Academic Press is an imprint of Elsevier 525 B Street, Suite 1800, San Diego, CA 92101-4495, USA 225 Wyman Street, Waltham, MA 02451, USA 32 Jamestown Road, London, NW1 7BY, UK The Boulevard, Langford Lane, Kidlington, Oxford, OX51 GB, UK Radarweg 29, PO Box 211, 1000 AE Amsterdam, The Netherlands First edition 2014 Copyright © 2014 Elsevier Inc All rights reserved No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means electronic, mechanical, photocopying, recording or otherwise without the prior written permission of the publisher Permissions may be sought directly from Elsevier’s Science & Technology Rights Department in Oxford, UK: phone (ỵ44) (0) 1865 843830; fax (ỵ44) (0) 1865 853333; email: permissions@elsevier.com Alternatively you can submit your request online by visiting the Elsevier web site at http://www.elsevier.com/locate/permissions, and selecting Obtaining permission to use Elsevier material Notice No responsibility is assumed by the publisher for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions or ideas contained in the material herein Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made ISBN: 978-0-12-411565-1 ISSN: 1099-4831 For information on all Academic Press publications visit Our website at www.store.elsevier.com Printed and bound in USA 14 15 10 CONTRIBUTORS Vikram Bhat Department of Chemistry, The University of Chicago, Chicago, Illinois, USA Apurva Dave Department of Chemistry, The University of Chicago, Chicago, Illinois, USA Michael T Davies-Coleman Department of Chemistry, University of the Western Cape, Bellville, South Africa Bernard Delpech Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS, Gif-sur-Yvette Cedex, France Seth B Herzon Department of Chemistry, Yale University, New Haven, Connecticut, USA Sandra M King Department of Chemistry, Yale University, New Haven, Connecticut, USA James A MacKay Department of Chemistry and Biochemistry, Elizabethtown College, Elizabethtown, Pennsylvania, USA Viresh H Rawal Department of Chemistry, The University of Chicago, Chicago, Illinois, USA Clinton G L Veale Department of Chemistry, Rhodes University, Grahamstown, South Africa vii PREFACE A broad range of different alkaloid classes is covered in four chapters of Volume 73 of The Alkaloids In Chapter 1, Clint Veale from Rhodes University in Grahamstown and Mike Davies-Coleman from the University of the Western Cape in Bellville (both in South Africa) are describing the recent fascinating development in the area of marine bi-, bis-, and trisindoles Previously, bisindole alkaloids were summarized in this series by Geoffrey Cordell and Edwin Saxton in Volume 20 (published in 1981) and by Toh-Seok Kam and Yeun-Mun Choo in Volume 63 (2006), but both reviews were dealing with bisindole alkaloids from terrestrial sources Volume 37 which was published in 1990 compiled a series of articles focusing on bisindole alkaloids from Catharanthus roseus (L.) J Sapi and G Massiot described noniridoid bisindole alkaloids from the marine environment, microorganisms, and plant species in Volume 47 (1995) Chapter is covering the isolation, bioactivity, and synthesis of biindoles, bisindoles, and trisindoles which have been obtained from diverse marine sources Vikram Bhat, Apurva Dave, James MacKay, and Viresh Rawal from the University of Chicago (USA) summarize the chemistry of hapalindoles, fischerindoles, ambiguines, and welwitindolinones in Chapter These relatively young classes of alkaloids (first report of hapalindoles in 1984, fischerindoles in 1992, ambiguines in 1992, and welwitindolinones in 1994) have not been treated so far in this series In their outstanding article, the authors are covering the occurrence, isolation, biological activity, biosynthesis, and total synthesis of these alkaloids In Chapter 3, Sandra King and Seth Herzon from Yale University in New Haven (USA) provide an overview on recent achievements in the field of the hasubanan and acutumine alkaloids The hasubanan and the acutumine alkaloids were treated first in this series by K.W Bentley in Volume 13 (published in 1971) in several subchapters under “morphine alkaloids.” Subsequently, the hasubanan alkaloids were reviewed as an independent class of alkaloids in two chapters, by Yasuo Inubushi and Toshiro Ibuka in Volume 16 (1977) and by Matao Matsui in Volume 33 (1988) Chapter summarizes the developments for both classes since their previous treatments focusing on occurrence, isolation of new alkaloids, total synthesis, biosynthesis, and pharmacology ix x Preface The saraine alkaloids described in Chapter also represent a relatively young family of alkaloids (first structure elucidation reported in 1986) They can be considered as members of the manzamine alkaloids and have been mentioned very briefly in the last review in this series on manzamine alkaloids which appeared in Volume 60 published in 2003 Because of their challenging structures and the tremendous development in this area, saraine alkaloids are now treated for the first time as an independent group Bernard Delpech from Gif-sur-Yvette in France has provided an excellent summary of the recent exciting development in the field of saraine alkaloids which is including the isolation, structure elucidation, biological properties, biogenetic proposals, and synthetic approaches Hans-Joachim Knoălker Technische Universitaăt Dresden, Dresden, Germany CHAPTER ONE Marine Bi-, Bis-, and Trisindole Alkaloids Clinton G L Veale*, Michael T Davies-Coleman†,1 *Department of Chemistry, Rhodes University, Grahamstown, South Africa † Department of Chemistry, University of the Western Cape, Bellville, South Africa Corresponding author: e-mail address: mdavies-coleman@uwc.ac.za Contents Introduction Marine Biindoles 2.1 Isolation and Bioactivity Marine Bisindole Enamides 3.1 Isolation and Bioactivity 3.2 Synthesis Marine Bisindole Imidazoles, Imidazolines, and 1H-Imidazol-5(4H)-Ones 4.1 Isolation and Bioactivity 4.2 Synthesis Marine Bisindole Piperazines and Pyrazinones 5.1 Isolation and Bioactivity 5.2 Synthesis Marine Bisindole Pyrimidines 6.1 Isolation and Biological Activity 6.2 Synthesis Marine Bisindole Dipeptides 7.1 Isolation and Bioactivity 7.2 Synthesis Marine-Fused Ring Bisindoles 8.1 Caulerpin and Caulersin 8.2 Aplysinopsin Dimers Miscellaneous Marine Bis- and Trisindoles 9.1 Isolation and Bioactivity References The Alkaloids, Volume 73 ISSN 1099-4831 http://dx.doi.org/10.1016/B978-0-12-411565-1.00001-9 # 2014 Elsevier Inc All rights reserved 4 5 10 10 16 18 18 25 38 38 38 39 39 44 45 45 49 54 54 60 Clinton G L Veale and Michael T Davies-Coleman ABBREVIATIONS Boc tert-butyl carbamate CDI 1,10 -carbonyldiimidazole DCC N,N0 -dicyclohexylcarbodiimide DCE dichloroethane DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone DMAP dimethylaminopyridine DMF dimethylformamide DMSO dimethyl sulfoxide HBpin pinacolborane HOBt hydroxybenzotriazole IBX 2-iodoxybenzoic acid MOM methoxymethyl NaHMDS sodium hexamethyldisilazide NBS N-bromosuccinimide NMO N-methylmorpholine-N-oxide PDC pyridinium dichromate Py pyridine SEM 2-trimethylsilylethyoxymethyl TBAF tetra-n-butylammonium fluoride TBS tert-butyldimethylsilyl t-BuLi tert-butyllithium Teoc 2-(trimethylsilyl)ethyl carbamate TFA trifluoroacetic acid THF tetrahydrofuran TIPS triisopropylsilyl TMS trimethylsilyl Ts tosyl INTRODUCTION The oceans cover nearly three-quarters of the world’s surface and totally dominate the biosphere Life in all its forms proliferates throughout the marine environment, and the secondary metabolism associated with the vast majority of marine life forms provides a cornucopia of novel secondary metabolites,1 many of which serendipitously exhibit medicinally relevant bioactivity Accessible metabolic nitrogen, generated via the complex oceanic nitrogen cycle that controls productivity in the oceans, is often in short supply relative to other nutrients,2 and although, as a result, bioactive nitrogen-containing marine secondary metabolites, for example, bisindole alkaloids, are generally isolated in low concentrations, they continue to elicit interest when encountered in targeted screening programs.3 This Marine Bi-, Bis-, and Trisindole Alkaloids contemporary and undiminished interest in marine alkaloid metabolites possessing two, and occasionally three, indole rings provides the rationale for this chapter This chapter of 130 bi-, bis-, and trisindole alkaloids (covering the chemistry literature up to June 2013) follows on from the past comprehensive review of marine bisindole alkaloids published nearly a decade ago4 and complements the extensive reviews of bisindole alkaloids that already appeared in this series.5a,b Aspects of the chemistry of marine bisindole alkaloids have occasionally appeared in more general reviews of marine alkaloids.6–9 Jiang and coworkers’ 2004 review focused entirely on marine bisindole alkaloids in which the two indole rings are separated by a heterocyclic moiety,4 while Mollica et al.’s recent review7 concentrated on marine-dibrominated compounds of which there are numerous bisindole examples Our chapter of marine metabolites containing two and three indole rings has been expanded to include compounds in which the two indole rings are bonded directly to each other (biindoles) and bis- and trisindoles in which the two and three indole rings, respectively, are separated by any functionality and not only by a heterocyclic ring Selected examples of fused ring bisindole compounds, for example, the caulerpins where one or both of the indole rings are fused to larger rings, are also included Miscellaneous bisindole alkaloids, in which the number of compounds reported thus far is too few to constitute a coherent structural class warranting separate treatment, are reviewed together Marine trisindole alkaloids are less common than bisindole alkaloids, and the few reported examples of the former class of compound are not reviewed here as a separate group but rather with the bisindoles with which they commonly co-occur Three themes, isolation, bioactivity, and synthesis, permeate this review Where possible, repetition with previous reviews is avoided, and if a comprehensive treatment of any of these themes has been provided in a previous review, the focus is shifted to provide a detailed review of the more recent work in the field Given the paucity of bioactive alkaloids isolated directly from marine sources, these compounds are often attractive synthetic targets and the syntheses of 28 marine bisindole alkaloids are comprehensively reviewed here Although substantive details of the biosynthesis of marine bi-, bis-, and trisindole alkaloids remain elusive, the logical amino acid precursors, namely, tryptophan and tyramine, are regularly invoked as precursors in putative biosynthetic sequences Four of these speculative biosyntheses are presented here Clinton G L Veale and Michael T Davies-Coleman MARINE BIINDOLES 2.1 Isolation and Bioactivity Indole dimers formed by either direct carbon–carbon, carbon–nitrogen, or nitrogen–nitrogen bonding between two indole subunits form a small class of marine biindole alkaloids, containing either alkyl amine, halogen, ether, thioether, or sulfoxide substituents, or combinations thereof, on both indole rings An investigation of the marine blue-green alga Rivularia firma, collected at Western Port, Victoria, Australia, yielded the first reported examples of biindoles from a marine source.10 A total of six biindole metabolites 1–6 were isolated from the alga with tri-, tetra-, and hexabromination patterns in addition to 3,30 - 3,10 - 4,10 -, and 4,30 -indole–indole linkages10 (Figure 1.1) While no optical rotation for the symmetrical compound was provided, the five remaining compounds were all optically active, with the chirality attributed to perpendicular dissymmetric planes induced by restricted rotation around the bond linking the indole rings.10 The absolute configuration of and was determined as R and S, respectively.11 A further collection of R firma made several years later from the same location yielded a seventh biindole 7, isomeric with 1.12 The red alga Laurencia brongniartii collected off Okinawa, Japan, was found to contain several simple polybrominated and sulfur-containing indoles in addition to the novel optically inactive polybrominated 3,30 biindole thioether 8.13 L brongniartii collected off the southern tip of Taiwan yielded a further two related thioether- and sulfoxide-substituted biindoles and 10 with only compound 10 displaying optical activity14 (Figure 1.2) Biindole 10 was reported to be cytotoxic against the P338 and HT-29 cancer cell lines; however, no IC50 or MIC values were provided.14 H N Br R2 Br R1 HN Br R1 3Ј Br R2 Br Br Br N 1Ј Br Br N H R1 = Br, R2 = H R1 = H, R2 = Br Figure 1.1 Biindoles 1–7 R2 N Br R1 1Ј Br Br 3Ј Br Br N H N H N H OMe OMe R1 = Br, R2 = Br R1 = Br, R2 = H R1 = H, R2 = Br Marine Bi-, Bis-, and Trisindole Alkaloids H N Br H N R2 OH 3Ј Br Br Br H2 N R1 Br NH2 Br N H R1 = R2 = SMe R1 = R2 = SOMe 10 R1 = SMe, R = SOMe OH N H 11 Dendridine A Figure 1.2 Biindoles 8–11 Finally, a Dictyodendrilla sp sponge also collected off Okinawa yielded a C2 symmetrical biindole, dendridine A (11)15 (Figure 1.2) A putative biosynthesis of this compound via direct 4,40 coupling of two tryptamine precursors was postulated 15 Although Tsuda et al.15 commented on the rarity of naturally occurring 7-hydroxyindoles, this substitution pattern is commonly encountered in many dragmacidin bisindoles.4 Dendridine A exhibited inhibitory action against two gram-positive bacteria Bacillus subtilis (IC50 8.3 mg/mL) and Micrococcus luteus (IC50 4.2 mg/mL) and the fungus Cryptococcus neoformans (IC50 8.3 mg/mL) in addition to weak cytotoxicity against murine leukemia L1210 cells (IC50 32.5 mg/mL).15 MARINE BISINDOLE ENAMIDES 3.1 Isolation and Bioactivity Two linear bisindole enamide alkaloids, chondriamide A (12) and B (13), derived from (E)-3-(indol-3-yl)acrylic acid (14) and (E)-3-(7-hydroxyindol-3-yl)acrylic acid (15), were isolated from the red alga, Chondria sp., collected off the rocky shores near Buenos Aires, Argentina.16 Examination of the more polar fractions of the algal extract led to the isolation and identification of 14 and 15, thus tentatively confirming the biosynthetic precursor status of these two compounds A third bisindole 16 was proposed by Seldes and coworkers to be an artifact arising from the initial ethanol extraction of the alga They consequently proposed that tryptophan was the other biosynthetic precursor of 12 and that decarboxylation after amidation would yield the naturally occurring enamides.16 The extract of the Chondria sp also yielded indole-3-carbaldehyde (17) and an interesting N-formylacrylamide 18, which are oxidation products observed in methanolic solutions of 12 when exposed to air.16 Chondriamides A and B were also isolated together with Clinton G L Veale and Michael T Davies-Coleman a novel Z isomer of 12 chondriamide C (19), from Chondria atropurpurea collected off the Uruguayan coast.17 Both 14 and (E)-3-(indol-3-yl)acrylamide (20) were also identified in the C atropurpurea extracts17 (Figure 1.3) Chondriamides A and B displayed similar cytotoxicity against KB cancer cells (0.5 and