Table Of Content/soquinoline
Alkaloids Research
1972-1977
/soquinoline
Alkaloids Research
1972-1977
Maurice Shamma
and Jerome L. Moniot
The Pennsylvania State University
University Park, Pennsylvania
Plenwn Press· New York and London
Library of Congress Cataloging in Publication Data
Shamma, Maurice, 1926-
Isoquinoline alkaloids research, 1972-1977.
Includes bibliographical references and index.
1. Alkaloids. 2. Isoquinoline. I. Moniot, Jerome L., joint author. II. Title.
QD421.S543 547.72 77-26929
ISBN-13: 978-1-4615-8821-4 e-ISBN-13: 978-1-4615-8819-1
DOl: 10.1007/978-1-4615-8819-1
©1978 Plenum Press, New York
Softcover reprint of the hardcover 1s t edition 1978
A Division of Plenum Publishing Corporation
227 West 17th Street, New York, N.Y. 10011
All rights reserved
No part of this book may be reproduced, stored in a retrieval system, or transmitted,
in any form or by any means, electronic, mechanical, photocopying, microfilming,
recording, or otherwise, without written permission from the Publisher
The authors who set out to say something that no
one has said before are to be regarded with mistrust.
Max J. Friedlander
PREFACE
Substantial advances in the realm of isoquinoline alkaloids have occurred since
The Isoquinoline Alkaloids, Chemistry and Pharmacology, was published in 1972.
The present volume represents an effort to describe important developments
since that time.
The organization of the present book is essentially the same as in The
Isoquinoline Alkaloids. Each chapter begins with a discussion of structural
elucidation and synthesis, a description of typical reactions then follows, and
the chapter ends with coverage of biogenesis, pharmacology, and spectroscopy.
New chapters have had to be added to describe the completely new alkaloidal
types discovered since 1972. These include baluchistanamine (an isoquinolone
benzylisoquinoline dimer), the aporphine-pavine dimers, the 4,5-dioxoapor
phines, the secoberbines, the 3-arylisoquinolines, eupolauridine, and very recently
imerubrine. Another new chapter discusses the chemistry of the aristolo
chic acids and aristolactams, a group of substituted phenanthrenes, obviously
of isoquinoline derivation in spite of the fact that they do not incorporate a
basic nitrogen function. The aristolochic acids and aristolactams were not in
cluded in The Isoquinoline Alkaloids even though they were known at the time
that book was written.
On the other hand, one group of alkaloids which was included in The
Isoquinoline Alkaloids and nevertheless was deemed not to belong properly
in the present work is the naphthalenoisoquinolines, which include ancistro
cladine and its relatives. These bases do not originate biogenetically· from
tyrosine, and beside incorporating tetrahydroisoquinoline moieties show no
clear structural relationship to the more orthodox isoquinoline alkaloids.
As with The Isoquinoline Alkaloids, not all known or new isoquinoline
alkaloids have been presented. Rather, selected examples have been discussed
to illustrate specific principles or methods. For a complete listing of the iso
quinoline alkaloids, the reader is referred to T. Kametani's The Chemistry of
the Isoquinoline Alkaloids, Vol. 2, * and also to the annual reviews on isoquinoline
alkaloids and the aporphinoids included in Specialist Periodical Reports, The
t
A lkalo ids.
* The Sendai Institute of Heterocyclic Chemistry, Sendai, Japan (1974).
t The Chemical Society, London.
vii
viii PREFACE
Percentage reaction yields are given in parentheses under the proper struc
tures. Infrared absorptions are quoted both in terms of wavelength and fre
quency. Ultraviolet log values are given in brackets following the values.
€ Amax
The literature up to about mid-1977 has been covered. All nuclear magnetic
resonance data are given in I) values, and were obtained in deuteriochloroform
solution unless stated otherwise. A special effort was made to include C-13
nuclear magnetic resonance values where available. The term "tetrahydroiso
quinoline" refers to the 1, 2,3,4-tetrahydro system, and the prefix" nor" relates
solely to the N-nor series.
The authors would like to thank Drs. A. Patra and A. S. Rothenberg, as
well as Mr. P. Chinnasamy, for commenting on the completed manuscript.
A special debt is due senior editor, Mr. Ellis Rosenberg, and assistant managing
editor, Ms. Betty Bruhns, for a dedicated effort in facilitating our work.
Maurice Shamma
Jerome L. Moniot
CONTENTS
Chapter 1. The Simple Isoquinolines
1.1. Introduction 1
1.2. Synthesis 2
1.2.1. Pictet-Spengier Cyclization 2
1.2.2. Bischler-Napieralski Cyclization 4
1.2.3. Pomeranz-Fritsch Cyclization 6
1.2.4. Photocyclization of N-Chloroacetylbenzylamines 7
1.2.5. Amination of Benzopyrylium Salts 7
1.2.6. A New Isoquinoline Synthesis via Ortho-Substituted
Benzylamines 8
1.2.7. Cyclization of Aralkenyl-Substituted Quaternary Ammonium
Salts . 8
1.3. Some Reactions of Simple Isoquinolines . 8
1.3.1. Oxidation . 8
1.3.2. Alkylation and Acylation 10
1.3.3. Fluorophore-Forming Reactions 14
1.3.4. Electrolytic Oxidation . 15
1.3.5. Rearrangements of 1,2-Dihydroisoquinolines 17
1.4. Biogenesis . 18
1.5. Pharmacology 20
1.6. CMR Spectroscopy 22
References and Notes 23
Chapter 2. The Benzylisoquinolines 27
2.1. Introduction 27
2.2. Synthesis 28
2.2.1. The Use of Reissert Compounds 28
2.2.2. Friedel-Crafts Alkylation and Acylation 29
2.2.3. Pictet-Spengler Condensation 31
2.2.4. The Pomeranz-Fritsch/Reissert Approach 32
2.2.5. Cyclization of N-Sulfonylphenethylamines 33
2.3. Reactions of Benzylisoquinolines . 34
2.3.1. Oxidation . 34
2.3.2. Reduction and the Chemistry of the Reduction Products. 34
2.3.3. Photolysis . 36
2.3.4. Acetonylation at C-6' . 38
2.3.5. Fission of Ring B 38
2.3.6. Rearrangement of 1,2-Dihydroisoquinolines 40
2.3.7. Transformation of a-Ketobenzylisoquinolines. 41
ix
x CONTENTS
2.3.8. Electrolytic Oxidation . 42
2.3.9. Oxidative Dimerization 43
2.4. Conversion of Benzylisoquinolines to Morphine 44
2.5. Cryptopleurospermine, an Unusual Natural a-Dione 46
2.6. Biogenesis . 47
2.7. Pharmacology 49
2.8. NMR Spectroscopy 51
2.9. UV Spectroscopy. 52
References and Notes 52
Chapter 3. The Isoquinolones 57
3.1. Introduction 57
3.2. Siamine 57
3.3. Synthesis and Reactions of Isoquinolones 58
References . 60
Chapter 4. The Pavines and Isopavines . 61
4.1. Synthesis 61
4.1.1. Pavines 61
4.1.2. Isopavines 64
4.2. Biogenesis . 68
4.3. Pharmacology 68
4.4. Spectroscopy and Crystallography . 68
References and Notes . 69
Chapter 5. The Bisbenzylisoquinolines 71
5.1. Introduction 71
5.2. Stepinonine, an Unusual Bisbenzylisoquinoline 81
5.3. Synthesis 84
5.3.1. The Cava Modification of the Ullmann Reaction 84
5.3.2. The Inubushi Synthesis of Obaberine and Trilobine 85
5.3.3. The Use of Reissert Compounds . 88
5.4. Controlled Oxidation 89
5.5. Some General Methods for Functional Group Modification of
Isoquinoline Alkaloids. 91
5.5.1. Selective Removal of an Aromatic Methyleliedioxy Group 91
5.5.2. Deoxygenation of a Phenol . 91
5.5.3. N-Demethylation of Tertiary Amines 91
5.5.4. N-Demethylation and N-Debenzylation of Quaternary
Ammonium Salts 92
5.5.5. O-Demethylation and O-Debenzylation of Aromatic Ethers 92
5.5.6. Methylenation of Catechols . 93
5.5.7. O-Methylation and Protection of Phenols 93
5.5.8. Aromatic Hydroxylation or Methoxylation 93
5.6. Biogenesis . 93
5.7. Pharmacology 97
CONTENTS xi
5.8. Spectral Measurements and CD Curves 97
5.9. X-Ray Diffraction 99
References and Notes . 100
Chapter 6. Baluchistanamine: An Isoquinolone-Benzylisoquinoline
Dimer. 103
6.1. Structure Elucidation and Synthesis 103
6.2. PMR Spectroscopy 105
6.3. UY Spectroscopy and Circular Dichroism 105
References . 105
Chapter 7. The Cularines lO7
7.1. Synthesis 107
7.2. Absolute Configuration. 109
7.3. An Approach to the Synthesis of Cancentrine . 110
7.4. CMR Spectroscopy 111
References . 111
Chapter 8. The Dibenzopyrrocolines 113
8.1. Synthesis 113
8.1.1. Benzyne Intermediates. 113
8.1.2. Enzymic Processes 115
References . 116
Chapter 9. The Proaporphines 117
9.1. Introduction 117
9.2. Revision of Stereochemistry of the Reduced Proaporphines 117
9.3. Synthesis 118
9.4. Pharmacology 119
9.5. Spectral Studies 119
References and Notes 120
Chapter 10. The Aporphines . 123
10.1. Introduction 123
10.2. Synthesis . 123
10.2.1. Photolysis 123
10.2.2. The Use of YOCI 126
3
10.2.3. The Use of YOF -TFA 126
3
10.2.4. Electrolytic Oxidation 135
10.2.5. Oxidation with Cuprous Chloride and Oxygen 136
10.2.6. The Use of Lead Tetraacetate; Hydroxylation at C-4 . 137
10.2.7. Benzyne Intermediates 138
10.2.8. Enzymic Oxidative Coupling . 139
10.2.9. Reissert Intermediates 139
10.2.10. Improved Pschorr CycIizations 140
10.2.11. Coupling with Thallium Tristrifluoroacetate 140
xii CONTENTS
10.3. Reactions of Aporphines 141
10.3.1. Oxidation and Formation of Dehydroaporphines and
Oxoaporphines 141
10.3.2. Selective Cleavage of the Methylenedioxy Substituent. 142
10.3.3. Dimerization. 144
10.304. Hofmann and Emde Degradations 144
10.3.5. O-Acetylation i44
10.3.6. Hydroxylation 145
10.3.7. Selective O-Demethylation and N-Demethylation 145
10.3.8. Protonation and Formylation of Dehydroaporphines . 146
lOA. Absolute Configuration 146
10.5. Biogenesis. 147
10.6. Pharmacology 150
10.7. NMR Spectroscopy 152
References and Notes. 154
Chapter II. Pakistanamine: A Proaporphine-Benzylisoquinoline Dimer. 157
11.1. Synthesis . 157
References and Notes . 158
Chapter 12. The Aporphine-Benzylisoquinoline Dimers . 159
12.1. Introduction 160
12.2. Structural Elucidation. 160
12.3. Synthesis . 161
12.4. Reactions . 162
12.5. Biogenesis. 163
12.6. Pharmacology 164
12.7. PMR Spectroscopy 165
References and Notes . 165
Chapter 13. The Aporphine-Pavine Dimers 167
13.1. Introduction 167
13.2. Structural Elucidation. 167-
13.3. UV and IR Spectroscopy 170
References. 171
Chapter 14. The Oxoaporphines 173
14.1. Introduction 173
14.2. Synthesis . 173
14.3. Pharmacology 175
14.4. Spectral Characteristics 175
References and Notes. 176
Chapter 15. The Phenanthrenes 179
15.1. Structural Elucidation and Synthesis 179
15.2. Pharmacology 180
