Table Of ContentFortsehriHe del' Chemie organiseher Naturstoffe
Progress in the
Chemist~
of Organie Natural Produets
6 0
Founded L Zeehmeister
~
Edited ~ W. Berz, G. W. Kir~, R. E. Moore,
W. Ste,lieh, and Ch. Tamm
Authors:
C. A. A. van Bfield, A.-M. Eklund, M. Petitou,
I. Wahlberg
Springer-Verlag
Men NewYorll lqqZ
Prof. W. HERZ, Department of Chemistry,
The Florida State University, Tallahassee, Florida, U.S.A.
Prof. G. W. KIRBY, Chemistry Department,
The University, Glasgow, Scotland
Prof. R. E. MOORE, Department of Chemistry,
University of Hawaii at Manoa, Honolulu, Hawaii, U.S.A.
Prof. Dr. W. STEGLlCR, Institut fiir Organische Chemie und Biochemie der Universitiit
Bonn, Bonn, Federal Republic of Germany
Prof. Dr. CR. TAMM, Institut fiir Organische Chemie der Universitiit Basel,
Basel, Switzerland
This work is subject to copyright.
All rights are reserved, whether the whole or part of the material is concerned, specifically those
of translation, reprinting, re-use of illustrations, broadcasting, reproduction by photocopying
machines or similar means, and storage in data banks.
© 1992 by Springer-Verlag/Wien
Library of Congress Catalog Card Number AC 39-1015
Typesetting: Macmillan India Ltd., Bangalore-25
Printed on acid free paper
With 59 Figure
ISBN-13: 978-3-7091-9227-6 e-ISBN-978-3-7091-9225-2
DOl: 10.1007/978-3-7091-9225-2
Contents
List of Contributors. . . . . . . . . . . . . . . . . . . . . . . VII
Cyclized Cembranoids of Natural Occurrence.
By I. WAHLBERG and A.-M. EKLUND
I. Introduction 2
A. Nomenclature and Structural Representation. 3
II. Cyc1ized Cembranoids from Tobacco. 5
III. Cyc1ized Cembranoids from Insects 9
A. Nasutitermitinae. . . 10
1. Bulbitermes Species . 10
2. Cortaritermes Species 10
3. Grallatotermes Species 13
4. Hospitalitermes Species. 13
5. Longipeditermes Species 14
6. Nasutitermes Species. 15
7. Subilitermes Species . 15
8. Trinervitermes Species 16
9. Velocitermes Species. 17
IV. Cyc1ized Cembranoids from Marine Invertebrates 17
A. Gorgonacea . . . . . . . . . . . . 43
1. Astrogorgia, Calicogorgia, Eunicella and Muricella Species 43
2. Briareum Species. . . . . . . 44
3. Erythropodium Species. . . . . 47
4. lunceella and Plexaureides Species. 48
B. A1cyonacea. . . . . 49
1. Alcyonium Species 49
2. Cespitularia Species . 51
3. Cladiella, Litophyton, Sclerophytum and Sinularia Species. 51
4. Gersemia Species. . 52
5. Minabea Species . . 52
6. Sarcophyton Species . 52
C. Stolonifera. . . . . 53
D. Pennatulacea. . . . 54
1. Cavernulina, Pteroides, Ptilosarcus, Renilla, Scytalium
and Stylatula Species 54
2. Veretillum Species. . . . . . . . . . . . . 55
VI Contents
Addendum. 120
Acknowledgements. 132
References. . . . 132
Chemical Synthesis of Heparin Fragments and Analogues.
By M. PETITOU and C.A.A. VAN BOECKL 143
1. Introduction. . . . 144
1.1 Heparin . . . . 144
1.2 Heparin Fragments 146
2. Synthesis of the Antithrombin Binding Site 147
2.1 Strategy . . . . . . . . . . . 148
2.2 Preparation of D-Glucuronic Acid Derivatives. 150
2.3 Preparation of L-Iduronic Acid Derivatives. . 151
2.4 Synthesis of the Fully Protected Pentasaccharides 154
2.5 Synthesis of Building Blocks from Natural Disaccharides . 155
2.5.1 Synthesis from Cellobiose. . 155
2.5.2 Synthesis from Maltose. . . . . . . . . . . 157
2.6 Deprotection and Functionalisation . . . . . . . . 158
2.7 Recent Results in the Synthesis of the Antithrombin Binding Site 160
2.7.1 Synthesis of the ex-Methyl Glycoside of the Antithrombin
Binding Site. . . . . . . . . . ... . . . . . . . 160
2.7.2 Synthesis of the N-Acetylated Antithrombin Binding Sequence . 161
3. Synthesis and Biological Properties of Analogues of the Antithrombin
Binding Site . . . . . . . . . . . . . . . . . . . . 162
3.1 Analogues lacking N, O-Sulphate Groups at Defined Positions. 162
3.2 Analogues with Modifications of the Carboxylate Groups at
Defined Positions. . . . . . . . . . . . . . . . . 167
3.3 A Potent Analogue with Extra 3-0-Sulphate Group at Unit H . 170
3.4 Analogues of the Extra Sulphated, Potent Analogue (81) 175
3.5 Analogues Containing "Opened" Uronic Acid Moieties 178
3.6 Analogues with Various Modifications . . . . 182
3.7 Alkylated Analogues of Heparin Pentasaccharides . . 186
4. Conformational Properties. . . . . . . . . . . . 194
5. Interaction of Heparin Pentasaccharide Fragments with Antithrombin III 200
Acknowledgements. 203
References. . 203
Author Index. 211
Subject Index. 217
General Index Vol. 21-60 225
List of Contributors
VAN BOECKL, Dr. C.A.A., Organon Scientific Development Group P.O. Box 20, NL-5340
Oss, The Netherlands.
EKLUND, Dr. A.-M., Reserca AB, Box 17007, S-I04 62 Stockholm, Sweden.
PETITOU, Dr. M., Sanofi Research, Rue de President S. Allende, F-94256 Gentilly, France.
WAHLBERG, Dr. I., Reserca AB, Box 17007, S-I04 62 Stockholm, Sweden.
Cyclized Cembranoids of Natural Occurrence
I. WAHLBERG and A.-M. EKLUND, Reserca AB, Stockholm, Sweden
Contents
I. Introduction . . . . . . . . . . . . . 2
A. Nomenclature and Structural Representation. 3
II. Cyclized Cembranoids from Tobacco. 5
III. Cyclized Cembranoids from Insects 9
A. Nasutitermitinae. . . 10
1. Bulbitermes Species . 10
2. Cortaritermes Species 10
3. Grallatotermes Species 13
4. H ospitalitermes Species. 13
5. Longipeditermes Species 14
6. Nasutitermes Species. 15
7. Subulitermes Species. 15
8. Trinervitermes Species 16
9. Velocitermes Species. 17
IV. Cyclized Cembranoids from Marine Invertebrates 17
A. Gorgonacea . . . . . . . . . . . . 43
1. Astrogargia, Calicogargia, Eunicella and Muricella Species 43
2. Briareum Species. . . . . . . 44
3. Erythrapadium Species. . . . . 47
4. Junceella and Plexaureides Species. 48
B. Alcyonacea. . . . 49
1. Alcyanium Species . . . . . . 49
2. Cespitularia Species. . . . . . 51
3. Cladiella, Litophyton, Sclerophytum and Sinularia Species. 51
4. Gersemia Species. . 52
5. Minabea Species . . 52
6. Sarcophyton Species. 52
C. Stolonifera. . . . . 53
D. Pennatulacea. . . . 54
1. Cavernulina, Pteroides, Ptilosarcus, Renilla, Scytalium
and Stylatula Species 54
2. Veretillum Species. 55
Addendum .... 120
Acknowledgements. 132
References. . . . 132
2 I. WAHLBERG and A.-M. EKLUND
I. Introduction
The structure of eunicillin (89), a carbobicyclic diterpenoid isolated
from the Mediterranean gorgonian Eunicella stricta, was reported in
1968 (1). At that time chlorine-containing diterpenoids had been dis
covered in the gorgonian Briareum asbestinum (2, 3), but it was not until
1977 that the structure of the first briaran, briarein A (211), was resolved
by X-ray analysis (4). The first trinervitane diterpenoid (26), which was
isolated from Trinervitermes termites, was reported in 1976 (5).
OAc
OAc
ACO'····
OH
0
89 211 26
The discovery of these compounds marked the appearance of a large
and growing group of diterpenoids which are commonly viewed as being
formed from cembrane precursors by secondary carbon-carbon bond
closures. It should be emphasized, however, that in the absence of
biosynthetic evidence the question of which groups of diterpenoids that
should be classified as cyclized cembranoids remains ambiguous. In the
present article we have included five tobacco diterpenoids (1-5) which.
possess prerequisite structural features and co occur with appropriate
cembrane precursors in tobacco. Although structurally reminiscent of
cyclized cembranoids, verticillanes, taxanes and cleomeolide are not
dealt with, since these diterpenoids of plant origin are not believed to
arise via preformed cembranoids (6-11).
The bi-, tri- and tetracyclic secotrinervitanoids, trinervitanoids and
kempanoids, which are present in the defensive secretions of soldiers of
higher termites, are most likely formed via cyclization of cembrane
precursors (12). It is also generally agreed that diterpenoids such as
briarans, cladiellins and asbestinins are correctly characterized as cyc
lized cembranoids (13-15). These compounds, which show a large struc
tural diversity, are constituents of marine invertebrates.
We have previously reviewed the cembranoids of natural occurrence
(16). Our intention in the present review is to follow a similar outline and
to give a comprehensive compilation of the naturally occurring cyclized
cembranoids as defined above, that have appeared in the literature
References, pp. 132-141
Cyc1ized Cembranoids of Natural Occurrence 3
through December 1991. Biogenetic relationships are also discussed. It
should be added that a review on cyclized cembranoids was published by
RALDUGIN and SHEVTSOV in 1987 (17), but their selection of diterpene
classes differs from ours.
The cyclized cembranoids are frequently heavily substituted and
contain several asymmetric centers. It has therefore been necessary to use
X-ray diffraction methods for elucidation of the stereostructures of many
compounds. References to these X-ray studies are given in Tables 1-3.
Like their presumed cembrane precursors, many cyclized cern bran
oids and particularly those of marine origin exhibit important biological
and pharmacological effects, this being one of the reasons for the great
interest in their structures and chemistry. Available references are given
in Table 3.
Very few cyclized cembranoids have been prepared synthetically.
KATO et al. (18-20) have completed the syntheses of two secotrinervitan
oids (7, 9) and DAUBEN et al. (21) have recently published the total
±
synthesis of ( )-kempene-2 (59). Another diterpenoid of insect origin,
longipenol (64), has been the target of a synthetic study (22) as has the
tobacco basmanoid 3 (see Tables 1 and 2) (23, 24).
A. Nomenclature and Structural Representation
The present article includes more than two hundred compounds
belonging to as many as sixteen different diterpene classes. The nomen
clature systems and principles employed in the literature vary among the
classes and also within certain classes. In the case of the cyclized
cembranoids of insect origin, the secotrinervitane, trinervitane and kem
pane nomenclatures are generally accepted (25). Nomenclatures for the
diterpene classes found in tobacco have also been established (26-28). In
addition to existing trivial names, we have therefore introduced a semi
systematic nomenclature based on skeletal type for the tobacco and
insect constituents listed in Tables 1 and 2, respectively. The R- and
S-system has been adopted to describe the configuration of each
compound.
The situation is different for the cyclized cembranoids of marine
origin. This is illustrated by the fact that some authors (14, 29, 30) employ
a briaran or briarein nomenclature based on the oxygen-containing
skeleton A, while a briarane nomenclature based on the carbon skeleton
B has been adopted by others (31). Similarly, both the asbestinin (C) and
asbestinane (D) nomenclatures are found in the literature (14, 32, 33).
Because of this lack of consensus, we have only included trivial names
4 I. WAHLBERG and A.-M. EKLUND
A B
C D
PrOco
OAc HO
0 ACO"·····
0 0
191a 192a
OAc HO
o ACO"·····
o o
191 192
and configurational R- and S-descriptors in Table 3. For unnamed
compounds, however, a semi-systematic nomenclature based on the
skeletal types defined in Section IV has been adopted.
The graphical representation of macrocyclic rings is not always
straightforward. This may lead to confusion as is illustrated for ptilosar
cone and brianthein X. Both compounds have (2S,9S)-configurations and
References, pp. 132-141
