128,133,135).A dehydro analog of 154 was obtained from narceine imide (116) N-oxide under the action of acetic anhydride (134). A great number of transformations has been performed on narceine imide (116) by Czech researchers. Oxidation with potassium permanganate in acetone or with nitric acid caused the cleavage of the alkaloid, giving rise to hemipinic imide (127).A similar result was noted by Ronsch (129,130)during Lemieux-Johnson oxidation of ene lactam 152 (129,130);in this reaction the basic component (156) was isolated as well. The use of hydrogen peroxide in acetone converted 116 to (Z)-narceine imide N-oxide, which under the action of acetic anhydride underwent N-dealkylation (135). Catalytic hydrogenation of 116 over Adams’ catalyst in acetic acid resulted in saturation of the stilbene double bond (127). Benzylation of the lactam N-H group occurred via the potassium salt; under these conditions, however, the tertiary nitrogen was benzylated and finally eliminated in a Hofmanntype process (133).Narceine imide (116) added bromine to form an unstable dibromo derivative from which hydrogen bromide was eliminated and 1bromonarceine imide (157) produced (133). In daylight the latter cyclizes to the aza analog of N-methyldehydronarcotinium salt (158) (133). l-Nitronarceine imide was synthesized by the action of silver nitrite on l-bromonarceine imide (133).

3. Biological Activity Some of the N-alkylated narceine amides and imides were tested for antibacterial effectiveness and showed activity of medium potency against Mycobacterium tuberculosis H37 Rv. Their antimycotic activity was also of medium strength. Coccidiostatic screening showed some effectiveness (100).

IV. SecobenzylisoquinolineAlkaloids So far only the three following 1,2-secobenzylisoquinolinealkaloids have been isolated from natural sources: cryptopleurospermine (159), saxoguattine (160), and pseudoronine (161). Cryptopleurospermine (159) was isolated from

280

MARIA D. ROZWADOWSKA

159 160

R+R=CH2 R=CH3

161

the bark of Cryptocaria pleurosperma White et Francis (Lauraceae) by Jones et al. (136) as a minor alkaloid (-0.004%), in 1970. Years later, in 1984, the second alkaloid of this class, saxoguattine (la),was found in extracts of the stem bark of Guatteria discolor R. E. Fries (Annonaceae, 0.0095%), by Hocquemiller et al. (137). More recently, Veznik et al. (138)have reported the isolation of pseudoronine (161) from the roots of Papaver pseudoorientale (Fedde) Med. (Papaveraceae, 0.0002%). These alkaloids are benzils and incorporate the characteristic N,Ndimethylaminoethyl side chain in ring A, probably formed in plants by oxidative degradation of the nitrogen-containing B ring of transient quaternary benzyltetrahydroisoquinolinium salts. They differ, however, in the type of oxygen substituents in rings A and C, which in the case of pseudoronine (161) have not yet been localized precisely. Some of the physical properties and spectral characteristics of 1,2-secobenzylisoquinolinealkaloids are given in Table VII. In the IR spectra two absorption bands between 1660-1650 and 16251605 cm-’ attributable to benzil grouping can be recognized. The presence of two carbonyl groups is best indicated by the I3C-NMR chemical shift. In spectrum of saxoguattine (160)they give rise to two signals located at 6193.8 and 195.7 (137). ‘H-NMR spectra, available for 159 and 161, exhibit an absorption pattern in the aromatic region typical for a 1,2,Ctrisubstituted benzene (.Ipara= 0). It is composed of two doublets originating from the H-2’ and H-3‘ protons and a doublet of doublets ascribed to H-6’. The main mass fragmentation of secobenzylisoquinoline alkaloids involves bond cleavage between the two benzylic carbonyls. This process is evidenced by the presence of peaks representing fragment ions at m / z 151, found in spectra of all these bases and attributed to the “lower” portion of the molecules, and ions at m / z 220,236, and 222, found in spectra of 159,160,and 161, respectively, formed from the “upper” part of the compounds. Similarly,as in the mass spectra of other secoisoquinolinealkaloids incorporating the aminoethyl substituent, the [H,C=N(CH,),]+ ion at m / z 58 is the base peak.

TABLE VII MELTING POINTS A N D SPECTRAL CHARACTERISTICS OF 1,2-SECOBENZYLlSoQUINOLINEALKALOIDS

Compound

Melting point ("C)

"ma,

(cm-')

'H NMR (6, CDCI,)

, Pmax H~OH,

Mass spectrum,

nm(logc)

m/z(%)

N-CH,

H-5

H-8

H-2'

H-5'

H-6'

Ref.

371 (M+) 220 (3) 151 (5) 58 (100) 387 (M+) 236 (23) 151 (23) 58 (100) 373(M+) 222 (13) 151 (18) 58 (100)

2.30

6.81

7.00

7.44d Jm=2Hz

6.90 d J0=9Hz

7.40 dd J0=9Hz Jm=2Hz

136,140. 142

2.46

6.83

7.10

7.44 d 6.90 d J,,,= 2.2 HZ J, = 9 Hz

-

_

-

~~

Cryptopleurospermine (159)

188-190 183-184 (Acetone)

Saxoguattine (160)

Oil

Pseudoronine (161)

249-252 (CH,OH)

3580 1660 1605 (CHCI,) 1652 (film)

233 (4.45) 284(4.13) 326 (4.16) 230 (4.33) 282 (4.08) 322 (4.03)

1650 211 1625 233 (Nujol) 285 315 (CH3OH)

-

-

7.47dd 137 J. = 9 Hz J,,,= 2.2 HZ

-

138

282

MARIA D. ROZWADOWSKA

1. Synthesis of Secobenzylisoquinoline Alkaloids Three total syntheses of cryptopleurospermine (159)and one of saxoguattine (la),based on similar synthetic strategies, have been performed. The carbon skeleton was constructed by connecting two simple aldehydes, isovanillin, used as the synthon of the “lower” part of the molecules, and aldehydes of type 49 and 156 for the “upper” part. Carbon-carbon bond formation between the synthons was achieved by applying the concept of Umpolung of reactivity of one of the aldehydes. Dunmore et al. (139)applied the 0-trimethylsilyl ether of cyanohydrin 162 as the carbonyl anion equivalent and isovanillin methoxymethyl ether (163)as the electrophilic partner (Scheme 27). The resulting condensation product 164,after mild acid hydrolysis accompanied by autoxidation yielded O-methoxymethylcryptopleurospermine, easily liberated from the protective group.

162

t

LDA

159

CHO I 164

OCH3 163 SCHEME 27

In the synthesis of cryptopleurospermine (159)(140)and saxoquattine (160) (141), Rozwadowska et al. adopted isovanillin for nucleophilic acylation, converting it to dithioacetal 165 (Scheme 28). The dilithio salt of 165 reacted readily with aldehyde urethane 166,available from hydrastinine (167),to form adduct 168,which on reduction afforded amine 169.During deblocking of the masking group in 169 autoxidation to lead directly to 159 occurred (140). Saxoguattine (160)was synthesized in likewise fashion, using aldehyde 170 and isovanillin derivative 165 as substrates (141). A modification (142)of the synthesis of cryptopleurospermine (159)applied the 0-benzoyl cyanohydrin of isovanillin benzyl ether (171) for nucleophilic

OCb

166 R+R=CH2 170 R=CH3

167

168

165

169 SCHEME 28

166

50% NaOH

TEBA

172 CH OCH&Hg 171

173 SCHEME 29

MARIA D. ROZWADOWSKA

284

acylation of aldehyde 166 (Scheme29). The resulting adduct 172 was reduced to amino diol 173, which after Swern oxidation and debenzylation gave 159. The above syntheseswere preceded by model investigations(143),as a result of which several unnatural 1,2-secoisoquinolines, e.g., 175- 177 were synthesized (Scheme 30). Finally, a reaction reported by Bentley and Murray (244) is worth mentioning since it may serve as a model for biosynthetic conversion of benzylisoquinoline alkaloids to the seco analogs (Scheme 30). Heating of ketolaudanosine (174) with methyliodide unexpectedly formed a seco derivative 175 along with to the quaternary salt. By all probability it arose from the methiodide of 174 by air oxidation followed by ring opening.

174

175 176 177

R=R1=CH3 R + R = R1+ R1=CH2 R + R = CH2 i R1= CH3

SCHEME 30

2. Transformations of Secobenzylisoquinoline Alkaloids Degradative studies were carried out on cryptopleurospermine (159) and saxoguattine (160) to complete the structure proof of these alkaloids (136,137). These bases were first reduced to diols 178 and 179, respectively, and then oxidized to produce two aldehydes, isovanillin and compounds 49 or 156 from 159 or 160, respectively. N/Ch

OH C ' H3

RO

H O W \ o H

OCH3 178 179

R+R=CH2 R=CH3

49 R+R=CH2 156 R 2 CH3

4. SECOISOQUINOLINE ALKALOIDS

285

V. Secobisbenzylisoquinolineand Secondimeric Iosquinoline Alkaloids A. SECOBISBENZYLISOQUINOLINE ALKALOIDS

1,a-Secobisbenzylisoquinoline alkaloids differ from their precursors, bisbenzylisoquinoline alkaloids, in that they have the C-1-C, bond broken in one of the two benzylisoquinoline units. It is postulated that, like other secoisoquinolines, they are formed in plants by oxidative degradation involving benzyl cleavage. It has been observed that oxidation occurs preferentially at the tetrahydroisoquinoline moiety, which is unsubstituted at C-8 (or C-8'), since the adjacent C-1 center is less hindered. With regard to the oxidation state of the C-1 and C, atoms secobisbenzylisoquinoline alkaloids are aldehyde lactams [baluchistanamine (180), secoobaberine (lsl),revolutinone (182), sindamine (183), curacautine (la), secantioquine (185), punjabine (186), and secolucidine (192)], lactam esters [gilgitine (187)and talcamine (ISS)],or aldehyde amines [jhelumine ((189)and chenabine (190)].Karakoramine (191),originating from the bisbenzyltetrahydroisoquinoline alkaloid incorporating only one diary1ether bridge, lacks the lactam moiety; in addition, it possesses a hydroxymethyl function in the C' aromatic ring. Moreover, these alkaloids like their parent precursors differ in number and in the position of diphenyl ether linkages. Karakamine (191)has only one such bond, whereas punjabine (186)and gilgitine (187)as much as three. Secantioquine (185)and secolucidine (192)represent a biphenyl system. A list of the secobisbenzylisoquinoline alkaloids with their species of origin is included in Table VIII. The secobisbenzylisoquinolinealkaloids have mainly been found among members of the family Berberidaceae, less frequently in the Annonaceae, and in only a single case in the Ranunculaceae. In Table IX some of the physical data and spectral features of secobisbenzylisoquinoline alkaloids are presented. All these natural products are optically active. The chiral center is at C-1, and the absolute configuration was determined on the basis of their CD spectra. According to Shamma et al. (146,147), a positive CD curve in the region between 225 and 210nm reflects a (1s) configuration. Except for sindamine (183)all the alkaloids show a positive CD curve in that crucial region, indicating (1s) stereochemistry. As evidenced in the literature these compounds should exhibit a positive specific rotation, which is indeed the case and secolucidine with karakoramine (191),jhelumine (189),chenabine (IW), (192).Nonetheless, the other alkaloids (180-188)are levorotatory. Shamma et al. (146,147)explained this departure by assuming that the latter compounds are substituted at (2-8, which forces the aromatic ring C to change its position from anti to syn with regard to the N-2 nitrogen. This change in conformation causes inversion of the sign of specific rotation.

286

MARIA D. ROZWADOWSKA

180 181

R =H R =CH3

186 R = CHO 187 R = COOCH3

182

189 R=H 190 R = C h

HO

cH3iNe O C Y c H m H 3 Cb-N

"NC -H3

+ \

'

CH) HO

185

H

'FOCb

192

g H

\

CHO

287

4. SECOISOQUINOLINE ALKALOIDS

TABLE VIII OCCURRENCE OF SECOBISBENZYLISOQUINOLINE ALKALOIDS Compound

Species ~

Baluchistanamine (180) Sindamine (183) Punjabine (186) Gilgitine (187) Jhelumine (189) Chenabine (190) Karakoramine (191) Curacautine (184) Talcamine (188) Secoobaberine(181) Secantioquine(185) Secolucidine(192) Revolutinone (182)

Family

Yield (%)

Ref. -

Berberidaceae Berberidaceae Berberidaceae Berberidaceae Berberidaceae Berberidaceae Berberidaceae Berberidaceae Berberidaceae Berberidaceae Annonaceae Annonaceae Annonaceae Ranunculaceae

0.00040 0.00022 0.m2

145 146 146 146 146 147 147 147 148 148 149

_ _ _ _ _ ~

Berberis baluchistanica Ahrendt Berheris lycium Royle Berberis lycium Royle Berberis lycium Royle Berberis lycium Royle Berberis lycium Royle Berberis lycium Royle Berberis lycium Royle Berberis buxifolia Lam. Berberis buxifolia Lam. Pseudoxandra aff. lucida Fries Pseudoxandra aff. lucida Fries Pseudoxandra sclerocarpa Maas. Thalictrum reuolutum DC.

0.m8

O.ooOo3 0.00011 0.00036 0.m2 O.oooO5

0.00006 0.003 0.009 0.001 5 0.00 19

I50 151 152

In UV spectra of secobisbenzylisoquinbline alkaloids possessing a phenolic hydroxy group para to the aldehyde function, a marked bathochromic shift is observed upon addition of base. In IR spectra absorption of the lactam group appears at 1645-1640 cm-’, that of the aldehyde function in the range between 1720 and 1680 cm-’, and that of the ester group at 1710 cm-’. In the ‘H-NMR spectra of these alkaloids and their synthetic congeners (154)the presence of two N-CH, groups is recorded. The amine N-CH, can be found between 62.20 and 2.55, the lactam one around 63.03-3.17. ‘H-NMR N O E measurements are ideally suited to the structural elucidation of dimeric isoquinoline alkaloids, and this method has been applied to the seco analogs as well (147,150). Application of double resonance and NOE techniques to their complex spectra enabled assignment of the three proton singlets to the corresponding methoxy groups and also facilitated the interpretation of the protons in the aromatic region. There is a pronounced downfield shift of aromatic protons belonging to the isoquinolone (B’) and aldehyde-substituted (C’) rings when compared to the parent bisbenzylisoquinoline alkaloids. The splitting pattern of protons belonging to the two lower aromatic rings is fairly characteristic. In spectra of derivatives possessing trisubstituted rings the H-10, H-13, and H-14 (or H-10, H-13’, and H-14’) protons appear as doublet of doublets (AMX system in which J,.,, = 0) with Jortho = 8.5-8.9 Hz and Jmeta= 1.8-2.5 Hz. In spectra of alkaloids in which aromatic rings are para disubstituted, the H-10, H-11, H-13, and H-l4(or H-10, H-1 l’, H-13’, and H-14’) protons form a characteristic A,B, system with Jortho = 8.5-8.9 Hz. The vicinal tetrasubstituted derivatives 184 and 188 give rise to an AX system

TABLE IX PHYSICAL AND SPECTRAL CHARACTERISTICS OF SECOBlSBENZYLlsoQUlNOLlNE ALKALOIDS

%ME

~-

'H NMR (6, CDCIJ

Compound Baluchistanamine

[a]","'""

(181)

Revolutinone

Aromatic protons

mlz (%)

nm (log E)

(cm-')

(ion type)

NZXH3

1720 1640

638 (M+) 411 (100)(193) 365 (194) 227 (195) 206 (1%)

2.35 3.10

Ring C

RingC'

CHO

Ref.

9.76

145, 153

149,

224 (4.57) 260 (4.05) 270 (4.06) 282 sh (3.97) 294 sh (3.90) 305 sh (3.80)

+ 5"

0 (286) +0.11(264) 0 (247) - 1.1 (230) 0 (216)

204 (4.62) 224 (4.57) 262 (4.1 1) 272 (4.13) 298 (4.06) (C2H50H) 205 sh (5.13) 250 (4.78) 258 (4.76) 272 (4.69) 280 sh (4.66) 301 sh (4.31) 208 (4.62) 259 (4.09) 270 (4.07) 283 (4.04)

1685 1640 (Film)

652 (M+) 411 (100)(193) 365 (194) 241 (1%) 206 (1%)

2.32 3.07

6.80-7.1 1 A,B2 system J = 8.5 HZ

7.04-7.54 ABX system J. = 8.5 HZ J,,, = 2 HZ

9.76

1697 1644

652 (M') 411 (100)(193) 241 (1%)

2.27 3.09

6.79-7.04 m

6.92-7.77 A,B, system J = 8.9 HZ

9.89

152, 153

1695 1645

2.31 3.04

6.70-7.01 m

7.03-7.81 A2B2system J = 8.8 Hz

9.91

146

207 (4.85) 223 sh (4.74) 271 (4.35)

1690 1640

638 (M+) 411 (100) (193) 365 (194) 227 (1%) 206 (1%) 682 (M') 41 1 (100) (193) 365 (194)

2.20 3.04

6.72-6.96 AB system J = 8.5 HZ

6.75-7.77 A,B, system J = 8.8 HZ

-

148

(CHCIJ

- lo"

-0.79 (396) -4.24 (260) 7.9 (230)

+

Positive

+ 5"

6.55-7.61 m

(C2H50H)

o (300) - 1.7 (255) 0 (245) 5 (232) 0 (220) 0 (320) - 1.5 (300) 0 (290)

+

Curacautine (184)

Mass spectrum, vCHcl3 mar

0 (290) +0.8 (263) 0 (253) -4.2 (231) 0 (220)

(182)

Sindamine (183)

,"':!:A

Negative

(180)"

Secoobaberine

CD (CH,OH) (A€,nm)

154

+ 1.7(285)

+ 3 (263)

Gilgitine ( 57)

Talcamine (188)

Negative

-2"

h) W 00

Jhelumine (189)

Chenabine (190)

*

+28"

+40"

0(249) - 16 (230) 0(218) +4.3 (214) 0(285) -4 (249) 0 (232) + 2(220) O(320) - 3 (295) 0(266) +4 (252) 0(245) -23 (230) 0(221) + 14(214) O(310) +2.3(286) 0(270) +5.3 (235) 0(217) +7 (210) O(310) +4(287) 0 (270) +8.3(236) 0(217) + 10(210)

Melting point, 122-124'C. Bathochrornic shift in alkaline solution.

282(4.29)

271 (1%) 206 (1%) 204

1710 224 (4.32) 250sh (3.96) 1645 285 (3.57) 325 (3.22) 1710 208 (4.95) 225 sh (4.79) 1640 260(4.41) 272 sh (4.27) 305 (3.67)

622(M+) 365 (100) (193) 257(1%)

2.53 3.17

712(M+) 411 (100) (193) 365 (194) 301 (195) 206 (1%) 204

2.24 3.04

211 (4.72) 227 sh (4.56) 281 (4.17) 326 (3.89)

610(M+) 383 (100)(193) 227(1%) 192(1%)

2.5

624(M+) 397(100) (193) 365 (193) 227(1%) 206 (1%)

2.5

1680

209 (4.72) 1680 227 sh (4.49) 281 (4.08) 326 (3.87)

6.92-7 7

A2B2system J

=

8.5 HZ

6.72-6.96

AB system

J = 8.5 HZ

6.75-6.78 A,B, system J

7.04-7.73

-

146

-

148

9.72

147

9.73

147

AMX system

J, = 8.5 HZ J,,, = 2.1 HZ

6.75-7.77 A,B, system J

=

8.5

HZ

7.04-7.58

AMX system Jo = 8.2HZ = 8.8HZ J,,, = 2.1 Hz

6.77s

7.04-7.59

AMX system

J. = 8.2Hz J,,, = 1.8HZ

(continues)

TABLE IX (Continued)

'H NMR(6,CDCl3) Mass spectrum,

CD (CH,OH) (A<,nm)

Compound Secantioquine (185)

-15" (CHC13)

Punjabine (186)

-40"

Karakoramine

+71"

(191)

Secolucidine (192)

+80" (CHCI,)

O(307) + 1.6 (300) + 3.9 (285) 0 (240) -9.3 (230) 0 (214) 0 (300) -3.6 (280) - 12.6 (247) 0 (232) + 10.4 (222) +2 (285) 0 (265) + 7.4 (230) -k 6 (222) + 14 (212) 0 (331) + (298) 0 (284) -8 (243) 0 (228) 5 (219)

+

yCHCli

A ~ ~ ~ o H , m.r nm (log t) (cm-')

206 (4.77) 225 (4.84) 272 (4.32) 288 (4.36)

1680 1640

237 (4.81) 274 (4.32) 325 (3.98)

1690 1645

208 (4.56) 226 sh (4.30) 283 (3.75)

-

222(4.63) 254 sh (4.32) 284 (4.12)

1680 1640 (Film)

Aromatic protons

m / z (%I

(ion type)

N2.CH3

Ring C

Ring C'

CHO

638 (M+) 397 (100)(193) 351 (194) 241 (1%) 192 (1%) 190 592 (M') 365 (100) (193) 227 (1%)

2.34 3.03

6.89-7.22 AMX system J,, = 8.5 HZ J, = 2.5 Hz

7.08-7.66 AMX system Jo = 8.5 HZ Jm = 2.5 Hz

9.84

1-70

2.54 3.17

6.94-7.18 A,B, system J = 8.5 HZ

7.11-7.54 AMX system Jo = 8.5 HZ J , = 2.1 HZ

9.74

146, 153

6.86 s 6.99 s

-

147

9.90

151

420 (M - l)+ 192 (100) (1%)

2.5

6.92-7.06 A, B, system

Ref.

J = 8.5 Hz

607(M + 1)+ 365 (100)(193) 241 (1%)

2.37 3.11

6.94-7.87 m

29 1

4. SECOISOQUINOLINE ALKALOIDS

with Jortho = 8.5 Hz, owing to the H-10and H-11protons composing two doublets. The aldehydic proton can be found within the range 69.27-9.91. The mass spectra of all secobisbenzylisoquindine alkaloids indicate that these substances undergo identical cleavage under electron impact. All of them give rise to molecular ion peaks, though of low intensity. The main fragmentation involves a benzylic cleavage between C-1and C,,producing fragment ions of type 193 and 194, which reflect the structures of the “upper” and “lower” parts of the molecules, respectively. The fragment ion of type 195 found in spectra of most of the alkaloids can be formed from 193 by the loss of methyl ether or methanol. Another fragment ion of type 1% is also frequently met and may represent the isoquinoline unit.

6I

194

CH3

195

196

I . Synthesis and Transformations of Secobisbenzylisoquinoline Alkaloids Many of the secobisbenzylisoquinoline alkaloids have been semisynthesized from the appropriate bisbenzylisoquinoline congeners by permanganate in acetone. In this method, worked out by Shamma and Foy (254), oxidation occurs at the tetrahydroisoquinoline unit which is unsubstituted at C-8. In this way the following seco bases were obtained from bisbenzylisoquinolines: baluchistanamine (180) from oxyacantine ( 1 4 9 , secoobaberine (181) from obaberine (245,149,254), revolutinone (182) from O-methylthalicberine (152), sindamine (183) from berbamine (146), curacautine (184) from calafatine ( I @ ) , and secantioquine (185) from antioquine (149).In addition, a series of unnatural secobisbenzylisoquinolineshave been similarly prepared

292

MARIA D. ROZWADOWSKA

from classic precursors. (154-256). The controlled oxidation method was employed in structural examination of natural secobisbenzylisoquinoline alkaloids and also proved to be very helpful in structure elucidation of the parent bisbenzylisoquinoline bases since the 'H-NMR spectra of the seco derivativeswere much easier to interpret (155).The types of oxidation, carried out in vitro, also using other oxidizing agents (e.g., CuC1,-0, or singlet oxygen) (157), seem to imitate the processes taking place in nature and thus may contribute to study of the problems of catabolism of isoquinoline alkaloids in general.

B. SECODIMERIC ISOQUINOLINE ALKALOIDS The following secodimeric alkaloids have been isolated from natural sources: (+)-hernandaline (197), from Hernandia ovigera L. (158), (-)natalinine (198) (259), and (+)-coyhaiquine (199) (160), the two latter from Berberis empetrifolia Lam. with the yields O.ooOo5 and O.ooOo8% ,respectively. Appropriate aporphine-benzylisoquinoline or proaporphine -benzylisoquinoline dimers are probably precursors of these seco alkaloids, although

P

197

Rex-(

DCH0 R1

198 R=Hi R1=OH 200 R=CH3 i RIzH

199

4. SECOISOQUINOLINE ALKALOIDS

293

there is also a supposition that the seco alkaloids precede the dimeric ones in the plant (158,163). Closely related to these seco dimeric bases is the synthetic compound neolumipakistanine (200), obtained by Shamma et al. (161) from pakistanamine by light-induced rearrangement. The absolute configuration around the C-6a chiral center in (-)-natalinhe (198) and (+)-coyhaiquine (199) was assigned as (R) on the grounds of CD spectra (159,160).The stereochemistryof the (2-13 spiro atom was determined by analysis of 'H-NMR spectra and NOE measurements (160). 1. Synthesis and Transformations of Secodimericisoquinoline Alkaloids

Two syntheses of hernandaline (197) have been carried out. Dutschewska and Mollov (162) prepared it by potassium permanganate in acetone oxidation of thalmelatine (201), while Cava et al. (158)performed the synthesis

201 202 204

R~R~=H R'CH3 i R1=H R = CH3 i R1=OCH3

KMn04

203 205 SCHEME 31

1 R=H d=OCH3

294

MARIA D. ROZWADOWSKA

by coupling (+)-methyllaurotetamine (an aporphine) with 6-bromoveratraldehyde. Several other oxidations applying potassium permanganate as the oxidant were carried out, resulting, however, in 6a,7-dehydro seco bases. In this way thalmelatine (201) and thalicarpine (202) were transformed to 6a,7dehydrohernandaline (203) (162,163)while adiantifoline (204) gave 205 (164) (Scheme 31). (+)-Thalifaberine analogously afforded the corresponding dehydro seco analog (I65).A microbial transformation of thalicarpine (202) to hernandalinol(l97, CHO = CH,OH) via hernandaline (197) was described by Nabih et al. (166).

VI. Secobenzophenanthridine Alkaloids In the course of detailed studies on the chemical constituents of rutaceous plants, genus Xanthoxylum, known to contain the antitumor benzophenanthridine alkaloids, Ishii et al. (167-173) have isolated four seco amide alkaloids: arnottianamide (206), iwamide (207), integriamide (208), and isoarnottianamide (209). Sharma et al. (174) have also found arnottianamide (206) in Toddia Asiatica.

206 207

R=CH3 RtH

208 209

R+R=CH2 R=CH3

It was postulated (169)that these amides are 8,8a-~ecobenzophenanthridine alkaloids produced by oxidative cleavage of ring B of the corresponding benzophenanthridines. The success of Baeyer-Villiger-type oxidations of the immonium bond of benzophenanthridine skeletons (168,171,172,I75) indicates that this type of oxidation could be a real biological pathway. Data concerning plants of occurrence, melting points, and spectral features of these alkaloids have been collected by Krane et al. (6).Some characteristic spectral features deserve attention. In IR spectra the amide band appears in the region between 1670 and 1646 cm-'. Among the 'H-NMR spectra, singlets of the N-methyl amide protons are situated between 62.97 and 3.27, and the

295

4. SECOISOQUINOLINE ALKALOIDS

formyl group proton occurs at 68.07-8.10. In spectra of 9,lO-substituted derivatives (206,207) two pairs of doublets due to two pairs of ortho protons and two singlets of para protons can be found in the aromatic zone. In the case of 10,ll-substituted compounds (208, 209) one pair of doublets and four singlets make a characteristic absorption pattern in this region. 1. Synthesis and Transformations of Secobenzophenanthridine alkaloids

Synthesis of all four 8,8a-secobenzophenanthridinealkaloids was carried out chiefly by Baeyer-Villiger oxidation of appropriate benzophenanthridines (Scheme 32). Thus, arnottianamide (206) was obtained from chelerythrine (210) (172,175), iwamide (207) from N-methyldecarine (211) (168,172),integriamide (208) from avicine (212) (171,172),and isoarnottiamide (209) from nitidine (213) (172,175).The proposed mechanism of this reaction (168,172,175) consists of initial attack of the peroxide ion on the C=N+ double bond followed by rearrangement and hydrolysis.

210

211 212 213

R =R1=OCH3 i R2= H R'OCH3 i R1=OHi'R%H R = H i R1+R2=OCH20 R =H RI=R~= OCH~

206 207 208 209

SCHEME 32

Synthesis of 216, an analog of the amide alkaloids, starting with ketone 214 was performed by Ishii et al. (176) (Scheme 33). The initial step involved the formation of cis secondary amine 215, which on N-formylation and dehydrogenation led to 216. Under Bischler-Napieralski conditions 216 could be recyclized to chelirubine (217). A total synthesis of 0-methylarnottianamide (223) was performed by Falck et al. (177)(Scheme 34). The regio- and stereospecific cycloaddition of the 2,4dinitrophenyl (DNP) salt of 6,7-methylenedioxyisoquinoline(218) with amethoxystyrene 219 resulted in 220. Compound 220 was hydrolyzed, then aromatized, and the resultant aldehyde was oxidized to carboxylic acid 221. Curtius rearrangement of the appropriate azide yielded urethane 222, which

215

214

1.CCL3CHO 2. DDQ

~ 0 ~ 1 3 RO

RO 216 R+R=CH2 226 R=CH3

217 R+R=CH2 227 R=CH3 SCHEME33

( " , r n N \

DNP

218

OCH3

CH~O

220 219

221

222

223 SCHEME 34

4. SECOlSOQUlNOLlNE ALKALOIDS

297

on reduction and N-formylation gave O-methylarnottianamide (223),identical with that prepared from arnottianamide (206) (172). The seco amide alkaloids have been subjected to various transformations, mainly for structure elucidation purposes. When treated with lithium aluminium hydride, arnottianamide (206) was converted to the tertiary amine, deoxyarnottianamide (224), which on methylation with the Rodionow reagent gave deoxy-O-methylarnottianamide(225) ( I 72,175). Arnottianamide (206) could be O-acetylated (174) as well as O-methylated with diazomethane in HMPA (172). Isoarnottianamide (208) was O-methylated to trimethoxy derivative 226, which under Bischler-Napieralski conditions recyclized to the benzophenantridine alkaloid, chelilutine (227)(176)(Scheme 33).

224 225

R= H R=Cb

VII. Secocularine and Secoquettamine Alkaloids

Cularine and quettamine alkaloids are postulated to be biogenetically derived from tetraoxygenated and trioxygenated benzyltetrahydroisoquinilines, respectively, by intramolecular oxidative coupling ( 178.179).The 1 ,2-seco derivatives are probably formed by in uiuo Hofmann degradation of corresponding quaternary salts. Listings of cularine and quettamine alkaloids and of their seco analogs, containing physical and spectral data as well as sources of occurrence, are provided in the reviews of Gozler and Shamma (178) and of Castedo and Suau (180).

A. SECOCULARINE ALKALOIDS Four naturally occurring secocularine alkaloids are known: secocularine (228), secocularidine (229),norsecocularine (230),and noyamine (231). The first three belong to the 1,2-seco class possessing the characteristic N,N-dimethylaminoethyl side chain and oxepine system, and the fourth is a 1,a-secoalkaloid

298

MARIA D. ROZWADOWSKA Y

CH3

‘R..

.d

O’.Q

u-1

CH30

ocH3

CH36

\OCh 231

incorporating an isoquinolone unit. Secocularidine (229),norsecocularine (230),and noyamine (231)were isolated from Corydalis clauiculata (L.) DC., secocularine (228)from Sarcocapnos crassifolia DC., by Castedo et al. (181183). The structures of these alkaloids were established by the same authors (180-183) on the grounds of spectral data analysis and synthesis. The UV spectra of 1,Zseco alkaloids are very similar to one another; however, only the spectrum of secocularidine (229)exhibits a bathochromic shift in basic solution, indicating a phenolic structure. Indeed, methylation of 229 with diazomethane afforded secocularine (228).In the mass spectra of the bases, peaks due to molecular ions are present. The main mass fragmentation involves the cleavage of the bond B to nitrogen and formation of a base peak from the ion [H,C=N(CH,),]+ or (H2C=NHCH3)+ and M - 58 or M - 44 ions as well. Other peaks such as those at m/z 165,152, and 139 found in spectra of all the substances suggest that they come from the “lower” part of the molecules. The assignment of all ‘H-NMR signals was based on NOE difference study. Two AB quarters seem to be a characteristic feature of the aromatic region. One of them, with the larger coupling constant (- 11 Hz), corresponds to C-1 and C, olefinic protons, the second one ( J = 8 Hz) to the aromatic H-5 and H-6 ortho protons.

-

1. Synthesis of Secocularine Alkaloids

Secocularine (228)and secocularidine (229)were synthesized by Hofmann degradation of the corresponding cularine and cularidine methiodides, respectively (181). Both secocularidine (229)and norsecocularine (230)were transformed to secocularine (228)by 0- and N-methylation, respectively (181,182). Total synthesis of noyaine (231) was achieved by Ullmann (232) condensation of 8-hydroxy-7-methoxy-2-methyltetrahydroisoquinoline with 6-bromoveratric acid methyl ester followed by oxidation of the intermediate 233 (183)(Scheme 35).

4. SECOISOQUINOLINE ALKALOIDS

299

SCHEME 35

B.

SECOQUETTAMINE ALKALOIDS

Secoquettamine (234) and dihydrosecoquettamine (235) together with their probable biogenetic precursor quettamine (236) form a small group of alkaloids. They were isolated by Shamma et al. (179)from Berberis baluchistanica in yields of 0.00036,0.00017, and 0.0012%, respectively. These alkaloids incorporate either a benzofuran or a dihydrobenzofuran ring within the molecular framework, and the seco ones possess the N,N-dimethylaminoethyl substituent. The structures of these bases were determined on the grounds of spectral data as well as by total synthesis. There is one chiral center at C, in dihydrosecoquettamine (235); however, the base was isolated in the form of a racemic mixture (179). The UV spectrum of secoquettamine (234) in comparison with that of the dihydro derivative 235 displays a bathochromic shift. The mass spectra of both seco bases exhibit molecular ion peaks and the base peak at m/z 58. Peaks

OH

234

9 OH 235

OH

236

300

MARIA D. ROZWADOWSKA

resulting from M - 58 ions are also recorded. However, other parts of the spectra are different, implicating differences in the fragmentation scheme for each of the alkaloids. In the 'H-NMR spectrum of secoquettamine (234) a one-proton singlet at 66.80 originating from H-1 incorporated in the furan ring is a characteristic feature, whereas in the spectrum of dihydroquettamine (235) two quartets centered at 62.98 and 3.36 along with a triplet at 65.64 represent the aliphatic protons of the dihydrofuran unit. 2 . Synthesis of Secoquettamine Alkaloids Several syntheses of secoquettamines have been performed. Seco compounds 234 and 235 were semisynthesized from quettamine (236)by Hofmann and Emde degradations, respectively (279). Chattopadhyay and Shamma (284) conducted a total synthesis of these bases with the intermediacy of quettamine (236)(Scheme 36). In this approach Reissert compound 237 served as substrate. On reaction with 4-benzyloxybenzaldehyde 237 supplied the addition product 238, which after N-methylation and sodium borohydride reduction afforded amino carbinol 239. Compound 239 was cyclized to

GHsCH20

CN

237

NaH/DMF

238

bH

239

240 SCHEME 36

30 1

4. SECOISOQUINOLINE ALKALOIDS

KC”+ C

CH3O OH

OCH2CgH5

’I

O

‘

OCH2CgHg

241 1.CH3NO2 2. LAH

1.Methylotion

c

H

3

o \

L

q

2-34

OCH2CgHg

242

SCHEME37

norquettamine 240. Only one racemic diastereomer was formed during the cyclization; it was the desired one in which H-1 and H, were situated trans to each other. N-Methylation furnished racemic quettamine (236), which was further transformed to 234 and 235. The key intermediate in another total synthesis of secoquettamine (234), elaborated by Stevenson et al. (285), was 2-arylbenzofuran 241 prepared by a coupling reaction of the copper salt of 4-benzyloxyphenylacetylene with bromoisovanillin (Scheme 37). In the ‘next step condensation with nitromethane and reduction gave amine 242, which when N-methylated and debenzylated resulted in secoquettamine (234). Addendum

G. Sariyar and M. Shamma [Phytochemistry 25, 2403 (1986)] recently reported the isolation of the corresponding aldehyde macrantaldehyde and macrantoline (6) and macrantoridine (7) from capsules of Papaver pseudoorientale. References 1. J. Pelletier, Anal. Chim.Phys. 50, 240,262 (1832). 2. M. Shamma and J. L. Moniot,”Isoquinolike AlkaloidsResearch 1972-1977.”Plenum Press, New York, 1978.

302

MARIA D. ROZWADOWSKA

3. M. Shamma, A. S. Rothenberg, G. S. Jayatilake, and S. F. Hussain, Tetrahedron 34, 635 (1978). 4. G. Blask6, D. Gula, and M. Shamma, J. Nut. Prod. 45, 105 (1982). 5. G. Blask6, V. Elango, B. Sener, A. J. Freyer, and M. Shamma, J. Org. Chem. 47,880 (1982). 6. B. D. Krane, M. 0.Fagbule, and M. Shamma, J. Nar. Prod. 47,1(1984). 7. F. Santavy, Alkaloids (N.Y.) 17,446 (1979). 8. D. B. MacLean, AIkaloids(N.Y.)29,253 (1985). 9. M. Shamma, “The Isoquinoline Alkaloids.” Academic Press, New York, 1972. 10. M. Shamma and M. Rahimizadeh, J. Nut. Prod. 49,398 (1986). 11. G. Sariyar and J. D. Phillipson, Phyrochemistry 16,2009 (1977). 12. G. Sariyar, Isranbul Uniu. Eczacilik Fak. Mecm. 12, 171 (1976); Chem. Absrr. 86, 185917~ (1977). 13. V. V. Melik-Gusednov, D. A. Murav’ eva, and V. A. Mnatsanyan, Khim. Prir. Soedin.. 239 (1979). 14. T. Kametani, M.Takemura, M. Ihara, and K. Fukumoto,J. Chem. Soc., Perkin Trans. I , 390 (1977). 15. T. Kametani, M. Takemura, M. Ihara, and K. Fukumoto, Heterocycles 4,723 (1976). 16. J. Gleye, A. Ahond, and E. Stanislas, Phytochemistry 13,675 (1974). 17. G. Nonaka, H. Okabe, I. Nishioka, and N. Takao, J. Pharm. SOC.Jpn. 93,87 (1973). 18. T. Gozler, M. Ali Oniir, R. D. Minard, and M. Shamma, J. Nut. Prod. 46,414 (1983). 19. L. D. Yakhontova, M. N. Komarova, M. E. Perel son, K. F. Blinova, and 0.N. Tolkachev, Khim. Prir. Soedin.. 624 (1972). 20. A. Ikuta and H. Itokawa, Phytochemistry 15,577 (1976). 21. L. D. Yakhontova, M. N. Komarova, 0. N. Tolkachev, and M. E. Perel son, Khim. Prir. Soedin., 491 (1978). 22. D. Walterova, V. Preininger, L. DolejS, F. Grambal, M. Kysely, I. Valka, and V. Simanek, Coll. Czech. Chem. Commun. 45,956 (1980). 23. K. Iwasa, M. Sugiura, and N. Takao, Chem. Pharm. Bull. 33,998 (1985). 24. V. Simanek, V. Preininger, F. Grambal, and L. DolejS, Heterocycles 9, 1233 (1978). 25. V. Simanek and V. Preininger, Heterocycles 6,475 (1977). 26. G. Nonaka and I. Nishioka, Chem. Pharm. Bull. 23,294 (1975). 27. K. Iwasa and N. Takao, Heterocycles 20, 1535 (1983). 28. D. W. Hughes and D. B. MacLean, AIkaloids(N. Y.) 18,217 (1981). 29. H. Ronsch, 2. Chem. 19,447 (1979). 30. M. Shamma, A. S. Rothenberg, and S. F. Hussain, Heterocycles 6,707 (1977). 31. M. Shamma, A. S. Rothenberg, G. S. Jayatilake, and S. F. Hussain, HeterocycIes5,41(1976). 32. M. Hanaoka, K. Nagami, and T. Imanishi, Heterocycles 12,497 (1979). 33. M. Hanaoka, K. Nagami, M. Inoue, and S. Yasuda, Chem. Pharm. Bull. 31,2685 (1983). 34. M. Hanaoka, K. Nagami, and T. Imanishi, Chem. Pharm. Bull. 27,1947 (1979). 35. M. Hanaoka, K. Nagami, S. Horima, and T. Imanishi, Heterocycles 15,297 (1981). 36. P. N. Sharma, K. C. Rice, and A. Brossi, Heterocycles 19, 1895 (1982). 37. T. Kametani, M. Takemura, K. Takahashi, M. Takeshita, M. Ihara, and K. Fukumoto, J . Chem. Soc., Perkin Trans. I , 1012 (1975). 38. T. Kametani, M. Takemura, K. Fukumoto, T. Terui, and A. Kozuka, Heterocycles 2,433 (1974). 39. T. Kametani, M. Takemura, K. Fukumoto, T. Terui, and A. Kozuka, J. Chem. Soc.. Perkin Trans. I , 2678 ( 1974).

40. T. Kametani, M. Takemura, K. Takahashi, M. Takeshita, M. Ihara, and K. Fukumoto, Heterocycles 2,653 (1974). 41. B. C. Nalliah and D. B. MacLean, Can J. Chem. 56, 1378 (1978).

4. SECOISOQUINOLINE ALKALOIDS

303

42. B. Gozler and M. Shamma, J. Chem. Soc., Perkin Trans. I , 2431 (1983). 43. B. Gozler, M. Shamma, Z. Mardirosyan, and V. Chervenkova, Nauch., Tr.-Plovdivski Vniu. 20 (3,Khim.), 123 (1982). 44. B. Gozler, M. Shamma, Z. Mardirossian, and V. Chervenkova, Heterocycles 19,2067 (1982). 45. N. S. Narasimhan, A. C. Ranade, and B. H. Bhide, Indian J. Chem. 20B,439 (1981). 46. M. D.Rozwadowska and D. Matecka Tetrahedron, in press. 47. W.-J. Kim, D.-U. Lee, and W. Wiegrebe, Arch. Pharm. (Weinheim, Ger.) 317, 438 (1984). 48. W. Wiegrebe, H. Reinhart, and J. Fricke, Pharm. Acta Helv. 48,420 (1973). 49. W. Wiegrebe and S . Prior, Chimia 32,256 (1978). 50. W. Wiegrebe, S. Prior, and K. K. Mayer, Arch. Pharm. (Weinheim, Ger.) 315,265 (1982). 51. S. Prior and W. Wiegrebe, Arch. Pharm. (Weinheim. Ger.) 315,273 (1982). 52. S.Prior and W . Wiegrebe, Sci. Pharm. 49,503 (1981). 53. S. Prior and W. Wiegrebe, Arch. Pharm. (Weinheim,Ger.)314,577 (1981). 54. H. Ronsch, Z. Chem. 24, 153 (1984). 55. V. Preininger, V. Simanek, and F. Santavy, Tetrahedron Lett.. 2109 (1969). 56. M. Hanaoka, M. Inoue, S. Yasuda, and T. Imanishi, Heterocycles 14,1791 (1980). 57. V. Simanek, A. Klasek, and F. Santavy, Tetrahedron Lett., 1779 (1973). 58. V. Simanek, L. Hruban, V. Preininger, A. NtmeEkovii, and A. Klasek, CON.Czech. Chem. Commun. 40,705 (1975). 59. V. Simanek, V. Preininger, F. Santavj, and L. DolejS, Heterocycles 6,711 (1977). 60. M. D.Rozwadowska and M. Chrzanowska, Tetrahedron 42,6021 (1986). 61. V. Simanek, A. Klasek, L. Hruban, V. Preininger, and F. Santavy, Tetrahedron Lett., 2171 (1974). 62. M. Chrzanowska, Ph.D. Thesis, A. Mickiewicz University, Poznan, Poland. 63. N. Takao and K. Iwasa, Chem. Pharm. Bull. 21,1587 (1973). 64. G.Nonaka and I. Nishioka, Chem. Pharm. Bull. 21,1410 (1973). 65. G. Nonaka, Y.Kodera, and I. Nishioka, Chem. Pharm. Bull. 21,1020 (1973). 66. M. A. Oniir, M. H. Abu Zarga, and T. Gozler, Planta Med. 41,70 (1986). I 67. A. Yagi, G. Nonaka, S. Nakayama, and I. Nishioka, Phytochemistry 16,1197 (1977). 68. K. Iwasa, Y. P. Gupta, and M. Cushman, J. Org. Chem. 46,4744(1981). 69. M. Cushman and W.-Ch. Wong, J. Org. Chem. 49,1278 (1984). 70. I. A. Israilov, M. S.Yunusov, and S . Yu. Yunusov, Khim. Prir. Soedin.. 537 (1978). 71. A. Jossang, M. Leboeuf, A. Cave, M. Damak, and C. Riche, C. R. Acud. Sci. Paris 284,467 (1977). 72. A. Jossang, M. Leboeuf, and A. Cave, Planta Med. 32,249 (1977). 73. G. R. Lenz and Ch.-M. Woo, J. Heterocycl. Chem. 18,691 (1981). 74. S. K. Chattopadhyay, A. B. Ray, D. J. Slatkin, and P. L. Schiff, Jr., Phytochemistry 22,2607 (1983). 75. E.Valencia, I. Weiss, M. Shamma, A. Urzua, and V. Fajardo, J. Nut. Prod. 47, 1050(1984). 76. G. Blasko, M. Shamma, A. A. Ansari, and Atta-ur-Rahman, Heterocycles 19,257 (1982). 77. S. Firdous, A. J. Freyer, M. Shamma, and A. Urzua, J. Am. Chem. SOC.106,6099 (1984). 78. W.-N. Wu, J. L. Beal, R. W. Doskotch, J. Nut. Prod. 43, 143 (1980). 79. M, Rahimizadeh, Planta Med. 41,339 (1986). 80. N. Murugesan and M. Shamma, Tetrahedron Lett., 4521 (1979). 81. N. Murugesan and M. Shamma, Heterocyles 14,585 (1980). 82. M. Hanaoka, M. Marutani, K. Saitoch, and C. Mukai, Heterocycles 23,2927 (1985). 83. H. Hara, M. Hosaka, 0.Hoshinon, and B. Umezawa, Tetrahedron Lett., 3809 (1978). 84. H.-Y. Cheng and R. W. Doskotch, J. Nut. Prod. 43, 151 (1980). 85. S. F. Hussain and M. Shamma, Tetrahedron Lett., 1693 (1980). 86. S.F. Hussain, R. D. Minard, A. J. Freyer, and M. Shamma, J. Nut. Prod. 44, 169(1981).

304 87. 88. 89. 90. 91. 92.

MARIA D. ROZWADOWSKA

G. Blasko and M. Shamma, Tetruhedron 40, 1971 (1984). B. Sener, B. Gozler, R. D. Minard, and M. Shamma, Phytochemistry 22,2073 (1983). B. Sener, Cuzi Uniu. Eczacilik Fuk. Derg. 3, 13 (1986); Chem. Abstr. 105,206252d (1986). R. Tambach and C. Jaeger, Ann. Chem. 349, 185 (1906). V. Preininger, J. Novak, V. Simanek, and F. Santavy, Pluntu Med. 33,396 (1978). V. Preininger, V. Simanek, 0. GaSi6, F. Santavy, and L. DolejS, Phytochemistry 12, 2513

(1973). 93. V. Preininger, J. Vesely, 0.GaSiC, V. Simanek, and L. DolejS, Coll. Czech. Chem. Commun. 40,699 (1975). 94. P. Forgacs, J. Provost, J.-F. Desconclois, A. Jehanno, and M. Pesson, C . R. Acud. Sci. Paris 279,855 (1974). 95. W. Klotzer, S. Teitel, and A. Brossi, Helu. Chim. Actu 55, 2228 (1972). 96. M. Freund and A. Rosenberg, Chem. Ber. 23,404 (1890). 97. P. Rabe and A. McMillian, Ann. Chem. 377,248 (1910). 98. C. R. Addinall and R. T. Major, J. Am. Chem. SOC.55,2153 (1933). 99. W. Klotzer and W. E. Oberhansli, Helu. Chim. Aclu 56,2107 (1973). 100. Z. Koblicova, J. KFeEkova, and J. Trojanek, cesk. Farm. 30, 177 (1981). 101. M. Freund and M. Heim, Chem. Ber. 23,2897 (1890). 102. P. Forgacs, J. Provost, R. Tiberghien, J.-F. Desconclois, G. Buffard, and M. Pesson, C. R. Acad. Sci. Paris 276, 105 (1973). 103. W. Klotzer, S. Teitel, and A. Brossi, Helu. Chim. Actu 54,2057 (1971). 104. W. Klotzer, S. Teitel, J. F. Blount, and A. Brossi, J. Am. Chem. SOC.93,4321 (1971). 105. W. Klotzer, S. Teitel, J. F. Blount, and A. Brossi, Monutsh. Chem. 103,435 (1972). 106. H. G. Kiryakov, Z. H. Mardirossian, P. P. Panov, Compt. Rend. Acud. Bulg. Sci. 34, 43 (1981). 107. M. Alimova and J. A. Israilov, Khim. Prir, Soedin.. 602 (1981). 108. M. E. Popova, A. N. Boeva, L. DolejS, V. Preininger, V. Simanek, and F. Santavy, Pluntu Med. 40,156 (1980). 109. W. Klotzer, S. Teitel, and A. Brossi, Monutsh. Chem. 103, 1210 (1972). 110. M . Freund, Ann. Chem. 277,20(1893). 111. P. Gorecki, Poznan. Tow. Przyjaciol Nauk, Wyd. Lek., Pr. Kom. Furm. 4,133 (1966); Chem. Abstr. 65,8973d (1966). 112. P. Gorecki, Poznan. Tow. Przyjaciol Nauk, Wyd. Lek., Pr. Kom. Furm. 5.86 (1966); Chem. Abstr. 67,32852d (1967). 113. H. G . Kiryakov and Z. H. Mardirossian, Comp. Rend. Acud. Bulg. Sci. 34,1717 (1981). 114. A. Brossi, W. Klotzer, and S. Teitel, US. Pat. 3,946,041 (1976); Chem. Abstr. 85, 33246t (1976). 115. P. Gorecki and M. DroZdZynska, Herbu Pol. 22,233 (1976). 116. H. G. Kiryakov, Z. H. Mardirossian, D. B. MacLean, and J. P. Ruder, Phytochemistry 20, 1721(1981). 117. B. Dasgupta, K. K. Seth, V. B. Pandey, and A. B. Ray, Pluntu Med. 50,481 (1984). 118. R. G. Rodrigo, R. H. Manske, H. L. Holland, and D. B. MacLean, Can. J. Chem. 54,471 (1976). 119. K. K. Seth, V. B. Pandey, A. B. Ray, B. Dasgupta, and S . A. Shah, Chem. Ind. (London), 744 ( 1979). 120. H.G. Kiryakov, Z. H. Mardirossian, and P. P. Panov, Compt. Rend. Acud. Bulg. Sci. 33, 1377 (1980). 121. H. G. Kiryakov, Z. H. Mardirossian, D. W. Hughes, and D. B. MacLean, Phytochernistry 19, 2507 (1980). 122. M. Freund and H. Michaelis, Ann. Chem. 286,248 (1895).

4. SECOISOQUINOLINE ALKALOIDS

123. 124. 125. 126. 127. 128. 129. 130. 131. 132. 133. 134. 135. 136. 137.

305

B. Proksa, Chem. Zuesfi 35,835 (1981). M. Shamma and J. L. Moniot, J. Chem. SOC.,Chem. Commun.. 89 (1975). M. Freund and A. Philips, Chem. Ber. 23,2910 (1890). M. Freund, Ann. Chem. 271,358 (1892). J. Hodkova, Z. Vesely, Z. Koblicova, J. Holubek, and J. Trojanek, Lloydia 35,61 (1972). J. Trojanek, Z. Koblicova, Z. Vesely, V. Suchan, and J. Holubek, CON. Czech. Chem. Commun. 40,681 (1975). H. Ronsch, Tetrahedron Left.,5121 (1969). H. Ronsch, Tetrahedron 37,371 (1981). I. A. Israilov, M. S. Yunusov, and S. Yu. Yunusov, Khim. Prir. Soedin., 588 (1970). Z. Vesely, J. Holubek, and J. Trojanek, Chem. Ind. (London),478 (1973). B. Proksa, M. Bobal, and S. Ko_vaC,Chem. Zuesfi 36,559 (1982). B. Proksa, Z. Voticky, and M. Stefek, Chem. Zuesfi 34,248 (1980). B. Proksa and Z . Voticky, Coll. Czech. Chem. Commun. 45,2125 (1980). S. R. Jones, J. A. Lamberton, A. A. Sioumis, and R. 1. Willing, Awl. J. Chem. 23,353 (1970). R. Hocquemiller, C. Debitus, F. Roblot, A. Cave, and H. Jacquemin, J. Nuf. Prod. 47, 353

(1984). 138. F. Veznik, E. Taborska, P. Sedmera, L. Dolejs, and J. Slavik, Coll. Czech. Chem. Commun.51, 1752 (1986). 139. G. C. Dunmore, R. H. Manske, and R. Rodrigo, Heterocycles 8,391 (1977). 140. M. D. Rozwadowska and M. Chrzanowska, Tetrahedron 42,6669 (1986). 141. M. D. Rozwadowska and M. Chrzanowska, l5fh ICJPAC Int. Symp. Chem. NUI. Prod. Hague, 1986, Absfr.. PA 31. 142. M. D. Rozwadowska, Pol. J. Chem. in press. 143. M. D. Rozwadowska and M. Chrzanowska, Tetrahedron 41,2885 (1985). 144. K. W. Bentley and A. W. Murray, J. Chem. SOC.,2487 (1963). 145. M. Shamma, J. E. Foy, and G. A. Miana, J. Am. Chem. SOC.%, 7809 (1974). 146. J. E. Leet, S. F. Hussain, R. D. Minard, and M. Shamma, Heferocycles 19,2355 (1982). 147. J. E. Leet, V. Elango, S. F. Hussain, and M. Shamma, Heterocycles 20,425 (1983). 148. J. E. Leet, V. Fajardo, A. Freyer, and M. Shamma, J. Naf. Prod. 46,908 (1983). 149. D. Cortes, J. Saez, R. Hocquemiller, and A. Cave, J. Naf.Prod. 48.76 (1985). 150. D. Cortes, J. Saez, R. Hocquemiller, and A. Cave, C . R. Acud. Sci. Paris 298,591 (1984). 151. D. Cortes, R. Hocquemiller, A. Cave, and J. Saez, J. Nut. Prod. 49,854 (1986). 152. J. Wu, J. L. Beal, W.-N. Wu, and R. W. Doskotch, J. Nut. Prod. 43,270(1980). 153. B. D. Krane and M. Shamma, J. Nut. Prod. 45,377 (1982). 154. M. Shamma and J. E. Foy, Tetrahedron Len., 2249 (1975). 155. M. Shamma and J. E. Foy, J. Org. Chem. 41, 1293 (1976). 156. J. Wu, J. L. Beal, and R. W. Doskotch, J. Org. Chem. 45,208 (1980). 157. S. Ruchirawat, U. Borvornvinyanant, K. Hantawong, and Y.Thebtaranonth, Heferocycles 6, 1119(1977). 158. M. P. Cava, K. Bessho, B. Douglas, S. Markey, and J. A. Weisbach, Tetrahedron L e f f .4279 . (1966). 159. V. Fajardo, F. Podesta, M. Shamma, and S. F. Hussain, Rev. Lutinoamer. Quim. 16 (2) 59 (1985). 160. V. Fajardo, H. Guinaudeau, V. Elango, and M. Shamma, J. Chem. SOC.,Chem. Commun., 1350 (1982). 161. S . F. Hussain, M. T. Siddiqui, G. ManiKumar, and M. Shamma, Tefrahedron Lptf.. 723 (1980). 162. H. B. Dutschewska and N. M. Mollov, Chew. Ber. 100,3135 (1967). 163. N. Mollov and H. B. Dutschewska, Tetrahedron Leff.,853 (1966).

306

MARIA D. ROZWADOWSKA

164. R. W. Doskotch, P. L. Schiff, Jr., and J. L. Beal, Tetrahedron Lett., 4999 (1968). 165. L.-Z. Lin, H. Wagner, and 0. Seligmann, PIanta Med. 49,55 (1983). 166. T. Nabih, P. J. Davis, J. F. Caputo, and J. P. Rosazza, J. Med. Chem. 20,914 (1977). 167. H. Ishii, T. Ishikawa, and J. Haginiwa, J. Pharm. SOC.Jpn. 97, 890 (1977). 168. T. Ishikawa and H. Ishii, Heterocycles 5,275 (1976). 169. H. Ishii, I.-% Chen, M. Akaike,T. Ishikawa, and S.-T. Lu,J. Pharm. SOC.Jpn. 102,182(1982). 170. H. Ishii, T. Ishikawa, S.-T. Lu, and 1.3. Chen, J. Pharm. SOC.Jpn. %, 1458(1976). 171. H. Ishii, 1 . 4 Chen, T. Ishikawa, and M. Ishikawa, Heterocycles 12, 1037 (1979). 172. H. Ishii, T. Ishikawa, S.-T. Lu, and 1.3. Chen, J. Chem. SOC..Perkin Trans. 1 . 1769 (1984). 173. H. Ishii and T. Ishikawa, J. Pharrn. SOC.Jpn. 101,663 (1981). 174. P. N. Sharma, A. Shoeb, R. S. Kapil, and S. P. Popli, Phytochemisfry 21,252 (1982). 175. H. Ishii, T. Ishikawa, S.-T. Lu, and 1.3. Chen, Tetrahedron Lett., 1203 (1976). 176. H. Ishii, T. Ishikawa, Y.-I. Ichikawa, and M. Sakamoto, Chem. Pharm. Bull. 25,3120(1977). 177. J. R. Falck, S. Manna, and C. Mioskowski, J. Am. Chem. SOC.105,631 (1983). 178. B. Gozler and M. Shamma, J. Nut. Prod. 47,753 (1984). 179. M. H. Abu Zarga, G. A. Miana, and M. Shamma, Tetrahedron Left.,541 (1981). 180. L. Castedo and R. Suau, AIkaloidF (N.Y.)29,287 (1986). 181. J. M. Boente, L. Castedo, D. Dominguez, A. Fariiia, A. Rodriguez de Lera, and M. C. Villaverde, Tetrahedron Left., 889 (1984). 182. J. M. Boente, D. Dominguez, and L. Castedo, Heterocycles 24,3359 (1986). 183. J. M. Boente, L. Castedo, D. Dominguez, and A. Rodriguez de Lera, Tetrahedron Lett., 5535 (1986). 184. S. Chattopadhyay and M. Shamma, Heterocycles 19,697 (1982). 185. T. Biftu, G. E. Schneiders, and R. Stevenson, J. Chem. Res. ( S ) , 270 (1982).

. CHAPTER 5.

HASUBANAN ALKALOIDS MATAOMAT~UI Department of Chemistry Daiichi College of Economics Dazaijiu Fukuoka 818.01. Japan

.

I . Introduction .......................................................... I1. Occurrence and Physical Constants ......................................

307 308 311 311 311 311

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

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

1V. New Alkaloids .................................... A . Methylstephavanine ............................ ................. 323 324 B. 6-Dihydroepistephamiersine &Acetate ...........................

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

325 326 326 327 328

D. Epihernandolinol ..................................................

................. ......................... G. Stephabenine ......................................................

H . Oxostephasunoline... 1. Oxoepistephamiersine ............................ J . Oxostephabenine ............................ K . Stephadiamine..................................................... L . Runanine .............................................. M . Prostephanaberrine ...................... V . Synthesis ............................................................. A. Synthesis via Aminoethylphenanthrene .............. ......... B. Synthesis via Ketonitrile . ....................................... C. Synthesis by Phenol Oxid ....................................... VI . Biosynthesis ..................................... VII . Pharmacology ........................................................ References ............................................................

330 331 332 333 335 335 339 339 339 342 344

I. Introduction The hasubanan alkaloids had been discussed as a subgroup of morphine alkaloids in Volume 13 of this treatise ( 1 ) until the succeeding review was published in 1977 (2);the two reviews cover the literature up to 1976.Since the 301

.

THE ALKALOIDS VOL 3 1 Copynght (( 1988 by Acddemic Press. Inc All nghts of reproduction in any rorm reserved

308

MATAO MATSUI

discovery of the first hasubanan alkaloid, hasubanonine (3),the number of members of this family has reached 41 to date. In the last decade, 13 new congeners including the hasubanalactam alkaloids (4), which possess a carbonyl group at C-16, were isolated and characterized from a sole source, the genus Stephania (Menispermaceae). NMR and mass spectroscopy as well as X-ray diffraction analysis have been ingeniously applied to structure elucidation in this field. On the other hand, synthetic investigation of the hasubanan alkaloids has led to continued discovery of new compounds possessing physiological activity. This chapter extends the information provided by the two preceding reviews (1,2) to the literature that appeared within the years 1976-1986, focusing on spectral data, structural elucidation, synthesis, biosynthesis, and pharmacology. Some references that appeared in the foregoing reviews are omitted from this chapter with exception of those related to the present treatise. Although previously presented in Volume 16 of this treatise (2),the numbering system of the hasubanan skeleton (la) and the hasubanalactam skeleton (lb), which is used in this chapter except for the most part of Section V, is represented anew. 2

11. Occurrence and Physical Constants

Table I gives a survey of the occurrence and physical constants of the hasubanan alkaloids, including the congeners offered in the previous review (2).

TABLE I OCCURRENCE AND PHYSICAL PROPERTIESOF HASUBANAN ALKALOIDS Occurrence Stephania abyssinica Walp.

Stephania cephalanta Hayata Stephania delauayi Diels Stephania hernandifolia Walp.

Stephania japonica Miers

A1kaloid

Metaphanine Stephabyssine Stephaboline Prostephabyssine Stephavanine Methylstephavanine 6-Dihydroepistephamiersine6-acetate Cepharamine Delavaine 16-Oxodelavaine Aknadicine Aknadinine Hernandine Methylhernandine Hernandolinol Hernandifoline Hernandoline 3-0-Demethylhernandifoline Protostephabyssine Stephisoferuline Metaphanine Prometaphanine 1boxoprometaphanine Homostephanoline

Formula (MW)

mP ("C) 233 178- 180 186- 188 196- 198 229 -230 243-245 (dec.)

'

-

186-187 140-150 221-222 156 70 197-199 152- 153 114-115 227-227.5 190-191b 148-149 196- 1911b 133-135 232 207' 115

'

(solvent)

Ref."

-21" (CHCI,) - 58.9" (CHCI,)

14 32 32 32 18 19 20 39 40 41 23 -25 23-25 42 43 26.28 44 45 46 32 47 15 37.38 33.34 48-50

+34.7" (MeOH) - 105" (MeOH)' + 30"(pyridine)

-35" (CHCI,) +85" (CHCI,) -248" (CHCI,) -240" (CHCIS) - 180" (CHCI,) -200" (EtOH) -283" (EtOH) -33" (EtOH) + 125" (EtOH) -97.9" (EtOH) -25" (EtOH)

- 105" (MeOH)' +48" (MeOH) -41" (CHCl,) - 32" (ML?OH)~ - 52" (CHCI,) -247.8" (CHCI,)

233 ~~

Data covered until 1986. Methiodide. Hydrobromide.

DI.[

~~

(continues)

TABLE I (Continued) Occurrence

Stephania japonica var. australis Hatushima

Stephania longa Loureiro

Stephania sinica Diels Stephania sasaki Hayata

Stephania rotunda Loureiro Stephania elegans

Alkaloid Hasubanonine 16-Oxohasubanonine Miersine Stephasunoline Stephamiersine Epistephamiersine Oxostephamiersine Stephabenine Oxostephasunoline Oxoepistephamiersine Oxostephabenine Stephadiamine Prostephanaberrine Haw banonine Metaphanine Oxostepharniersine Stephabyssine Longaninine Stephaboline Longanone Stephabyssine Prostephabyssine Runanine Aknadilactam Aknadinine Bisaknadinine Cepharamine Epihernandolinol Hasubanonine Aknadinine

Formula (MW)

mp ("C)

[ale (solvent)

Ref."

116-1 17 161 222 233 165 98 290 170 217 227 272-273 (dm.) 180 225 (dec.)

-219" (E~OH) - 105.2" (EtOH) 121.4" (CHCI,) + 33" (CHCI,) +64.1" (CHCI,) 88.3" (CHCI,) - 15.24" (CHCI,) + 199.36" (CHCI,) + 104.88" (CHCI,) + 65" (CHCI,) +51.8" (CHCI,) -219.1" (CHCl,)

3 33 1.2,51 17 17 17 17.34 10 4

-

-

-

+ 101.0" (EtOH) + 37.5" (MeOH) 86.5" (CHCI,) -9.8" (CHCl,) - 126.4" (CHCl,) -400" (CHCI,) - 189" (CHCI,) - 183" (MeOH)' - 253.3" (CHCI,)

197-199 190-192 161-162 178-180 120-123 100-102 -

210-214' 198-200

-

114 66 -70

+

+

+

-

- 16" (EtOH) -214" (MeOH) - 289" (F4eOH)

11

7 6 12 52 52 52 52 29,31 29,31

30,31 31 31 35 23.87 88 5,2I.22 53 27 27 27

5. HASUBANAN ALKALOIDS

31 1

111. spectroscopy

A. 'H-NMR SPECTROSCOPY Table I1 presents 'H-NMR data of the hasubanan alkaloids obtained since 'H-NMR spectroscopy was accelerated together with the improvement of measuring instruments. NOE, INDOR, and two-dimensional NMR experiments(7) have been undertaken to resolve the question of stereochemistry at the chiral centers. 1976. During the period 1976-1986, the application of

B. I3C-NMR SPECTROSCOPY A major study on "C-NMR spectroscopy of hasubanan alkaloids was carried out by Matsui et al. (8)(Table 111). They proposed assignments of all carbon atoms including the direct and long-range hetero coupling. The C-9 and N-methyl carbons of hasubanan alkaloids reveal shifts of 6 and 20 ppm higher frequency than those reported for morphinan alkaloids (9).On the other hand, the N-methyl carbons of hasubanans exhibit a lower frequency shift of -10 ppm relative to those of hasubanalactam-type alkaloids (8). These results have been utilized for structure elucidation in later works

- -

(4,7,10-12).

C. MASSSPECTROSCOPY Mass spectroscopy studies in this field have been discussed in detail in Volume 16 of this treatise (2).Subsequent discovery of new congeners revealed further interrelationships between fragmentation patterns and structural features (13). Therefore, from diagnosis of the fragmentation pattern of a certain hasubanan alkaloid, it is possible to assume to some extent the gross structure; further, judging from the combination of the mass spectra, NMR, and IR data, one might define the location of a substituent, including stereochemistry, prior to a chemical procedure. The cleavage patterns characteristic of hasubanan alkaloids are classified into four groups, the metaphanine type, the stephamiersine type, the oxostephasunoline type, and the hasubanonine type (13). I . Metaphanine-Type Cleavage

Table IV lists alkaloids that reveal the metaphanine-type cleavage in their mass spectra (13). In the case of metaphanine (2) ( 1 3 , the most abundant ion peak was observed at m / z 245 and other significant ion peaks at m / z 243 and

312

MATAO MATSUI

TABLE I1 'NMR SPECTRAL DATAOF NEWHASUBANAN ALKALOIDS Compound Methylstephavanine (6)

Aromatic H 6.44 s (C-1)

C-5 H

C-6 H

C-7 H

-

5.52 bs (W 14)

3.80 d (J 6.0)

4.17 m

3.65 d (J 4.18)

6.56 s (C-4) N,O-Dimeth ylstephine (19)b

6.52 s (C-I)

6.69 s (C-4) bDihydroepistephamiersine 6-acetate (7)

4.08 bs (W 14)

6.64 d (J 8.0)

-

6.70 d (J 8.0)

Stephabenine(13)

6.44 s (C-1)

-

5.54 m

3.82 d (J 4.40)

4.23-4.10 m

3.39 d (J 3.73)

6.58 s (C-4) Oxostephasunoline (4)

6.80 d (J 8.13) (C-1)

a, 1.79 dd

(J 2.41, 14.73)

Oxoepistephamiersine (14)

6.70 d (J 8.13) (C-2)

8,2.83 dd , (J 3.96, 14.73)

6.76 d (J 8.46) (C-I)

-

-

4.13 s

6.68 d (J 8.46) (C-2) Oxostephabenine (15)

6.48 s (C-1)

a, 2.13 dd

5.45-5.59 m

3.60 d (J 4.18)

4.15-4.09 m

3.44 d ( J 3.91)

(J 3.08, 15.49) 6.62 s ((2-4)

b, 2.54 dd

6.57 s (C-1)

a, 1.94 dd

(J 3.52, 15.49) N,O-Dimeth yloxostephine (20)*

(J 2.91, 14.77)

6.70 s (C-4)

8, 2.41 dd (J 3.42, 14.77)

Data (since 1976) cover the new alkaloids and their derivatives subsequent to the last review in this treatise (2). Derivative from natural product. After exchange with D,O.

313

5. HASUBANAN ALKALOIDS

C-9 H -

a, 1.51 d ( J 10.5)

C-10 H 4.91 d (6.0)

4.82 d (J 6.37)

OMe

NMe

3.44 (C-7), 3.58 (C-8),

2.62

3.90 (C-3, c-4) 3.44 (C-7), 3.52 (C-8)

2.54

Other signals

5.26 d (J 1.8), 5.72 d (J 1.8) (-OCH,O-), 6.64.6.84, 7.33 (aromatic 3H) 5.90 d (J 1.32), 5.92 d (J 1.32) (-OCH,O-)

Ref." 19

10.19

p, 2.70 dd (J 6.37, 10.5) -

a, 1.55 d

4.85 d (J 6.0)

4.91 d (J 6.37)

(J 10.77)

/I, 2.73 dd (J 6.37, 10.77) a, 1.66 d (J 10.76)

4.94 d (J 6.37)

b, 3.19 dd (I 6.37, 10.76) a, 1.61 d

(J 11.20) b, 2.94 dd (J 6.37, 11.20) a, 1.67 d (J 10.77)

3.42 (C-7), 3.52 (C-8), 3.80, 3.89 (aromatic OMe) 3.41 (C-7), 3.55 (C-8)

2.52

3.48 (C-7), 3.84 (C-4).

3.06

2.58

b, 2.96 dd (J 6.34, 10.87)

I0

4

(J 10.33, C-6 OH),

4.87 d (J 6.37)

4.96 d (J 6.15)

3.49 (C-7), 3.59 (C-8), 3.83 (C-4), 3.91 (C-3) 3.43 (C-7), 3.61 (C-8)

3.14

3.46 (C-7), 3.60 (C-8)

3.01

3.05

(J 6.15, 10.77) (J 10.87)

5.15 d (J I%), 5.70 d (J 1.54) (-OCH,O-), 7.09-7.54 (aromatic 5H) 2.48 d (J 17.14), 3.05 d (J 17.14)

3.92 (C-3)

b, 2.96 dd a, 1.64 d

20

4.88 d (J 6.34)

4.20 s (C-8 OH) -

5.23 d (J 1.54) 5.75 d (J 1.54) (-OCH,O-), 7.13 - 7.49 (aromatic 5H) 5.95 d (J 1.46), 5.96 d (J 1.46) (-OCH,O-), 2.45 d (J 15.86), 2.85 d (J 15.86) (C-15 H A 2.34 d (J 9.58, C-6 OH)

I1

7

7

(continues)

314

MATAO MATSUI

TABLE I1 (Continued) Compound Stephadiamine (16)

Prostephanaberrine (18)

Aromatic H

C-6 H

C-7 H

5.68 dd (J 3.31,6.42)

-

C-5 H

7.00 d (J 8.0) (C-I) 6.80 d (J 8.0) (C-2) 6.73 s (C-I)

a, 2.61 dd

(J 3.31, 14.84) 7.02 s ((2-4)

j,2.80 dd (J 6.42, 14.84)

Stephanaberrine (26)b

6.64 s (C-I) 6.72 s (C-4)

Longaninine (11)

6.52 s (C-I, C-2)

a, 1.98 dd

4.18 m

3.64 d (J 4.0)

(J 2.5, 14.5)

j,3.10 dd Longanone (12)

6.48 s (C-I, C-2)

Dihydrolonganone

6.51 s ( G I , C-2)

(J 3.5, 14.5) d (J 12.0)

a, 3.02

-

4.27 s

j,3.28 d (J 12.0)

Runanine (17)

a, 1.97 dd

4.15 m

(J 2.5, 15.0)

6.47 s (C-I) 6.64 s (C-4)

Dihydrorunanine (24)b

6.50 s (C-I)

Bisaknadinine (8)

6.70 s (C-4) 6.57 s (C-2, C-2’)

Epihernandolinol(9)

6.48 d (J 7.5) 6.50 d (J 7.5)

j.3.07 dd (J 3.5, 15.0) ax, 2.60 d (J 13.2) eq, 3.00 d (J 13.2) -

4.25 t

3.67 d (J 4.0)

315

5. HASUBANAN ALKALOIDS

C-9 H

-

a, 1.81 dd

(J 7.82, 13.37)

C-10 H

OMe

NMe

5.39 dd (J 2.0, 4.3)

3.87 (2x OMe)

2.54

4.70 dd (J 5.42, 7.82)'

3.60 ((2-7)

2.31

4.98 d (J 6.16)

-

2.53

4.88 d (J 6.0)

3.41,3.76

2.58

2.12 d (J 10.0, C-6 OH), 4.02 s (C-8 OH), 6.30 s (C-4 OH)

29.31

4.78 d (J 6.0)

3.45, 3.51, 3.76

2.63

6.04 s (C-4 OH)

30.31

4.84 d (J 6.0)

3.43,3.53, 3.73

2.55

2.33 d (J 10.0, C-6 OH), 6.39 s (C-4 OH)

30,31

2.5 1

1.8-2.2 m (C-15 Hz,C-16 Hz)

35

2.5

-

35

/I, 2.38 dd (J 5.42, 13.37)

a, 1.68 d

( J 10.88)

Other signals

-

5.91 d (J 1.47), 5.92 d (J 1.47) (-OCH,O-), 2.14-2.25 m (C-15 HA 2.53-2.13 m (C-16 HZ) 5.95 s (-OCH,O-), 5.10 s (C-8 OH)

Ref.' 6

I2

I2

/I, 2.75 dd ( J 6.16, 10.88) a, 1.58 d (J 11.0)

/I, 2.91 dd (J 6.0, 11.O) 1.49 d (J 10.5)

1.50 d (J 10.5)

2.72-2.9 m (C-9 H,, C-10 H2)

.

3.61 (C-7) 4.05 (C-8), 3.79,3.80 (C-2, c-3) 3.60,3.70, 3.81, 3.90 3.66,3.83, 4.06 ( 6 x OMe) 3.50, 3.70 ( 3 x OMe)

2.48 (2 x NMe) 2.40

6.06 bs ((2-4, C-4 OH) -

21.22

27

316

MATAO MATSUI

TABLE I11 "C-NMR SPECTRAL DATAOF %ME HASUBANAN ALKALOIDS Stephamiersine"

Epistephamiersine"

Oxostephamiersine"

Dihydrostephamiersine"

Dihydrooxostephamiersine"

119.6 d 110.4 d 153.3 s 148.2 s 43.5 dd 206.6 s 81.7 d 105.5 s 38.3 t 76.1 d 133.8 s 132.9 s 52.9 s 74.6 s 29.3 dd 54.1 t 55.7 q 60.3 q 58.6 q 47.7 q 36.3 q

119.6 d 110.4 d 153.2 s 147.5 s 46.3 dd 202.9 s 88.3 d 106.9 s 38.3 t 76.7 d 133.6 s 131.8 s 53.2 s 75.3 s 28.8 dd 54.1 t 55.7 q 60.2 q 59.1 q 50.8 q 35.9 q

119.7 d 111.3d 153.4 s 148.4 s 42.3 dd 204.6 s 80.6 d 104.3 s 34.6 t 75.4 d 133.7 s 129.9 s 47.0 s 71.9 s 44.4 dd 172.3 s 55.7 q 60.3 q 58.0 q 47.7 q 27.8 q

-

-

-

119.9 d 110.4 d 153.7 s 148.4 s 33.6 dd 71.4 d 75.3 d 102.4 s 34.5 t 74.6 d 133.6 s 132.4 s 43.1 s 71.4 s 45.0 dd 172.8 s 55.7 q 60.4 q 58.4 q 47.9 q 27.7 q -

-

-

-

119.5 d 109.8 d 153.6 s 148.3 s 34.9 dd 68.4 d 76.5 d 104.2 s 37.4 t 76.5 d 137.3 s 133.0 s 49.0 s 73.8 s 28.5 dd 54.2 t 55.6 q 60.3 q 59.1 q 47.7 q 37.7 q -

c-1'

-

-

C-2', C-6' c-3'. c-5' C-4'

-

-

-

-

-

-

-

-

-

-

-

-

-

-

Carbon

c-1 c-2 c-3 c-4 c-5 C-6 c-7 C-8 c-9 c-10 c-11 c-12 C-13 C-14 C-15 C-16 C-3 OMe C-4 OMe C-7 OMe C-8 OMe NMe -OCH20Ester C=O Other aromatic

From Ref. 8.

' From Ref. 4.

From Ref. 10.

-

From Ref. I / . From Ref. 7. From Ref. 1.2.

244 (2,15).The structural features of this group are summarized as follows: (1) possession of an acetal or a hemiacetal ether linkage between C-8 and C-10, and (2) either absence of a substituent or presence of a hydroxyl group or ester moiety at C-6. Because a large number of hasubanan alkaloids follow this cleavage pattern, the metaphanine-type cleavage may be one of the primary pattern for all hasubanan alkaloids (16). 2. Stephamiersine-Type Cleavage Table V surveys alkaloids that exhibit the stephamiersine-type cleavage (13). In the spectrum of stephamiersine (3)(17), the most abundant ion peak

317

5. HASUBANAN ALKALOIDS

Oxostephasunoline (4)*

Stephabenine (13)’

Oxoepistephamiersine (14)d

Oxostephabenine (15)’

Prostephanaberrine (18)’

N,O-Dimethyloxostephine (20)’

120.0 1 110.58 153.79 148.29 33.30 64.63 75.26 100.51 37.90 79.81 132.74 132.53 49.90 72.17 44.92 174.08 55.70 60.52 56.73

107.01 d 147.69 d 144.71 s 106.01 d 36.68 t 68.00 d 81.60 d 103.38 s 37.49 dd 77.10 d 137.01 s 133.50 s 49.68 s 77.08 s 29.37 dd 53.91 t -

120.39 d 111.45d 153.49 s 148.34 s 44.54 dd 200.74 s 88.53 d 105.71 s 33.21 t 76.01 d 133.61 s 129.22 s 46.76 s 74.99 s 46.00 dd 173.60 s 55.86 q 60.47 q 59.55 q 52.28 q 28.44 q

107.06 d 148.13 s 145.47 s 106.41 d 36.86 dd 66.48 d 81.97 d 101.48 s 33.16 dd 76.10 d 133.55 s 132.58 s 46.62 s 73.85 s 45.78 dd 173.32 s

106.21 147.38 146.10 106.36 34.70 112.23 151.49 195.77 32.04 66.11 137.26 131.25 49.37 69.67 36.35 51.19

-

-

57.87 q 52.07 q 28.34 q 100.94 dd 166.06 s

55.11 35.15 100.95

107.98 d 148.61 s 145.86 s 105.76 d 4 1.02 dd 66.10 d 81.79 d 102.24 s 33.32 dd 16.23 d 134.69 s 132.42 s 43.67 s 73.14 s 45.84 dd 173.27 s 57.00 q 52.34 q 28.17 q 101.37 dd -

-

27.8 1 -

-

-

-

57.65 q 51.58 q 38.58 q 100.56 dd 166.28 s 129.64 s 129.87 d 127.49 d 132.31 d

-

-

129.38 s 129.55 d 127.54 d 129.82 d

-

0

2

-

-

-

-

-

-

-

318

MATAO MATSUI

TABLE IV MASSSPECTRAL DATAFOR HASUBANAN ALKALOIDS OF METAPHANINE-TYPE CLEAVAGE Compound Metaphanine (2)'

Stephabyssine"

Stephaboline"

Stephasunoline"

Dihydrostephamiersine"

Dih ydroepistephamiersine"

Methylstephavanine (6)

ml 345 (M+) 245 244 243 230 228 331 (M+) 23 I 230 229 215 214 333 (M+) 23 1 230 229 215 214 377 (M') 245 244 243 230 213 391 (M+) 245 244 243 230 213 391 (M+) 245 244 243 230 213 539 (M+) 229 228

Relative intensity (%) 50.2 100 30.9 32.2 33.9

Formula

Ref. 14.15.52

10.0

13.9 100 23.8 27.5 6.2 4.8 23.4 100 35.8 17.1 9.1 5.9 13.3 100 20.7 8.7 16.7 24.7 3.2 100 27.3 11.3 23.1 29.5 1.3 100 20.6 8.3 23.3 26.8 5 100 68

31.32

29,31,32

I7,31,33

17

17.20

19

Data were obtained anew on a high resolution mass spectrometer by direct inlet probe at 70 eV (Ref. 13).

319

5. HASUBANAN ALKALOIDS

TABLE IV (Continued) Relative intensity (%)

Compound

mlz

N, 0-Dimethylstephine (19)

375 (M') 229 228 227 214 198 433 (M') 245 329 (M+) 229 228 213 363 (M') 348 23 1 230 229 216 377 ( M+) 23 1

6-Dih ydroepistephamiersine &acetate (7) Stephanaberrine (26)

Longaninine (1 1)

Dihydrolonganone(21)

Formula

Ref.

5.6 100 81.6 47.3 5.4 9.7

100 17.1 100 91.5 2.5 -

100 -

C23H31N07

2o

C18H19N05

I2

C14HISN02 C 1 4 H 14N02

C13H11N02

Cl9Hz5NO,

29.31

Cl4Hl7N02

-

100

was observed at m / z 243 rather than m / z 245 which is the base ion peak characteristic of metaphanine (2). The structural features common to this group are possession of an acetal ether linkage between C-8 and C-10 and a ketone group at C-6 (17) except stephadiamine (16).

OMe

3

320

MATAO MATSUI

MASS

TABLE V SPECTRAL DATAFOR HASUBANAN ALKALOIDS OF STEPHAMIERSINE-TY PE CLEAVAGE

Compound Stephamiersine (3)"

Epistephamiersine"

Oxostephamiersine"

Oxoepistephamiersine (14)

Stephadiamine (16)

10-0-Acetylprostephanaberrine(25)

Longanone (12)

a

m/z

389 (M') 245 244 243 228 213 389 (M+) 245 244 243 228 213 403 258 251 242 221 403 (M') 258 251 242 221 344 (M') 243 385 (M') 251 228 221 315 (M') 360 230 229 199

Relative intensity (%) 4.1 11.0 50.2 100 19.6 48.2 13.5 9.1 46.8 100 15.5 33.1 26.2 31.2 100 12.6 2.6 33.4 32.1 100 12.6 2.6

Formula

Ref.

CISH17N02

C1SH17N02

C21H2SN07

I1

c l S H l SN03

-

100 35.2 56.1 21.8 100 -

100

-

Data were obtained anew on a high resolution mass spectrometer by direct inlet probe at 70 eV (Ref. 13).

32 1

5. HASUBANAN ALKALOIDS

3. Oxostephasunoline-Type Cleavage

Table VI gives mass spectral data for members that show the oxostephasunoline-type cleavage (13). These fragmentation patterns obviously differ from those of the foregoing two groups, indicating the presence of a hydroxyl group at C-6 and a y-lactam. In the case of oxostephasunoline (4) (4), the most abundant ion peak appears at m / z 258.

I

OMe

4 TABLE VI MASS SPECTRAL DATAFOR HASUBANAN ALKALOIDS OF OXOSTEPHAUNOLINE-TYPE CLEAVAGE Compound Oxostephasunoline (4)

Dih ydrooxostephamiersine"

N,O-Dimethyloxostephine (20)

mlz

Relative intensity (%)

391 (M+) 258 257 243 227 212 405 (M') 258 257 243 242 227 389 (M') 242 24 1 216 214

40.2 100 44.0 13.4 36.4 9.3 63.3 100 76.4 15.4 48.0 41.1 17.2 100 54.7 6.1 5.0

Formula

Ref.

C21H25NOS

4

c I SH16N03

c2 1H27N07

17

c l SH16N03

C20H23N07

7

CI,H,2NO,

Data were obtained anew on a high resolution mass spectrometer by direct inlet probe at 70 eV (Ref. 13).

322

MATAO MATSUI

TABLE VII MASSSPECTRAL DATAFOR HASUBANAN ALKALOIDS OF HASUBANONINE-TYPE CLEAVAGE Compound Hasubanonine (5)"

Homostephanoline"

Aknadinine 16-Oxohasubanonine

Iso-6-deh ydrostephine

Prostephanaberrine (18)

mjz

373 (M+) 316 315 314 258 245 243 359 ( M + ) 302 30 1 257 245 244 23 1 359 (M') 30 1 387 (M') 372 315 314 27 1 345 ( M + ) 30 1 343 (M') 257 245 227

Relative intensity (%)

Formula

Ref

55.7 22.5 100

64.0 26.6 15.4 10.3 65.2 26.6 100

c l S H I9O5

C 2 0 H 2 5 N 0 5 13.50 c l 7 H 17O5

13.1 11.6 43.4 28.0

C14H17N02

-

C2OH25NO5

100

45.5 24.8 100

23-27

C16H I3O6

C21H25N06

c2 I

33

I9O5

56.4 12.4 -

100

16.0 100

51.4 18.5

Data were obtained anew on a high resolulion mass spectrometer by direct inlet probe at 70 eV (Ref. 13).

4 . Hasubanonine-Type Cleavage

Table VII gives a survey of alkaloids that exhibit the hasubanonine-type cleavage. The characteristic fragmentation pattern of this group, possessing an a$-unsaturated carbonyl group in ring C, is significantly different from other groups. In the case of hasubanonine (5) (3), the most abundant and nitrogen-free ion peak was observed at m / z 315, which is important for structure elucidation of this group (2,13).

5. HASUBANAN ALKALOIDS

323

OMe

5

IV. New Alkaloids A. METHYLSTEPHAVANINE

During a search for physiologically active compounds in South African plants, a new hasubanan ester acetal alkaloid, methylstephavanine (6)*, was isolated from Stephania abyssinica (19). The 'H-NMR spectrum of the new alkaloid 6 exhibited signals for one methylenedioxy, one N-methyl, and four methoxyl groups (19) (Table 11). Its mass spectrum revealed the most abundant ion peak at m f z 229, indicating a close resemblance to the known hasubanan alkaloid, stephavanine (18). Basic hydrolysis of 6 afforded alcohol 19 and methyl veratrate. The 'HNMR spectrum of 19 (Table 11) revealed the presence of one methylenedioxy, one N-methyl, and two methoxyl groups. The mass spectrum (Table IV) exhibited the most abundant and significant ion peak at m/z229 indicative of metaphanine-type cleavage. Treatment of an aqueous THF solution of stephavanine (18) with excess sodium hydride and methyl iodide gave N,O-dimethylstephine, a compound identical to alcohol 19. Thus, the structure of the new alkaloid 6 was established by chemical correlation with stephavanine (19).

* This alkaloid was unnamed in the original reference (19). Considering the structural resemblance to stephavanine ( M ) , the present author has tentatively named this alkaloid methylstephavanine.

324

MATAO MATSUI

Me 0,

1

I

OMe

OMe

6 B. 6-DIHYDROEPISTEPHAMERSINE6-ACETATE 6-Dihydroepistephamiersine 6-acetate (7)was isolated from Stephania abyssinica as a homogeneous oil. The UV spectrum showed an absorption maximum at 286 nm, and the IR spectrum exhibited a band corresponding to an aliphatic ester carbonyl group at 1725 cm-' (20). The 'H-NMRdata are summarized in Table 11. In chemical investigations, hydrolysis of 7 with barium methoxide gave an alcohol identical with 6-dihydroepistephamiersine (17), which on further treatment with mineral acid gave the known alkaloid, stephasunoline (17). Thus structure 7 was proposed for 6-dihydroepistephamiersine 6-acetate (20).

OMe

7

325

5 . HASUBANAN ALKALOIDS

C. BISAKNADININE Bisaknadinine (8), a dimeric hasubanan alkaloid containing a biphenyl linkage, was isolated from Stephania sasaki collected in Taiwan (21). Its UV spectrum showed absorption maxima at 263 and 293 nm. The IR spectrum exhibited bands at 3550 and 1660 cm-' corresponding to a hydroxyl group and an a,/l-unsaturated ketone. The 'H-NMR spectrum (Table 11) revealed the presence of methoxyl, N-methyl, and hydroxyl groups, which suggested close similarity to that of aknadinine (4-demethylhasubanonine) (23-26) except for the relative intensity of aromatic proton being reduced one-half. The mass spectrum showed the molecular ion peak at m/z 716. From these findings, it was assumed that bisaknadinine (8)was a dimer composed of two identical radicals each lacking one aromatic proton from the aknadinine molecule (21,22). In the INDOR experiment of 8, an NOE ehancement was observed between the aromatic proton (66.57) and the methoxyl protons (63.83) owing to ortho interraction. It was concluded, therefore, that the position of biphenyl bond is at C-1 of the monomer, aknadinine. This was also supported by a negative Gibbs' test of the dimer (8)(21,22).

-Me Me

I OMe

I

OMe

8 Oxidation of aknadinine with silver nitrate gave a pair of dimeric compounds, one of which was identical to the naturally occurring bisaknadinine (8) and the other assumed to be a stereoisomer arising from an axial chirality concerning the mode of biphenyl linkage (21,22). It was impossible, however, to determine from ORD and CD measurements whether the isomer is of natural bisaknadinine (8). Therefore, unambiguous proof of the stereochemistry was achieved, using the X-ray diffraction method>and the

326

MATAO MATSUI

configuration of the biphenyl linkage was determined as (R) (5). Thus, bisaknadinine (8)is a dimeric hasubanan alkaloid produced by para oxidative coupling of the phenolic hydroxyl group of aknadinine (5,21,22).

D. EPIHERNANDOLINOL Epihernandolinol(9)was isolated from Stephania elegans together with the known hasubanan alkaloids, hasubanonine (5) and aknadinine (27). The UV spectrum of epihernandolinol(9) revealed absorption maxima at 237 and 284 nm, the latter of which shifts to 288 nm on addition of alkali, indicating the phenolic nature of the molecule. The IR spectrum exhibited a hydroxyl band at 3360 cm-'. In the 'H-NMR spectrum (Table 11), there were signals for one N-methyl and three methoxyl groups. The mass spectrum (Table VII) revealed a molecular ion peak at m/z 361 and other significant ion peaks at m/z 301 (base ion peak), 231, and 230, indicating hasubanan-type cleavage (13). Sodium borohydride reduction of aknadinine gave a pair of epimeric alcohols, one of which was found to be identical to natural epihernandolinol and the other identical to the known alkaloid hernandolinol(l0) (28). As the structure of hernandolinol(l0) had been proposed without resolution of the stereochemistry (28), the stereochemistry of epihernandolinol (9) was not definitely established (27).

OMe

9, 10 E.

LONGANININE

Longaninine (11)was isolated from the roots and stems of Stephania longa collected in Hainan Island, China (29-31). This alkaloid was once named longanine, but the name was soon changed to longaninine to avoid confusion

5. HASUBANAN ALKALOIDS

327

with a neutral compound, longanin (31).The UV spectrum of longaninine (11) showed an absorption maximum at 284 nm, and the IR spectrum exhibited bands at 3520, 1625, and 1592 cm-'. The 'H-NMR spectrum (Table 11) revealed close similarity to that of stephasunoline (I7) excepting the number of methoxyl groups. The mass spectrum (Table IV) exhibited the most abundant ion peak at m/z 23 1, characteristic of metaphanine-type cleavage (29,31). Methylation of longaninine (11) with diazomethane yielded a nonphenolic base, whose spectral and physical properties were identical to those reported for stephasunoline (17). From these findings, the structure of longaninine (11) was assigned as 4-0-demethylstephasunoline (29,31).

1

OMe

11 F. LONGANONE Longanone (12) was isolated from Stephania longa together with longaninine (11) and three other known hasubanan alkaloids, stephaboline (32), stephabyssine (32), and prostephabyssine (3132). The UV spectrum of longanone (12) showed an absorption maximum at 286 nm, and its IR spectrum exhibited bands at 1730 and 1625 cm-'.In the mass spectrum (Table V), the most abundant ion peak occurred at m/z 229, indicating stephamiersine-type cleavage. The 'H-NMR spectrum (Table 11)showed the presence of two aromatic protons, one hydroxyl, one N-methyl, and three methoxyl groups (30,31).From these spectral findings, it seemed most likely that longanone (12) possesses a carbonyl group at C-6 and two methoxyl groups at C-7 and C-8. Further, comparison of the 'H-NMR spectra of longaninine (11)and longanone (12) suggested that longanone (12) must be 80-methyl-6-oxolonganinine (30.31).

328

MATAO MATSUI

-Me

N-Me

“OMe

1

OMe

12

I OMe

21

Sodium borohydride reduction of longanone (12) yielded a stereoselective product, dihydrolonganone (21). The ‘H-NMR spectrum of 21 (Table 11) revealed C-5 methylene protons at 63.07 (lH, doublet of doublets, J = 3.5 and 15 Hz) and 6 1.97 (lH, doublet of doublets, J = 2.5 and 15 Hz), a C-6 proton on the hydroxyl-bearing carbon at 64.15 (multiplet), and a C-7 proton at 63.67 (lH, doublet, J = 4.0 Hz). The values of coupling constants corresponded to those of axial-equatorial or equatorial-equatorial coupling, indicating the absence of diaxial coupling. Therefore, the C-6 hydroxyl group has the p-axial configuration, and the C-7 methoxyl group is /3-equatorial (30,31).Further treatment of dihydrolonganone (21) with hydrochloric acid gave a hemiacetaltype alkaloid, 8-0-demethyldihydrolonganone(1l), which was identical to naturally occurring longaninine (30.31).From these results, structure 12 was assigned to longanone.

G. STEPHABENINE Stephabenine (13) was isolated from the fruits of Stephuniu Juponicu together with two unidentified alkaloids (10). The UV spectrum of stephabenine (13) showed absorption maxima at 260 and 294 nm, and the IR spectrum exhibited bands at 1702 and 1600 cm-’. The mass spectrum revealed the molecular ion peak at m/z 479 (1 1.28%),with the most abundant peak at m/z 228 and another significant peak at m/z 229 (77.5%)(10).The ‘H-NMR data (Table 11) coupled with mass spectral findings suggested that stephabenine (13) is of the hasubanan type carrying a benzoate moiety. The highfield shift and splitting pattern of the methylenedioxy protons (65.70, lH, doublet, J = 1.54 Hz and 65.15, lH, doublet, J = 1.54 Hz) were ascribable to the close proximity of the benzoate to the methylenedioxy group, indicating a B-axial orientation for the ester (10).

5. HASUBANAN ALKALOIDS

329

0 II

-C-

1

OMe

Alkaline hydrolysis of stephabenine (13) gave benzoic acid and a basic component identical to authentic N,O-dimethylstephine (19) (19). Thus, structure 13 was proposed for stephabenine (10). H. OXOSTEPHASUNOLINE Oxostephasunoline (4) was isolated from the roots of Stephania japonica (4). The UV spectrum of oxostephasunoline (4) showed an absorption maximum at 286 nm, and the IR spectrum depicted bands at 3550,3500, and 1670cm-', indicating the presence of a hydroxyl group and a y-lactam. The mass spectrum (Table VI) exhibited the most abundant ion peak at m/z 258, and the 'H-NMR spectrum (Table 11) revealed the presence of three methoxyl and one N-methyl group. The downfield shift (63.06) of the N-methyl resonance indicated that oxostephasunoline (4) was a y-lactam, which was further supported by the IR band at 1670 cm-', significant features of the mass spectrum (Table VI), and the I3C-NMR spectrum (Table 111). On exhaustive 'H-NMR analysis similar to the case of stephasunoline (17), the structure of oxostephasunoline (4) including the stereochemistry was practically proved (4). Finally, the structure of oxostephasunoline (4) was confirmed by the following chemical correlation with several known hasubanan alkaloids. Heating the new alkaloid 4 in an ethanolic hydroxide solution gave 16oxoprometaphanine (33),which on treatment with dilute hydrochloric acid yielded 16-oxometaphanine (33).Thus structure 4 was proposed for oxostephasunoline (4). As stated in Section I, the hasubanan alkaloids carrying a

330

MATAO MATSUI

carbonyl group at C- 16 exhibit characteristic chemical and spectral properties. The skeletal type 4 was therefore separated from the hasubanan type and named hasubanalactam (4).

I. OXOEPISTEPHAMIERSINE Oxoepistephamiersine (14) was isolated from the roots of Stephania japonica as the seventh hasubanalactam congener (ZZ). The U V spectrum of oxoepistephamiersine (14) showed an absorption maximum at 284 nm, and the IR spectrum exhibited bands of a six-membered ketone at 1745 cm-' and y-lactam at 1690 cm-'. The mass spectrum (Table V) revealed the most abundant ion peak at m/z 257, indicating stephamiersine-type cleavage (13). Since oxoepistephamiersine was identical to the y-lactam (14) derived from permanganate oxidation of epistephamiersine (Z7), structure 14 was proposed for oxoepistephamiersine (ZZ).

I

OMe

14 J. OXOSTEPHABENINE Oxostephabenine (15) was isolated from the fruits of Stephania japonica (7). The UV spectrum of 15 showed absorption maxima at 294 and 230 nm, and the IR spectrum depicted bands at 1700, 1680, and 1600 cm-'. Its mass spectrum revealed a molecular ion peak at m/z 493 (17%), the most abundant ion peak at m/z 241 (C,,H, ,NO3),and another significant ion peak at m/z 242 (60%, Cl,Hl2NO3). The 'H-NMR (Table 11) and 13C-NMR (Table 111) spectra exhibited close similarity to those of stephabenine (13) (10)except for N-methyl resonance (7).

33 1

5 . HASUBANAN ALKALOIDS

Alkaline hydrolysis of oxostephabenine (15) gave benzoic acid and a ylactam derivative newly named N,O-dimethyloxostephine (20). The mass spectrum of 20 (Table VI) revealed the most abundant ion peak at m/z 242, corresponding to oxostephasunoline-type cleavage (7.13). In the 'H-NMR spectrum (Table 11), an enhancement was observed between the C-5 a-axial proton (61.94)and the C-7 proton (63.44), indicating a 1,3-diaxial interaction. The C-7 methoxyl group, therefore, should be in the /3-equatorial configuration. These findings were supported by long-range coupling between the C-7 proton (63.44) and the C-10 a-equatorial proton (64.88) through five 0bonds and one oxygen atom (7). Permanganate oxidation of stephabenine (13) (10)gave 16-oxostephabenine, identical to structure 15. Thus, the structures of oxostephabenine and N,O-dimethyloxostephine were established by the combination of spectral and chemical evidence as 15 and 20, respectively (13).

K. STEPHADIAMINE Stephadiamine (16) was isolated as a minor component from the ethanolic extract of the whole plant of Stephania japonica collected in Taiwan (6). The IR spectrum of stephadiamine (16) exhibited bands at 3375 (NH,) and 1720cm-' (6-lactone), and the 'H-NMR spectrum (Table 11)showed the presence of one N-methyl and two methoxyl groups. Its mass spectrum revealed a base ion peak at m/z 243 of stephamiersine-type cleavage (Table V) (6). On treatment with acetic anhydride and pyridine, stephadiamine (16) was converted to N-acetylstephadiamine (22), which was hydrolyzed with potassium hydroxide followed by methylation, after acidification with dilute hydrochloric acid, with diazomethane to yield a hydroxy ester (23) in 93%

-Me Me

+COZ NH-Ac

23

332

MATAO MATSUI

yield (6). Its IR spectrum showed bands at 3280 (NH and OH), 1730 (ester), and 1666 cm- * (amide). This chemical conversion substantiated the presence of the lactone group in 16 (6). The relative stereochemistry of stephadiamine (16) was clarified by X-ray diffraction analysis, using the direct method, and the absolute configuration was solved by the heavy-atom method, using the N-p-bromobenzoyl derivative (6). Stephadiamine (16), a C-norhasubanan alkaloid, is not regarded as a hasubanan congener in the strict sense, but as a new member of a-amino acid derivatives (6).

L. RUNANINE Runanine (17) was isolated from the roots of Stephania sinica, a species found in the Chinese provinces of Heibei, Gueizhou, and Yunnan (35).The 'H-NMR spectrum of runanine (17)(Table 11) revealed the presence of two aromatic protons, C-5 methylene protons, one N-methyl, and four methoxyl groups. An NOE effect (10%enhancement)was observed between the protons of two methoxyl groups (63.79 and 3.80) and the aromatic protons (66.47 and 6.64), but the same phenomenon was not observed for the other methoxyl protons (63.61 and 4.05). Therefore, the former methoxyls should be situated on ring A. From the further observation of an NOE (22.6% enhancement) between the aromatic C-4 proton (66.64) and one (63.00)of the C-5 methylene protons, it was assumed that the two methoxyl groups (63.79 and 3.80)should be located at C-2 and C-3, respectively. The absence of signals for olefinic OMe

OMe I

OMe

OMe

17

24

5. HASUBANAN ALKALOIDS

333

protons suggested that the remaining two methoxyl groups (63.61 and 4.05) are located at C-7 and C-8 in ring C. On the other hand, two pairs of signals arising from an A2B, system were observed, one of which was assigned to the protons on the ethylamine linkage and the other to the protons at C-9 and C10. Judging from the lack of a signal due to the C-9 proton (around 63.6-3.8) which appears in sinomenine-type alkaloids (36),the ethylamine linkage can be regarded as being situated between C-13 and C-14 (35). Potassium borohydride reduction of runanine (17) yielded dihydrorunanine (a), the 'H-NMR spectrum of which (Table 11)exhibited a triplet (64.25),the proton bearing the hydroxyl group coupling with those of C-5 (35). The optical activity of runanine (17), [a]D -4oo", was similar to that of hasubanonine (5), [a],, -214" (3); therefore, it was concluded that the ethylamine linkage must have the same configuration as hasubanonine [C-13 (R) and C-14 (S)]. From these results, structure 17 was proposed for runanine (35);however, no application of mass spectral data to the structure elucidation was presented (35). M. PROSTEPHANABERRINE Prostephanaberrine (18) was isolated from the fresh fruits of Stephuniu japonica together with the other hasubanan alkaloids, stephabenine (13) and oxostephabenine (15)(12). The U V spectrum of prostephanaberrine (18) showed an absorption maximum at 273 nm, and its IR spectrum exhibited bands for a hydroxyl group (3580 cm-') and an a,fl-unsaturated ketone (1670 and 1640cm-'). The 'H-NMR spectrum (Table 11) indicated the presence of a methylenedioxy, a methoxyl, an N-methyl, an olefinic proton, and two aromatic protons. The mass spectrum (Table VIII) revealed a molecular ion peak at m/z 343 and the most abundant nitrogen-free ion peak at m/z 257 (CI5Hl3O4)together with another significant peak at m/z 245 (CI4Hl5NO3). Therefore, it was assumed that ring C possesses a conjugated ketone system bearing an enolic methyl ether and an olefinic proton adjacent to methylene protons. Furthermore, in the 'H-NMR spectrum, the signal pattern of the aromatic protons (observed as singlets at 66.73 and 7.02) suggested that the methylenedioxy group must be located at C-2 and C-3. From the presence of an NOE effect between the singlet (66.73) and the doublet of doublets (64.70), the doublet of doublets was assigned to the proton on the hydroxyl-bearing c-10(12). Prostephanaberrine (18) was thus assumed to be a congener closely related to prometaphanine (37,38) and prostephabyssine (32) except for the methylenedioxy group (Z2). The structures of prometaphanine, prostephabyssine, and 16-oxoprometaphanine (33) have been reported as a solvent-dependent

334

MATAO MATSUI

OMe

0

26

equilibrium mixture of the a,/?-unsaturated ketone and the hemiacetal, but prostephanaberrine (18) was found to exist in the ketone form only (22). Treatment of prostephanaberrine (18) with acetic anhydride and pyridine gave 10-0-acetylderivative 25, which on treatment with aqueous hydrochloric acid under mild conditions gave stephanaberrine (26), which could also be prepared from 18 in the same manner (12). The IR spectrum of stephanaberrine (26) displayed bands at 3460 (OH) and 1725 cm-' (six-membered ketone), and the 'H-NMR spectrum (Table 11) exhibited the presence of a methylenedioxy, an N-methyl group, and a C-10 proton as a doublet coupling with the C-9 /? proton, but no signals due to the methoxyl and olefinic protons were observable. The mass spectrum (Table IV) revealed the most abundant ion at m/z 229 (C14H1,NO,), corresponding to metaphanine-type cleavage and suggesting a significant transformation in ring C of prostephanaberrine (18). Thus, from the above reaction sequence and the spectral findings, it was assumed that the C-7 enolic methyl ether of 18 was hydrolyzed to a ketone function and that the C-10 hydroxyl and C-8 ketone carbonyl groups were converted to a hemiacetal linkage between C-8 and C-10 to furnish the metaphanine-type derivative, stephanaberrine (26) (22). On direct comparison of stephanaberrine (26) and metaphanine (2) (25), close similarity of the 'H-NMR and mass spectra was observed. The stereochemical problem of the ethylamine linkage was resolved by the fact that the optical activity of 26, [.ID -47.5", agrees with that of 2, [.ID -41.4" (12).Thus, structures 18 and 26 were proposed for prostephanaberrine and stephanaberrine, respectively (12).

5. HASUBANAN ALKALOIDS

335

V. Synthesis Synthesis of the hasubanan skeleton has been presented in Volume 16 of this treatise ( 2 )in terms of the following schemes:(1) via ketolactones (54-60), (2) via ketonitriles (55,60), (3) via cyclic enamines (56-59,61), (4) via spiroketone (62-64), and ( 5 ) by phenol oxidation (65). Moreover, the review (2) introduced total syntheses of the hasubanan alkaloids, cepharamine (55,58,60,66),hasubanonine (67), aknadinine (67), and metaphanine (68). These alkaloids were synthesized via the common intermediate ketolactam, with the exception of one of the two cepharamine syntheses, a method utilizing photocyclization (66). In the succeeding decade, synthetic investigations in this field have focused on discovery of new analgesics and narcotic antagonists rather than on interest in the syntheses of naturally occurring alkaloids.

A.

SYNTHESIS VIA AMINOETHYLPHENANTHRENE

The Bristol-Myers group has devised some synthetic routes to hasubanan derivatives (Scheme 1) from the common intermediate, 4a-(2-aminoethyl)1,2,3,4,4a,9-hexahydro-6-methoxyphenanthrene(27), prepared from 7methoxytetralone via the spiroketone (69- 75). The following synthetic methods therefore succeed the “Synthesis via Spiroketone” section of the foregoing review (2).Aminoethylphenanthrene 27 was treated with ethyl chloroformate and triethylamine to yield the unsaturated urethane 28. Urethane 28 was reduced with LAH to N-methyl derivative 29, which was then converted to amide 30. Oxidation of amide 30 with rn-chloroperbenzoic acid furnished stereoselectively a-epoxide 33, which on treatment with alkali gave a separable mixture (1 :1) of 9a-hydroxy-3-methoxy-N-methylhasubanan (36) and its isomorphinan derivative in an overall yield of 48% from 27 (70). Epoxides 34 and 35, on treatment with dilute perchloric acid in THF, yielded 9a-hydroxy-3-methoxyhasubanans37 and 38 in good yield. The epimeric 3,9fl-dihydroxyhasubanan (40) was prepared from the 9a epimer 37 by the following reaction steps: (1) treatment of 37 with phosphorus oxychloride afforded oxazolidone 39 via an intramolecular displacement-inversion, and (2) demethylation of 39 with boron tribromide gave the demethylated compound, which when reduced with LAH furnished 3Qfl-dihydroxy-Nmethylhasubanan (40) (72). Further attempts to effect a one-step synthesis of the hasubanan skeleton via acid-catalyzed cyclization of urethane 28 and unsaturated amides 31 and 32 were explored, using trifluoroacetic acid (TFA) (Scheme 1). Treatment of

8

336 Me0

MATAO MATSUI

8-..

R

33 R = N M e C O C F 3 34 R = NHCOzEt 35 R = N H C O ~

I 36R=Me 37 R = C O z E t

27

R=NH;!

41

R=COzEt

28 R = NHCOzEt

42R=Me

29 R = N H M e

4 3 R = H

30 R = N M e C O C F 3 31 R = N H C O C F 3 32 R = N H C O ~

39

40

38~=cod SCHEME I

SCHEME 1

28,31, and 32 with TFA at reflux temperature furnished the corresponding hasubanans 41, 42, and 43 in good yield. Alkaline hydrolysis of 41 gave 3-methoxyhasubanan (43) which could be easily transformed to the various N-substituted 3-hydroxyhasubanans (72). Compound 27, moreover, was condensed with benzaldehyde to give a Schiff base (44), which was bromi-

337

5. HASUBANAN ALKALOIDS

27

44

45 SCHEME 2

nated and then hydrolyzed to yield 9a-bromo-3-methoxyhasubanan(45) in essentially quantitative yield (Scheme 2). Product 45 was converted to various N-substituted morphinan derivatives, e.g., 3,14-dihydroxy-N-cyclopropylmethylmorphinan (73). Another synthetic route to 3-methylhasubanan (43), proposed by Lattes et al. (74),consists of the intramolecular aminomercuration (75)of aminoethylphenanthrene 27. The key intermediate 27 was treated with mercury(I1) acetate in THF/water to yield 9-acetoxymercury-3-methoxyhasubanan(46), as depicted in Scheme 3, and then the reaction product 46 was successively treated with benzyltriethylammonium chloride, sodium hydroxide, and sodium borohydride to furnish the target, 3-methylhasubanan (43) (74).

27

43

46 SCHEME 3

r:

T

T u)

0

5. HASUBANAN ALKALOIDS

339

B. SYNTHESIS VIA KETONITRILE

The Hoffmann-La Roche group (76)has devised a new simple route to 3hydroxy-N-methylhasubanan (52) via ketonitrile 48 (Scheme 4).Condensation of 2-(rn-methoxyphenyl)cyclohexanone(47) and chloroacetonitrile gave ketonitrile 48, which was subjected to successive treatment with butyllithium and ethyl acetate to yield alcohol 49. Compound 49 was dehydrated with phosphorus oxychloride and pyridine, followed by catalytic hydrogenation, to give tricyclic indolineester 50. Intramolecular cyclization of 50 with hydrochloric acid furnished tetracyclic aminoketone 51. The last stages in the sequence consist of Huang-Minlon reduction of 51, followed by Nmethylation and O-demethylation to yield the desired product, ( &)-3hydroxy-N-methylhasubanan (52). The structure of 52 was proved by single crystal X-ray analysis of the hydrobromide (76).

C. SYNTHESIS BY

PHENOL

OXIDATION

Phenol oxidation of reticurine derivatives to the cepharamine analogs and cepharamine (56)was undertaken by Kametani et al. (65,66,77).The unique directing effect of thalium(II1) trifluoroacetate (TTFA) for para-ortho oxidative coupling in the reticurine system (78) was extended to the seco derivatives by Schwartz and Wallace (79,80). Oxidative coupling of Ntrifluoroacetylsecoreticuline (53) with TTFA in anhydrous dichloromethane gave dienone 54 in a 15-27% yield (Scheme 5). Hydrolysis of 54 with methanolic potassium carbonate and spontaneous cyclization of the resulting amine gave a 75% yield of the enone hasubanan derivative 55 (79.80).Enone 55 had previously been prepared by photocyclization of the bromosecoreticurine derivative (66)in low yield, and it was converted by transesterification to (*)-cepharamine (56) (66,80).

VI. Biosynthesis During the period 1976-1986,biosynthetic studies on hasubanan alkaloids were carried out by Battersby et al. (82-84) for hasubanonine (5) together with protostephanine (57). The two alkaloids, isolated from Stephania japonica, arise from the same precursor, and their unusual structures are of biosynthetic interest, namely, the vicinally trioxygenated ring C in 5 and the unique natural example of a dibenz[d,f] azonine skeleton in 57.

:

0

0 z

rz

8 E

z

0

34 1

5. HASUBANAN ALKALOIDS

5a

61 R = H 62 R = M e

__j

N-Me Me0

N-Me

OH OMe

0

5

65 ?H

OMe

N-Me Me0

OH

0

66

67R=H 68 R = M e

57 SCHEME 6

Degradation of 5 and 57 revealed that both skeletons are built from two C,-C2 units derivable from tyrosine (81,82).Many 14C-labeledisoquinolines, which on biogenetic grounds could be possible late precursors of both alkaloids, were prepared and fed to Stephania japonica plants, after which the labeled alkaloids were isolated. Isoquinolines 59-64, lacking the

342

MATAO MATSUI

C-3 methoxyl group in the benzyl ring resulted, in incorporation in the alkaloids, but isoquinolines 67 and 68, with the 4-hydroxy-3-methoxy pattern in the benzyl ring, were not incorporated (82-84). These results allow delineation of the requirement for later precursors of 5 and 57, as shown in Scheme 6. Ring C and the ethylamine linkage are derived in oioo from the diphenolic amine 58, which combines with another tyrosine-derived building block to give 1-benzyl-6-methoxyisoquinolines59 or 60. Then a second hydroxylation takes place in the benzyl ring to furnish benzylisoquinolines 61 or 62, and methylation of the original phenolic oxygen occurs to form isoquinolines 63 or 64. The incorporation of all the isoquinolines both as secondary amines and as their N-methyl derivatives indicates that the timing of N-methylation is not critical (83,84).Although later stages in the sequence could not be defined exactly, it was assumed that para-ortho oxidative coupling directed by the 7-hydroxy substitutent of 1-benzylisoquinoline precursors 63 or 64 leads to hasubanonine (5) via the dienone 65, and para-para coupling of precursors 63 and 64 to protostephanine (57) via dienone 66. These cases are unique in requiring two phenolic hydroxyl groups in one of the rings undergoing oxidative coupling (83,84).

72 R=CH~-CH-CH~

VII. Pharmacology Four synthetic hasubanan alkaloids, 3,9/l-dihydro-N-methylhasubanan

(a), 3,9a-dihydroxy-N-methylhasubanan (69), 3,9cr-dihydroxy-N-cyclopro-

pylmethylhasubanan (70), and 3-hydroxy-N-cyclopropylmethylhasubanan

343

5. HASUBANAN ALKALOIDS

TABLE VIII ACTIVITY OF ANALGFSICAND NARCOTIC ANTAGONIST SOMEHASUBANAN ALKALOIDS I N MICE" ED50(mglWb Compound

Analgesic activity'

Antagonist activityd

40

9 20

>40

69

70 71

24 13

40 15 >40

' From Refs. 72 and 85. Subcutaneous injection. Phenylquinone writhing in mice. Oxomorphone-induced Straub tail.

(71), have been subjected to screening tests for analgesic and narcotic antagonist activity in mice (Table VIII) (72). Although some were found to possess a moderate level of activity, none was considered to be of therapeutic value (72). A couple of synthetic congeners, 3-methoxyhasubanan(43) and 3-methoxyN-allylhasubanan (72), were also assessed by determination of their affinity for opiate receptors (74).The specific binding to these receptors was investigated in cerebral tissues using the potent morphinelike drug, 3H-labeled etorophine (86). The affinities of 43 and 72 were low compared to the reference compounds, i.e., morphine, nalorphine, and levorphanol, as shown in Table IX. TABLE IX DISPLACEMENT POTENCY OF HASUBANAN ON THE SPECIFIC BINDINGTO RAT ALKALOIDS OF [3H)ETORPHINE" BRAINHOM~GENATES Compound

GO(PW

3-Methoxyhasubanan (43) 3-Methoxy-N-allylhasubanan (72) Morphine Codeine Levorphanol Dextrorphan Nalorphine

76 4 > lo00 0.17 f 0.010 15*1 0.023f 0.005 680 50 0.041 f 0.002

*

From Ref. 74. Values represent means f SD from three or more log-probit determinations, each using five or six concentrations of drug.

344

MATAO MATSUI

However, the affinity of 43 was higher than that of the allylic derivative 72 and near to that of codeine, though 5-fold less (74). Recently, some naturally occurring hasubanan alkaloids have been submitted to screening for antitumor activity, but the results, as far as we know, remain obscure.

Acknowledgment

I would like to thank Miss Takae Takebayashi for help in collection of literature on hasubanan alkaloids.

References

1. K. W. Bentley, Alkaloids(N.K) 13, 131 (1971). 2. Y. Inubushi and T. Ibuka, Alkaloih ( N .Y.) 16,393 (1977). 3. M. Tomita, T. Ibuka, Y. Inubushi, Y. Watanabe, and M. Matsui, Tetrahedron Lett., 2937 (1964); M. Tomita, T. Ibuka, Y. Inubushi, Y. Watanabe, and M. Matsui, Chem. Pharm. Bull. 13, 53 (1965). 4. M. Matsui and Y . Watanabe, J . Nat. Prod. 47,465 (1984). 5. J. Kunitomo, M. Satoh, M. Inoue, and T. Ishida, Heterocycles 16,351 (1981). 6. T. Toga, N. Akimoto, and T. Ibuka, Chem. Pharm. Bull. 32,4223 (1984). 7. Y. Yamamura and M. Matsui, J. Nat. Prod. 48,746 (1985). 8. M. Matsui, Y. Watanabe, and T. Hinomoto, J . Nat. Prod. 45,247 (1982). 9. F. 1. Carroll, C. G. Moreland, G. A. Brine, and J. A. Kepler, J. Org. Chem. 37, 1881 (1972); F. W. Wehrli, Chem. Commun., 379 (1973); Y. Terui, K. Torii, S. Maeda, and Y. S . Sawa, Tetrahedron Lett., 2853 (1975). 10. S . Kondo, M. Matsui, and Y. Watanabe, Chem. Pharm. Bull. 31,2574 (1983). 11. M. Matsui, Y. Yamamura, T. Takebayashi, K. Iwaki, Y. Takami, K. Kunitake, F. Koga, S. Urasaki, and Y. Watanabe, J. Nat. Prod. 47, 858 (1984). 12. M. Matsui and Y. Yamamura, J. Naf. Prod. 49,588 (1986). 13. M. Matsui, Duiichi Yukka Daigaku Kenkyu Nenpo 16, 1 (1985); Chem. Abstr. 106, 18894m (1987). 14. H. L. de Waal, B. J. Prinsloo, and R. R.Amdt, Tetrahedron Left.,6169 (1966). 15. M. Tomita, T. Ibuka, Y. Inubushi, and T. Takeda, Tetrahedron Lptt., 3605 (1964); M. Tomita, T. Ibuka, Y. Inubushi, and T. Takeda, Chem. Pharm. Bull. 13,695,705 (1965). 16. M. Tomita, A. Kato, and T. Ibuka, Tetrahedron Left.,1019 (1965); M. Tomita, A. Kato, and T. Ibuka, Mass Specfrosc. (Tokyo) 30, 115 (1965). 17. M. Matsui, Y. Watanabe, T. Ibuka, and K. Tanaka, Tetrahedron Lett.. 4263 (1973); M. Matsui, Y. Watanabe, T. Ibuka, and K. Tanaka, Chem. Pharm. Bull. 23, 1323 (1975). 18. S. M. Kupchan, M. I. Suffness, R. J. McClure, and G. A. Sim, J. Am. Chem. SOC.92,5756 (1970).

5.

HASUBANAN ALKALOIDS

345

19. A. J. van Wyk and A. Wiechers, J. S. Afr. Chem. Inst. 27,95 (1974). 20. A. J. van Wyk, J. S. Afr. Chem. Insf. 28,284(1975). 21. J. Kunitomo, Y. Murakami, M. Oshikata, T. Shingu, M. Akasu, S.-T. Lu, and 1.4. Chen, Phytochemistry 19,2735 (1980). 22. J. Kunitomo, M. Oshikata, and Y. Murakami, Heterocycles 14, 175(1980). 23. B. K. Moza, B. Bhaduri, D. K. Basu, J. Kunitomo, Y. Okamoto, E. Yuge, N. Nagai, and T. Ibuka, Tefruhedron26,427 (1970). 24. S. M. Kupchan, M. I. Suffness,D. N. J. White, A. T. McPhail, and G. M. Sim, J. Org. Chem. 33, 4529 (1968). 25. B. K. Moza and D. K. Basu, Indian J. Chem. 5,581 (1967). 26. A. B. Ray, S.Chattopadhyay, R. M. Tripathi, S. S.Gambhir, and P. K. Das, Pluntu Med. 35, 167 ( 1979). 27. R. S.Singh, P. Kumar, and D. S. Bhakuni, J. Nut. Prod. 44,664 (1981). 28. I. I. Fadeeva, T. N. Il'inskaya, M. E. Perl'son, and A. D. Kuzovkov, Khim. Prir. Soedin. 6,492 (1970). 29. A.-N. Lao, Y.-L. Gao, Z.-J. Tang, and R.4. Xu, Yuo Hsueh Hsueh Puo 15,696 (1980);Chem. Ahsrr. 95,49252j (1981). 30. A.-N. Lao, Z.-J. Tang, and R.-S. Xu, Yuoxue Xuebuo 16,940 (1981); Chem. Absrr. 96,196523~ (1982). 31. A.-N. Lao, Y.-L. Gao, Z.-J. Tang, Y.-H. Wang, X.-X.Zhang, C.-G. Wang, and R.4. Xu, Huuxue Xuebuo 40, 1038 (1982);Chem. Abstr. 98,50385~(1983). 32. S. M. Kupchan, A. J. Liepa, and T. Fujita, J. Org. Chem. 38, 151 (1973). 33. Y. Watanabe, M. Matsui, and M. Uchida, Phytochembfry 14,2695 (1975). 34. M. Matsui, T. Kabashima, K. Ishida, T. Takebayashi, and Y.Watanabe, J. Nut. Prod. 45,497 (1982). 35. Z.-D. Min, G. Lin, G.-X. Xu,M. Iinuma, T. Tanaka, and M. Mizuno, Phyrochemistry 24,3084 (1985). 36. M. E. Perel'son, I. I. Fadeeva, and T. N. Il'inskaya, Khim. Prir. Soedin. 11,188 (1979.. 37. M. Tomita, T. Ibuka, and Y.Inubushi, Tetrahedron Lett.. 3167 (1964). 38. M. Tomita, Y. Inubushi, and T. Ibuka, Yukuguku Zusshi 87, 381 (1967); Chem. Abstr. 67, , 73723f (1967). 39. M. Tomita and M. Kozuka, Tetrahedron Lett., 6229 (1966). 40. I. I. Fadeeva, T. N. Il'inskaya, M. E. Perel'son, and A. D. Kuzovkov, Khim. Prir. Soedin. 7,784 (1971);Chem. Absfr.76, 141108~ (1972). 41. T. N. Il'inskaya, M. E. Perel'son, 1. I. Fadeeva, D. A. Fesenko, and 0. N. Tolkachev, Khim. Prir. Soedin. 8, 129 (1972);Chem. Absfr.77,98719d (1972). 42. T. N. Il'inskaya, D. A. Fesenko, 1. I. Fadeeva, M. E. Perel'son, and 0. N. Tolkachev, Khim. Prir. Soedin. 7, 180 (1971);Chem. Absfr. 75,36408b (1971). 43. I. I. Fadeeva, D. A. Fesenko, T. N. Il'inskaya, M. E. Perel'son, and 0. N. Tolkachev, Khim. Prir. Soedin. 7,455 (1971);Chem. Abstr. 75,49369q (1971). 44. D. A. Fesenko, I. I. Fadeeva, T. N. Il'inskaya, M. E. Perel'son, and 0.N. Tolkachev, Khim. Prir. Soedin. 7, 158 (1971);Chem. Abstr. 75,49369q (1971). 45. 1. I. Fadeeva, M. E. Perel'son, T. N. Il'inskaya, and A. D. Kuzovkov, Furmufsiyu (Moscow) 19, 28 (1970); Chem. Absfr. 73, 25717j (1970); 1. I. Fadeeva, A. D. Kuzovkov, and T. N. Il'inskaya, Khim. Prir. Soedin. 3, 106 (1967);Chem. Abstr. 67,43966 (1967). 46. I. I. Fadeeva, M. E. Perel'son, 0. N. Tolkachev, T. N. Il'inskaya, and D. A. Fesenko, Khim. Prir. Soedin. 8, 130(1972);Chem. Abstr. 77,72561~(1972). 47. S.M. Kupchan and M. I. Suffness, Tetrahedron Lert., 4975 (1970). 48. M. Tomita, Y. Watanabe, and K. Okui, Yukuguku Zmshi 76,856 (1956); Chem. Absfr. 50, 14789f (1956).

346

MATAO MATSUI

49. Y. Watanabe, M. Matsui, and K. Ido, Yakugaku Zasshi 85, 584 (1965); Chem. Abstr. 63, 11630~(1965). 50. T. Ibuka and M. Kitano, Chem. Pharm. Bull. 15, 1939 (1967). 51. A. R. Battersby, S. R. Ruchirawat, T. Stanton, and C. W. Thornber, unpublished; C. W. Thornber, Phytochemistry 9, 157 (1970). 52. M. Matsui, M. Uchida, I. Usuki, Y.Saionji, H. Murata, and Y . Watanabe, Phytochemistry 18, 1087 (1979). 53. M. Kozuka, K. Miyaji,T. Sawada, and M. Tomita,J. Nut. Prod. 48,341 (1985). 54. M. Tomita, M. Kitano, and T. Ibuka, Tetrahedron Lett., 3391 (1968). 55. Y.Inubushi, T. Ibuka, and M. Kitano, Tetrahedron Lett., 1611 (1969). 56. D. A. Evans, Tetrahedron Lett., 1573 (1969). 57. S.L. Keely, Jr., A. J. Martinez, and F. C. Tahk, Tetrahedron Lett., 2763 (1969). 58. S. L. Keely, Jr., A. J. Martinez, and F. C. Tahk, Tetrahedron 26,4729 (1970). 59. D. A. Evans, C. A. Bryan, and G. M. Wahl, J. Org. Chem. 35,4122 (1970). 60. Y. Inubushi, M. Kitano, and T. Ibuka, Chem. Pharm. Bull. 19, 1820(1971). 61. D. A. Evans, C. A. Bryan, and C. L. Sims, J . Am. Chem. SOC.94,2891 (1972). 62. 1. Monkovic and T. T. Conway, U.S. Patent 3,775,414 (1973). 63. I. Monkovic,T. T. Conway, H. Wong, Y. G. Perron, I. J. Pachter,and B. Belleau,J. Am. Chem. SOC.95,7910(1973). 64. S.Shiotani and T. Kometani, Tetrahedron Lett., 767 (1976). 65. T. Kametani, T. Kobari, and K. Fukumoto, J. Chem. Soc.. Chem. Commun.. 288 (1972). 66. T. Kametani, H. Nemoto, T. Kobari, K. Shishido, and Fukumoto, Chem. Ind. (London),538 (1972). 67. T. Ibuka, K. Tanaka, and Y . Inubushi, Tetrahedron Lett., 481 1 (1970); T. Ibuka, K. Tanaka, and Y . Inubushi, Chem. Pharm. Bull. 22,782 (1974). 68. T. Ibuka, K. Tanaka, and Y . Inubushi, Tetrahedron Lert., 1393 (1972); T. Ibuka, K.Tanaka, and Y. Inubushi, Chem. Pharm. Bull. 22,907 (1974). 69. M. Saucier and I. Monkovic, Can. J. Chem. 52,2736 (1974). 70. B. Belleau, H.Wong, I. Monkovic, and Y.G . Perron, J. Chem. Soc.. Chem. Commun., 603 (1974). 71. I. Monkovic, H. Wong, B. Belleau, I. J. Pachter, and Y.G. Perron, Can. J. Chem. 53, 2515 (1975). 72. I. Monkovic and H. Wong, Can. J. Chem. 54,883 (1976). 73. I. Monkovic, H. Wong, and G. Lim, US. Patent 3,980,641 (1976); Chem. Abstr. 86, 56660 (1977). 74. M. C. Benhamou, V. Speziale, A. Lattes, C. Gouarderes, and J. Cros, Eur. J. Med. 16, 263 (1981); Chem. Abstr. 95, 150969~(1981). 75. J. J. Perie, J. P. Laval, J. Roussel, and A. Lattes, Tetrahedron 28,675 (1972). 76. H. Bruderer, D. Knopp, and J. J. Daly, Helu. Chim. Acta 60, 1935 (1977). 77. T. Kametani, T. Kobari, K. Shishido, and K. Fukumoto, Tetrahedron 30,1059 (1974). 78. ,M. A. Schwartz and I. S. Mami, J. Am. Chem. SOC.97,1239 (1975). 79. M. A. Schwartz, IUPAC Int. Symp. Chem. Nut. Prod., Ilth 4, (Part 2), 274 (1978); Chem. Abstr. 92,59050~(1980). 80. M. A. Schwartz and R. A. Wallace, Tetrahedron Lett., 3257 (1979). 81. A. R. Battersby, R. C. F. Jones, R. Kazlauskas, A. P. Ottridge, C. Poupat, and J. Staunton, J . Chem. Soc., Perkin Trans. I , 2010(1981). 82. A. R. Battersby, R. C. F. Jones, R. Kazlauskas, C. W. Thornber, S. Ruchirawat, and J. Staunton, J. Chem. SOC.,Perkin Trans. 1,2016(1981). 83. A. R. Battersby, A. Minta, A. P. Ottridge, and J. Staunton, Tetrahedron Lett., 1321 (1977).

5. HASUBANAN ALKALOIDS

347

84. A. R. Battersby, R. C. F. Jones, A. Minta, A. P. Ottridge,andJ. Staunton,J. Chem. SOC.,Perkin Trans. I , 2030 (1981). 85. I. Monkovic, H. Wong, A. W. Pircio, Y. G. Perron, I. J. Pachter, and B. Belleau, Can. J. Chem. 53, 3094 (197.5). 86. E. J. Simon, J. M. Hiller, and I. Edelman, Proc. Natl. Acad. Sci., U.S.A. 68, 1947 (1973). 87. J. Kunitomo, Y. Okamoto, E. Yuge, and Y. Nagai, Tetrahedron Lett.. 3287 (1969). 88. J. Kunitomo, Y. Okamoto, E. Yuge, and Y. Nagai, Yakugaku Zasshi89,1691(1969); Chem. Absrr. 71, 113125d(1969).

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CUMULATIVE INDEX OF TITLES Aconitum alkaloids, 4, 275 (1954) diterpenoid, 7, 473 (1960) C,9 diterpenes, 12, 2 (1970) Cl0 diterpenes, 12, 136 (1970) Acridine alkaloids, 2, 353 (1952) Acridone alkaloids, experimental antitumor activity of acronycine, 21, 1 (1983) Actinomycetes, isoquinolinequinones, 21, 55 (1983) N-Acyliminium ions as intermediates in alkaloid synthesis, 32. 271 (1988) Ajmaline-Sarpagine alkaloids. 8, 789 (1%5), 11, 41 (1968) Alkaloid structures spectral methods, study, 24, 287 (1985) unknown structure minor alkaloids, 5, 301 (1955), 7, 509 (1960) unclassified alkaloids, 10, 545 (1%7), 12, 455 (1970), 13, 397 (1971), 14, 507 (1973), 15, 263 (1975), 16, 511 (1977) Alkaloids in the plant. 1, 15 (1950), 6, 1 (1960) Alkaloids from Ants and insects, 31, 193 (1987) Aspe~gillus,29, 185 (1986) Iburidiantha species, 30, 223 (1987) Tabernaemontma, 27, 1 (1986) Alstonia alkaloids, 8, 159 (1%5), 12, 207 (1970). 14, 157 (1973) Amaryllidaceae alkaloids, 2, 331 (1952), 6, 289 (1960). 11, 307 (1%8), 15, 83 (1975). 30, 251 (1987) Amphibian alkaloids, 21, 139 (1983) Analgesics, 5, 1 (1955) Anesthetics, local, 5, 211 (1955) Anthranilic acid, related to quinoline alkaloids, 17, 105 (1979) Antimalarials, 5, 141 (1955) Antitumor alkaloids, 25, 1 (1985) Apocynaceae alkaloids, steroids, 9, 305 (1967) Aporphine alkaloids, 4, 119 (1954), 9, 1 (1%7), 24, 153 (1985) Arirtolochia alkaloids. 31, 29 (1987) Arktotelin alkaloids, 24, 113 (1985) Aspidosperm alkaloids, 8, 336 (1965), 11, 205 (1968), 17, 199 (1979) Azafluoranthene alkaloids, 23, 301 (1984)

Bases simple, 8, 1 (1%5) simple indole, 10, 491 (1967)

349

350

CUMULATIVE INDEX OF TITLES

Benzophenanthridine alkaloids, 26, 185 (1985) Benzylisoquinolinealkaloids, 4, 29 (1954). 10, 402 (1%7) Bisbenzylisoquinolinealkaloids, 4. 199 (1954), 7, 439 (1960),9. 133 (1%7), 13, 303 (1971), 30, l(1987) occurrence, 16,249 (1977) structure, 16, 249 (1977) pharmacology, 16, 249 (1977) synthesis, 16, 319 (1977) Bisindole alkaloids, 20, 1 (1981) h x u s alkaloids, steroids, 9,305 (1%7), 14, 1 (1973) CacrUs alkaloids, 4. 23 (1954) Calabar bean alkaloids, 8. 27 (1%5), 10, 383 (1%7), 13, 213 (1971) Calabash curare alkaloids, 8, 515 (1965). 11, 189 (1968) Calycanthaceae alkaloids, 8, 581 (1%5) Camptothecin, 21, 101 (1983) Cancentrine alkaloids, 14. 407 (1973) Capsicum species, pungent principle of, 23, 227 (1984) Carbazole alkaloids, 13, 273 (1971), 26, 1 (1985) Carboline alkaloids, 8,47 (1%5), 26, 1 (1985) 0-Carboline congeners and ipecac alkaloids, 22, 1 (1983) Cardioactive alkaloids, 5, 79 (1955) Celestraceae alkaloids, 16, 215 (1977) Cephulotuxus alkaloids, 23, 157 (1984) Chemotaxonomy of papaveraceae and fumaridaceae, 29, 1 (1986) Chromone alkaloids, 31. 67 (1987) Cinchonu alkaloids, 14, 181 (1973) chemistry, 3, 1 (1953) Colchicine, 2, 261 (1952), 6, 247 (1960), 11, 407 (1%8). 23. 1 (1984) Configuration and conformation, elucidation by X-ray diffraction, 22, 51 (1983) Corynantheine, yohimbine, and related alkaloids, 27, 131 (1986) Cularine alkaloids, 4. 249 (1954). 10,463 (1%7). 29, 287 (1986) Curare-like effects, 5, 259 (1955) Cyclopeptide alkaloids, 15, 165 (1975)

Daphniphyllum alkaloids, 15. 41 (1975), 29, 265 (1986) Delphinium alkaloids, 4, 275 (1954) diterpenoid, 7, 473 (1960) C,,-diterpenes. 12, 2 (1970) Cm-diterpenes. 12, 136 (1970) Dibenzopyrrocolinealkaloids, 31, 101 (1987) Diplowhyncus alkaloids, 8, 336 (1%5) C,*-Diterpene alkaloids Aconifum. 12, 2 (1970) Delphinium. 12, 2 (1970) Gufryu, 12,2 (1970) structure, 17, 1 (1970) synthesis, 17, 1 (1979) CZo-Diterpenealkaloids Aconifum, 12, 136 (1970) chemistry, 18, 99 (1981)

CUMULATIVE INDEX OF TITLES

Delphinium, 12, 136 (1970) Gurryu, 12, 136 (1970) Distribution of alkaloids in traditional Chinese medicinal plants, 32, 241 (1988) Diterpenoid alkaloids

Aconitum, 7, 473 (1%0), 12, 2 (1970) Delphinium, 7, 473 (1960). 12, 2 (1970) Gurryu, 7, 473 (1960), 12, 2 (1960) general introduction, 12, xv (1970) C,*-diterpenes, 12, 2 (1970) C,,-diterpenes, 12, 136 (1970)

Eburnamine-Vincamine alkaloids, 8. 250 (1%5), 11, 125 (1%8). 20. 297 (1981) Elaeocarpus alkaloids, 6, 325 (1960) Elucidation, by X-ray diffraction structural formula, 22, 51 (1983) configuration, 22. 51 (1983) conformation, 22, 51 (1983) Enamide cyclizations, application in alkaloid synthesis, 22. 189 (1983) Enzymatic transformation of alkaloids, microbial and in uitm, 18, 323 (1981) Ephedra bases, 3, 339 (1953) Ergot alkaloids, 8, 726 (1965). 15. 1 (1975) Erythrinu alkaloids, 2, 499 (1952), 7, 201 (1960). 9, 483 (1%7), 18, 1 (1981) Erythmphleum alkaloids, 4, 265 (1954), 10, 287 (1%7) Eupomufh alkaloids, 24. 1 (1985) Forensic chemistry, alkaloids, 12, 514 (1970) by chromatographic methods, 32, 1 (1988)

GuIbuIimimu alkaloids, 9, 529 (1967). 13, 227 (1971) Gurryu alkaloids diterpenoid, 7, 473 (1960) C,,V-diterpenes, 12, 2 (1970) C,,-diterpenes, 12, 136 (1970) Geisscnsprmum alkaloids, 8, 679 (1%5) Gelsemium alkaloids, 8, 93 (1%5) Glycosides, monoterpene alkaloids, 17, 545 (1979)

Huplophyton cimicidum alkaloids, 8, 673 (1965) Hasubanan alkaloids, 16, 393 (1977)

Holarrhenu group, steroid alkaloids, 7, 319 (1960) Hunrerh alkaloids, 8, 250 (1965)

h g u alkaloids, 8, 203 (1965), 11, 79 (1968) Imidazole alkaloids, 3, 201 (1953), 22, 281 (1983) Indole alkaloids, 2, 369 (1952), 7, 1 (1960). 26, 1 (1985) distribution in plants, 11, 1 (1%8) simple, including fl-carbolines and flcarbazoles. 26. 1 (1985) Indole bases, simple, 10, 491 (1967) Indolizidine, simple and quinolizidine alkaloids, 28, 183 (1986) 2.2'-Indolylquinuclidine alkaloids, chemistry, 8, 238 (1%5), 11, 73 (1%8) In uitm and microbial enzymatic transformation of alkaloids. 18, 323 (1981)

351

352

CUMULATIVE INDEX OF TITLES

Ipecac alkaloids, 3, 363 (1953), 7, 419 (1960), 13, 189 (1971). 22, 1 (1983) 0-Carboline alkaloids, 22. 1 (1983) Isolation of alkaloids, 1. 1 (1950) Isoquinoline alkaloids, 7, 423 (1960) biosynthesis 4, 1 (1954) "C-NMR Spectra. 18, 217 (1981) simple isoquinoline alkalaoids. 4, 7 (1954), 21, 255 (1983) Isoquinolinequinones, from actinomycetes and sponges, 21, 55 (1983)

Kopsia alkaloids, 8, 336 (1%5) Local anesthetics, alkaloids, 5. 211 (1955) Localization of alkaloids in the plant, 1, 15 (1950), 6, 1 (1960) Lupine alkaloids, 3, 119 (1953). 7, 253 (1960). 9, 175 (1967), 31, 116 (1987) Lycopodium alkaloids, 5, 265 (1955). 7, 505 (1960), 10, 306 (1967). 14, 347 (1973), 26, 241 (1985)

Lythracae alkaloids, 18, 263 (1981) Mammalian alkaloids, 21, 329 (1983) Marine alkaloids, 24, 25 (1985) Maytansinoids, 23, 71 (1984) Melodinus alkaloids, 11, 205 (1968) Mesembrine alkaloids, 9, 467 (1967) Metabolic transformation of alkaloids, 27, 323 (1986) Microbial and in vim enzymatic transformation of alkaloids. 18, 323 (1981) Mifmgynu alkaloids, 8, 59 (1%5), 10. 521 (1967). 14, 123 (1973) Monoterpene alkaloids, 16. 431 (1977) glycosides, 17, 545 (1979) Morphine alkaloids, 2, 1 (part 1. 1952). 2, 161 (part 2, 1952), 6, 219-(1%0), 13, 1 (1971) Muscarine alkaloids, 23, 327 (1984) Mydriatic alkaloids, 5, 243 (1955) a-Naphthaphenanthridine alkaloids, 4, 253 (1954), 10, 485 (1%7) Naphthyl isoquinoline alkaloids, 29, 141 (1986) Narcotics, 5, 1 (1955) "C-NMR spectra of isoquinoline alkaloids, 18, 217 (1981) Nuphr alkaloids, 9. 441 (1967), 16, 181 (1977)

Ochmsia alkaloids, 8, 336 (1965), 11, 205 (1968) Ournuparia alkaloids, 8, 59 (1965), 10, 521 (1967) Oxaporphine alklaloids, 14, 225 (1973) Oxindole alkaloids, 14. 83 (1973) Papavernaceae alkaloids, 10, 467 (1967), 12, 333 (1970). 17, 385 (1979) pharmacology. 15, 207 (1975) toxicology, 15. 207 (1975) Pavine and isopavine alkaloids, 31, 317 (1987) kkntacenrs alkaloids, 8, 250 (1965) Peptide alkaloids, 26, 299 (1985) Phenanthroindolizidinealkaloids, 19, 193 (1981) Phenanthroquinolne alkaloids, 19, 193 (1981)

CUMULATIVE INDEX OF TITLES

353

0-Phenethylamines, 3, 313 (1953) Phenethylisoquinoline alkaloids, 14, 265 (1973) Phthalideisoquinoline alkaloids, 4, 167 (1954), 7, 433 (1960), 9, 117 (1967), 24, 253 (1985) Picmlma alkaloids, 14, 157 (1973) Picmlima nifih alkaloids, 8, 119 (1%5), 10, 501 (1967) Piperidine alkaloids, 26, 89 (1985) Plant systematics, 16, 1 (1977) PIeiocarpa alkaloids, 8, 336 (1965), 11, 205 (1968) Polyamine alkaloids, putrescine, spermidine, spermine, 22. 85 (1983) Pressor alkaloids, 5. 229 (1955) hfoberberine alkaloids. 4, 77 (1954), 9, 41 (1967), 28, 95 (1986) Protopine alkaloids, 4. 147 (1954) Aeucocinchona alkaloids, 8, 694 (1965) Putrescine and related polyamine alkaloids, 22, 85 (1983) Pyridine alkaloids, 1, 165 (1950), 6, 123 (1960), 11, 459 (1968). 26, 89 (1985) Pyrrolidine alkaloids, 1, 91 (1950), 6, 31 (1960), 27, 270 (1986) Pyrroliidine alkaloids, 1. 107 (1950), 6, 35 (1960). 12, 246 (1970), 26. 327 (1985) Quinazolidine alkaloids, see Indolizidine Alkaloids Quinazoline alkaloids, 3, 101 (1953). 7, 247 (1960), 29. 99 (1986) Quinazolinocarbolines, 8, 55 (1965), 21, 29 (1983) Quinoline alkaloids other than Cinchona, 3, 65 (1953). 7, 229 (1960) related to anthranilic acid, 17, 105 (1979), 32, 341 (1988)

Rauwo#ka alkaloids, 8, 287 (1%5) Reissert synthesis of isoquinoline and indole alkaloids, 31, 1 (1987) Reserpine, chemistry, 8. 287 (1965) Respiratory stimulants, 5, 109 (1955) Rhoeadine alkaloids, 28, 1 (1986)

Salamandm group, steroids, 9, 427 (1967) Scelefium alkaloids, 19, 1 (1981) Senecio alkaloids, see Pyrrolizidine alkaloids Securinega alkaloids, 14, 425 (1973) Sinomenine, 2, 219 (1952)

Solanum alkaloids chemistry, 3. 247 (1953) steroids, 7, 343 (1960), 10, 1 (1%7), 19, 81 (1981) Sources of alkaloids, 1, 1 (1950) Spectral methods. alkaloid structures, 24, 287 (1985) Spermidine and related polyamine alkaloids, 22. 85 (1983) Spermine and related polyamine alkaloids, 22, 85 (1983) Spirobenzylisoquinolinealkaloids, 13, 165 (1971) Sponges, isoquinolinequinones, 21, 55 (1983) Stemona alkaloids, 9, 545 (1967) Steroid alkaloids Apocynaceae, 9, 305 (1%7), 32, 79 (1988) B w group, 9, 305 (1967). 14, 1 (1973). 32, 79 (1988) Holarrhena group, 7. 319 (1960) SaIamandm group, 9, 427 (1967)

354

CUMULATIVE lNDEX OF TITLES

Solanum group, 7, 343 (1960). 10, 1 (1967), 19, 81 (1981) Verotnrm group, 7, 363 (1960). 10. 193 (1967), 14, 1 (1973) Stimulants respiratory, 5, 109 (1955) uterine, 5, 163 (1955) Structural formula, elucidation by X-ray diffraction. 22, 51 (1983) Strychnos alkaloids, 1, 375 (part 1-1950). 2, 513 (part 2-1952), 6, 179 (1960). 8. 515, 592 (1%5), 11, 189 (1%8) Sulfur-containing alkaloids, 26, 53 (1985) &us alkaloids, 10, 597 (1%7) Toxicology, Papaveraceae alkaloids, 15, 207 (1975) Transformation of alkaloids, enzymatic, microbial and in vifro, 18, 323 (1981) Tropane alkaloids. chemistry. 1, 271 (1950). 6, 145 (1960), 9, 269 (1%7), 13. 351 (1971), 16. 83 (1977) Tropoloisoquinolinealkaloids, 23, 301 (1984) Tropolonic Colchicum alkaloids, 23, 1 (1984) Tyophom alkaloids, 9. 517 (1%7)

Uterine stimulants, 5. 163 (1955) kmtmm alkaloids chemistry, 3, 247 (1952) steroids, 7, 363 (1960). 10, 193 (1%7), 14, 1 (1973) “Vinca” alkaloids, 8, 272 (1965). 11, 99 (1968) Vmcunga alkaloids, 8, 203 (1%5), 11. 79 (1968)

X-Raydiffraction, elucidation of structural formula, configuration, and conformation. 22, 51 (1983)

Yohimbe alkaloids, 8, 694 (1965) Yohimbine alkaloids, 11, 145 (1%8), 27, 131 (1986). see ah0 Coryantheine

INDEX

A Adiantifoline, 294 Adlumiceine, 269 Adlumidiceine, 269 Adlumidiceine enol lactone, 265, 267 Adlumidine, 263 Aknadicine, 309 Aknadilactam, 310 Aknadinine, 309, 310 Akuammidine-N-oxide, 84, 97 Alkaloid KD-A, -B,-C, -D, -E,-F,12, 31 synthesis of, 41 Allocryptopine, 201 Alpigenine, 210 Alpigenine diol, 210 Alpinigenine, 190 Anhydrovobasinediol, 123, 134 Anisodamine, 8, 30 Anisodine, 10 configuration of, 32 pharmacology of, 70 Antioquine, 291 Aobamidine, 265, 267 Aobamine, 234, 236, 241 Apoatropine, 5, 29 Apohyoscine, 10,29 Aponoratropine, 5, 29 Aponorhyoscine, 10 Aporphine alkaloids, from tetrahydroberberines, 222 Amottianamide. 294 3-Arylisoquinoline alkaloids, 179, 250 Atropine, 29 Atroscine, 10,30

B Baluchistanamine, 285, 287, 291 Baogonteng A, 16, 27 Belladonnine, 18. 32 Bellendine, 14, 27 synthesis of. 41

Benzophenanthridinealkaloids, 170 from berbines, biomimetic-t ype, synthesis of, 175 Benzoylecgonine, 11 8-Benzyltetrahydroberberine,145 Berberine cleavage with sodium in liquid ammonia. 155 conversion into naphthyl compounds, 151 0-demethylation with aluminum chloride, 153 0-demethylation with boron trichloride, 154 reaction with chloroform, 169 Smile rearrangement, 156 oxidation with potassium ferricyanide, 149 Berberine chloride, conversion of, 260 Berberinephenolbetaine, 161 Berbithine, 256 Bicuculline, 263, 265 Bicucullinidine. 270 Bicucullinine, 270, 271, 272 Bisaknadinine, 310, 325 Brugine, 5.29 Butropine, 4, 28

C

Canadaline, 181, 234, 236 Canadalisol, 234, 235, 236 Canadine, 217 Canadine methochloride, 245 Capnoidine, 263 Catuabine A, 9 Catuabine B, 9, 32 Catuabine C, 8, 31 Cepharamine, 309, 310 Chalcostrobamine, 17, 29 synthesis of, 43 Chelerythrine, 171 Chenabine, 285, 289 Chilenamine, 214

355

356

INDEX

Chilenine, 215 Cocaine, 11, 30 biosynthesis of, 50 synthesis of, 40 Cochlearine, 29 Confoline, 6, 30 Convolamine, 6, 30 Convolidine, 5, 29 Convoline, 6, 30 Convolvidine Convolvine, 5 , 30 Convosine, 72, 74 Coptisine, 191, 239 Coptisinephenolbetaine, 149 Corlumine, 263 Corybulbine, 216 Corydaine, 192, 200 Corydalic acid methyl ester, 144, 250 Corydaline, 216, 217 Corydalisol, 181, 234, 235, 236 Corydalispirone, 234, 236 Corydamine, 179, 250 Corynoline, 177, 251 Coryrutine, 264, 269 Coyhaiquine, 292 Cryptopine, 201 Cryptopleurospermine, 279, 281 Curacautine, 285, 289 8, 14-Cycloberberines, 164 Cycloberbine, 190

D Darlingine, 14, 28 Datumetin, 5 , 29 Dehydrobicuculline, 239 Dehydrohernandaline, 294 Dehydrohydrastine, 200 Delavaine, 309 Demethylhernandifoline, 309 Deoxyarnottianarnide, 297 Dihydrobellendine, 15, 27 Dihydrocoptisine, 149 Dihydrodarlingine, 15, 28 synthesis of, 43 Dihydroepistephamiersine acetate, 309, 324 Dihydrofumariline, 190, 206 Dihydroisobellendine, 15, 27 Dihydrokouminol, 106 Dihydrolonganone, 328

Dihydronitidine, 173 Dihydroparfurnidine, 206 Dihydrorugosinone, 256 Dihydrosanguinarine, 171 Dihydrosecoquettamine, 299 Dihydrostrobiline, 15, 27 Dihydrotaxilarnine, 256 Dihydroxhelerythrine, 171 Diketo acids, of secophthalideisoquinolines, 27 1 Dimeric alkaloids, 285

E Ecgonine, 11, 27 Emetine, from protoberberines, 222 Enol lactones, of secophthalideisoquinolines, 265 11-Epicorynoline, 177 Epidihydrobellendine, 15, 28 Epihernandolinol, 326 Epiophicarpine, 162 Epiophiocarpine, 149 Epistephamiersine, 310

F Fagarine, 204 Famarofine, 208 Ferrugine, 17, 28 Ferruginine, 16, 27 Fumaramine, 264, 275, 277 Fumaricine, photolysis of, 190, 239 Fumaridine, 275 Fumariflorine, 262 Fumariline, 190 Fumaritridine, 206, 209 Fumaritrine, 206, 209 Fumschleicherine, 264, 275

G Gelsedine, 84, 91, 93 Gelsemicine, 84, 91 Gelsemine, synthesis of, 85, 86 Gelsemium alkaloids biosynthesis, 132 clinical applications, 137

357

INDEX

pharmacology, 135 tabulation, 84 toxicity, 136 Gelsenicine, 84, 94 Gelsevirine, 85, 88 Gilgitine, 285, 289

H Hasubanalactam alkaloids, 308 Hasubanan alkaloids, 307 biosynthesis, 339 occurrence, 308 pharmacology, 342 spectral properties, 311 synthesis, 335 Hasubanonine, 308, 310 Helumine, 285, 289 Hernandaline, 292 Hernandifoline, 309 Hernandine, 309 Hernandoline, 309 Hernandolinol, 309. 326 Homostephanoline, 309 Humantenidine, 84,94,95 Humantenine, 99 Humantenirine, 84, 99, 100 Humantenmine, 95 Hydrastines. 263 from berberines, 195 by photooxidation of phenolbetaines, 197 from prechilenine, 198 from spirobenzylisoquinolines.200 14-Hydroxy-8,13-dioxoberberine,163 13-Hydroxyberberine,162 12-Hydroxychelidonine,178 Hydroxygardnerine, 129 Hydroxygelsedine, 84, 93 Hydroxygelsemicine, 84. 92. 93 Hydroxylopinine, 145 13-Hydroxyprotoberberines, 218 Hydroxystylopine, 149 Hydroxytropanes, synthesis of, 74 Hydroxyvobasinediol, 126 Hygrine, 49 Hyoscyamine, 5 , 29 Hypecorine, 234, 236 Hypecorinine, 234, 236 Hypecumine, 250

I Indenobenzazepine alkaloids, 204 via cycloberbines. 208 from phenolic dihydroprotoberberines, 204 from phthalideisoquinolines, 207 from protopines, 204 from spirobenzylisoquinolines,205 tabulation. 165, 167 Integriamide, 294 Isoanhydroberberilate, 162 Isoarnottianamide, 294 Isobellendine, 14, 27 synthesis of, 42, 45 Isochromanes, 243 Isodihydrokoumine, 109 Isoindolobenzazepine alkaloids, Schopfs base, 214 Isonorkoumine, 109 Isoporoidine, 4, 28 Iwamide, 294

K Karachine, 224 Karakamine, 285 hakorarnine, 285. 289 Keto acids, of secophthalideisoquinolines,268 Knightalbinol, 14. 30 Knightinol, 12, 30 synthesis of, 43 Knightolamine, 14, 31 Knightoline, 13, 30 Koumicine, 84, 97 Koumidine, 97, 98, 134 Koumine, 104 chemical reactions, 84. 115 stereochemistry, 110 X-ray structure, 114 Kouminidine, 84, 131 Kounidine, 84, 132

L Lahoramine, 206 Lahorine, 206 Laudanosine, conversion of, 241 Ledecorine, 222, 256

358

INDEX

Littorine, 5, 30 Longaninine, 310, 326 Longanone, 310. 327

Norscopolamine, 30 Norsecocularine, 297 Nortropacocaine, 28 Noyamine, 297

M 0

Macrantaline, 234, 236 Macrantoridine, 234, 235, 236 Magallanesine, 169 Mesocorydaline, 144 Mesotetrahydrocorysamine, 145, 253 Metaphanine, 309 Meteloidine, 9. 28 biosynthesis of, 50 Methoxyberberal, 162 8-Methoxyberberinephenolbetaine,161 Methoxykoumine, 129 Methylcanadine, 217 Methylhernandine, 309 13-Methylprotoberberine, 149 8-Methylprotoberberines,217 Methylstephavanine, 309, 323 Miersine, 310 Muramine, 201, 203 N N-Formylcorydamine, 250 N-Methylhydrasteine, 264, 269 N-Methylhydrastine,265 N-Methyloxohydrasteine, 271 Narceine, 269 Narceine amide, 275 Narceine enol lactone, 265 Narceine imide, 278 Narcotine, 263 Narlumidine, 264, 272. 274 Natalinhe, 292 Neodihydrokoumine, 120 Neolumipakistanine,293 Nitidine, 295 Noratropine, 5. 29, 44 Norchelerythrine, 174 Norcocahe, 44 Norhydrastine, 198 Norhyoscine, 10 Norhyoscyamine, 5, 29 Norledecorine, 222, 260 Nornarceine, 269

O-Methylfumarofine, 206 O-Methylprechilenine, 163 Ochrobirine, 191, 200 Ophiocarpine, Oppenauer oxidation of, 149, 172 Opiate receptor affinity, 343 of hasubanan alkaloids, 343 Oxoallocryptopine, 202 Oxodelavaine, 309 Oxoepistephamiersine,310, 330 Oxogelsemine, 85, 88 Oxogelsevirine, 85, 88 13C-NMR data, 90 Oxohasubanonine, 310 Oxometaphanine, 329 Oxoprometaphanine, 309 Oxostephabenine, 310, 330 Oxostephamiersine, 310 Oxostephasunoline, 310, 329 Oxotetrahydroberberine, photoinduced rearrangement. 184 Oxybisberberine, 163 Oxychelerythrine, 176

P Palmatine, conversion of, 190 Palmatine chloride, conversion of, 260 Pavine alkaloids, from tetrahydroberberines, 221 Peshawarine, 181, 246, 247 spectral data of, 248 synthesis of, 249 Peshawarinediol, 247 spectral data of, 248 synthesis of. 249 Phthalideisoquinoline alkaloids. from 8-methoxyberberinephenolbetaine,195 Phyllalbine, 5 Physochlaine, 8, 31 Physoperuvine, 16, 27 Polyberbine, 256, 257

INDEX Polycarpine, 256, 257 Poroidine, 4, 28 Prechilenine, 163, 215 Prostephabyssine, 309 Prostephanaberrine, 310, 333 Proteaceous alkaloids, biosynthesis of, 51 Protoberberine alkaloids. synthesis, 216 Protoberberinephenolbetaines,159 Protoberberines biosynthetic relationship of, 142 Birch reduction of, 147 cleavage with chloroformates, 156 Hofmann degradation of, 143 oxidation with lead tetraacetate, 156 photocycliition of, 171 ring D-inversion of, 218 tetraoxygenated compounds, 220 Von Braun degradation of, 145 Protoemetine, 223 Protopine alkaloids from indenobenzazepines, 203 by N-oxide rearrangement, 201 by photooxidation. 202 Protopine N-oxide, 239 Protostephabyssine, 309 Protostephanaberrine, 333 Pseudobenzylisoquinoline alkaloids, 256 Pseudohypecorine, 244 Pseudoprotopine, 204 Pseudoronine, 279, 281 Pseudotropine, 27 synthesis of, 39 Punjabine, 285, 289

R Raddeanamine, 194 Raddeanidine, 194 Raddeanine, 188 Raddeanone, 194 Rankinidine, 84, 99, 102 Retroprotoberberine alkaloids, 216 Retroprotoberberines, 221 Revohtinone, 285, 289 Rhoeadine, 249 Rhoeadine alkaloids through photochemical cyclization, 213 by photooxygenation of indenobenzazepines, 210 from spirobenzylisoquinolines, 209

359

Rhoeagenine, 249 Rhoeagenine diol, 210 Rhoeageninediol methosalt, 249 Rugosinone, 222, 256 Runanine, 310, 332 S

Sanguinarine, 171, 179 Saxoguattine, 279, 281 Schizanthin A, 8, 31 Schizanthin B, 19, 32 Schizanthine C,72, 74 Scopine, 10,27 Scopodonnine, 18, 32 Scopolamine, 10,30 biosynthesis of, 50 configuration. 32 Secantioquine, 285, 289 Secobenzylisoquinolinealkaloids, 279 Secoberbine alkaloids. from tetrahydroberberines, 180 7,8-Secoberbine alkaloids, 233 hydrolysis of, 244 oxidation and reduction of, 244 synthesis of, 238 tabulation of, 234 6.7-Secoberbine alkaloids, 250 physical data of, 252 synthesis, 253 8.8-Secoberbine alkaloids, 256 physical data of, 258, 259 synthesis of, 260 Secocularidine, 297 Secocularine, 297 Secoisoquinolinealkaloids, 231 Secolucidine, 285, 289 Secoobaberine, 285, 289 Secophthalideisoquinolinealkaloids, tabulation, 263 Secoquettamine, 299 Secoquettamine alkaloids, 299 Sempervirine, 84. 96, 103 Sewercinine, 193 Sibiricine, 192 Sindamine, 285, 289 Spirobenzylisoquinolinealkaloids via cycloberbines. 189 from indenobenzazepines. 187 from quinonemethides, 182 by Stevens rearrangement, 186

360

INDEX

Spirobenzylisoquinolines,from berberines, 164

Stephabenine, 310, 328 Stephaboline, 309, 310 Stephabyssine, 309 Stephadiamine, 310, 331 Stephamiersine, 310 Stephasunoline, 310 Stephavanine, 309 Stephisoferuline, 309 Stevens rearrangement, of tetrahydroberberines. 186 Strictosidine, 134 Strobamine, 15, 29 synthesis of, 43 Strobiline, 14, 27 biosynthesis of, 51 Strobolamine, 15, 29 Stylopine, 235 Subhirsine, 19, 32

T Talcamine, 285, 289 Taxilamine, 256 Tetrahydroberberine, 145 Tetrahydroberberines,from secoberbines,

Thalictrofoline, 144 Tropacocaine, 7, 28 synthesis of, 39 Tropane alkaloids biosynthesis of, 46 botanical classification of, 26 'H-NMR and IT-NMR spectroscopy. 53 MS, 61 N-demethylation of, 44 pharmacology of, 70 structures of, 4-25 and 72-74 synthesis of, 26-41 Tropic acid, biosynthesis of, 48 Tropine, 27 Tropinone, 16. 27 synthesis, 32 Truxilline, 19, 32

V Valeroidine, 8, 28 Valtropine, 4, 28 Vobasine, 122 synthesis, 130

245

Tetrahydrocoptisine, 179, 245, 251, 253 Tetrahydrocorysamine, 216, 217, 251, 253 Tetrahydrokouminol, 106 Tetrahydropalmatine, 149 conversion into muramine, 203 Tetrahydropseudocoptisine,220 Thalictricavine, 144, 217 Thalictricavine metho salt, Stevens rearrangement, 186

X

Xylopinine, 220

Y Yenhusomidine, 194. 200 Yenhusomine, 189