The Alkaloids: Chemistry and Biology, Vol. 65

THE ALKALOIDS Chemistry and Biology VOLUME

65 Edited by

Geoffrey A. Cordell Evanston, Illinois

Amsterdam  Boston  Heidelberg  London  New York  Oxford Paris  San Diego  San Francisco  Singapore  Sydney  Tokyo Academic Press is an imprint of Elsevier

ACADEMIC PRESS

Academic Press is an imprint of Elsevier 84 Theobald’s Road, London WC1X 8RR, UK Radarweg 29, PO Box 211, 1000 AE Amsterdam, The Netherlands Linacre House, Jordan Hill, Oxford OX2 8DP, UK 30 Corporate Drive, Suite 400, Burlington, MA 01803, USA 525 B Street, Suite 1900, San Diego, CA 92101-4495, USA First edition 2008 Copyright r 2008 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 (+44) (0) 1865 843830; fax (+44) (0) 1865 853333; email: [email protected]. 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: 978-0-12-374296-4 ISSN: 1099-4831 For information on all Academic Press publications visit our website at books.elsevier.com

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CONTRIBUTORS Hans-Joachim Kno¨lker, Department Chemie, Technische Universita¨t Dresden, Dresden, Germany Kethiri R. Reddy, Department Chemie, Technische Universita¨t Dresden, Dresden, Germany

vii

PREFACE This is the latest volume in the series ‘‘The Alkaloids: Chemistry and Biology’’ and covers a group of alkaloids comprising the carbazole nucleus. Single-topic volumes in this series have been rare, and the last one discussed antitumor alkaloids and was published as Volume 25 in 1985. This is the first volume dedicated to a single alkaloid structure type since Volume 8, which dealt with the monoterpene indole alkaloids over 40 years ago. This background places in context how significant this remarkably extensive and exceptionally well-organized single volume review of the ‘‘Chemistry and Biology of Carbazole Alkaloids’’ by Kno¨lker and Reddy actually is. It brings together for the first time all of the alkaloids that have been isolated from plant, microbial, and marine sources, which possess, in any aspect of their structure, a carbazole nucleus. The alkaloids are reviewed from the detailed aspects of their structure elucidation, and for the first time an approach is offered with respect to an overall view of their biogenetic pathways, which differ substantially based on the further structural elements of which the carbazole is a core feature. These discussions are followed by a detailed exposition of how the significance of these alkaloids has been enhanced through the determination of several important, clinically relevant, biological properties. Finally, the authors offer a comprehensive presentation of the many synthetic approaches to the various carbazole alkaloids, from the simple alkaloids to the more complex alkaloids, including the bis-alkaloids.

Geoffrey A. Cordell Evanston, Illinois, USA

ix

CH A PT ER

1 Introduction

The initial discovery of carbazole in the anthracene fraction of coal tar followed by the first isolation of the antimicrobial murrayanine (3-formyl-1-methoxycarbazole) from the plant Murraya koenigii Spreng., started the enormous development of carbazole chemistry. Since then, there has been a strong interest in this area by chemists and biologists due to the intriguing structural features and promising biological activities associated with many carbazole alkaloids. The progress in the chemistry of carbazole alkaloids is emphasized by the publication of several reviews and book chapters covering the field (1–10). In this series, three earlier reviews on carbazole alkaloids were published by Kapil (1), Husson (2), and Chakraborty (3) in the Volumes 13, 26, and 44, respectively. The present chapter introduces a new classification of carbazole alkaloids and summarizes the recent synthetic efforts. The nomenclature of carbazole alkaloids used in this review is that of Chemical Abstracts. As shown in Scheme 1.1, the conventional tricyclic ring system of carbazole 1 is denoted by A, B, and C, and the numbering starts from ring A. The term carbazole generally refers to a 9H-carbazole. Several hypotheses have been proposed for the biogenesis of carbazole alkaloids (see Chapter 3 of this review). However, there is no deep experimental knowledge of the biosynthesis of this class of alkaloids. A comparison of the structural features of carbazole alkaloids isolated from higher plants suggests that 3-methylcarbazole (2) may represent the key intermediate in their biosynthesis (Scheme 1.1). In the present review, we summarize the occurrence, biogenesis, biological activity, and the chemistry of carbazole alkaloids, which have been classified based on their natural sources, ring system, and substitution pattern. While a comprehensive overview is given on all carbazole alkaloids isolated from natural sources, only their total syntheses published since 1990 are discussed.

7

4

5

6

C 8

B 8a

A

N9 9a H

Me

3

4b 4a

2

N H

1

1

2 3-Methylcarbazole

Carbazole Numbering

Scheme 1.1

1

CH A PT ER

2 Occurrence, Isolation, and Structure Elucidation

A large number of carbazole alkaloids has been isolated from higher plants of the genera Murraya, Glycosmis, and Clausena, all belonging to the family Rutaceae (subtribe Clauseninae, tribe Clauseneae, subfamily Aurantioideae). The occurrence of carbazole alkaloids in these three genera of the Rutaceae is of chemotaxonomic importance and justifies their classification as an independent subtribe. Carbazoles have also been reported from other genera, such as Micromelum of the family Rutaceae (subtribe Micromelinae), Ekebergia of the Meliaceae, and Cimicifuga of the Ranunculaceae. The genus Murraya, especially the species Murraya euchrestifolia Hayata, represents the richest source of carbazole alkaloids among all terrestrial plants. Various monomeric and also bis-carbazole alkaloids, formed by the combination of two of the monomeric units, have been reported from the genus Murraya. It is noteworthy that, while Murraya koenigii grown in Indian soil did not afford any bis-carbazole alkaloids, the same species grown in a green house in Japan from seeds collected in Taiwan generated bis-carbazole alkaloids. Depending on the seasonal and geographical variation, the genus Murraya is known to provide different alkaloids. Moreover, carbazole alkaloids have been isolated from several different Streptomyces species. The indolocarbazole alkaloids have been obtained from microorganisms, slime molds, and marine sources. Further natural sources for carbazole alkaloids are for example the blue-green alga Hyella caespitosa, species of the genera Aspergillus, Actinomadura, Didemnum, and Iotrochota, and the human pathogenic yeast Malassezia furfur. The natural sources of carbazole alkaloids are listed in Table 2.1. Carbazole and various alkylcarbazoles have also been obtained from other sources, such as coal tar, petroleum oil, soil humus, the polluted atmosphere of industrial areas, as well as cigarette smoke.

I. CARBAZOLE ALKALOIDS FROM HIGHER PLANTS The isolation of carbazole (1), 3-methylcarbazole (2), and several oxidized derivatives of 3-methylcarbazole from taxonomically related higher plants of the genera Glycosmis, Clausena, and Murraya (family Rutaceae) indicates that the aromatic methyl group of the biogenetic key intermediate 3-methylcarbazole can be eliminated oxidatively (5,6). Most of the carbazole alkaloids isolated from the 3

4

Chemistry and Biology of Carbazole Alkaloids

Table 2.1

Biological sources of carbazole alkaloids

A. Higher plants

B. Other sources (i) Microbial sources (schizomycophyta)

(ii) Marine sources (cyanophyta)

(iii) Diverse sources

Murraya euchrestifolia Hayata M. koenigii Spreng. M. siamensis Craib. Clausena anisata Hook. C. heptaphylla Wight & Arn. C. excavata Burm f. C. indica Oliver C. lansium (Lour.) Skeels C. harmandiana Pierre ex. Guillaumin [syn. C. wampi (Blanco) Oliv.] G. arborea (Roxb.) DC. G. parviflora (Sims) Little G. mauritiana Tanaka G. montana Pierre Glycosmis pentaphylla (Retz.) DC. (syn. G. arborea (Roxb.) DC. Micromelum ceylanicum Wight M. hirsutum Oliver Ekebergia senegalensis Fuss. Cimicifuga simplex Wormsk. ex DC. Streptoverticillium ehimense S. mobaraense Streptomyces chromofuscus DC 118 S. exfoliates 2419-SVT2 Streptomyces sp. S. staurosporeus Anaya Actinomadura madurae A. melliaura Arcyria denudata Aspergillus flavus A. tubingensis Nocardia aerocoligenes Nocardiopsis dassonvillei Nocardiopsis sp. Hyella caespitosa Bron et Flah Tedania ignis Nostoc sphaericum Tolypothrix tjipanasensis New Zealand Ascidian Australian Ascidian Didemnum sp. Marine Sponge Iotrochota sp. Marine Sponge Dictyodendrilla verongiformis Bovine urine Malassezia furfur (human pathogenic yeast)

Occurrence, Isolation, and Structure Elucidation

5

Rutaceae family (11) have a one-carbon-substituent at position 3 of the carbazole nucleus and an oxygen substituent at position 1 or 2. The structure of these alkaloids can vary from simple substituted carbazoles to molecules containing complex terpene moieties.

A. Tricyclic Carbazole Alkaloids 1 Carbazole Carbazole (1) was isolated first from the anthracene fraction of coal tar in 1872 by Graebe and Glaser (12). In 1987, almost a century later, Bhattacharyya et al. reported for the first time the isolation of carbazole (1) from a plant source, Glycomis pentaphylla (13) (Scheme 2.1). Structural assignment of carbazole (1) was based on UV, IR, and mass spectral data, as well as direct comparison with an authentic sample.

2 3-Methylcarbazole and Non-Oxygenated Congeners Chakraborty (14), Joshi (15), and Connolly et al. (16) reported independently the isolation of 3-methylcarbazole (2) from the roots of different Clausena species, such as Clausena heptaphylla, Clausena indica, and Clausena anisata. In 1987, Bhattacharyya et al. isolated 3-methylcarbazole (2), along with carbazole (1), from the root bark of Glycosmis pentaphylla (13). A decade later, 3-methylcarbazole (2) was obtained by Chakrabarty et al. from the chloroform extract of the roots of M. koenigii (17). In 1998, Wu et al. isolated 3-methylcarbazole (2) during a study of the antiplatelet aggregation activity of the acetone extract of the root bark of M. euchrestifolia (18). In the IR spectrum (nmax 3450, 1600, 1493, 1390, 885, 808 cm1), the band at 808 cm1, which is characteristic of 3-methylcarbazole, confirms the position of the methyl group (19). The UV spectrum (lmax 230, 236, 243, 260, 296, 330 nm) was superimposible with that of 3-methylcarbazole and confirmed the structural assignment (20,21). In 1988, Furukawa et al. reported the isolation of 3-formylcarbazole (3) from the root bark of M. euchrestifolia (22). Three years later, McChesney and El-Feraly isolated 3-formylcarbazole (3), along with methyl carbazole-3-carboxylate (4), from the roots of Clausena lansium (23). The roots of this ornamental tree are used in traditional medicine in Taiwan to treat bronchitis and malaria (23). In 1992, Bhattacharyya et al. described the isolation and structural elucidation of 3-formylcarbazole (3) from G. pentaphylla (24). 3-Formylcarbazole has UV spectral characteristics as reported previously in the literature (25–27). The IR spectrum showed the band of an NH group (3460 cm1) and of a conjugated carbonyl function (1685 cm1). The 1H-NMR and 13C-NMR

N H 1 Carbazole

Scheme 2.1

6

Chemistry and Biology of Carbazole Alkaloids

Me

CHO

N H

N H

2 3-Methylcarbazole

3 3-Formylcarbazole

COOMe

N H 4 Methyl carbazole-3-carboxylate

Scheme 2.2

Me

Me

N COOC2H5

N CHO

5 9-Carbethoxy-3-methylcarbazole

6 9-Formyl-3-methylcarbazole

Scheme 2.3

spectrum confirmed the presence of an aldehyde group at position 3. In the aromatic region, the 1H-NMR spectrum of methyl carbazole-3-carboxylate (4) is very similar to that of 3-formylcarbazole (3). The methyl ester was indicated by a singlet at d 3.91 for the methoxy group and, in the 13C-NMR spectrum, by a signal at d 168.0 for the ester carbonyl group. In addition to the spectroscopic proof, chemical support was derived from transformation into the corresponding acid and remethylation with diazomethane to afford methyl carbazole-3-carboxylate (4) (Scheme 2.2). In 1997, Chakrabarty et al. reported the isolation of 9-carbethoxy-3-methylcarbazole (5) and 9-formyl-3-methylcarbazole (6) from the roots of M. koenigii (17). These metabolites are the first 9-formyl and 9-carbethoxy carbazole derivatives obtained from plant sources. 9-Formyl-3-methylcarbazole (6) showed weak cytotoxicity against both mouse melanoma B16 and adriamycin-resistant P388 mouse leukemia cell lines. The structural assignment of these two alkaloids was based on the IR- and 1 H-NMR spectra which were lacking any signal of an NH group. Additional structural support for 9-carbethoxy-3-methylcarbazole (5) was provided by the similarity of the UV absorption spectrum with that of a synthetic sample, obtained by reaction of 3-methylcarbazole with ethyl chloroformate in the presence of base. Further structural support for 9-formyl-3-methylcarbazole (6) was derived from a comparison of the UV spectrum and the IR carbonyl absorption (1696 cm1) with those of an authentic sample of 9-formyl-3-methylcarbazole (1700 cm1), prepared by the treatment of 3-methylcarbazole (2) with 98% formic acid (17) (Scheme 2.3).

3 1-Oxygenated Tricyclic Carbazole Alkaloids The higher plants of the genus Murraya (family Rutaceae), which are trees growing in Southern Asia, are the major source of 1-oxygenated carbazole alkaloids. Extracts of the leaves and bark of this tree have been used in traditional medicine for analgesia and local anesthesia, and for the treatment of eczema, rheumatism, and dropsy. Murrayafoline A (7) was isolated from the ethanolic extract of the root bark of M. euchrestifolia collected in Taiwan (28,29). Recently, Cuong et al. isolated the same alkaloid from Glycosmis stenocarpa Guillaumin collected in Northern Vietnam (30).

Occurrence, Isolation, and Structure Elucidation

R2

R

N H

Me R1

R3 OMe

R4

7 Murrayafoline A

7

N H

OMe

7 Murrayafoline A R1,R2,R3,R4 = H 12 Murrayastine

R = Me 8 Koenoline R = CH2OH

R1,R2 = H; R3,R4 = OMe 13 Clausenapin

9 Murrayanine

R1 = prenyl; R2,R3,R4 = H 14 Clausenine

R = CHO 10 Mukoeic acid R = COOH

R1,R3,R4 = H; R2 = OMe

11 Mukonine R = COOMe

Scheme 2.4

The UV spectrum [lmax 225, 243, 251 (sh), 292, 330, and 334 (sh) nm] of murrayafoline-A (7) was similar to that of other 1-oxygenated carbazoles. The 1HNMR spectrum of (7), with a three-proton signal at d 6.97.3 and a signal at d 7.87 for H-5, indicated an unsubstituted C-ring. The signals for a methoxy substituent at d 3.76 and an aromatic methyl group at d 2.40, along with the signals for H-4 and H-2 at d 7.33 and 6.55, respectively, suggested a C-1 methoxy and a C-3 methyl group. This regiochemistry was confirmed by NOE experiments. Thus, murrayafoline-A (7) was assigned as 1-methoxy-3-methylcarbazole, previously described as an intermediate in the synthesis of murrayanine (9) (Scheme 2.4) (31). The cytotoxic carbazole alkaloid koenoline (8) was isolated from the root bark of M. koenigii (32). Koenoline exhibited the characteristic UV spectrum (lmax 241, 251, 289, and 323 nm) of a 1-methoxycarbazole derivative. In addition, the IR spectrum indicated an NH (3445 cm1) and an OH group (3235 cm1), as well as an aromatic system (1585 and 1500 cm1). The 1H-NMR spectrum showed the signals of an aromatic methoxy (d 4.01), a benzylic methylene group (d 4.5), H-2 and H-4 as two broad singlets at d 6.95 and 7.66, and an unsubstituted C-ring. Based on these spectroscopic data, koenoline was structurally assigned as 8. Further confirmation was derived from the 13C-NMR data and a partial synthesis by sodium borohydride reduction of murrayanine (9) (31). Chakraborty et al. reported the isolation of murrayanine (9) independently from two different genera of the family Rutaceae, M. koenigii (33) and C. heptaphylla (34). More recently, Cuong et al. isolated murrayanine (9) from G. stenocarpa Guillaumin from Northern Vietnam (30). Murrayanine (9) showed antimicrobial properties against human pathogenic fungi (35). The UV spectrum of murrayanine (9) (lmax 238, 244, 273, 288, and 327 nm) was strikingly similar to that of 3-formylcarbazole (3). The IR spectrum showed the presence of an NH group (3450 cm1), an aromatic aldehyde (2800, 1681 cm1), and an aromatic ring (1631, 1613, 1585 cm1). In addition, peaks at 850 and 725 cm1 suggested tetra- and di-substituted aromatic rings. The 1H-NMR spectrum showed an aldehyde proton (d 9.98), an aromatic

8

Chemistry and Biology of Carbazole Alkaloids

methoxy group (d 3.96), and six aromatic protons (d 8.09, 7.39). The spectroscopic data confirmed structure 9 (3-formyl-1-methoxycarbazole) for murrayanine. This structural assignment was further supported by chemical transformation into known carbazole derivatives. Mukoeic acid (10) was obtained from the stem bark of M. koenigii. It represents the first carbazole carboxylic acid isolated from a plant source (36,37). The characteristic UV spectrum (lmax 235, 270, and 320 nm) of a 1-methoxycarbazole derivative, as well as the presence of bands for an NH (3431 cm1), a COOH group (1690 cm1), and a substituted aromatic ring (1635, 1613, 1609, 763, and 735 cm1) in the IR spectrum, supported the assigned structure. The 1H-NMR spectrum of methyl mukoate, obtained by methylation of mukoeic acid with diazomethane, showed the presence of a carbomethoxy and a methoxy group at d 4.02 and 4.07, and a deshielded aromatic proton at d 8.53 (assigned to the proton at C-4 of the carbazole framework). In addition to the spectroscopic data, further structural support was derived from decarboxylation of mukoeic acid to 1-methoxycarbazole. This chemical transformation suggested the presence of a carboxylic group at C-3 and a methoxy group at C-1. The corresponding methyl ester of mukoeic acid, mukonine (11), was also isolated from M. koenigii (4). The UV spectrum (lmax 236, 274, and 320 nm) was very similar to that of mukoeic acid. The IR spectrum showed bands for an NH (3350 cm1) and a COOMe group (1700 cm1), and for an aromatic system (1600, 1510 cm1). The data indicated that mukonine was a methyl 1-methoxycarbazole-3carboxylate, which was confirmed by hydrolysis of mukonine to mukoeic acid. The co-occurrence of murrayafoline-A (7), koenoline (8), murrayanine (9), mukoeic acid (10), and mukonine (11) in plants of the genus Murraya suggests that they are biosynthesized by in vivo oxidation of murrayafoline-A (7) (Scheme 2.4). In 1986, Furukawa et al. isolated murrayastine (12) from the stem bark of M. euchrestifolia collected in Taiwan (38). The UV spectrum (lmax 224, 247, 255, 298, 322, and 336 nm) and the IR spectrum (nmax 1630 and 1585 cm1) indicated a carbazole framework. The 1H-NMR spectrum showed an aromatic methyl signal (d 2.47), three aromatic methoxy groups (d 3.95, 3.96, and 4.00), and meta-coupled H-4 (d 7.32) and H-2 (d 6.65) signals. The enhancement of the signals at H-2 and H-4 on irradiation at the aromatic methyl group suggested C-3 as the position for the methyl group. The ortho-coupled H-5 signal (d 7.56, d, J=8.0 Hz) demonstrated that positions C-5 and C-6 were unsubstituted. The spectral data suggested structure 12 for murrayastine, which was confirmed by synthesis (38). Clausenapin (13) was isolated from the leaves of C. heptaphylla (39). Prior to its isolation, it was known as a Huang–Minlon reduction product of indizoline (4). The UV spectrum of clausenapin (lmax 224, 240, 250, 290, 320, and 335 nm) was similar to that of 1-methoxycarbazole, which was also supported by the IR data. The 1H-NMR spectrum showed signals for a prenyl side chain (d 1.75, 1.85, 3.62, and 5.3), an aromatic methyl (d 2.28), an unsubstituted C ring (d 7.1–7.4 and 7.9), and a H-4 singlet (d 7.5). Isolation of 3-methylcarbazole from zinc dust distillation, the similarity of the UV spectrum with 1-methoxycarbazole, and the singlet for the proton at C-4 suggested that the prenyl chain was at position 2. From these spectral studies, structure 13 was assigned to clausenapin. This structure was further supported by the previously reported Huang–Minlon reduction product of indizoline (16) (see Scheme 2.5) (4).

Occurrence, Isolation, and Structure Elucidation

9

In 1995, Chowdhury et al. isolated clausenine (14) from the alcoholic extract of the stem bark of C. anisata (40). The UV (lmax 226, 242, 299, 298, 340, and 354 nm) and the IR spectrum showed the presence of an NH group (3400 cm1) and a substituted aromatic system with a carbazole framework (1580, 1218, 940, 840, 820 cm1). The 1 H-NMR spectrum exhibited an aromatic methyl signal (d 2.42), two aromatic methoxy groups (d 3.80 and 3.92), and meta-coupled H-4 (d 7.54) and H-2 (d 6.74) signals. The ortho-coupled H-8 (d 7.32, d, J=8.0 Hz), along with the ortho- and metacoupled H-7 signal (d 6.92, dd, J=8.0, 2.0 Hz), and the meta-coupled H-5 (d 7.44, d, J=2.0 Hz) demonstrated that the positions C-2, C-4, C-5, C-7, and C-8 were unsubstituted. Based on all these spectral data, structure 14 was assigned to clausenine (Scheme 2.4). 6-Methoxymurrayanine (3) (3-formyl-1,6-dimethoxycarbazole) (15) was isolated from the roots of C. lansium (23). The roots of C. lansium were used to treat bronchitis and malaria. The UV (lmax 227, 239, 251, 294, 335, and 349 nm) and IR spectra showed the presence of a 3-formylcarbazole framework. The 1H-NMR data were similar to murrayanine (9), with an additional methoxy group for one of the aromatic hydrogens at the C-ring of the carbazole. Since the signal for H-5 (d 7.90) is not orthocoupled, an additional methoxy could be located at C-6. This structural conclusion was also supported by the 13C-NMR spectrum. Indizoline (16) was isolated from the roots of C. indica (15). The UV spectrum (lmax 237, 247, 275, 294, and 330 nm) is similar to 3-formylcarbazole (with the exception of a hyperchromic shift of the maximum at l 275 nm), which was also supported by the IR data. The 1H-NMR spectrum showed signals at d 1.70 (3H, J=1.0 Hz, methyl), 1.85 (3H, J=1.0 Hz, methyl), 3.9 (2H, benzylic methylene), and 5.25 (1H, vinylic proton) indicative of the presence of a prenyl side chain attached to the aromatic ring. Moreover, the presence of an aromatic methoxy group (d 3.29), an aldehyde (d 10.3), an unsubstituted C-ring (d 7.4, 3H, m and d 8.02, 1H, dd, J=2, 7 Hz), and a deshielded H-4 singlet (d 8.4), due to the proximity of the aldehyde function at C-3, were observed. On Huang–Minlon reduction, indizoline gave a compound having a UV spectrum similar to that of 1-methoxycarbazole. The singlet nature of the C-4 proton and the substitution at the positions 1 and 3, strongly suggested that the prenyl side chain was located at C-2. On this basis, indizoline was formulated as 16. This assignment was confirmed by an independent synthesis of its reduction product 13 (see Scheme 2.4) (4), which later was isolated from C. heptaphylla and named clausenapin (13) (see Scheme 2.4) (39). Although ekeberginine (17) is an alkaloid closely related structurally to indizoline (16), it was isolated from two different sources, the stem bark of Ekebergia senegalensis (Meliaceae) (41) and the combined extracts of the stem bark and roots of C. anisata (16). The 1H-NMR spectrum 17 was similar to that of indizoline, except for the absence of the deshielded C-4 proton and the presence of a C-2 proton at d 7.43 as a singlet. The position of the prenyl group was unambiguously assigned at C-4 of the carbazole ring by using 2D long-range dC/dH correlation combined with the 1D proton-coupled 13C-NMR spectrum. Thus, C-4b has 3J correlations with H-6 and H-8, while C-4a has 3J correlations with H-5 and the C-1 methylene protons of the prenyl group. Therefore, structure 17 was assigned to ekeberginine. This structural assignment also supports the structure of readily formed N-methylekeberginine. Clausenal (18) was isolated from the ethanolic extract of the leaves of C. heptaphylla. Clausenal showed promising activity against Gram-positive and

10

Chemistry and Biology of Carbazole Alkaloids

R2

R3

R

CHO

COOMe

R1

R4 N H

R5

N H

OMe

9 Murrayanine 1

2

3

4

OMe

11 Mukonine 5

R=H

R ,R ,R ,R ,R = H 15 6-Methoxymurrayanine (3-Formyl-1,6-dimethoxycarbazole)

20 Clausamine D R = prenyl

R1,R2,R4,R5 = H; R3 = OMe 16 Indizoline

21 Clausamine E R = (E) HC CHC(OH)Me2

R1 = prenyl; R2,R3,R4,R5 = H

22 Clausamine G R = (E) HC CHC(OOH)Me2

17 Ekeberginine R1,R3,R4,R5 = H; R2 = prenyl 18 Clausenal R1,R2,R3,R4 = H; R5 = OMe 19 Clausine Q R1,R2,R3,R5 = H; R4 = OH

Scheme 2.5

Gram-negative bacteria, and fungi (42). The UV spectrum (lmax 231, 257, 261, and 327 nm) is characteristic of a 3-formylcarbazole. The IR data suggested the presence of an NH (3400 cm1), an aldehyde (1660 cm1), and an aromatic ring (1610, 1576 cm1). The 1H-NMR spectrum showed signals for NH (d 8.80, br s), CHO (d 10.28, s), H-4 (d 8.60, d, J=2.8 Hz), H-5 (d 7.78, dd, J=8.0, 1.5 Hz), H-2 (d 7.44, d, J=1.8 Hz), H-6 (7.25, m), H-7 (d 6.98, dd, J=8.0, 1.8 Hz), as well as two singlets for two aromatic methoxy groups (d 4.07, 4.02). In addition, a mass spectral fragment at m/z 227 represented a formylcarbazole residue, while the peaks at m/z 240 (M+–15) and 212 (22715) suggested the presence of two aromatic methoxy groups. In consideration of the 1H-NMR and 13C-NMR data, the two methoxy groups were placed at C-1 and C-8, and the formyl group at C-3. Based on these spectral data, the structure of clausenal was assigned as 1,8-dimethoxy-3-formylcarbazole (18). This structure was confirmed by synthesis using a Japp–Klingemann reaction and Fischer indolization. Clausine Q (19) was isolated from the acetone extract of the root bark of Clausena excavata (43). The UV spectrum (lmax 242, 286, 297, 325, and 338 nm) was characteristic of a 3-formylcarbazole. The 1H-NMR spectrum showed the presence of CHO (d 10.01, s), H-4 (d 8.19, d, J=1.2 Hz), H-5 (d 7.99, d, J=8.0 Hz), H-2 (d 7.38, d, J=1.2 Hz), H-6 (d 6.84, dd, J=8.5, 2.2 Hz), H-8 (d 7.07, d, J=2.2 Hz), and an aromatic methoxy group (d 4.06). Two meta-coupled protons (H-2 and H-4), a meta-coupled proton at C-8, and an ortho- and meta-coupled proton at C-6 suggested clausine Q to be a 1,7-disubstituted-3-formylcarbazole. The positional assignments for OH at C-7 and OMe at C-1 were confirmed by NOE experiments. Thus, the structure of clausine Q suggested was established as 19 (Scheme 2.5). In 2000, Itoigawa et al. (44) isolated clausamine D (20), clausamine E (21), and clausamine G (22) from the acetone extract of branches of C. anisata. Clausamine G is

Occurrence, Isolation, and Structure Elucidation

11

the first example of a naturally occurring, peroxygenated carbazole alkaloid. All of these carbazole alkaloids showed antitumor-promoting activity against TPA (12-Otetradecanoylphorbol-13-acetate)-induced EBV-EA (Epstein–Barr virus early antigen) activation (44). The UV spectrum (lmax 222, 240, 248, 256, 269, 310, 321, and 335 nm) of clausamine D (20) was characteristic of a 1-oxygenated 3-carbomethoxy carbazole. The IR spectrum showed the presence of NH (3467 cm1) and COOMe (1709 cm1). The presence of a carbomethoxy functionality at the carbazole nucleus was additionally confirmed by the characteristic mass fragmentation at m/z 292 (M+OMe) and 264 (M+COOMe). The 1H-NMR spectrum showed the presence of a prenyl side chain attached to the aromatic ring, and a set of four C–H protons at d 8.14 (d, J=8.1 Hz), 7.27 (t, J=8.1 Hz), 7.44 (t, J=8.1 Hz), and 7.49 (d, J=8.1 Hz) for H-5, H-6, H-7, and H-8, respectively. Moreover, the 1H-NMR spectrum exhibited a singlet at d 7.46 for H-2 and two signals for aromatic methoxy groups at d 4.03 and 3.93. These data, combined with biogenetic considerations, suggested the presence of a 1-oxygenated 3-substituted carbazole skeleton with no substituents on the C-ring. NOE results, combined with 1H and 13C-NMR data, unequivocally confirmed structure 20 for clausamine D. This structure was also supported by the synthesis of 20 via O-methylation of clausine F (32) (see Scheme 2.7). The UV spectrum (lmax 224, 239, 273, 322, and 337 nm) of clausamine E (21) was similar to that of clausamine D (20). The 1H-NMR spectrum also showed a signal pattern similar to that of clausamine D, except for the absence of signals of a prenyl group. Doublets at d 7.37 and 6.00 with a large coupling constant of J=16.1 Hz indicated the presence of an (E)-disubstituted double bond. Moreover, a 6-proton-singlet at d 1.55 due to two methyl groups was observed. These data, and two significant mass fragment ion peaks at m/z 321 (M+H2O) and 280 (M+C(OH)Me2), suggested the presence of the side chain [(E)-CHQCHC(OH)Me2]. Based on these data, structure 21 was assigned to clausamine E. The UV spectrum (lmax 223, 236, 270, 313, 321, and 333 nm) of clausamine G (22) and the doublets in the 1H-NMR spectrum at d 7.47 and 5.92 with a large coupling constant of J=16.5 Hz indicated the presence of an (E)-disubstituted double bond. A 6-proton-singlet at d 1.60 resulted from two equivalent methyl groups. These data confirmed the similarity of clausamine G (22) and clausamine E (21). The observation of a broad singlet at d 9.56, exchangeable with D2O, together with a significant mass fragment ion peak at m/z 281 (M+C(OOH)Me2+H) suggested the presence of a side chain [(E)-CHQCHC(OOH)Me2]. Based on the spectral data, structure 22 was assigned to clausamine G. This structure was additionally supported by transformation of clausamine G into clausamine E on reaction with triphenylphosphine (Scheme 2.5). 1-Hydroxy-3-methylcarbazole (23) was isolated from the stem bark of M. koenigii (45). The UV spectrum (lmax 225, 242, 290, and 331 nm) was similar to that of 3-methylcarbazole (2) (see Scheme 2.2). The IR spectrum showed the presence of an NH group (3400 cm1), an OH substituent (3283 cm1), and an aromatic ring (1615, 1580 cm1). The aromatic region of the 1H-NMR spectrum showed an unsubstituted C-ring along with a proton at C-4 (doublet at d 7.5, J=2.0 Hz) exhibiting a meta-coupling with the proton at C-2. Based on this evidence, the alkaloid was assigned as 1-hydroxy-3-methylcarbazole (23). Further structural support was

12

Chemistry and Biology of Carbazole Alkaloids

derived from a zinc dust distillation of 1-hydroxy-3-methylcarbazole (23), which led to 3-methylcarbazole (2) (see Scheme 2.2). O-Demethylmurrayanine (24) was isolated from the combined extracts of the stem bark and roots of C. anisata (16). Preliminary color tests of the isolated fraction showed a phenolic hydroxy group. The UV spectrum (lmax 226, 244, 255, 278, 291, 336, and 346 nm) gave evidence for a 3-formylcarbazole. The presence of a hydroxy group and a conjugated aldehyde group was additionally confirmed by the strong absorptions at 3460 and 1670 cm1 in the IR spectrum. The 1H-NMR spectrum showed the presence of deshielded meta-coupled (J=1.4 Hz) protons at d 8.15 and 7.33 (H-4 and H-2), along with the proton of an aldehyde group (d 9.89) and an orthodisubstituted aromatic ring pattern for the unsubstituted C ring. The structural assignment was additionally supported by the 13C-NMR spectrum and led to structure 24 for O-demethylmurrayanine. In 1996, Wu et al. reported the isolation of clausine E (25) from the stem bark of C. excavata (46). One year later, Ito et al. reported the isolation of the same alkaloid from the same source and named it clauszoline-I (25) (47). This alkaloid showed inhibition of rabbit platelet aggregation and caused vasocontraction. The UV, IR, and 1 H-NMR spectra were similar to those of mukoeic acid (10) with respect to the position of substituents. The presence of a carbomethoxy group at C-3 was indicated by an IR band at 1703 cm1. Moreover, two significant mass fragments at m/z 210 (M+OMe) and 182 (M+COOMe) confirmed the presence of a carbomethoxy group. On the basis of these spectral data, structure 25 was assigned to clausine E (clauszoline-I) (Scheme 2.6). Chowdhury et al. isolated 6,7-dimethoxy-1-hydroxy-3-methylcarbazole (26) from the leaves of M. koenigii (48). This alkaloid has shown high activity against both Gram-positive and Gram-negative bacteria and fungi. The UV spectrum (lmax 235, 285, 305, and 330 nm) was characteristic of a carbazole nucleus. Besides a color test, the presence of a phenolic hydroxy group was confirmed by a strong absorption at 3305 cm1 in the IR spectrum. The 1H-NMR signal for the hydroxy proton was similar to that of 1-hydroxycarbazole. In carbazole alkaloids the protons at C-4 and C-5 appear at higher field. Therefore, the signals at d 7.64 and 7.45 were assigned to

R

N H

R1

Me

R2 OH

R3

N H

OH

23 1-Hydroxy-3-methylcarbazole R = Me

23 1-Hydroxy-3-methylcarbazole

24 O-Demethylmurrayanine R = CHO

26 6,7-Dimethoxy-1-hydroxy-3-methylcarbazole

25 Clausine E (Clauszoline-I) R = COOMe

R1,R2,R3 = H R1,R2 = OMe; R3 = H 27 Murrayafoline B R1=H; R2 = OMe, R3 = prenyl 28 Clausenol R1 = OMe; R2,R3 = H

Scheme 2.6

Occurrence, Isolation, and Structure Elucidation

13

H-4 and H-5. However, the proton at d 7.45 is comparatively more shielded, suggesting the presence of a methoxy group at the ortho position. The singlet nature of this proton also suggests two methoxy groups at adjacent positions. The proton at d 7.45 was thus assigned to H-5 and the meta-coupled doublet at d 7.64 to H-4. Consequently, the methyl group could be attached to C-3. The singlet at d 6.85 was assigned to H-8, and a meta-coupled doublet at d 6.80 was assigned to H-2. All of the spectral evidence confirmed this alkaloid as 6,7-dimethoxy-1-hydroxy-3-methylcarbazole (26). Further structural support came from its 13C-NMR spectrum, as well as its preparation as an advanced synthetic intermediate in the total synthesis of koeniginequinone B (114) (49) (see Section I.A.7, Scheme 2.21). Murrayafoline-B (27) was obtained as a colorless syrup from the root bark of M. euchrestifolia (29). The UV spectrum (lmax 230, 247, 255, 302, and 324 nm), and a bathochromic shift in alkali solution, indicated a phenolic carbazole. Additional support was derived from its IR data (nmax 3600, 3475, 1620, 1595 cm1). The 1 H-NMR spectrum showed the presence of an aromatic methyl group (d 2.42), an aromatic methoxy group (d 3.90), and a prenyl side chain (d 1.72, 1.88, 3.90, and 5.31). Moreover, it exhibited two broad singlets arising from H-2 (d 6.56) and H-4 (d 7.32), and two signals with ortho-coupling for H-5 (d 7.72, J=9.0 Hz) and H-6 (d 6.82, J=9.0 Hz). These spectral data led to structure 27 for murrayafoline-B, which was additionally confirmed by its photooxidation to murrayaquinone B (108) (29) (see Scheme 2.21). Clausenol (28) was isolated from the alcoholic extract of the stem bark of C. anisata (40). The UV (lmax 228, 253, 303, and 356 nm) and the IR spectrum [nmax 3395 (NH, OH), 1620, 1580 (aromatic ring system), 975, 850, and 820 cm1 (substituted aromatic ring)] suggested the presence of a carbazole ring. The 1H-NMR spectrum was very similar to that of clausenine (14), except for the signal of a hydroxy group at d 10.56 (exchangeable with deuterium oxide), which was present instead of a methoxy signal. This assignment was additionally supported by a color test, as well as the transformation of 28 into clausenine (14) by methylation with diazomethane (see Scheme 2.4). The spectral data and the chemical transformation confirmed structure 28 for clausenol. Additional structural support was derived from total synthesis using a Japp–Klingemann reaction and Fischer indolization (40) (Scheme 2.6). In 1992, Wu et al. isolated two new 4-prenylcarbazole alkaloids, clausine D (29) and clausine F (32), from the stem bark of C. excavata, collected in Taiwan. These alkaloids showed inhibition of platelet aggregation (50). Four years later, clausine I (30) was isolated from the same natural source, along with clausine E (25). This alkaloid showed inhibition of rabbit platelet aggregation and caused vasocontraction (46). Clausine I (30) and clausine E (25) have the same molecular formula. However, clausine I (30) is regioisomeric to lansine (69) (see Scheme 2.14). In the same year, clausine J (31a) and clausine G (33) were isolated from the same natural source (51) (Scheme 2.7). The UV spectrum (lmax 225, 242, 253, 276, 289, and 351 nm) of clausine D (29) was similar to that of O-demethylmurrayanine (24), which also represents a 3-formyl-1hydroxycarbazole framework. The presence of a hydroxy group and a conjugated aldehyde group was further supported by strong absorptions at 3380 and 1655 cm1 in the IR spectrum. The 1H-NMR spectrum was very similar to that of O-demethylmurrayanine, except for the presence of a prenyl group (d 1.65,

14

Chemistry and Biology of Carbazole Alkaloids

R1

R2 R3

R1

R2

CHO

COOMe

R3 N H

N H

OH

24 O-Demethylmurrayanine

25 Clausine E (Clauszoline-I) R1,R2,R3 = H

R1,R2,R3 = H 29 Clausine D 1

OH

32 Clausine F 2

3

R1 = prenyl; R2,R3 = H

R =prenyl; R ,R = H 30 Clausine I R1,R3 = H; R2 = OMe 31a Clausine J R1 = H; R2 = OMe; R3 = OH 31b Clausine Z

33 Clausine G R1,R3 = H; R2 = OMe 34 Clausine R R1,R2 = H; R3 = OH 35 Clausamine F

R1,R3 = H; R2 = OH

R1 = (E ) HC CHC(OH)Me2; R2,R3 = H

Scheme 2.7

1.88, 4.33, and 5.26) and the absence of a strongly deshielded proton at C-4. The presence of a prenyl group was further confirmed by the observation of a mass fragmentation ion at m/z 223 (M+CHQCMe2H) and by the 13C-NMR signals at d 27.2 (t), 123.9 (d), 132.7 (s), 18.3 (q), and 26.6 (q). The location of the prenyl side chain at C-4 was further explained by the downfield shift of the benzylic protons of the prenyl group at d 4.33. These spectral data suggested structure 29 for clausine D, which was unambiguously confirmed by its NOESY and HMBC spectra (50). The UV spectrum (lmax 223, 242, 255, 278, 296, 341, and 353 nm) of clausine I (30) resembled that of O-demethylmurrayanine (24), which suggests a 1-hydroxy-3formylcarbazole framework. The presence of a hydroxy group and a conjugated aldehyde group was further confirmed in the IR spectrum by strong absorptions at 3400 and 1640 cm1, respectively. The 1H-NMR spectrum was similar to that of O-demethylmurrayanine, except for the presence of a methoxy group at d 3.98 and the coupling pattern of the C-ring, which shows an ortho-coupled proton at C-8 (d 7.56, d, J=9.0 Hz), an ortho- and meta-coupled proton at C-7 (d 7.10, dd, J=9.0, 2.5 Hz), and a meta-coupled proton at C-5 (d 7.78, d, J=2.5 Hz). The spectral data indicated that clausine I has a structure similar to O-demethylmurrayanine, but with a methoxy group at the 6-position. Based on this evidence, structure 30 was assigned to clausine I. This assignment was additionally supported by NOESY and HMBC experiments (46). The UV spectrum (lmax 235, 255, 289, 305, and 347 nm) of clausine J (31a) was similar to that of O-demethylmurrayanine (24) and thus indicated a 1-hydroxy-3formylcarbazole skeleton. The presence of a hydroxy group and a conjugated aldehyde group was confirmed by strong absorptions at 3430 and 1650 cm1 in the IR spectrum. The 1H-NMR signal for the hydroxy proton of 31a was similar to that of 1-hydroxycarbazole at d 9.31. The signal for the 3-formyl proton at d 9.94, along with signals for two meta-coupled protons, H-2 and H-4 (J=1.0 Hz) at d 7.30 and 8.10

Occurrence, Isolation, and Structure Elucidation

15

supported the 1-hydroxy-3-formylcarbazole partial structure. This assignment was strongly supported by NOE’s of the signal for the formyl proton with the two protons H-2 and H-4. Based on this NOE experiment, the additional two singlets at d 7.09 and 7.74 were assigned to H-8 and H-5, respectively. The signals for an additional hydroxy group at d 7.80 and for a methoxy group at d 3.98, along with the existence of an NOE between the methoxy group and H-5, indicated that the methoxy group is attached to C-6, while the second hydroxy group is at C-7. On the basis of these spectral data, structure 31a was assigned to clausine J representing 1,7-dihydroxy-3-formyl-6-methoxycarbazole (51). In 2005, Potterat et al. reported the isolation of clausine Z (31b) from the ethanolic extract of the stem and leaves of C. excavata. This alkaloid exhibits inhibitory activity against cyclin-dependent kinase 5 (CDK5) and has protective effects on cerebellar granule neurons in vitro (52). The UV spectrum (lmax 223, 243, 256, 279, 299, 340, and 357 nm) was similar to that of clausine I (30), which indicates a 1-hydroxy-3formylcarbazole framework. The presence of a hydroxy group and a conjugated aldehyde group was confirmed by strong absorptions at 3407 and 1649 cm1 in the IR spectrum. The 1H-NMR data were very similar to those of clausine I (30) however, instead of a methoxy signal an additional hydroxy signal was present at d 9.07, which was exchangeable with deuterium oxide. The spectral data suggest that clausine Z has a 6-O-demethylclausine I structure and thus, structure 31b was assigned to clausine Z. Additional support for this structural assignment derived from ROESY, HSQC, and HMBC experiments. The UV spectrum (lmax 244, 269, and 323 nm) of clausine F (32) resembled that of mukoeic acid (10) (see Scheme 2.4) indicating a 1-oxygenated-3-carboxycarbazole framework. The 1H-NMR spectrum was very similar to that of clausine D (29), except for the presence of a carbomethoxy signal at d 3.83 instead of an aldehyde proton at d 10.34 as in clausine D. The presence of a carbomethoxy group was also supported in the IR spectrum by a band at 1670 cm1 for an aromatic ester. The presence of a carbomethoxy group was further supported by the mass fragmentation ion at m/z 250 (M+COOMe). The 13C-NMR spectrum exhibited signals for a carbonyl carbon and for a methoxy group at d 168.85 and 51.53, respectively. Based on these spectral data and additionally supported by NOESY and HMBC experiments, structure 32 was assigned to clausine F (50). The UV spectrum (lmax 224, 272, 282, 316, and 353 nm) of clausine G (33) showed a strong similarity to that of clausine I (30). The aromatic region in the 1H-NMR spectrum was also very similar to clausine I with respect to the chemical shifts and splitting pattern. The presence of a carbomethoxy group at C-3 was indicated by the signal of a methoxy group at d 3.89 in the 1H-NMR spectrum, a carbonyl signal at d 168.0 in the 13C-NMR spectrum, and a band at 1670 cm1 in the IR spectrum. Based on these spectral data, clausine G was assigned as 3-carbomethoxy-1-hydroxy-6methoxycarbazole (33). This structural assignment was additionally confirmed by NOE experiments and 1H13C long-range correlations in the HMBC spectrum (51). Clausine R (34) was isolated from the acetone extract of the root bark of C. excavata (43). The UV spectrum (lmax 241, 282, and 320 nm) resembled that of mukoeic acid (10) (see Scheme 2.4), which indicated a 1-oxygenated 3-carboxycarbazole framework. The 1H-NMR spectrum is similar to that of clausine Q (19) (see Scheme 2.5), except for the presence of a carbomethoxy signal at d 3.86 instead of the aldehyde proton at d 10.01 as in clausine Q. The presence of a carbomethoxy group

16

Chemistry and Biology of Carbazole Alkaloids

was also supported in the IR spectrum by a band at 1695 cm1 for an aromatic ester, and by the mass fragmentation ion at m/z 198 (M+COOMe). The signal of the methoxy group at d 3.86 showed no NOE with the signals of any other protons. The presence of an NOE between the signals for the hydroxy group at d 8.89 and H-2 at d 7.48 and NOEs between the signals for the second hydroxy group at d 8.41 with H-6 at d 6.79 and H-8 at d 7.03 suggested one hydroxy group to be located at C-1 and the other at C-7. Based on these spectral data, structure 19 was assigned to clausine R. Clausamine F (35) was isolated along with other clausamine derivatives (20–22) (see Scheme 2.5) from the acetone extract of branches of C. anisata. All these alkaloids showed antitumor-promoting activity against TPA-induced EBV-EA (Epstein-Barr virus early antigen) activation in Raji cells (44). The UV spectrum (lmax 223, 242, 272, 324, and 341 nm) and the IR spectrum (nmax 1508, 1558, 1699, 3300, and 3456 cm1) of clausamine F (35) were similar to that of clausamine E (21). These absorptions are characteristic of a 1-oxygenated 3-carbomethoxy carbazole framework. The 1H-NMR spectrum also showed a signal pattern similar to that of clausamine E. However, instead of the singlet for the C-1 methoxy group, an additional broad D2O exchangeable signal was apparent, which was assigned to the hydroxy group. The spectral data confirmed structure 35 for clausamine F (Scheme 2.7). In 1996 Wu et al. isolated the optically active carbazole–pyranocoumarin dimer, carbazomarin-A (36) from the methanolic extract of the stem bark of C. excavata. This was the first carbon–carbon linked carbazole–pyranocoumarin dimer found in nature. Although its optical rotation value is known ([a] 27.03, c 0.0259, CHCl3), its absolute configuration has not been assigned (53). The UV spectrum (lmax 215, 240, 253, 267, 326, 338, and 356 nm) and the IR spectrum (nmax 1595, 1610, 1670, and 3400 cm1) of carbazomarin-A (36) clearly indicated a 1-oxygenated 3-carboxycarbazole alkaloid. The aromatic region in the 1 H-NMR spectrum shows four, mutually coupled protons at d 7.26 (1H, m), 7.43 (2H, m), and 8.03 (1H, d, J=8.0 Hz), assigned to a non-substituted C-ring. The strongly deshielded singlet at d 8.21 was assigned to C-4 of the substituted A-ring. The 1H13C long-range correlation between the carbonyl carbon (d 173.3) and H-4 (d 8.21) suggested that the carbomethoxy substituent is attached at C-3. The other signals in the olefinic and aromatic region were found to be very similar to those of nordentatin, a 8u-dimethylallyl-5u-hydroxy-dimethylpyranocoumarin nucleus (54). In contrast to nordentatin, one double bond of the pyran ring was reduced to a single bond, which presented a –CH2CH– group as double doublet (dd) at d 2.11, 2.25, and 5.17. The carbon–carbon linkage between C-2 and C-4v of the carbazole and the dihydropyranocoumarin framework was established based on NOESY and 1H13C long-range correlations in the HMBC spectrum. The mass fragmentation ions at m/z 312 (M+[C14H11NO3] carbazole nucleus) and at 241 (M+[C19H22O4] dihydropyranocoumarinH) provided additional support for the carbazole–pyranocoumarin dimer. From these spectral data, structure 36 was assigned to carbazomarin-A (53) (Scheme 2.8).

4 2-Oxygenated Tricyclic Carbazole Alkaloids Among the large number of carbazole alkaloids that have been isolated from M. koenigii are also many 2-oxygenated derivatives. In 1985, Bhattacharyya et al. isolated 2-methoxy-3-methylcarbazole (37) from the petroleum ether extract of the seeds of M. koenigii (55). The UV spectrum (lmax 235, 255, 300, and 328 nm) and the IR

Occurrence, Isolation, and Structure Elucidation

17

MeO O 2

N H

HO OH

4''

O

O

O

36 Carbazomarin-A

Scheme 2.8

spectrum (nmax 750, 820, 1208, 1600, and 1640 cm1) suggested a carbazole skeleton. In the 1H-NMR spectrum, a complex multiplet of four, mutually coupled protons at d 7.207.40 indicated a non-substituted C-ring. In addition, the signals for an aromatic methoxy group (d 3.77), an aromatic methyl group (d 2.35), and H-4 (d 7.50) and H-1 (d 6.95) confirmed 2-methoxy-3-methylcarbazole (37) as the structure. Further support was obtained by transformation of 37 into known derivatives (14,56). In 1990, Lange et al. isolated O-methylmukonal (38) from the roots of Murraya siamensis (57). Two years later, Bhattacharyya et al. reported the isolation of the same alkaloid from the roots of a different natural source, G. pentaphylla, and named it glycosinine (38) (24). More recently, Kongkathip et al. reported the isolation of O-methylmukonal (38) from the rhizomes and the roots of another natural source, C. excavata (58). Moreover, they reported for the first time that 38 showed anti-HIV-1 activity. The UV and IR spectral data of O-methylmukonal (38) indicated the presence of a 3-formylcarbazole skeleton. The 1H-NMR spectrum showed signals at d 8.88, 10.49, and 3.99 for the NH, CHO, and aromatic methoxy groups, respectively. In addition, four aromatic protons at d 7.40 (d, J=8.0 Hz), 7.38 (t, J=8.0 Hz), 7.25 (t, J=8.0 Hz), and 8.00 (d, J=8.0 Hz) for H-8, H-7, H-6, and H-5, respectively, confirmed that the C-ring was unsubstituted. The deshielded singlet at d 8.56 was assigned to H-4 and the singlet at d 6.88 was assigned to H-1. On the basis of this spectroscopic evidence, structure 38 was proposed for O-methylmukonal (glycosinine) (57). This assignment was additionally supported by the 13C-NMR data and by oxidation of 2-methoxy-3methylcarbazole (37) with DDQ to O-methylmukonal (38) (24). In 1993, Wu et al. reported the isolation of clausine L (O-methylmukonidine) (39) from the leaves of C. excavata (59). One year later, Bhattacharyya et al. isolated the same alkaloid from the stem bark of a different natural source, M. koenigii, and named it methyl 2-methoxycarbazole-3-carboxylate (39) (45). The UV spectrum (lmax 235, 242, 269, 281, 319, and 333 nm) showed the presence of a 2-oxygenated-3carbonylcarbazole nucleus. The IR spectrum indicated an NH group (3350 cm1), a COOMe group (1700 cm1), and an aromatic system (1635, 1605 cm1). In the 1HNMR spectrum, four mutually coupled aromatic protons at d 8.07, 7.48, 7.34, and 7.19 showed that the C-ring was lacking substituents. The presence of a deshielded singlet at d 8.52, which was assigned to a proton at C-4 ortho to the carbomethoxy group, in addition to a further sharp singlet at d 7.14 for H-1, established the position

18

Chemistry and Biology of Carbazole Alkaloids

R2

R

R1

Me

OMe

OMe

N H

N H 37 2-Methoxy-3-methylcarbazole

37 2-Methoxy-3-methylcarbazole R = Me

R1,R2 = H 40 Glycozolidine

38 O-Methylmukonal (Glycosinine) R = CHO 39 Clausine L (O-Methylmukonidine, Methyl 2-methoxycarbazole-3-carboxylate) R = COOMe

R1 = H; R2 = OMe 41 Glycozolidol R1 = H; R2 = OH 42 Glybomine A R1 = OMe; R2 = H

Scheme 2.9

of the aromatic methoxy group at C-2. On the basis of these spectroscopic data, structure 39 was assigned to clausine L. Moreover, this assignment was supported by the 13C-NMR spectrum and NOE experiments (Scheme 2.9). In 1966, Chakraborty et al. reported the isolation of glycozolidine (40) from the root bark of G. pentaphylla (60,61). In 1999, glycozolidine (40) was also isolated by Chakravarty et al. from the roots of a different Glycosmis species, Glycosmis arborea (62). The IR spectrum of 40 exhibited bands at nmax 3450 (NH), 1625 (aromatic system), 1208 (aromatic methyl ether), 813 cm1 (substituted aromatic ring). The IR data, in agreement with the UV spectrum (lmax 233, 237, 260, and 309 nm), indicated the presence of a carbazole ring system. The 1H-NMR spectrum showed signals of an aromatic methyl group (d 2.35), two aromatic methoxy groups (d 3.77 and 3.90) and two, non-ortho-coupled protons, H-4 and H-5, at d 7.17 and 7.45, respectively. In addition, two aromatic protons at d 6.97 and 7.02, along with a shielded aromatic proton at d 6.52, were shown. The 1H-NMR signals and their coupling pattern suggested that glycozolidine has substituents at C-2, C-3, and C-6. The spectroscopic assignment was additionally supported by the following chemical transformations of glycozolidine: first, zinc dust distillation to 3-methylcarbazole; second, heating with solid potassium hydroxide at 270–3001C to afford 2,6-dihydroxy-3-methylcarbazole; and third, chemoselective demethylation with hydrogen bromide (48%) to 6-hydroxy-2-methoxy-3-methylcarbazole. Raney-nickel reduction of 6-hydroxy-2methoxy-3-methylcarbazole via the corresponding tosylate afforded 2-methoxy-3methylcarbazole. Based on these degradation studies and the spectral data, structure 40 was assigned to glycozolidine (61,62). This structural assignment was confirmed by total synthesis of the natural product (63,64). Two decades later, Bhattacharyya et al. reported the isolation of glycozolidol (41) from the roots of G. pentaphylla (65). This alkaloid attracted interest due to its antibacterial activity against Gram-positive and Gram-negative bacteria. The UV spectrum (lmax 232, 260, and 305 nm) showed the presence of a carbazole nucleus. The IR spectrum exhibited bands at 3500 (OH), 3440 (NH), 1625, 1600 (aromatic system), 1380 (C-methyl), 1208 (aromatic ether), and 850 cm1 (substituted aromatic system). In the 1H-NMR spectrum, singlets for an aromatic methyl group (d 2.38), an

Occurrence, Isolation, and Structure Elucidation

19

aromatic methoxy group (d 3.7), and H-1 and H-4 at d 6.92 and 7.45 were visible and indicated substituents at C-2 and C-3. The signal for H-5 appeared as a meta-coupled doublet at d 7.2 (J=2.0 Hz), H-7 as an ortho- and meta-coupled doublet of doublets at d 6.75 (J=8.0, 2.0 Hz), and H-8 as an ortho-coupled doublet at d 7.08 (J=8.0 Hz). Thus, a 6-substitution of the carbazole was suggested. In addition to these peaks, two broad singlets at d 10.8 and 8.0, both exchangeable with D2O, confirmed the presence of hydroxy and NH protons. The resonance of the hydroxy proton of glycozolidol was similar to that of 6-hydroxy-3-methylcarbazole (66,67), a fact which supports a 6-hydroxycarbazole. On the basis of these spectroscopic data, structure 41 was assigned to glycozolidol. Additional support for this assignment was derived from the methylation of glycozolidol (41) with diazomethane to glycozolidine (40) (60–62). In 2004, Itoigawa and Furukawa et al. reported the isolation of glybomine A (42) from the stem of G. arborea collected at Mymensing in Dhaka, Bangladesh (68). Glybomine A was the first example of a 2,5-dioxygenated carbazole alkaloid from a natural source and showed antitumor-promoting activity against (12-O-tetradecanoylphorbol-13-acetate) TPA-induced EBV-EA activation. The UV spectrum (lmax 239, 294, 330, and 316 nm) and the IR absorption at nmax 3475 cm1 for a NH, confirmed the carbazole framework. The 1H-NMR spectrum exhibited signals for an aromatic methyl group (d 2.29), two aromatic methoxy groups (d 3.87, 4.03), and an NH group (d 10.09). Moreover, in the aromatic region, two singlets at d 6.99 and 7.94 and three signals for contiguous protons at d 6.65, 7.02, and 7.18 were observed. The spectroscopic data, supported by NOE experiments, suggested the two methoxy groups to be at positions 2 and 5, and the methyl group at position 3 on the carbazole system. Therefore, structure 42 was assigned to glybomine A (Scheme 2.9). Furukawa et al. isolated isomurrayafoline B (43) (69) and murrayaline A (44) (38,70) from the root bark of M. euchrestifolia collected in Taiwan. The UV spectrum [lmax 213, 237, 264, 310, and 330 (sh) nm] of isomurrayafoline B (43) was characteristic of a carbazole nucleus. The 1H-NMR spectrum showed the presence of an aromatic methyl group (d 2.38), an aromatic methoxy group (d 3.90), a prenyl side chain (d 1.74, 1.88, 3.60, and 5.30), and two broad singlets at d 4.74 and 7.70, exchangeable with D2O, for OH and NH. In the aromatic region, two broad singlets arising from H-1 (d 6.82) and H-4 (d 7.67), and ortho-coupled proton signals (J=8.0 Hz) for H-5 (d 7.70) and H-6 (d 6.82) suggested C-2, C-3, C-7, and C-8 as the positions of the substituents. In NOE experiments, irradiation at the signal for the methyl group resulted in an enhancement of the signal for H-4, irradiation at the methoxy group led to an enhancement of H-6, and irradiation at the signal for the benzylic methylene protons of the prenyl moiety led to no signal enhancement. Thus, structure 43 was assigned to isomurrayafoline B (69). The UV spectrum [lmax 226, 260 (sh), 304, and 383 nm] and the IR spectrum (nmax 1580, 1590, 1600, 1630, 1650, and 3370 cm1) of murrayaline A (44) indicated a carbazole derivative with a formyl group (1650 cm1). The 1H-NMR spectrum confirmed this assignment from the signals for one aromatic methyl (d 2.35) and two aromatic methoxy groups (d 3.90, 3.98), as well as the signals of four aromatic protons at d 6.91 (s), 7.95 (s), 6.77 (d, J=9.0 Hz), and 8.02 (d, J=9.0 Hz). In NOE experiments, irradiation at the signal for the aromatic methyl group led to an enhancement of the signal for H-4 and irradiation at the signals for the methoxy groups resulted in an enhancement of the signals for H-1 and H-6. These NOEs indicated the positions 2 and 7 for the two methoxy groups and position 3 for the

20

Chemistry and Biology of Carbazole Alkaloids

methyl group. Therefore, murrayaline A was formulated as 2,7-dimethoxy-8-formyl3-methylcarbazole (44). This structural assignment was confirmed by synthesis (38). Reisch et al. isolated murrayanol (45) from the fruits of M. koenigii (71). The UV spectrum [lmax 208, 236, 262, 296 (sh), 316 (sh), and 328 (sh) nm] and the IR spectrum (nmax 1470, 1540, 1610, 1650, 2960, 3440, and 3560 cm1) suggested a phenolic carbazole derivative. The 1H-NMR spectrum showed characteristic signals of a geranyl side chain, signals for the OH and NH protons at d 4.76 and 7.73 (exchangeable with D2O), a methyl group at C-3 (d 2.38), and a methoxy group at C-7 (d 3.91). The presence of a geranyl group was additionally confirmed by the mass fragmentation ion at m/z 240 (M+CHQCMeCH2CH2CHQCMe2). On cyclization, murrayanol provided 9-methoxymahanimbicine (for mahanimbicine (147), see Scheme 2.28). This transformation demonstrated the similarity of their substitution pattern. Based on the spectroscopic and chemical evidence, structure 45 was assigned to murrayanol (Scheme 2.10). Clausine P (46) was isolated from the acetone extract of the root bark of C. excavata (43). The UV spectrum [lmax 212, 236, 251 (sh), 261 (sh), 290 (sh), 317, and 330 nm] and the IR spectrum (nmax 1635 and 3400 cm1) were characteristic of a carbazole derivative. The 1H-NMR spectrum exhibited a signal for a methyl group (d 2.29) at C-3 and two methoxy groups (d 3.89, 3.96) at C-2 and C-8. In the aromatic region, three, mutually ortho-coupled (J=7.8 Hz) protons at d 6.85, 7.03, and 7.54 were assigned to H-7, H-6, and H-5, respectively. Two singlets at d 7.06 and 7.76 were assigned to H-1 and H-4. These assignments for the 1H-NMR signals were additionally supported by NOEs between 3-Me (d 2.29) and H-4 (d 7.76), 2-OMe (d 3.89) and H-1 (d 7.06), and 8-OMe (d 3.96) and H-7 (d 6.85). The spectroscopic data confirmed that 46 is the structure of clausine P. Bhattacharyya and Chowdhury reported the isolation of glycozolidal (47) from the roots of G. pentaphylla (72). The UV and the IR data of glycozolidal were characteristic of a 3-formylcarbazole. The 1H-NMR spectrum showed signals for a formyl group (d 9.9), two aromatic methoxy groups (d 3.7 and 3.9), a proton at C-4 (d 8.4, deshielded due to the formyl group at C-3), and a meta-coupled (J=2.0 Hz)

R1

Me R1

R2

OMe R2

N H

43 Isomurrayafoline B

R1 = OH; R2 = geranyl

R1,R2,R3 = H 47 Glycozolidal R1 = OMe, R2, R3 = H 48 7-Methoxy-O-methylmukonal (3-Formyl-2,7-dimethoxycarbazole) R1,R3 = H; R2 = OMe

46 Clausine P R1 = H; R2 = OMe

N H

38 O-Methylmukonal (Glycosinine)

R1 = OMe; R2 = CHO 45 Murrayanol

OMe R3

R1 = OMe; R2 = prenyl 44 Murrayaline A

CHO

49 Atanisatin R1,R2 = H; R3 = prenyl

Scheme 2.10

Occurrence, Isolation, and Structure Elucidation

21

proton at C-5 (d 7.6), indicating a substitution at C-6. The proton at C-4 showed neither an ortho- nor a meta-coupling, which indicated the presence of a substituent at C-2. Following all these spectral observations, structure 47 was formulated for glycozolidal. This assignment was confirmed by synthesis of glycozolidal (47) from glycozolidine (40) (see Scheme 2.9) using DDQ oxidation (72). Lange et al. isolated 7-methoxy-O-methylmukonal (3) (3-formyl-2,7-dimethoxycarbazole) (48) from the roots of M. siamensis (57). More recently, Kongkathip et al. described the isolation of the same natural product from the rhizomes and roots of C. excavata (58). This group also reported for the first time the anti-HIV-1 activity of 7-methoxy-O-methylmukonal (48). The UV and IR data indicated a 3-formylcarbazole derivative. The 1H-NMR spectral data were similar to those of O-methylmukonal (38) (see Scheme 2.9), except for the presence of an additional methoxy group at d 3.90. The signals for H-5 at d 7.87 with an ortho-coupling (J=8.3 Hz), and for H-6 at d 6.88 with an ortho- and a meta-coupling (J=8.3, 2.2 Hz), suggested C-7 as the position of this methoxy group. Based on the spectroscopic evidence and additional support by the 13C-NMR data, structure 48 was assigned to 7-methoxy-O-methylmukonal. Okorie reported the isolation of atanisatin (49) from the stem of C. anisata (73) (Scheme 2.10). In 1996, Wu et al. isolated clausine H (50) and clausine K (51) from the stem bark of C. excavata (46). These alkaloids showed an inhibition of rabbit platelet aggregation and caused vasocontraction. Later, Ito et al. isolated clausine H and clausine K from the same natural source and named them clauszoline C (50) (74) and clauszoline-J (51) (47). More recently, Kongkathip et al. isolated clauszoline-J (51) from the rhizomes and roots of the same natural source, C. excavata, and described its anti-HIV-1 activity (58). The UV and IR data of clausine H (clauszoline-C) (50) indicated the presence of a carbazole nucleus. The 1H-NMR spectrum showed signals of three methoxy groups at d 3.82, 3.86, and 3.89. In the aromatic region, a deshielded singlet for H-4 at d 8.40 indicated the presence of a carbomethoxy group at C-3 and a methoxy group at C-2. The H-5 at d 7.94 with an ortho-coupling (J=7.7 Hz), H-6 at d 6.82 with an ortho- and a meta-coupling (J=7.7, 2.4 Hz) and H-8 at d 7.02 with a meta-coupling (J=2.4 Hz) indicated the presence of a methoxy group at C-7. The singlet at d 7.10 for H-1 led to the proposed structure with a second methoxy group at C-2. Moreover, a characteristic IR band at nmax 1710 cm1, two significant mass fragments at m/z 254 (M+OMe) and 223 (M+COOMeH), and the 13C-NMR signals at d 167.41 and 51.62 suggested the presence of a carbomethoxy substituent at the carbazole framework. Based on the spectroscopic data and additional support from NOE experiments, structure 50 was assigned to clausine H (clauszoline-C) (Scheme 2.11). The UV, IR, and 1H-NMR spectra of clausine K (clauszoline-J) (51) were almost identical to those of clausine H (clauszoline-C) (50). The most significant difference between their spectra was the presence of IR bands at nmax 3315 (br) and 1666 cm1 and the absence of one methoxy group resonance in the 1H-NMR spectrum, which indicated the presence of a carboxy group instead of a carbomethoxy group at C-3 of the carbazole framework. This conclusion was supported by two characteristic mass fragments at m/z 254 (M+OH) and 226 (M+COOH). The spectroscopic evidence combined with NOE experiments led to structure 51 for clausine K (clauszoline-J). This assignment was confirmed by methylation of 51 with diazomethane to afford clausine H (50) (46) (Scheme 2.11).

22

Chemistry and Biology of Carbazole Alkaloids

COOR1 R2

R

OMe

OH

N H

N H

39 Clausine L (O-Methylmukonidine, Methyl 2-methoxycarbazole-3-carboxylate) R1 = Me; R2 = H 50 Clausine H (Clauszoline-C) R1 = Me; R2 = OMe 51 Clausine K (Clauszoline-J)

52 2-Hydroxy-3-methylcarbazole R = Me 53 Mukonal R = CHO 54 Mukonidine R = COOMe

R1 = H; R2 = OMe

Scheme 2.11

In the mid-1980s, Bhattacharyya and Chakraborty isolated 2-hydroxy-3-methylcarbazole (52) (75) and mukonal (53) (76) from the roots and stem bark of M. koenigii. The UV and IR spectra of 2-hydroxy-3-methylcarbazole (52) confirmed the presence of an aromatic carbazole system. The 1H-NMR spectrum showed an aromatic methyl group at d 2.33 and two proton signals at d 8.1 and 8.2 for OH and NH, respectively, both of which were exchangeable with D2O. In the aromatic region of the 1H-NMR spectrum, a complex 4-proton-multiplet at d 7.18.0 indicated a non-substituted C-ring of the carbazole nucleus. The shielded singlet at d 7.0 and the deshielded singlet at d 7.68, assigned to H-1 and H-4, respectively, indicated the presence of a methyl group at C-3 and a hydroxy group at C-2. On zinc dust distillation, 2-hydroxy-3-methylcarbazole afforded 3-methylcarbazole, indicating the presence of a methyl group at C-3. Based on the spectroscopic data and chemical transformations, structure 52 was assigned as 2-hydroxy-3-methylcarbazole (75). Further confirmation for this structural assignment was derived from direct comparison with an authentic sample of synthetic material (56). The UV spectrum (lmax 234, 247, 278, 297, 316, and 342 nm) and the IR spectrum [nmax 1590, 1610 (aromatic system), 1640 (chelated aldehyde), and 3380 (OH, NH) cm1] of mukonal (53) are characteristic of a 3-formylcarbazole derivative. This conclusion was supported by the 1H-NMR spectrum which showed a singlet for an aldehyde proton at d 10.16 and two signals at d 11.0 and 11.76 for NH and OH, both exchangeable with D2O. In the aromatic region, a complex, four-proton-multiplet at d 7.38.0 suggested that ring C of the carbazole nucleus is unsubstituted. The deshielded singlet at d 8.4 was assigned to H-4, which is ortho to the aldehyde group. The position of the hydroxy group was assigned at C-2, because of its chelation to the formyl group, and based on the fact that H-4 exhibited no meta-coupling. The shielded singlet of H-1 at d 7.0 supported this assignment. On decarbonylation with Pd/C, mukonal provided 2-hydroxycarbazole, confirming the position of the hydroxy group at C-2. Based on the spectroscopic and chemical support, structure 53 was assigned to mukonal (76). A direct comparison with an authentic sample of synthetic material confirmed this assignment (77). In 1978, Chakraborty et al. reported the isolation of mukonidine (54) from the stem bark of M. koenigii (78). In their investigation of the root bark of C. excavata in

Occurrence, Isolation, and Structure Elucidation

23

1993, Wu et al. isolated mukonidine (54) along with its O-methyl derivative, clausine L (39) (see Scheme 2.9) (59). However, the spectroscopic and physical data of Chakraborty’s O-methylmukonidine were not identical with those of clausine L (59,78). Based on the agreement of the data of synthetic mukonidine with those of Wu’s mukonidine (59), it was concluded that Chakraborty’s mukonidine (78) may have a different structure (79–81). The UV, IR, and 1H-NMR spectra of mukonidine (54) were very similar to those of clausine L (39) (see Scheme 2.9), except for the presence of a signal for an aromatic hydroxy group at d 11.07 instead of an aromatic methoxy group. Based on the spectroscopic evidence Wu et al. assigned structure 54 to mukonidine (59). Four years later, this structural assignment was strongly supported by comparison with the spectroscopic data of synthetic mukonidine (80,81) (Scheme 2.11). In 1993, Furukawa et al. isolated mukoenine-A (55) from the root and stem bark of M. koenigii (82). One year later, Reisch et al. reported the isolation of the same natural product from the same natural source and named it girinimbilol (83). The UV spectrum [lmax 217, 238, 260 (sh), 288, 300, 321 (sh), 333, and 356 nm] of mukoenine-A (55) exhibited the typical absorption of a 2-oxygenated carbazole derivative. The 1 H-NMR spectrum showed the signal for an aromatic methyl group at d 2.40, a broad singlet at d 7.84 for the NH group, and a further singlet at d 5.18 for the OH group. The presence of a prenyl group was indicated by the signals at d 1.79 and 1.91 (each singlets for three protons), 3.62 (2H, d, J=7.1 Hz), and 5.37 (1H, t, J=7.1 Hz). Further support for the prenyl group was derived from the characteristic mass fragmentation ion at m/z 209 (M+CHQCMe2H). In the aromatic region of the 1 H-NMR spectrum, a four-proton signal including a low-field H-5 at d 7.93 (1H, d, J=7.7 Hz), suggested an unsubstituted carbazole C-ring. The high-field singlet at d 7.68 was assigned to H-4. NOE experiments were used to identify the positions of the methyl, hydroxy, and prenyl groups at C-3, C-2, and C-1, respectively. Based on this spectroscopic evidence, structure 55 was assigned to mukoenine-A (Scheme 2.12). R2

Me

R1

Me

OH N H

OH R3

R

52 2-Hydroxy-3-methylcarbazole R=H

N H

57 Carbalexin A R1 = OMe; R2,R3 = H 58 Carbalexin B

55 Mukoenine-A (Girinimbilol) R = prenyl

R1,R2 = H; R3 = OMe

56 Mahanimbinol (Mahanimbilol)

59 Carbalexin C R1,R3 = H; R2 = OMe

R = geranyl

60 Glybomine B R1 = prenyl; R2 = OMe; R3 = H 61 Glybomine C R1 = prenyl; R2 = OH; R3 = H

Scheme 2.12

24

Chemistry and Biology of Carbazole Alkaloids

In 1980, Rama Rao et al. isolated mahanimbinol (56) from the stem wood of M. koenigii (84). Fourteen years later, Reisch et al. reported the isolation of the same natural product from the same natural source and named it mahanimbilol (83). In 2001, Boyd et al. also reported the isolation of mahanimbilol from the organic extract of M. siamensis (85). The UV, IR, and 1H-NMR spectra of mahanimbinol (56) are very similar to those of mukoenine-A (55), with the exception of differences in the signals resulting from the side chain at C-1. The 1H-NMR spectrum showed three signals for methyl groups at d 1.58, 1.65, and 1.86, a 4-proton-multiplet at d 2.032.14, a doublet for the benzylic methylene group at d 3.56, and two multiplets for vinyl protons at d 5.04 and 5.34. These data indicate that 56 has a geranyl group at C-1 instead of the prenyl group of 55. Further support for this conclusion was derived from the mass fragmentation ion at m/z 210 (M+CHQCMeCH2CH2CHQCMe2). The structural similarity of mahanimbinol (56) and mukoenine-A (55) was additionally confirmed by the 13 C-NMR chemical shifts. Based on the spectroscopic data, mahanimbinol was structurally assigned as 56 (Scheme 2.12). In 2001, Greger et al. isolated the stress-induced carbazole phytoalexins carbalexin A (57), B (58), and C (59) from the leaves of Glycosmis parviflora. These carbazole alkaloids showed strong antifungal activity in bioautographic tests on TLC plates with Cladosporium herbarum (86). The UV spectrum (lmax 239, 293, 317, and 330 nm) of carbalexin A (57) showed the typical absorptions of a 2-hydroxy-3-methylcarbazole framework. The 1H-NMR spectrum exhibited signals of an aromatic methyl group at d 2.41, an aromatic methoxy group at d 4.07, and an NH group at d 7.89. Moreover, the aromatic region showed a shielded singlet at d 6.82 for H-1, a deshielded singlet at d 8.02 for H-4, and three contiguous, mutually ortho-coupled (J=8.0 Hz) protons at d 6.65, 7.25, and 6.98 for H-6, H-7, and H-8, respectively. Based on these spectroscopic data, the following positions were assigned to the substituents: C-2 for the hydroxy group, C-3 for the methyl group, and C-5 for the methoxy group. Therefore, structure 57 was assigned to carbalexin A (Scheme 2.12). The UV and the IR spectrum of carbalexin B (58) were very similar to those of carbalexin A, indicating the presence of a 2-hydroxy-3-methylcarbazole skeleton also for carbalexin B. The 1H-NMR spectrum showed the presence of singlets for an aromatic methyl group at d 2.40 and an aromatic methoxy group at d 4.00, and a broad singlet for an NH group at d 8.04. In the aromatic region, the two singlets for H-1 at d 6.87 and H-4 at d 7.76 suggested a similar substitution pattern at the A-ring of the carbazole framework of 58 as found for carbalexin A (57). The three, mutually orthocoupled (J=8.0 Hz) protons at d 6.83, 7.11, and 7.55 were assigned to H-7, H-6, and H-5, respectively, and indicated that the position of the methoxy group was at C-8. Based on this spectroscopic support, structure 58 was assigned to carbalexin B (Scheme 2.12). The UV spectrum [lmax 231, 263 (sh), and 310 nm] of carbalexin C (59) indicated a 2-hydroxy-3-methylcarbazole. The 1H-NMR spectrum showed signals for an aromatic methyl group (d 2.40), an aromatic methoxy group (d 3.91), a shielded singlet for H-1 (d 6.52), and two, non-ortho-coupled proton signals for H-4 and H-5 (d 7.74 and 7.44). The ortho-coupling (J=8.6 Hz) of the aromatic protons H-7 at d 6.96 and H-8 at d 7.25, and the meta-coupling (J=2.5 Hz) between H-5 at d 7.44 and H-7 at d 6.96, indicated that the methoxy group is located at C-6. Based on these spectral data, structure 59 was assigned to carbalexin C (Scheme 2.12).

Occurrence, Isolation, and Structure Elucidation

25

In 2004, Furukawa and co-workers reported the isolation of glybomine B (60) and glybomine C (61), along with glybomine A (42) (see Scheme 2.9), from the stem of G. arborea (68). This group of carbazole alkaloids showed antitumor-promoting activity against (12-O-tetradecanoylphorbol-13-acetate) TPA-induced EBV-EA activation. The UV spectrum [lmax 217, 263 (sh), 307, 336 (sh), and 339 nm] of glybomine B (60) indicated a 2,6-dioxygenated-3-methylcarbazole derivative. The 1H-NMR spectrum exhibited signals for an aromatic methyl group (d 2.39), an aromatic methoxy group (d 3.87), a prenyl side chain (d 1.70, 1.93, 3.92, 5.32), and two broad singlets, which were exchangeable with D2O, for the OH and the NH group (d 4.85 and 7.68). In the aromatic region, H-1 and H-4 appeared as singlets at d 6.77 and 7.82, indicating the presence of substituents at C-2 and C-3. The two doublets for H-7 and H-8 at d 6.99 and 7.13 with an ortho-coupling (J=8.4 Hz) demonstrated that two further substituents were present at C-5 and C-6. The individual positions of the hydroxy group at C-2, the methyl group at C-3, the prenyl group at C-5, and the methoxy group at C-6 were confirmed by NOE experiments. These spectroscopic data, supported by the results of HMBC correlations, led to the assignment of structure 60 for glybomine B. The UV and the IR spectrum of glybomine C (61) were similar to those of glybomine B (60). In the 1H-NMR spectrum of glybomine C (61), the chemical shifts of the signals and their coupling pattern were to a large extent in agreement with that of glybomine B (60), except for the signal of the methoxy group of glybomine B (d 3.87) which was not present. Based on the spectroscopic data and supported by the results of NOE experiments and HMBC correlations, structure 61 was assigned for glybomine C (Scheme 2.12). In 1991, Furukawa et al. described the isolation and structural elucidation of euchrestine-C (62) (87) and of racemic euchrestine-E (63) (70) from the stem bark of M. euchrestifolia. The UV spectrum (lmax 212, 237, 266, 306, 320, and 329 nm) of euchrestine-C (62) showed the typical absorptions for a 2,7-dioxygenated carbazole skeleton. Further support for this assignment of the framework derived from its IR spectrum (nmax 3380, 3470, and 3600 cm1). The 1H-NMR spectrum exhibited the signals characteristic of a geranyl side chain and of an aromatic methyl group (d 2.38). The geranyl group was additionally confirmed by the presence of the characteristic mass fragmentation ion at m/z 226 (M+CHQCMeCH2 CH2CHQCMe2). In the aromatic region, H-1 and H-4 appeared as singlets at d 6.81 and 7.65, respectively, suggesting substitution at C-2 and C-3. The two doublets for H-6 and H-5 at d 6.70 and 7.63 with an ortho-coupling (J=8.4 Hz) indicated further substituents at C-7 and C-8. Based on this spectroscopic evidence, structure 62 was assigned to euchrestine-C (Scheme 2.13).

Me HO

OH N H

Me HO O

62 Euchrestine-C

OH N H

63 Euchrestine-E

Scheme 2.13

26

Chemistry and Biology of Carbazole Alkaloids

The UV and IR spectra of euchrestine-E (63) were similar to those of euchrestineC (62). The pattern of signals in the 1H-NMR spectrum resembled that of euchrestine-C, except for the signals of some protons of the side chain. The characteristic 1H-NMR data and the mass fragment ion at m/z 226 (resulting from the cleavage of a benzylic bond in the molecular ion) indicated the presence of a geranyl side chain with an oxirane ring. Based on the spectroscopic data and additional support by two-dimensional 1H1H correlation spectroscopy (1H1H COSY), structure 63 was assigned to euchrestine-E (Scheme 2.13). In 1991, Furukawa et al. reported the isolation of murrayaline-B (64) (70), euchrestine-A (65), euchrestine-B (66), and euchrestine-D (67) (87) from the stem bark of M. euchrestifolia. Ten years later, Nakatani et al. reported the isolation of euchrestine-B (66) from the leaves of a different natural source, M. koenigii. Euchrestine-B showed radical scavenging activity against 1,1-diphenyl-2-picrylhydrazyl (DPPH) (88). The UV spectrum [lmax 223, 259 (sh), 303, and 380 nm] and the IR spectrum (nmax 1600, 1635, 1660, 3380, and 3400 cm1) of murrayaline-B (64) were similar to those of murrayaline-A (44) (see Scheme 2.10). The 1H-NMR spectrum showed the presence of an aromatic methyl group (d 2.34) and an aromatic methoxy group (d 4.02). In the aromatic region, H-1 and H-4 appeared as singlets at d 7.20 and 7.73 indicating a substitution at C-2 and C-3. The two doublets for H-6 and H-5, respectively, at d 6.89 and 8.16 with an ortho-coupling (J=8.7 Hz), indicated the presence of two further substituents at C-7 and C-8. The sharp singlet at d 10.58, characteristic of an aldehyde group, suggested that murrayaline-B represents a formylcarbazole. Two deuterium-exchangeable broad singlets at d 8.42 and 10.79 indicated the presence of an OH and NH group. These spectroscopic data supported by NOE experiments led to structure 64 for murrayaline-B. The transformation of murrayaline-B (64) into murrayaline-A (44) by O-methylation with methyl iodide confirmed this structural assignment (70). The UV spectrum (lmax 213, 236, 265, 295, 313, 318, and 329 nm) of euchrestine-A (65) was very similar to that of euchrestine-C (62) (see Scheme 2.13). The fact that the structures were closely related was additionally supported by the IR data (nmax 3400, 3470, and 3600 cm1). Also, the coupling pattern in the 1H-NMR spectrum of euchrestine-A was similar to that of euchrestine-C, except for the presence of a prenyl side chain (d 1.78, 1.89, 3.59, and 5.36) at C-8 instead of the geranyl group. The presence of a prenyl group was confirmed by a mass fragmentation ion at m/z 225 (M+CHQCMe2H). Based on the spectroscopic data, structure 65 was assigned to euchrestine-A (87). The UV spectrum (lmax 212, 238, 264, 310, 318, and 331 nm) and the IR spectrum (nmax 3380, 3470, and 3600 cm1) of euchrestine-B (66) were very similar to those of euchrestine-C (62) (see Scheme 2.13). The 1H-NMR spectrum of euchrestine-B showed strong agreement with that of euchrestine-C, including the presence of a geranyl side chain at C-8. However, the 3-proton-singlet at d 3.90 indicated the presence of a methoxy group instead of the hydroxy group at C-7. This regiochemical assignment was supported by NOE experiments. The spectroscopic data led to structure 66 for euchrestine-B (87). The UV spectrum [lmax 212, 238, 265, 312, and 321 (sh) nm] and the IR spectrum (nmax 3600, 3470, and 3380 cm1) of euchrestine-D (67) showed the characteristic absorptions of a 2,6-dioxygenated carbazole framework. The 1H-NMR spectrum

Occurrence, Isolation, and Structure Elucidation

R1

Me R2O 3

R

CHO

R2

OH N H

27

OH N H

1

R

64 Murrayaline-B

53 Mukonal

R1 = H; R2=Me; R3 = CHO

R1,R2 = H

65 Euchrestine-A R1,R2 = H; R3 = prenyl 66 Euchrestine-B R1 = H; R2 = Me; R3 = geranyl 67 Euchrestine-D

68 7-Methoxymukonal (3-Formyl-2-hydroxy7-methoxycarbazole) R1 = H; R2 = OMe 69 Lansine R1 = OMe; R2 = H

R1 = geranyl; R2,R3 = H

70 Clausanitin R1 = H; R2 = prenyl

Scheme 2.14

exhibited signals of an aromatic methyl group (d 2.38) and a geranyl side chain. The presence of a geranyl side chain was additionally supported by a mass fragmentation ion at m/z 226 (M+CHQCMeCH2CH2CHQCMe2). In the aromatic region of the 1H-NMR spectrum, H-4 appeared as a singlet at d 7.56 indicating the presence of substituents at C-1, C-2, and C-3. The ortho-coupling (J=8.4 Hz) of H-5 at d 7.74 and the ortho- and meta-coupling (J=8.4, 2.4 Hz) of H-6 at d 6.68 suggested a substitution at C-7. This conclusion was in agreement with the presence of a metacoupled (J=2.4 Hz) H-8 at d 6.82. Treatment of euchrestine-D with diazomethane gave the corresponding dimethyl ether. NOE experiments with this dimethyl ether unequivocally confirmed structure 67 for euchrestine-D (Scheme 2.14) (87). In 1988, Pummangura et al. reported the isolation of 7-methoxymukonal (3) (3-formyl-2-hydroxy-7-methoxycarbazole) (68) from the root bark of Clausena harmandiana (89). The UV spectrum [lmax 224, 240, 290 (sh), 300, and 338 nm] and the IR spectrum (nmax 1640 and 3280 cm1) of 7-methoxymukonal indicated the presence of a 3-formylcarbazole with a chelated hydroxy group. The 1H-NMR spectrum showed a close similarity with that of 7-methoxy-O-methylmukonal (48) (see Scheme 2.10), except for the signal of one methoxy group which was replaced by the signal of a hydroxy group (d 11.40) and was chelated to the formyl group (d 10.11) at C-3. Based on the spectroscopic data and additional support by the 13C-NMR spectrum, structure 68 was assigned to 7-methoxymukonal (3) (3-formyl-2-hydroxy7-methoxycarbazole) (89). In 1980, Kapil et al. reported the isolation of lansine (69) from the ethanolic extract of the leaves of C. lansium (90). The UV spectrum (lmax 233, 248, 309, 340 and 368 nm) was characteristic of a 3-formylcarbazole. The IR spectrum (nmax 1620, 1645, and 3300 cm1) confirmed the presence of an NH group and a chelated carbonyl function. The 1H-NMR spectrum demonstrated a strong agreement with that of glycozolidal (47) (see Scheme 2.10), except for the signal of one methoxy group which was replaced by the signal of a hydroxy group and was chelated to the formyl group (d 9.91) at C-3. The spectroscopic data led to structure 69 for lansine. This

28

Chemistry and Biology of Carbazole Alkaloids

structural assignment was additionally supported by O-methylation of lansine with methyl iodide to O-methyllansine, which was identical in all spectral data with 2,6-dimethoxy-3-formylcarbazole (27) (glycozolidal) (72). In 1975, Okorie reported the isolation of clausanitin (70) from the roots of C. anisata (73). The UV spectrum [lmax 239, 249 (sh), 278, 288 (sh), 297, and 340 nm] and the IR spectrum (nmax 1610, 1635, 3300, and 3400 cm1) of clausanitin were characteristic of a 3-formylcarbazole derivative. The 1H-NMR spectrum showed the presence of sharp singlets for a formyl proton (d 9.87) and a deuterium-exchangeable hydroxy proton (d 11.75) along with the signals of a prenyl side chain (d 1.72, 1.85, 3.62, 5.33). In the aromatic region, two singlets, assigned to H-1 (d 7.34) and H-4 (d 8.00), appeared at shielded and deshielded positions, and indicated the presence of a formyl group at C-3 and of a hydroxy group at C-2. Moreover, the ortho-coupling (J=7.0 Hz) of the signal for H-5 at d 7.90, the ortho- and meta-coupling (J=7.0, 2.0 Hz) of the signal for H-6 at d 7.31, and the presence of an additional aromatic signal for H-8 at d 7.37 suggested that the prenyl side chain was located at C-7. Based on these spectroscopic data, structure 70 was assigned to clausanitin (Scheme 2.14). In 1996, Wu et al. reported the isolation of clausine A (71) from the methanol extract of the stem bark of C. excavata (51). The UV spectrum (lmax 202, 218, 241, 268 (sh), 275, 288, and 352 nm) and the IR spectrum [nmax 1625 (aromatic system), 1650 (chelated aldehyde), and 3400 (OH or NH) cm1] of clausine A were very similar to those of mukonal (53) (see Scheme 2.11), which indicated a 3-formyl-2-hydroxycarbazole framework. This assignment was supported by the 1H-NMR spectrum which showed a singlet for an aldehyde proton at d 9.99 and two D2O-exchangeable proton signals at d 10.85 and 11.42 for the NH and OH group, respectively. The presence of a 3-formyl and a 2-hydroxy group was also evident by the upfield shift of H-1 (d 6.94) and the downfield shift of H-4 (d 8.44). In addition to these two singlets, the aromatic region exhibited the signals of three mutually ortho-coupled (J=8.0 Hz) protons at d 6.99, 7.17, and 7.68, assigned to H-7, H-6, and H-5 at the C-ring of the carbazole nucleus. Thus, the position of the methoxy group (3-proton-singlet at d 3.99) was concluded to be at C-8. On the basis of the spectroscopic evidence, structure 71 was assigned to clausine A (Scheme 2.15). Three years later, Wu et al. reported the isolation of clausine O (72) from the acetone extract of the root bark of C. excavata (43). The UV spectrum [lmax 223, 240, 252 (sh), 291 (sh), 301, 321 (sh), and 340 nm] and the IR spectrum (nmax 1620, 3330 and 3375 cm1) of clausine O indicated a 3-formylcarbazole framework with a chelated hydroxy group. The 1H-NMR spectrum showed strong agreement with that of 7methoxymukonal (68) (see Scheme 2.14), except for the methoxy group at the C-ring of the carbazole nucleus which was replaced by a further hydroxy group (d 8.46). The hydroxy group on the carbazole-A-ring was chelated to the formyl group (d 9.95) at C-3. The spectroscopic data led to structure 72 for clausine O. In 1997, Ito et al. isolated clauszoline-M (73) from the roots, the stem bark, and the leaves of C. excavata (47). The characteristic absorptions in the UV and the IR spectrum indicated a 3-formyl-2-hydroxy-carbazole framework. The IR band at (nmax 1651 cm1) and the 1H-NMR signals at d 9.99 (CHO) and 11.44 (OH, D2Oexchangeable) suggested the presence of strongly hydrogen-bonded formyl and hydroxy groups, thus supporting the 3-formyl-2-hydroxycarbazole moiety. In addition to these peaks, the 1H-NMR spectrum showed in the aromatic region

Occurrence, Isolation, and Structure Elucidation

R2

CHO R1 R2

CHO

R3

OH N H

OH R4

71 Clausine A

N H

R1

76 Heptaphylline

R1 = H; R2 = OMe

R1 = prenyl; R2,R3,R4 = H

72 Clausine O R1 = OH; R2 = H

77 Heptazoline

73 Clauszoline-M

78 6-Methoxyheptaphylline

R1 = prenyl; R2,R3 = H; R4 = OH R1 = prenyl; R2 = OMe; R3,R4 = H

R1 = H; R2 = OH 74 Murrayaline-C

79 7-Methoxyheptaphylline

R1 = OMe; R2 = CHO 75 Murrayaline-D 1

29

2

R = OMe; R = geranyl

R1 = prenyl; R2,R4 = H; R3 = OMe 80 Clausine B R1,R3 = H; R2,R4 = OMe 81 Clausine S R1 = CH2CH(OH)C(Me) CH2; R2,R3,R4 = H

Scheme 2.15

three, mutually ortho-coupled (J=7.7 Hz) proton signals at d 6.90, 7.05 and 7.58, which were assigned to H-7, H-6, and H-5, respectively. The two singlets at d 6.94 and 8.40 resulted from H-1 and a deshielded H-4, respectively. Based on these spectroscopic data and additional support from the 13C-NMR spectrum, structure 73 was assigned to clauszoline-M. In 1991, Furukawa et al. isolated murrayaline-C (74) and murrayaline-D (75) from the stem bark of M. euchrestifolia collected in Taiwan (70). The UV spectrum [lmax 223, 259 (sh), 303, and 380 nm] and the IR spectrum (nmax 1610, 1640, 1660, 3400, and 3420 cm1) of murrayaline-C (74) indicated the presence of a 3-formyl-2-hydroxycarbazole framework. The 1H-NMR spectrum of murrayaline-C (74) showed a similar signal and coupling pattern as that of murrayaline-B (64) (see Scheme 2.14), except for the signal of the aromatic methyl group, which was missing and replaced by two additional low-field singlets at d 9.95 and 11.41. The signal at d 9.95 was typical of an aldehyde proton attached at C-3. The other singlet at d 11.41 was assigned to a strongly hydrogen-bonded hydroxy proton located ortho to the aldehyde group. These assignments were additionally supported by NOE experiments. On the basis of the spectroscopic evidence, structure 74 was assigned to murrayaline-C (70). The UV spectrum [lmax 243, 255 (sh), 287, 330, 357, 364, and 368 nm] and the IR spectrum [nmax 1582, 1620 (aromatic system), 1680 (chelated aldehyde), and 3400 (OH or NH) cm1] of murrayaline-D (75) were characteristic of a 3-formyl-2-hydroxycarbazole. This assignment was supported by the 1H-NMR spectrum, which showed a singlet for an aldehyde proton at d 9.98 and a D2O-exchangeable proton signal at d 8.54 for an NH group. In addition to these two peaks, the 1H-NMR spectrum exhibited signals for an aromatic methoxy group at d 3.95 and for the

30

Chemistry and Biology of Carbazole Alkaloids

geranyl side chain. The presence of a geranyl side chain was additionally supported by the mass fragmentation ion at m/z 254 (M+CHQCMeCH2CH2CHQCMe2). In the aromatic region, two, mutually ortho-coupled (J=8.8 Hz) proton signals for H-5 at d 7.88 and H-6 at d 6.95 confirmed the substitution pattern of the C-ring. The two singlets for H-1 at d 7.40 and H-4 at d 8.08 (deshielded by the formyl group at C-3) supported the regiochemical assignments for the substituents on the A-ring. Based on these spectral data, structure 75 was assigned to murrayaline-D (70). Various heptaphylline derivatives, differing in their substitution pattern of the C-ring, were isolated from different Clausena species. In 1967, Joshi et al. reported the isolation of heptaphylline (76) from the roots of C. heptaphylla (26). The UV spectrum (lmax 234, 278, 298, and 346 nm) and the IR spectrum [nmax 1618 (aromatic system), 1640 (chelated aldehyde), and 3300 (OH or NH) cm1] of heptaphylline were characteristic of a 3-formyl-2-hydroxycarbazole. The 1H-NMR spectrum showed signals for a prenyl side chain (d 1.66, 1.83, 3.60, and 5.35), a formyl substituent (d 9.9), an NH group (d 10.3), and a chelated hydroxy group (d 11.7). In the aromatic region, a multiplet of four protons at d 7.18.3 indicated an unsubstituted C-ring and the singlet at d 8.25 for H-4 was strongly deshielded due to the presence of an orthoformyl group. Based on these spectroscopic data, structure 76 was assigned to heptaphylline (26,91). This assignment was additionally supported by synthesis of heptaphylline starting from 3-formyl-2-hydroxy-carbazole and prenyl bromide (91) (Scheme 2.15). In 1970, Chakraborty et al. described the isolation of heptazoline (77) from the stem bark of C. heptaphylla (92). The UV spectrum (lmax 240, 275, and 298 nm) and the IR spectrum (nmax 1500, 1580, 1623, 3150, and 3450 cm1) of heptazoline indicated the presence of a 3-formyl-2-hydroxycarbazole framework. The 1H-NMR spectrum showed signals for a prenyl side chain (d 1.65, 1.81, 3.63, and 5.30), a formyl group (d 9.91), a D2O-exchangeable NH group (d 11.25), and two phenolic hydroxy groups (d 9.82 and 11.5). In the aromatic region, H-4 of the carbazole nucleus was strongly deshielded and appeared as a singlet at d 8.28 indicating the close proximity of the formyl group at C-3 and the absence of a proton at C-2. The proton at C-5 appeared as doublet of doublets with an ortho- and a meta-coupling (J=8.0, 2.0 Hz) indicating the presence of protons at C-6 and C-7 and the presence of a substituent at C-8, which thus was assigned as the position of the second hydroxy group. Based on this spectroscopic analysis, structure 77 was assigned to heptazoline. In 1972, Joshi et al. isolated 6-methoxyheptaphylline (78) from the roots of C. indica (93). The UV spectrum (lmax 235, 283, 311, and 341 nm) of 6-methoxyheptaphylline closely resembled that of heptaphylline (76), and thus indicated a 3-formyl-2-hydroxycarbazole framework containing a chelated hydroxy group. This assignment was supported by the IR spectrum. The 1H-NMR spectrum confirmed the similarity with heptaphylline (76), but also showed the presence of an additional methoxy group at d 3.29. The position of the methoxy group was unequivocally assigned at C-6. This regiochemical assignment was deduced from the signals for the aromatic protons of the carbazole C-ring, which appeared as a doublet with a metacoupling (J=2.0 Hz) at d 7.45 (H-5), a doublet with an ortho-coupling (J=7.5 Hz) at d 7.3 (H-8), and a doublet of doublets with an ortho- and a meta-coupling (J=7.5, 2.0 Hz) at d 7.0 (H-7). Based on these spectroscopic data, structure 78 was assigned to 6-methoxyheptaphylline.

Occurrence, Isolation, and Structure Elucidation

31

In 1988, Pummangura et al. reported the isolation of 7-methoxyheptaphylline (79) from the root bark of C. harmandiana (89). The UV spectrum [lmax 224, 240, 290 (sh), 300, and 338 nm] and the IR spectrum (nmax 1640 and 3280 cm1) of 7-methoxyheptaphylline were very similar to those of 7-methoxymukonal (68) (see Scheme 2.14), indicating the presence of a 3-formyl-2-hydroxycarbazole with a chelated hydroxy group. The 1H-NMR spectrum confirmed the similarity with 7-methoxymukonal (68), but showed signals for an additional prenyl side chain (d 1.63, 1.79, 3.53, and 5.29). The presence of a prenyl group was supported by the mass fragmentation ion at m/z 253 (M+CHQCMe2H). The absence of an upfield aromatic singlet of H-1 as for 7-methoxymukonal (68), indicated that the prenyl group was located at C-1. These spectroscopic data were strongly supported by the 13C-NMR spectrum and thus, led to the assignment of structure 79 for 7-methoxyheptaphylline (89,94). In 1996, Wu et al. isolated clausine B (80) from the stem bark of C. excavata (46). Clausine B showed inhibition of rabbit platelet aggregation and caused vasocontraction. Three years later, the same group described the isolation and structural elucidation of an optically active ([a]D +159.09, c 0.0022, MeOH) carbazole alkaloid, clausine S (81) from the root bark of C. excavata. The absolute stereochemistry of clausine S is still unknown (43). The UV spectrum (lmax 235, 269, 278, 304, and 357 nm) and the IR spectrum [nmax 1600, 1610 (aromatic system), 1640 (chelated aldehyde), and 3400 (OH, NH) cm1] of clausine B (80) were similar to those of mukonal (53) (see Scheme 2.11) and thus indicated a 3-formyl-2-hydroxycarbazole framework. This assignment was confirmed by the 1H-NMR spectrum, which showed a singlet of an aldehyde proton at d 9.95 and two D2O-exchangeable proton signals at d 10.60 and 11.36 for the NH and OH groups, respectively. Moreover, the 1H-NMR spectrum exhibited two, threeproton singlets at d 3.87 and 3.96 for two methoxy groups. In the aromatic region, the singlet for H-1 was shielded at d 6.89 and the singlet for H-4 was deshielded at d 8.38. These signals and their chemical shifts confirmed the presence of a formyl group at C-3 and of a hydroxy group at C-2. The two doublets at d 6.62 for H-7 and at d 7.24 for H-5 with a meta-coupling (J=2.0 Hz) suggested that the two methoxy groups were located at C-6 and C-8. These spectroscopic assignments were additionally supported by NOE and HMBC experiments and led to structure 80 for clausine B (46). The UV and IR spectra of clausine S (81) were similar to those of clausine B (80) indicating a 3-formyl-2-hydroxy-carbazole. Further support for this assignment derived from the 1H-NMR spectrum, which showed a singlet of an aldehyde proton at d 9.98, a signal for the hydroxy group at d 11.81, and a deshielded singlet at d 8.35 for H-4. Moreover, four signals of mutually ortho-coupled (J=8.0 Hz) protons at d 7.21, 7.37, 7.53, and 8.07 indicated that the C-ring was unsubstituted. The presence of one set of CH2CH-ABX signals at d 3.05 (dd, J=14.0, 8.6 Hz), 3.28 (dd, J=14.0, 4.0 Hz) and 4.49 (m), singlets at d 4.74 and 4.92 for a terminal olefinic methylene group, a signal at d 1.86 for an olefinic methyl group, and a D2O-exchangeable doublet (J=4.0 Hz) at d 4.30 for the aliphatic hydroxy group suggested a CH2CH(OH)C(Me)QCH2 side chain at C-1. The presence of this side chain was additionally confirmed by the mass fragmentation ion at m/z 224 [M+CH2CH(OH)C(Me)QCH2], which results from cleavage at the benzylic position. On the basis of these spectroscopic data, structure 81 was assigned to clausine S (Scheme 2.15) (43).

32

Chemistry and Biology of Carbazole Alkaloids

CHO R1 R2

N H

CHO

OH OH

OH R

N H

OH 82 Clauszoline-D

84 Clauszoline-F R = OH

R1 = H; R2 = OH

85 Clausenatine A (Mukoenine-B) R=H

83 Clausine U R1 = OH; R2 = H

Scheme 2.16

In 1996, Ito et al. reported the isolation of clauszoline-D (82) and clauszoline-F (84) from the stem bark of C. excavata (74). Clauszoline-D (82) was obtained from nature in racemic form. Three years later, Wu et al. described the isolation of clausine U (83) and clausenatine A (85) from the acetone extract of the root bark of the same natural source (43). Clausine U (83) was isolated in optically active form ([a]D72.85, c 0.0151, MeOH). However, the absolute stereochemistry of clausine U is still unknown (43). Prior to the isolation of clausenatine A (85), Furukawa et al. reported in 1993 the isolation of the same natural product from the root and stem bark of M. koenigii and named it mukoenine-B (82) (Scheme 2.16). The UV spectrum [lmax 217, 242, 276, 292, 301 (sh), and 356 nm] of clauszoline-D (82) is characteristic of a 2,8-dioxygenated 3-formylcarbazole. Moreover, the IR spectrum [nmax 1600 (aromatic system), 1631 (chelated aldehyde), and 3330 (OH or NH) cm1] of clauszoline-D confirmed a 3-formyl-2-hydroxycarbazole. The 1H-NMR spectrum showed signals for a formyl group at d 9.97, an NH group at d 10.43, and two hydroxy groups at d 11.77 and 8.95. A deshielded singlet at d 8.30 for H-4 suggested that the formyl substituent was located at C-3. Three, mutually orthocoupled (J=7.7 Hz) signals at d 7.57, 7.05, and 6.88 for H-5, H-6, and H-7, respectively, indicated the presence of a substituent at C-8. The substituent at C-1 was shown to be a dihydroxylated prenyl chain, indicated by two signals for methyl groups at d 1.30 and 1.31, attached to an oxygen-substituted tertiary carbon, and an ABX signal with geminal and vicinal couplings at d 3.46 (1H, dd, J=14.3, 1.8 Hz) and 2.89 (1H, dd, J=9.5, 14.3 Hz), and two signals for OH groups at d 4.28 and 3.72. Two characteristic mass fragmentation ions at m/z 270 [M+C(OH)Me2] and 240 + [M CH(OH)C(OH)Me2] additionally supported the presence of this side chain. The spectroscopic assignments were confirmed by NOE experiments and led to structure 82 for clauszoline-D (74) (Scheme 2.16). The UV spectrum [lmax 221, 240 (sh), 245, 254, 288, 303 (sh), 324 (sh), and 339 nm] and the IR spectrum (nmax 1620, and 3400 cm1) of clausine U (83) were very similar to those of clauszoline-D (82) and indicated a 3-formyl-2-hydroxycarbazole framework. The 1H-NMR spectrum confirmed the similarity of clausine U to clauszoline-D, but showed the signal for an additional hydroxy group at C-7. This regiochemistry was deduced from the signals for the aromatic protons, which appeared as a doublet with an ortho-coupling (J=8.3 Hz) at d 7.85 (H-5), a doublet of doublets with an ortho- and a meta-coupling (J=8.3, 2.0 Hz) at d 6.76 (H-6), and a

Occurrence, Isolation, and Structure Elucidation

33

doublet with a meta-coupling (J=2.0 Hz) at d 6.96 (H-8). These spectroscopic data, additionally supported by the 13C-NMR spectrum, as well as HMQC, HMBC, and NOESY spectra, led to structure 83 for clausine U (43). The UV spectrum [lmax 216, 242, 276, 291, 300 (sh), and 354 nm] of clauszoline-F (84) is characteristic of a 2,8-dioxygenated 3-formylcarbazole chromophore. Moreover, the IR spectrum [nmax 1585 (aromatic system), 1630 (chelated aldehyde), and 3300 (OH or NH) cm1] of clauszoline-F indicated a 3-formyl-2-hydroxycarbazole. The 1H-NMR spectrum differs from that of clauszoline-D (82) only in the presence of signals for a geranyl side chain instead of those for a dihydroxyisopentyl side chain. This geranyl side chain was further supported by the mass fragmentation ion at m/z 240 (M+CHQCMeCH2CH2CHQCMe2). The position of the geranyl side chain at C-1 was unequivocally confirmed by NOE experiments. Because of the structural similarity to clauszoline-D, and based on the spectroscopic data, structure 84 was assigned to clauszoline-F (74). The UV spectrum [lmax 222, 238, 284 (sh), 294, 331, and 342 (sh) nm] supported by the IR spectrum of clausenatine A (mukoenine-B) (85) indicated the presence of a 3-formylcarbazole with a chelated hydroxy group. The 1H-NMR spectrum was very similar to that of clauszoline-F (84), except for the lack of a signal for a second hydroxy group on the C-ring of the carbazole nucleus. This was confirmed by the signals of four protons at d 8.04 (d, J=7.8 Hz), 7.18 (t, J=7.8 Hz), 7.33 (t, J=7.8 Hz), 7.44 (d, J=7.8 Hz) for H-5, H-6, H-7, and H-8, respectively, indicating an unsubstituted Cring. The spectroscopic data led to the assignment of structure 85 for clausenatine A (mukoenine-B) (43,82) (Scheme 2.16).

5 C-Ring Oxygenated Tricyclic Carbazole Alkaloids Since 1966, several carbazole alkaloids which are oxygenated at the C-ring were isolated from different natural sources. Glycozoline (86) was the first member of this class of alkaloids and was obtained from the stem bark of G. pentaphylla (95,96). In 1991, glycozoline (86) was also isolated by McChesney and El-Feraly from the roots of C. lansium (23). In Taiwan, the roots of this ornamental tree are used in traditional medicine for the treatment of bronchitis and malaria (23). In 1999, Chakravarty et al. isolated glycozoline (86) from the roots of G. arborea (62). The UV spectrum (lmax 227, 252, 264, and 304 nm) and the IR spectrum [nmax 1208 (aromatic ether), 1380 (C-methyl), 1595, 1600 (aromatic system), and 3500 (NH) cm1] of glycozoline were characteristic of a 6-methoxycarbazole framework. The 1H-NMR spectrum showed the presence of signals for an NH group (d 7.80), two aromatic protons (d 7.50), a multiplet of four aromatic protons (d 6.807.18), an aromatic methoxy group (d 3.90), and an aromatic methyl group (d 2.50). The spectroscopic data confirmed that glycozoline is 6-methoxy-3-methylcarbazole (86) (96,62). Chemical support for this structural assignment was derived through transformation into known carbazole derivatives (96) and total synthesis (97). In 2001, Chakravarty et al. described the isolation and structural elucidation of glycoborine (87) from the roots of G. arborea (98). The UV spectrum (lmax 244, 287, 324, and 337 nm) of glycoborine was characteristic of a carbazole chromophore. The 1 H-NMR spectrum showed the presence of signals for an NH proton (d 7.87), an aromatic methoxy group (d 4.06), and an aromatic methyl group (d 2.52). A strongly deshielded signal at d 8.11 for H-4 suggested that the methyl group is located at C-3 and the methoxy group at C-5. Two, mutually ortho-coupled (J=7.9 Hz) protons at

34

Chemistry and Biology of Carbazole Alkaloids

R2

R1

Me

R1

R2O

Me

R3 R4

N H

R3

86 Glycozoline

91 Glycozolinine (Glycozolinol)

R1,R3,R4 = H; R2 = OMe 87 Glycoborine 1

N H

R1,R2,R3 = H 92 Glycomaurrol

2

3

4

R = OMe; R ,R ,R = H 88 Glycozolicine R1,R2,R3 = H; R4 = OMe 89 Siamenol R1,R4 = H; R2 = prenyl; R3 = OH 90 Clausenalene

R1 = prenyl; R2,R3 = H 93 Eustifoline-C R1 = geranyl; R2,R3 = H 94 1-Formyl-3-methoxy-6-methylcarbazole (8-Formyl-6-methoxy-3-methylcarbazole) R1 = H; R2 = Me; R3 = CHO

R1,R4 = H; R2,R3 = -OCH2O-

Scheme 2.17

d 7.25 and 7.19 for H-1 and H-2, respectively, supported this assignment for the regiochemistry of the A-ring. Three signals of contiguous protons at d 6.65 (d, J=7.9 Hz), 6.98 (dd, J=7.9, 0.6 Hz), and 7.30 (dd, J=7.9, 7.9 Hz) for H-6, H-8, and H-7, respectively, indicated that the location of the methoxy substituent must be C-5. The spectroscopic data, supported by 13C-NMR, COSY, NOESY, HSQC, and HMBC spectra, led to 5-methoxy-3-methylcarbazole as the structure of glycoborine (87). This assignment was additionally confirmed by synthesis (98). In 1992, Bhattacharyya et al. reported the isolation of glycozolicine (88) from the roots of G. pentaphylla, and originally assigned the structure as 5-methoxy-3methylcarbazole (24). On their isolation of glycoborine (87) in 2001, Chakravarty et al. reassigned glycozolicine (88) as 8-methoxy-3-methylcarbazole (98) (Scheme 2.17). The UV spectrum (lmax 227, 244, 288, 325, and 330 nm) and the IR spectrum [nmax 1380 (C-methyl), 1590, 1610 (aromatic system), and 3450 (NH) cm1] of glycozolicine indicated a 3-methylcarbazole. The 1H-NMR spectrum exhibited signals for an NH proton at d 8.16, an aromatic methoxy group at d 4.00, and an aromatic methyl group at d 2.52. In the aromatic region, a deshielded broad singlet at d 7.84 for H-4 suggested that C-3 is the position of the methyl substituent. This regiochemical assignment was supported by the presence of signals for two, mutually ortho-coupled (J=8.2 Hz) protons at d 7.34 (H-1) and d 7.23 (H-2). Signals for three contiguous protons at d 6.88 (d, J=7.6 Hz), 7.13 (dd, J=7.6, 7.6 Hz), and 7.64 (d, J=7.6 Hz) for H-7, H-6, and H-5, respectively, indicated that the methoxy substituent must at C-8. Based on these spectroscopic data, and supported by the 13 C-NMR, COSY, NOESY, HSQC, and HMBC spectra, glycozolicine was assigned as 8-methoxy-3-methylcarbazole (88). This structural assignment was confirmed by synthesis via Fischer indolization of 2-methoxyphenylhydrazine and 4-methylcyclohexanone (98). In 2000, Boyd et al. described the isolation of siamenol (89) from the organic extract of M. siamensis (85). Siamenol exhibited HIV-inhibitory activity. The UV

Occurrence, Isolation, and Structure Elucidation

35

spectrum [lmax 216, 238, 261, 308, and 328 (sh) nm] and the IR spectrum indicated the presence of a 3-methylcarbazole. The 1H-NMR spectrum showed signals for a prenyl side chain (d 1.75, 3.42, and 5.43) and an aromatic methyl group (d 2.42). The presence of a prenyl group was further supported by the mass fragmentation ion at m/z 210 (M+CHQCMe2). In the aromatic region, the signals for H-4 at d 7.63 with a meta-coupling (d, J=1.0 Hz), H-1 at d 7.17 with an ortho-coupling (d, J=8.5 Hz), and H-2 with an ortho- and a meta-coupling (dd, J=8.5, 1.0 Hz) at d 7.01 suggested a substitution at C-3. The two singlets at d 6.81 for H-8 and at d 7.62 for H-5 indicated that two additional substituents are present at C-6 and C-7. Based on these spectroscopic data and additional support from the 13C-NMR, COSY, NOESY, HMQC, and HMBC spectra, structure 89 was assigned to siamenol. In 1993, Bhattacharyya et al. reported the isolation of clausenalene (90) from the stem bark of C. heptaphylla (99). This was the first report of a methylenedioxycarbazole alkaloid from a plant source. The UV spectrum (lmax 236, 312, 336, and 353 nm) and the IR spectrum [nmax 1520, 1620 (aromatic system), and 3391 (NH) cm1] of clausenalene indicated, by their characteristic absorptions, the presence of a carbazole nucleus. The 1H-NMR spectrum showed signals for an NH proton at d 7.90, an aromatic methyl group at d 2.30, and an aromatic methylenedioxy group at d 6.00. In the aromatic region, a deshielded singlet at d 7.74 for H-4 and two, mutually ortho-coupled (J=7.0 Hz) protons at d 7.10 for H-1 and d 7.30 and for H-2, suggested that C-3 is the position of the methyl substituent. Moreover, a deshielded singlet at d 7.45 for H-5 and a shielded singlet at d 6.80 for H-8 indicated that the methylenedioxy function is bound to C-6 and C-7. The spectroscopic data together with the 13C-NMR spectrum led to the conclusion that clausenalene (90) was 3-methyl-6,7-methylenedioxycarbazole. This structural assignment was confirmed by a total synthesis using a Japp–Klingemann reaction and Fischer indolization starting from 2-hydroxymethylene-5-methylcyclohexanone and 3,4-methylenedioxyphenyldiazonium chloride. In 1983, Mukherjee et al. described the isolation and structural elucidation of glycozolinine (91) from the seeds of G. pentaphylla (66). One year later, Bhattacharyya et al. reported the isolation of the same carbazole alkaloid from the roots of the same source and renamed it glycozolinol (91) (67). The UV spectrum (lmax 224, 254, 269, and 298 nm) and the IR spectrum [nmax 1390 (C-methyl), 1570, 1630 (aromatic system), and 3440 (NH) cm1] of glycozolinine (glycozolinol) (91) were very similar to those of glycozoline (86), indicating the presence of a 6-oxygenated-3methylcarbazole framework. The 1H-NMR spectrum emphasized the close similarity of glycozolinine (glycozolinol) (91) to glycozoline (86), with the exception of the signal for a hydroxy group at d 11.04, instead of a signal for a methoxy group. These spectroscopic data led to structure 91 for glycozolinine (glycozolinol). Additional chemical support for this structural assignment was derived from transformation into known carbazole derivatives, including conversion into glycozoline by treatment with diazomethane (66), and total synthesis (67). In 1989, Reisch et al. described the isolation and structural elucidation of glycomaurrol (92) from the dichloromethane extract of the stem bark of Glycosmis mauritiana (100). Glycomaurrol (92) was considered as a biogenetic precursor of glycomaurin (eustifoline-A) (172) (see Chapter 2.5, Scheme 2.36). The UV spectrum [lmax 230, 243 (sh), 255 (sh), 268 (sh), 289 (sh), 298, and 327 nm] indicated the presence of a 6-oxygenated-3-methylcarbazole framework. The 1H-NMR spectrum

36

Chemistry and Biology of Carbazole Alkaloids

showed two, deuterium-exchangeable, broad singlets at d 4.87 and 7.82 for the protons of the OH and NH groups, respectively. The IR spectrum confirmed the presence of these functional groups from the bands at nmax 3390 for OH and 3200 cm1 for NH. Moreover, the 1H-NMR spectrum exhibited signals for an aromatic methyl group (d 2.52) and a prenyl side chain (d 1.76, 1.95, 3.99, and 5.40). The presence of a prenyl group was additionally supported by the mass fragmentation ion at m/z 209 (M+CHQCMe2H). In the aromatic region, a deshielded broad singlet at d 7.93 for H-4, and a multiplet at d 7.197.31 for H-1 and H-2, suggested the presence of a methyl substituent at C-3. For the C-ring, two, mutually ortho-coupled (J=8.5 Hz) protons at d 6.95 and 7.13 confirmed the positions of the prenyl side chain at C-5 and of the hydroxy group at C-6 of the carbazole framework. Based on these spectroscopic data and the 13C-NMR spectrum, structure 92 was assigned to glycomaurrol. Further chemical support for this structural assignment was derived from transformation into known carbazole derivatives. In 1990, Ito and Furukawa described the isolation and structural elucidation of eustifoline-C (93) from the root bark of M. euchrestifolia collected in Taiwan in December (101). Eustifoline-C (93) was considered a biogenetic precursor of eustifoline-B (173) (see Chapter 2.5, Scheme 2.36). The UV spectrum (lmax 231, 258, 268, 290, 300, 325, and 357 nm) and the IR spectrum of eustifoline-C were very similar to those of glycomaurrol (92). The 1H-NMR spectrum emphasized the close similarity of eustifoline-C (93) to glycomaurrol (92), with the exception of the signals for a geranyl side chain at C-5 instead of the signals for the prenyl group. The presence of a geranyl side chain was additionally supported by the mass fragmentation ion at m/z 210 (M+CHQCMeCH2CH2CHQCMe2) resulting from cleavage at the benzylic position. The position of the geranyl side chain as a substituent at C-5 of the carbazole framework was supported by NOE experiments with O-methyleustifoline-C, which was prepared by treatment of eustifoline-C with diazomethane. Based on the spectroscopic evidence, structure 93 was assigned to eustifoline-C. In 2001, Chowdhury et al. isolated 1-formyl-3-methoxy-6-methylcarbazole (8-formyl-6-methoxy-3-methylcarbazole) (94) from the leaves of M. koenigii (48). This carbazole alkaloid exhibited inhibitory activity against both Gram-positive and Gram-negative bacteria, and against fungi. The UV spectrum (lmax 227, 262, 303, and 398 nm) was characteristic of a 1-formylcarbazole (=8-formylcarbazole) nucleus. This assignment was supported by the IR spectrum [nmax 1208 (aromatic ether), 1580, 1605 (aromatic system), 1665 (CQO), 2760 (aldehyde C–H) and 3405 (NH) cm1]. The 1H-NMR spectrum showed the presence of signals for an aldehyde proton at d 10.50, an NH proton at d 9.61, an aromatic methyl group at d 2.32, and an aromatic methoxy group at d 4.03. In the aromatic region, the protons at the C-ring, H-5 (d 8.05, d, J=2.5 Hz) and H-7 (d 7.45, d, J=2.5 Hz) exhibited no ortho-coupling, and thus indicated a substitution at C-6. The meta-coupling of H-4 (d 7.82, d, J=2.5 Hz) indicated that the position of the methyl group was C-3. Based on the UV spectrum, the formyl group was assigned to position 8. The 1H-NMR spectrum indicated the presence of a formyl and a methoxy group on the same ring of the carbazole skeleton. The spectroscopic evidence led to 1-formyl-3-methoxy-6-methylcarbazole (8-formyl-6-methoxy-3-methylcarbazole) (94). This structural assignment was additionally confirmed by transformation of 1-formyl-3-methoxy-6-methylcarbazole

Occurrence, Isolation, and Structure Elucidation

CHO

CH2OH

MeO

37

N H

MeO

95 Mukoline

N H

96 Mukolidine

Scheme 2.18

into a known natural product, glycozoline (86), on decarbonylation with Pd–C, and by total synthesis (46) (Scheme 2.17). In 1982, Chakraborty et al. described the isolation and structural elucidation of mukoline (95) and mukolidine (96) from the roots of M. koenigii (102) (Scheme 2.18). The UV spectrum (lmax 221, 242, 252, 258, 280, 290, and 320 nm) and the IR spectrum (nmax 1610, 3240, and 3440 cm1) of mukoline (95) indicated the presence of an 8-(1-)methoxycarbazole chromophore. The 1H-NMR spectrum showed signals for an NH proton at d 8.22, a hydroxy group at d 4.45, deshielded benzylic methylene protons at d 4.75, and an aromatic methoxy group at d 3.90. The aromatic region exhibited a doublet with meta-coupling (J=2.0 Hz) for H-4, and signals for five further protons in the range of d 7.007.90. Based on these spectroscopic data, structure 95 was assigned for mukoline. This structural assignment was chemically supported by transformation into the corresponding O-acetyl and N-methyl derivatives, total synthesis, and conversion into mukolidine (96) by oxidation with active MnO2 (102). The UV spectrum (lmax 238, 248, 275, 290, and 330 nm) and the IR spectrum (nmax 1660, and 3185 cm1) of mukolidine (96) indicated a 3-formylcarbazole framework. The 1H-NMR spectrum exhibited signals for an aldehyde proton at d 10.80, an NH proton at d 8.60, and an aromatic methoxy group at d 4.05. The aromatic region showed signals for H-4 at d 8.15, H-5 at d 8.08, and four other aromatic protons between d 7.307.60. Based on these spectroscopic data, structure 96 was assigned to mukolidine. This structural assignment was supported by transformation into mukoline (95) on borohydride reduction, and by synthesis starting from 2(hydroxymethylene)cyclohexanone and toluenediazonium chloride using Japp– Klingemann conditions (102) (Scheme 2.18). In 1991, McChesney and El-Feraly described the isolation and structural elucidation of 3-formyl-6-methoxycarbazole (97) from the roots of C. lansium (23). The roots of this ornamental tree are used in traditional medicine in Taiwan to treat bronchitis and malaria (23). In 2005, Franzblau et al. isolated the same natural product from the stem bark of Micromelum hirsutum (103). They reported that 3-formyl-6-methoxycarbazole (97) shows in vitro anti-TB activity against the H37Rv strain of Mycobacterium tuberculosis. The UV spectrum (lmax 229, 245, 281, 297, and 334 nm) and the IR spectrum (nmax 1675, and 3310 cm1) indicated a 3-formylcarbazole framework for this alkaloid. The 1 H-NMR spectrum exhibited signals for an aldehyde proton at d 10.06, an NH proton at d 10.72, and an aromatic methoxy group at d 3.90. In the aromatic region, H-5 (d 7.80) and H-7 (d 7.10) showed a mutual meta-coupling (J=2.4 Hz), and H-8 (d 7.40) appeared as a doublet with an ortho-coupling (J=8.8 Hz). Thus, these signals suggested C-6 as the position of the methoxy substituent. The deshielded signal for

38

Chemistry and Biology of Carbazole Alkaloids

H-4 (d 8.66, br s) with no ortho-coupling, and the mutually ortho-coupled (J=8.2 Hz) signals for H-1 (d 7.58) and H-2 (d 7.92), indicated that the formyl substituent was located at C-3. The spectroscopic data confirmed the structure as 3-formyl-6methoxycarbazole (97). This assignment was additionally supported by the 13 C-NMR spectrum. In 1997, Ito et al. described the isolation and structural elucidation of clauszolineK (98) from the stem bark of C. excavata (47). The UV spectrum of clauszoline-K indicated a 3-formylcarbazole. The IR spectrum with a band at nmax 1680 cm1, and the 1H-NMR spectrum with a singlet at d 10.08, confirmed the presence of a formyl group. Moreover, the 1H-NMR spectrum showed a singlet for an aromatic methoxy group at d 3.92 and two sets of three-spin systems in the aromatic region. The first set showed signals for H-1 at d 7.47 (d, J=8.4 Hz), H-2 at d 7.91 (dd, J=8.4, 1.5 Hz), and H-4 at d 8.51 (d, J=1.5 Hz). The most deshielded signal at d 8.51 was assigned to H-4 due to the ortho-formyl group. Another set of signals for aromatic protons at d 6.94 (dd, J=8.4, 2.2 Hz), 6.96 (d, J=2.2 Hz), and 8.00 (d, J=8.4 Hz) was assigned to H-6, H-8, and H-5, respectively. Additional NOE experiments supported the assignment of the proton signals. The spectroscopic data confirmed that structure 98 represents clauszoline-K. In 1992, Furukawa et al. reported the isolation of 3-formyl-7-hydroxycarbazole (99) from the root bark of M. euchrestifolia (104). The UV spectrum [lmax 233, 245 (sh), 273, 288, and 326 nm] and the IR spectrum (nmax 1673 and 3336 cm1) of 3-formyl-7hydroxycarbazole were very similar to those of clauszoline-K (98), indicating a 3-formylcarbazole framework. The 1H-NMR spectrum confirmed the structural similarity to clauszoline-K, and showed the presence of a hydroxy group instead of the methoxy group. All of the spectroscopic data supported the structure of 3-formyl-7-hydroxycarbazole (99) (Scheme 2.19). In 2005, Franzblau et al. isolated micromeline (100) from the stem bark of M. hirsutum (103). This alkaloid exhibited in vitro anti-TB activity against the H37Rv strain of Mycobacterium tuberculosis and against the Erdman strain of M. tuberculosis

R2

R1

R2

CHO

R3

COOR1

R3 N H

N H

97 3-Formyl-6-methoxycarbazole R1,R3 = H; R2 = OMe

101 Clausine C (Clauszoline-L) R1 = Me; R2 = H; R3 = OMe

98 Clauszoline-K

102 Clausine M R1 = Me; R2 = H; R3 = OH

R1,R2 = H; R3 = OMe 99 3-Formyl-7-hydroxycarbazole R1,R2 = H; R3 = OH

103 Clausine N R1,R2 = H; R3 = OMe 104 Methyl 6-methoxycarbazole3-carboxylate

100 Micromeline R1 = prenyl; R2 = OH; R3 = H

R1 = Me; R2 = OMe; R3 = H

Scheme 2.19

Occurrence, Isolation, and Structure Elucidation

39

in a J774 mouse macrophage model. The UV spectrum (lmax 316 and 329 nm) and the IR spectrum [nmax 1670 (conjugated carbonyl), 3317 (OH), and 3394 (NH) cm1] of micromeline indicated the presence of a 3-formylcarbazole. This assignment was supported by the 1H-NMR spectrum which showed signals for an aldehyde proton at d 10.05, an NH proton at d 10.67, an OH proton at d 7.99, and a prenyl side chain at d 1.69, 1.99, 4.02, and 5.32. A deshielded doublet of doublets with meta- and paracoupling (J=1.6, 0.5 Hz) at d 8.65 for H-4, and two, mutually ortho-coupled (J=8.5 Hz) signals for H-1 at d 7.60 and for H-2 at d 7.91, confirmed that C-3 is the position of the formyl substituent. For the C-ring of the carbazole framework, two, mutually orthocoupled (J=8.5 Hz) protons at d 7.11 and 7.29 suggested the positions of the prenyl side chain and the hydroxy group at C-5 and C-6, respectively. Based on these spectroscopic data and additional support by the 13C-NMR, COSY, NOESY, HMQC, and HMBC spectra, structure 100 was assigned to micromeline. In 1996, Wu et al. described the isolation and structural elucidation of clausine C (101) from the stem bark of C. excavata (51). One year later, Ito et al. isolated the same natural product from the same source and named it clauszoline-L (101) (47). The UV spectrum [lmax 218, 238 (sh), 248, 281, and 320 (sh) nm] was characteristic of a 3-carbomethoxycarbazole. This assignment was supported by the IR spectrum [nmax 1610 (aromatic system), 1709 (carbomethoxy), and 3469 (NH) cm1]. The 1HNMR spectrum resembled that of clauszoline-K (98), except for the appearance of an additional methoxy signal instead of the signal for the formyl group at C-3. The additional methoxy signal at d 3.97 in the 1H-NMR spectrum, an IR band at 1709 cm1, and two significant mass fragments at m/z 224 (M+OMe) and 196 (M+COOMe) indicated the presence of a carbomethoxy group at C-3. Based on these spectroscopic data, which were supported by NOE experiments (47), structure 101 was assigned to clausine C (clauszoline-L). In 1999, Wu et al. described the isolation and structural elucidation of clausine M (102) and clausine N (103) from the acetone extract of the root bark of C. excavata (43). The UV spectrum [lmax 219, 239 (sh), 249, 283, and 318 (sh) nm] and the IR spectrum [nmax 1610 (aromatic system), 1690 (carbomethoxy), 3330 (OH), and 3375 (NH) cm1] of clausine M (102) were similar to those of clausine C (101), indicating a 3-carbomethoxycarbazole framework. The 1H-NMR spectrum confirmed the structural similarity to clausine C (101), but showed a signal for a hydroxy group at d 8.51 instead of the methoxy signal. The presence of a hydroxy group was supported by the IR band at 3330 cm1. The spectroscopic data led to structure 102 for clausine M. This structural assignment was additionally supported by NOE experiments (43). Clausine N (103) represents an isomer of clausine M (102) and shows similar UV and IR spectra. The 1H-NMR spectrum confirmed the structural similarity to clausine M (102), but exhibited signals for a methoxy group at C-7 (d 3.88) and for a carboxyl group at C-3 instead of the signals for the carboxymethyl and hydroxy groups. The presence of a methoxy substituent was confirmed by two characteristic mass fragments at m/z 226 (M+Me) and 198 (M+COMe). Based on these spectroscopic data, structure 103 was assigned to clausine N (43). In 1991, McChesney and El-Feraly reported the isolation of methyl 6-methoxycarbazole-3-carboxylate (104) from the roots of C. lansium (23). In Taiwan the roots of this ornamental tree are used in folk medicine for the treatment of bronchitis and malaria (23). The UV spectrum [lmax 227, 241 (sh), 266 (sh), and 285 nm] and the IR

40

Chemistry and Biology of Carbazole Alkaloids

spectrum (nmax 1705 and 3300 cm1) of methyl 6-methoxycarbazole-3-carboxylate (104) closely resembled those of clausine C (101), indicating the structural similarity. The 1H-NMR spectrum showed signals for an NH proton at d 10.36 and two aromatic methoxy groups at d 3.96 and 4.03. In the aromatic region, H-5 at d 7.70 and H-7 at d 7.18 exhibited a mutual meta-coupling (J=1.8 Hz), and H-8 at d 7.42 appeared as a doublet with an ortho-coupling (J=7.8 Hz). These signals indicated that the location of the methoxy substituent was at C-6 on the C-ring. The deshielded signal for H-4 (d 8.93, br s) was also lacking an ortho-coupling, and the two protons H-1 (d 7.48) and H-2 (d 8.27) showed a mutual ortho-coupling (J=7.8 Hz). Thus, for the A-ring it was concluded that the methyl ester was located at C-3. The presence of a methyl ester group was supported by the IR band at 1705 cm1. The spectroscopic data confirmed the structure of methyl 6-methoxycarbazole-3-carboxylate (104) (Scheme 2.19).

6 9-Oxygenated Tricyclic Carbazole Alkaloids In 1988, Furukawa et al. reported the isolation of N-methoxy-3-formylcarbazole (3-formyl-9-methoxycarbazole) (105) from the root bark of M. euchrestifolia (22). This was the first example of a 9-oxygenated tricyclic carbazole alkaloid isolated from a natural source. The UV spectrum (lmax 236, 272, 288, and 320 nm) and the IR spectrum (nmax 1600, 1620, and 1680 cm1) of N-methoxy-3-formylcarbazole (105) indicated the presence of a 3-formylcarbazole framework. This assignment was confirmed by the 1H-NMR spectrum which showed the signal for an aldehyde proton at d 10.12. Moreover, the 1H-NMR spectrum resembled closely that of 3-formylcarbazole, and exhibited an additional signal for a methoxy group at d 4.27. The presence of a methoxy substituent was supported by the mass fragment at m/z 194 (M+OMe). The absence of an NH proton in the 1H-NMR spectrum, and the presence of seven aromatic CH signals in the 13C-NMR and DEPT spectrum, led to the assignment of the methoxy group at the N-atom. These spectral data confirmed the structure of N-methoxy-3-formylcarbazole (105) (Scheme 2.20). Four years later, Furukawa et al. described the isolation and structural elucidation of N-methoxy-3-hydroxymethylcarbazole (3-hydroxymethyl-9-methoxycarbazole) (106) from the root bark of M. euchrestifolia (104). The UV spectrum (lmax 237, 263, 283, and 334 nm) of N-methoxy-3-hydroxymethylcarbazole (106) was similar to that of N-methoxy-3-formylcarbazole (105), but exhibited some bathochromic shifts of the bands. The 1H-NMR spectrum confirmed the structural similarity to N-methoxy-3formylcarbazole, but showed the signal for a hydroxymethyl group at d 4.86 instead of the signal for a formyl group. The presence of a hydroxymethyl group was supported by an IR band at 3450 cm1 and a characteristic mass fragment at m/z 167. The 13C-NMR spectrum of N-methoxy-3-hydroxymethylcarbazole supported the CH2OH

CHO

N OMe

N OMe 105 3-Formyl-9-methoxycarbazole (N-methoxy-3-formylcarbazole)

106 3-Hydroxymethyl-9-methoxycarbazole (N-methoxy-3-hydroxymethylcarbazole)

Scheme 2.20

Occurrence, Isolation, and Structure Elucidation

41

structural similarity to N-methoxy-3-formylcarbazole. The spectroscopic data confirmed the structure of N-methoxy-3-hydroxymethylcarbazole (106). This assignment was additionally supported by NOE experiments and chemical transformation into known carbazole derivatives.

7 Tricyclic Carbazole-1,4-quinone Alkaloids The carbazole-1,4-quinones represent an important family of carbazole alkaloids (105,106). Except for clausenaquinone A (112), all carbazole-1,4-quinones isolated from natural sources have a 3-methylcarbazole-1,4-quinone skeleton. The plants of the genus Murraya (Rutaceae) are the major natural source of carbazole-1,4-quinone alkaloids. In 1983, Furukawa et al. reported the first isolation of a carbazole-1, 4-quinone, murrayaquinone A (107), from the root bark of M. euchrestifolia collected in Taiwan (28,29). In subsequent years, the same group reported the isolation of various carbazole-1,4-quinones from the root or stem bark of the same plant: murrayaquinone B (108) (28,29), murrayaquinone C (109) (28,29), murrayaquinone D (110) (29), and murrayaquinone E (111) (70) (Scheme 2.21). The UV spectrum [lmax 225, 258, 293 (sh), and 398 nm] and the IR spectrum (nmax 1595, 1650, and 3200 cm1) of murrayaquinone A (107) indicated the presence of a carbazole-1,4-quinone nucleus. This was supported by the 13C-NMR spectrum with two signals for carbonyl carbons at d 183.40 and 180.40. The 1H-NMR spectrum showed signals for a vinylic methyl group as a doublet (J=1.5 Hz) at d 2.19 and an olefinic proton as a quartet (J=1.5 Hz) at d 6.51, both exhibiting a long-range coupling. In the aromatic region, a signal for a deshielded proton which appeared as a doublet of triplets (J=1.0, 5.0 Hz) at d 8.23 could be assigned to H-5 due to the deshielding effect of the C-4 carbonyl moiety. A three-proton multiplet at d 7.30–7.60 was assigned to H-6, H-7, and H-8. The spectroscopic data and a total synthesis confirmed structure 107 for murrayaquinone A (28,29). O

O

R2

Me

R1

R1

R3O R2

N H

N H

O

107 Murrayaquinone A

O

112 Clausenaquinone A

R1,R2 = H

R1 = OMe; R2 = Me; R3 = H

108 Murrayaquinone B

113 Koeniginequinone A R1,R3 = Me; R2 = H

R1 = OMe; R2 = prenyl 109 Murrayaquinone C

114 Koeniginequinone B

R1 = OMe; R2 = geranyl

R1,R3 = Me; R2 = OMe

110 Murrayaquinone D R1 = OH; R2 = geranyl 111 Murrayaquinone E R1 = OH; R2 = prenyl

Scheme 2.21

42

Chemistry and Biology of Carbazole Alkaloids

The UV spectrum [lmax 231, 264, 310 (sh), and 404 nm] and the IR spectrum (nmax 1610, 1640, 1655, and 3280 cm1) of murrayaquinone B (108) were very similar to those of murrayaquinone A (107), indicating a carbazole-1,4-quinone framework. This assignment was supported by the 13C-NMR spectrum which exhibited two signals for carbonyl carbons at d 183.70 and 179.80. The 1H-NMR spectrum showed signals for a vinylic methyl group as a doublet at d 2.13 and an olefinic proton as a quartet at d 6.42, both with an allylic coupling (J=1.5 Hz), an aromatic methoxy group at d 3.91, and a prenyl side chain (d 1.74, 1.85, 3.57, and 5.23). The presence of a prenyl side chain was supported by the mass fragmentation ion at m/z 254 (M+CHQCMe2). In the aromatic region, two, mutually ortho-coupled (J=9.0 Hz) protons at d 7.02 and 7.98 could be assigned to H-6 and H-5. Moreover, the observation of an NOE of 15.9% between the signals for H-6 at d 6.02 and the methoxy group at d 3.91 confirmed the position of the methoxy group at C-7 and of the prenyl group at C-8. On the basis of these spectroscopic data, structure 108 was assigned to murrayaquinone B (28,29). The UV spectrum [lmax 233, 267, and 410 nm] and the IR spectrum (nmax 1610, 1645, 1655, and 3440 cm1) of murrayaquinone C (109) were very similar to those of murrayaquinone B (108), indicating a carbazole-1,4-quinone framework. This assignment was supported by two signals for carbonyl carbons in the 13C-NMR spectrum at d 183.60 and 179.70. The 1H-NMR spectrum confirmed the structural similarity to murrayaquinone B (108), and also exhibited signals for a geranyl side chain instead of the signals for a prenyl side chain. The mass fragmentation ion at m/z 308 (M+CHQCMeCH2CH2CHQCMe2), resulting from cleavage at the benzylic position, supported the presence of a geranyl side chain. The spectroscopic data, confirmed by NOE experiments and total synthesis, led to structure 109 for murrayaquinone C (28,29). The UV spectrum [lmax 234, 266, and 415 nm] and the IR spectrum (nmax 1610, 1645, 1660, and 3440 cm1) of murrayaquinone D (110) were very similar to those of murrayaquinone C (109), thus indicating the presence of a carbazole-1,4-quinone framework. The 1H-NMR spectrum confirmed the structural similarity to murrayaquinone C (109), but showed the signal for a hydroxy group (d 5.52) instead of the signal for a methoxy group. Based on the spectroscopic data, structure 110 was assigned to murrayaquinone D (29). The UV spectrum [lmax 232, 262, and 406 nm] and the IR spectrum (nmax 1620, 1650, 3400, and 3430 cm1) of murrayaquinone E (111) resembled those of murrayaquinone B (108) and indicated the presence of a carbazole-1,4-quinone framework. In the IR spectrum, the bands at nmax 1620 and 1650 cm1 are characteristic of a carbazole-1,4-quinone. The 1H-NMR spectrum confirmed the similarity to murrayaquinone B (108), but exhibited the signal of a hydroxy group instead of the signal for a methoxy group. The presence of a hydroxy group was supported by the mass fragmentation ion at m/z 278 (M+OH). These spectroscopic data led to structure 111 for murrayaquinone E (70). In 1994, Wu et al. described the isolation and structural elucidation of clausenaquinone A (112) from the stem bark of C. excavata (107). This carbazole1,4-quinone alkaloid exhibited potent inhibitory activity of rabbit platelet aggregation induced by arachidonic acid, as well as cytotoxicity in the HCT-8, RPMI-7951, and TE-671 tumor cells. The UV spectrum (lmax 228, 265, 295, and 419 nm) and the IR spectrum (nmax 1600, 1625, 1660, 3260, and 3370 cm1) of clausenaquinone A

Occurrence, Isolation, and Structure Elucidation

43

indicated a carbazole-1,4-quinone. The 1H-NMR spectrum showed signals for an aromatic methyl group at d 2.33, an aromatic methoxy group at d 3.88, and a vinyl proton at d 5.78 assigned to H-2. A deshielded broad singlet at d 8.17 for H-5 suggested the presence of a carbonyl group at C-4 and a methyl group at C-6. A shielded broad singlet at d 7.04 could be assigned to H-8. A broad singlet at d 7.82, corresponding to a D2O-exchangeable proton, confirmed the presence of a hydroxy group at C-7. Based on the spectroscopic data, structure 112 was assigned to clausenaquinone A. This structural assignment was additionally supported by HMBC spectra and by total synthesis (107). In 1998, Saha and Chowdhury described the isolation of koeniginequinone A (113) and koeniginequinone B (114) from the stem bark of M. koenigii (49), which represented the first report of carbazole-1,4-quinone alkaloids from this plant. The UV spectrum [lmax 227, 260, and 286 (sh), 387 nm] and the IR spectrum (nmax 1639, 1652, and 3280 cm1) of koeniginequinone A (113) indicated a carbazole-1, 4-quinone framework. In the IR spectrum, the bands at nmax 1639 and 1652 cm1 are typical of a carbazole-1,4-quinone. The 1H-NMR spectrum showed signals for a vinylic methyl group (doublet at d 2.09), an olefinic proton (quartet at d 6.39, both with an allylic coupling of J=1.3 Hz), and an aromatic methoxy group at d 3.81. In the aromatic region, two, mutually ortho-coupled (J=8.0 Hz) protons at d 8.03 and 6.93 were assigned to H-5 and H-6, respectively, due to the deshielding effect of the C-4 carbonyl moiety and the shielding effect of the methoxy group at C-7. A shielded doublet at d 7.04 with a meta-coupling (J=1.8 Hz) was assigned to H-8, confirming the position of the methoxy group at C-7. These spectroscopic data led to the structure of 7-methoxy-3-methylcarbazole-1,4-quinone (113) for koeniginequinone A. This assignment was confirmed by synthesis using a Japp–Klingemann reaction and Fischer indolization (49). The UV spectrum [lmax 225, 263, 293 (sh), and 464 nm] and the IR spectrum (nmax 1641, 1650, and 3284 cm1) of koeniginequinone B (114) indicated a carbazole-1, 4-quinone. The presence of this framework was supported by the characteristic carbazole-1,4-quinone bands in the IR spectrum at nmax 1641 and 1650 cm1. The 1HNMR spectrum showed signals for a vinylic methyl group (doublet at d 2.12), an olefinic proton (quartet at d 6.42, both with an allylic coupling of J=1.2 Hz), and two aromatic methoxy groups at d 3.94 and 3.97. In the aromatic region, the singlet at d 7.56 for H-5 was deshielded by the C-4 carbonyl moiety, and the shielded singlet at d 6.84 was assigned to H-8. Moreover, these signals confirmed the positions of the two methoxy groups at C-6 and C-7. Based on the spectroscopic data, koeniginequinone B was assigned as 6,7-dimethoxy-3-methylcarbazole-1,4-quinone (114). A total synthesis by a Japp–Klingemann reaction and Fischer indolization supported this structural assignment (49) (Scheme 2.21).

B. Pyranocarbazole Alkaloids 1 Pyrano[3,2-a]carbazole Alkaloids In 1964, Chakraborty et al. isolated girinimbine (115) from the stem bark of M. koenigii (108). Girinimbine represented the first pyrano[3,2-a]carbazole alkaloid isolated from natural sources. Later, Joshi et al. isolated the same alkaloid from the roots of a different source, C. heptaphylla (91). Based on chemical degradation studies,

44

Chemistry and Biology of Carbazole Alkaloids

Chakraborty et al. proposed originally that the pyran ring and the aromatic methyl group of girinimbine are attached to different aromatic rings of the carbazole framework (108). Five years later, Dutta and Quasim reassigned the structure of girinimbine based on NMR studies and proposed that the pyran ring and the methyl group of girinimbine are connected to the same aromatic ring (109). This structural assignment was in agreement with biogenetic considerations and supported by Joshi et al. (91,110). The UV spectrum (lmax 223, 238, 288, 330, 342, and 358 nm) of girinimbine (115) indicated a carbazole. The IR spectrum (nmax 1580, 1620, and 3290 cm1) showed the presence of an NH function and an aromatic system. The 1H-NMR spectrum exhibited signals for an NH at d 7.75, two aromatic protons at d 7.50, three aromatic protons at d 7.08, and an aromatic methyl group at d 2.23. A six-proton singlet at d 1.42 and symmetrical doublets at d 5.45 and 6.25 suggested a 2,2-dimethyl-D3-pyran ring fused to the carbazole nucleus. The presence of a 2,2-dimethyl-D3-pyran ring was supported by the mass fragmentation ion at m/z 248 (M+Me). Based on these spectroscopic data, structure 115 was assigned to girinimbine. In 1968, Narasimhan et al. reported the isolation of koenimbin (116) from the fruits of M. koenigii (111). One year later, Kapil et al. isolated the same carbazole alkaloid from the leaves of the same source (112). The UV spectrum (lmax 230, 240, 300, 340, and 360 nm) and the IR spectrum (nmax 1580, 1650, and 3400 cm1) of koenimbin (116) indicated a carbazole framework. The 1H-NMR spectrum showed signals for an NH, an aromatic methoxy group, and an aromatic methyl group. In the aromatic region, two deshielded singlets at d 7.61 and 7.40 were assigned to H-4 and H-5, respectively. The proton at C-5 was slightly shielded compared to the corresponding proton of mahanimbine (139) (see Scheme 2.27). Therefore, the position of the methoxy group was assigned to C-6. Moreover, the 1H-NMR spectrum confirmed the presence of a fused 2,2-dimethyl-D3-pyran ring. The spectroscopic data were supported by chemical transformation into known carbazole derivatives and led to 6-methoxygirinimbine (116) as the structure for koenimbin (111). In 1969, Kapil et al. described the isolation and structural elucidation of koenigicine (118) (6,7-dimethoxygirinimbine) from the leaves of M. koenigii (112). Only one year later, Joshi and Narasimhan isolated from the same natural source an identical carbazole alkaloid and named it koenimbidine (110) and koenidine (113). During their investigation Narasimhan et al. isolated, along with koenidine (118), koenine (117) and koenigine (119), which differ in the oxygen substitution pattern at the positions 6 and 7 (113). In 1982, Bowen and Perera reported the isolation of koenigine (119) from the leaves of Micromelum zeylanicum, a species restricted to Sri Lanka. The name of the plant in Sinhalese is Walkarapincha (wild M. koenigii) (114). The 1H-NMR spectra confirm that all these alkaloids have a pyrano[3,2-a]carbazole framework (Scheme 2.22). Koenine (117) gave a positive ferric chloride test, which indicated the presence of a phenolic group. The 1H-NMR spectrum showed signals for an aromatic methyl group and a 2,2-dimethyl-D3-pyran ring. In the aromatic region, H-7 (d 6.74) exhibited an ortho-coupling (J=8.0 Hz) with H-8 (d 7.18), and a meta-coupling (J=2.0 Hz) with H-5 (d 7.20). The signal for H-4 appeared at (d 7.55) as a deshielded singlet. The 1H-NMR spectroscopic data unambiguously confirmed the positions of the 2,2-dimethyl-D3-pyran ring at C-1 and C-2, the methyl group at C-3, and the hydroxy group at C-6. Therefore, koenine was assigned as 6-hydroxygirinimbine

Occurrence, Isolation, and Structure Elucidation

R

R1

Me O N H

Me

Me

R2 O

O N H

Me

Me Me

115 Girinimbine R=H

118 Koenigicine (Koenimbidine, Koenidine)

116 Koenimbin R = OMe

119 Koenigine

117 Koenine R = OH

45

R1 = OMe; R2 = Me R1 = OMe; R2 = H 120 Murrayamine-A (7-Hydroxygirinimbine, Mukoenine-C) R1,R2 = H 120a O-Methylmurrayamine A R1 = H; R2 = Me

Scheme 2.22

(117). This structural assignment was confirmed by the conversion of koenine into koenimbin via methylation (113). The UV spectra of koenigicine (118) and koenigine (119) were strikingly similar to the UV spectrum of koenimbin (116), indicating a similar carbazole chromophore. The 1H-NMR spectrum of koenigicine (118) showed signals for an aromatic methyl group, two aromatic methoxy groups and a 2,2-dimethyl-D3-pyran ring. The signal for H-4 represented a deshielded singlet at d 7.58, suggesting the presence of a methyl substituent at C-3 and a 2,2-dimethyl-D3-pyran ring fused at C-1 and C-2. The 2,2-dimethyl-D3-pyran ring was confirmed by the mass fragmentation ion at m/z 308 (M+Me). In addition, H-5 appeared as a deshielded singlet at d 7.48 and H-8 as a shielded singlet at d 6.93, which confirmed the positions of the two methoxy groups at C-6 and C-7. Based on these spectroscopic data, koenigicine was assigned as 6,7-dimethoxygirinimbine (118) (112,113). The 1H-NMR spectrum of koenigine (119) was similar to that of koenigicine (118). However, koenigine has one hydroxy group and one methoxy group instead of two methoxy groups, as in koenigicine. The presence of a hydroxy group was supported by a positive ferric chloride test. Based on the chemical shift of H-8 (d 6.81) in koenigine the position of the hydroxy group was assigned to C-7. The spectroscopic data led to structure 119 for koenigine. This structural assignment was supported by conversion of koenigine into koenigicine via methylation (113). In 1991, Wu reported the isolation of murrayamine-A (120) from the leaves of M. euchrestifolia (115). Two years later, Furukawa et al. isolated the same alkaloid from the roots of M. koenigii and named it mukoenine-C (82). The UV spectrum [lmax 221, 240, 287 (sh), 294, 342, 349, and 360 nm] of murrayamine-A indicated a carbazole framework. The 1H-NMR spectrum showed singlets for an NH group at d 7.76 and a phenolic hydroxy group at d 4.91. This was supported by IR bands at 3419 and 3044 cm1. In the aromatic region, H-4 appeared as a deshielded singlet at d 7.53, suggesting that the methyl substituent at C-3 and the 2,2-dimethyl-D3-pyran ring were fused at C-1 and C-2. The presence of a 2,2-dimethyl-D3-pyran ring was

46

Chemistry and Biology of Carbazole Alkaloids

confirmed by the mass fragmentation ion at m/z 264 (M+Me). The signals for H-5 with an ortho-coupling (J=8.2 Hz) at d 7.72, and H-6 with an ortho- and a meta-coupling (J=8.2, 2.2 Hz) at d 6.68, suggested C-7 as the position for the hydroxy group. This assignment was in agreement with the meta-coupling (J=2.2 Hz) of H-8 at d 6.81. The position of the hydroxy group at C-7 was supported by the marked diamagnetic shifts observed for the signals of H-6 (D 0.21) and H-8 (D 0.3) of O-acetylmurrayamine A. Therefore, murrayamine-A was assigned as 7-hydroxygirinimbine (120) (82,115). In 2003, Nakatani et al. reported the isolation of O-methylmurrayamine A (120a) from the leaves of M. koenigii. O-Methylmurrayamine A (120a) showed radical scavenging activity against the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical (116). Prior to its isolation from nature, this alkaloid was known as a synthetic derivative of murrayamine-A (120), obtained by methylation with diazomethane (115). The UV spectrum [lmax 221, 240, 283 (sh), 294, 341 (sh), and 357 (sh) nm] of O-methylmurrayamine A (120a) was very similar to that of murrayamine-A (120), indicating the presence of a pyranocarbazole framework. This was supported by the IR spectrum. The 1H-NMR spectrum of O-methylmurrayamine A differs from that of murrayamine-A only by the signal of an aromatic methoxy group at d 3.90 instead of a hydroxy group. In the 13C-NMR spectrum, the signal for the methoxy group appeared at d 55.7. Based on the spectroscopic data, structure 120a was assigned to O-methylmurrayamine A (116) (Scheme 2.22). In 1997, Mester and Reisch described the isolation and structural elucidation of mupamine (121) from the root bark of C. anisata (117). The UV spectrum of mupamine (121) resembled that of girinimbine (115) (see Scheme 2.22), indicating the presence of a similar chromophore. The 1H-NMR spectrum showed signals for an NH group at d 8.03 and an aromatic methoxy group at d 3.99. This assignment was supported by IR bands at 3370 and 2840 cm1. In the aromatic region, H-4 appeared as a deshielded singlet at d 7.63, suggesting the presence of a methyl substituent at C-3 and a 2,2-dimethyl-D3-pyran ring fused at C-1 and C-2. The 2,2-dimethyl-D3-pyran ring was confirmed by the mass fragmentation ion at m/z 278 (M+Me). Moreover, the aromatic region showed three, mutually ortho-coupled (J=7.8 Hz) signals for H-5, H-6, and H-7 at d 7.53, 7.09, and 6.80, respectively, suggesting C-8 as the position of the methoxy group. The spectroscopic data led to 8-methoxygirinimbine (121) as the structure for mupamine (117). In 1983, Ganguly et al. reported the isolation of mukonicine (122) from the leaves of M. koenigii (118). The UV spectrum of mukonicine (122) resembled that of koenimbin (116) (see Scheme 2.22), indicating a similar chromophore. This assignment was supported by the IR spectrum [nmax 1385 (C-Me), 1648 (C-OMe), and 3440 (NH) cm1]. The 1H-NMR spectrum showed signals for an NH proton at d 7.81, an aromatic methyl group at d 2.30, two aromatic methoxy groups at d 3.90, and a 2,2-dimethyl-D3-pyran ring. In the aromatic region, the signal for H-4 appeared as a deshielded singlet at d 7.56, suggesting the regiochemistry with a methyl group at C-3 and a 2,2-dimethyl-D3pyran ring fused at C-1 and C-2. The presence of a 2,2-dimethyl-D3-pyran ring was supported by the mass fragmentation ion at m/z 308 (M+Me). The signal for H-5 appeared at higher field (d 7.40), indicating that one of the two methoxy groups was located at C-6, similar to koenimbin (116) (see Scheme 2.22). The position of the second methoxy group was assigned to C-8 because the signal for H-7 appeared at much higher field (d 6.88) than H-5. Therefore, mukonicine was assigned as 6,8-dimethoxygirinimbine (122) (118).

Occurrence, Isolation, and Structure Elucidation

47

In 2003, Hao et al. isolated from the aerial parts of M. koenigii the optically active carbazole alkaloid 123, with a rare arylpropanyl substitution, and named it murrayanine (119). However, since 1965 murrayanine is known as 3-formyl-1methoxycarbazole (9) isolated by Chakraborty et al. from the stem bark of M. koenigii (33,34) (see Scheme 2.4). Therefore, in order to avoid confusion in the future, we suggest to rename this ‘‘new murrayanine’’ as murrayanine B (123) and this name is used for 123 throughout this article. Murrayanine B (123) showed a specific rotation of ½a25 D þ 8:0 (c 0.74, MeOH), but its absolute configuration is not known. The UV spectrum (lmax 225, 238, 300, and 342 nm) of murrayanine B (123) indicated a carbazole framework. The 1H-NMR spectrum exhibited signals for an NH and a phenolic hydroxy group as two broad singlets at d 9.73 and 4.75. The IR spectrum supported this assignment with bands at 3440 and 3410 cm1. Moreover, the 1 H-NMR spectrum showed the presence of a koenigine (119) moiety (see Scheme 2.22) and an 11-carbon residue. The structure of the latter was indicated by signals for a –OCH2–CHR1–CHR2–O– group. This assignment was supported by the mass fragmentation ion at m/z 210 (M307) as well as COSY and HMBC spectra. The 1H-NMR spectrum showed the presence of an isolated, two-spin system at d 6.81 with a meta-coupling (J=1.9 Hz), indicating a symmetrically substituted aromatic residue. The presence of two methoxy groups on this aromatic ring at C-6v and C-8v was revealed by NMR analysis, while the hydroxy group at C-7v was determined with the help of mass and NMR spectroscopic data. The NMR spectra of murrayanine B and koenigine differed at C-8. The signal for C-8 in the 13C-NMR spectrum of murrayanine B indicated substitution, whereas a CH signal was observed for the C-8 of koenigine. This assignment was confirmed by 1H–13C longrange correlations between H-2v at d 3.88 and the carbons at d 148.3 (C-7), 110.9 (C-8), and 131.8 (C-8a), as well as between the methylene protons at d 4.02 (H-1v) and the carbon at d 110.9 (C-8). The connection of C-7 and C-3v via an oxygen was determined by the 1H–13C long-range correlations between H-3v at d 5.46 and C-7 at d 148.3. The relative configuration of C-2v and C-3v was determined as trans based on the coupling constant (J=7.8 Hz) and ROESY correlations between H-1v and H-3v. The spectroscopic data led to structure 123 for murrayanine B (119) (Scheme 2.23). Chakraborty et al. reported the isolation of murrayacine (124), a formyl analog of girinimbine from two different natural sources M. koenigii (120,121) and C. heptaphylla (122). The UV spectrum (lmax 226, 282, and 301 nm) and the IR spectrum (nmax 1675 and 3250 cm1) of murrayacine (124) indicated R

Me O

MeO

N H

MeO 7

O

Me

3′′

H

Me

4′′

5′′

121 Mupamine R=H

4b 4a 8

9 8a

N H H 1′′ OH 9′′

2′′

Me

4

5

6

9a

O

1 1′

3′ 2′

6′′

MeO

7′′

8′′

OMe

OH

122 Mukonicine R = OMe

123 Murrayanine-B

Scheme 2.23

Me Me

48

Chemistry and Biology of Carbazole Alkaloids

a 3-formylcarbazole. The presence of a formyl group was confirmed by the formation of a 2,4-dinitrophenylhydrazone. The 1H-NMR spectrum showed signals for an aldehyde proton (d 10.68), an NH (d 12.0), and a 2,2-dimethyl-D3pyran ring. The deshielded singlet at d 8.40 for H-4 suggested the position of the formyl substituent at C-3 and the 2,2-dimethyl-D3-pyran ring fused to C-1 and C-2. The presence of a 2,2-dimethyl-D3-pyran ring was confirmed by the mass fragmentation ion at m/z 262 (M+Me). A multiplet of four aromatic protons at d 7.35–8.15 indicated an unsubstituted C-ring. Based on the spectroscopic data, structure 124 was assigned to murrayacine. This assignment was supported by the transformation of 124 into known carbazole derivatives (110,121). In 1990, Lange et al. isolated 7-methoxymurrayacine (125) from the roots of M. siamensis (57). The UV and IR spectra of 7-methoxymurrayacine (125) were very similar to those of murrayacine (124) indicating a 3-formylcarbazole. The 1H-NMR spectrum of 7-methoxymurrayacine also resembled that of murrayacine. However, the C-ring substitution pattern was similar to that of murrayamine-A (120) (see Scheme 2.22), indicating the presence of a substituent at C-7. This regiochemical assignment was supported by the 1H-NMR spectrum which showed an orthocoupled (J=8.4 Hz) H-5 at d 7.84, an ortho- and meta-coupled (J=8.4, 2.2 Hz) H-6 at d 6.86, and a meta-coupled (J=2.2 Hz) H-8 at d 6.90. These spectroscopic data led to structure 125 for 7-methoxymurrayacine. In 1996, Ito et al. reported the isolation of clauszoline-G (126) from the stem bark of C. excavata collected in Singapore (74). The UV spectrum [lmax 204, 234, 245 (sh), 278, 300, and 361 nm] and the IR spectrum (nmax 1578, 1631, 1658, and 3263 cm1) of clauszoline-G (126) indicated a 3-formylcarbazole framework. The 1H-NMR spectrum showed signals for an NH at d 10.58, a phenolic hydroxy group at d 8.90, and a formyl group at d 10.48. In the aromatic region, H-4 appeared as a deshielded singlet at d 8.33, suggesting the position of the formyl substituent at C-3 and the 2,2-dimethyl-D3-pyran ring fused to C-1 and C-2. The presence of a 2,2dimethyl-D3-pyran ring was confirmed by the mass fragmentation ion at m/z 278 (M+Me). In the aromatic region, the 1H-NMR spectrum showed signals for three, mutually ortho-coupled (J=7.7 Hz) protons at d 7.61, 7.04, and 6.88 (H-5, H-6, and H-7), suggesting the presence of a substituent at C-8. Based on these spectral data, clauszoline-G was assigned as 8-hydroxymurrayacin (126). In 1974, Chakraborty et al. isolated heptazolidine (127) from C. heptaphylla (123). The UV spectrum (lmax 230, 238, 278, 282, and 335 nm) and the IR spectrum (nmax 965, 1190, 1510, 1650, and 3400 cm1) of heptazolidine indicated a pyranocarbazole framework. The 1H-NMR spectrum showed signals for an NH (d 8.1), an aromatic methoxy group (d 3.98), and an aromatic methyl group (d 2.3). The shielded singlet at d 7.50 was assigned to H-5 and indicated the position of the methoxy group to be at C-6. Moreover, the aromatic region exhibited a meta-coupled (J=2.0 Hz) signal at d 7.67 for H-4, and two, mutually ortho-coupled (J=8.5 Hz) signals at d 7.18 and 6.94. The coupling pattern of the 1H-NMR spectrum suggested the position of the methyl group at C-3 and the presence of a 2,2-dimethyl-D3-pyran ring fused to C-7 and C-8 of the carbazole framework. This assignment was supported by the mass fragmentation ion at m/z 278 (M+Me). The spectroscopic data were additionally confirmed by transformation into known carbazole derivatives as well as total synthesis, and led to structure 127 for heptazolidine (123,124).

49

Occurrence, Isolation, and Structure Elucidation

CHO O N H

CHO

N H

Me

124 Murrayacine

Me

O

MeO

Me

CHO

Me

125 7-Methoxymurrayacine

OMe O N H

127 Heptazolidine

O

Me HO

N H

Me

CHO

O N H

O

Me

126 Clauszoline-G

Me Me

Me

O

Me Me

128 Euchrestifoline

HO

N H

Me Me

129 Heptazolicine

Scheme 2.24

In 1996, Wu et al. reported the isolation of euchrestifoline (128) from the leaves of M. euchrestifolia collected in May (125). Depending on the season, a constitutional variation is observed for the carbazole alkaloids obtained from the leaves of this species. Previously, 128 was prepared by Chakraborty and Islam as an intermediate for the synthesis of girinimbine (115) (126) (see Scheme 2.22). The UV spectrum (lmax 231, 255, 284, 291, 330, and 386 nm) of euchrestifoline was typical of a carbazole. The 1 H-NMR spectrum showed singlets for an aromatic methyl group at d 2.39 and H-4 at d 8.02. The deshielding of H-4 suggested the position of the methyl group at C-3. Moreover, the four mutually coupled signals at d 7.23, 7.39, 7.48, and 7.95 for H-6, H-7, H-8, and H-5, indicated an unsubstituted C-ring. A broad signal at low field (d 10.14) along with IR bands at 3440 (NH) and 1650 (CQO) cm1 suggested the presence of a keto-carbazole with an intramolecular hydrogen bonding. The remaining signals, including two methyl groups adjacent to the oxygen functionality as singlet at d 1.54 and a singlet for a methylene group at d 2.83, confirmed the dimethylpyranone ring fused to C-1 and C-2 of the carbazole framework. Based on these spectral data, structure 128 was assigned to euchrestifoline (125). In 1984, Chowdhury et al. isolated heptazolicine (129) from the roots of C. heptaphylla (127). The UV spectrum (lmax 242, 275, and 300 nm) of heptazolicine (129) indicated a 3-formylcarbazole. This assignment was supported by the IR spectrum [nmax 1700 (CHO), 3000 (NH), and 3260 (OH, hydrogen-bonded) cm1]. The 1H-NMR spectrum showed signals for an NH at d 10.4, a phenolic hydroxy group at d 11.2, and a formyl group at d 9.8. Two symmetrical triplets (J=7 Hz) at d 3.03 and d 1.98, along with a sharp singlet for six protons at d 1.45, indicated the 2,2-dimethyldihydropyran ring. The presence of a 2,2-dimethyldihydropyran ring was supported by the mass fragmentation ion at m/z 280 (M+Me). In the aromatic region, H-4 appeared as a deshielded singlet at d 8.3, suggesting the position of the formyl substituent at C-3 and the 2,2-dimethyldihydropyran fused to C-1 and C-2. The ortho- and meta-coupling (J=8.0, 2.0 Hz) of H-5 at d 7.5 showed that C-6 and C-7 were unsubstituted. This conclusion was in agreement with the two-proton multiplet at d 6.7–7.2 for H-6 and H-7. The signals for the aromatic protons and the downfield shift of the hydroxy proton (d 11.2) confirmed the position of the hydroxy group at

50

Chemistry and Biology of Carbazole Alkaloids

R1

CHO R1

O R2

N H

Me

R2

O N H

Me OH

130 Clauszoline-E

HO

Me

Me OH

132 Clausine W R1 = CHO; R2 = OH

R1 = H; R2 = OH

133 Dihydroxygirinimbine

131 Clausine T R1 = OH; R2 = H

R1 = Me; R2 = H

Scheme 2.25

C-8. The spectroscopic data, supported by transformation into known carbazole derivatives, led to structure 129 for heptazolicine (Scheme 2.24). In 1996, Ito et al. isolated clauszoline-E (130) from the stem bark of C. excavata in racemic form (74). The UV spectrum (lmax 242, 273, and 292 nm) of clauszoline-E (130) indicated a 3-formylcarbazole framework. This assignment was supported by the IR spectrum [nmax 1650 (CHO), 3479 (NH), and 3287 (OH) cm1]. The 1H-NMR spectrum showed signals for an NH at d 11.30, a phenolic hydroxy group at d 9.85, and a formyl group at d 10.35. The presence of a 2,2-dimethyl-3-hydroxydihydropyran ring was indicated by two three-proton singlets at d 1.38 and 1.30 for the geminal dimethyl group attached to the a-oxygen carbon atom, a multiplet at d 3.83 coupled (1H, J=5.5 Hz) with a hydroxy proton at d 5.32, and a doublet of doublets due to the benzylic methylene group at d 3.17 (1H, J=17.1, 5.1 Hz) and 2.83 (1H, J=17.1, 7.0 Hz). In the aromatic region, H-4 appeared as a deshielded singlet at d 8.24, suggesting the position of the formyl substituent at C-3 and the 2,2-dimethyl-3hydroxydihydropyran fused to C-1 and C-2. Three, mutually ortho-coupled (J=7.7 Hz) signals for H-5, H-6, and H-7 at d 7.52, 6.97, and 6.80, respectively, suggested the position of the hydroxy group at C-8. Based on the spectroscopic data, which were additionally supported by 13C-NMR, NOE, and HMBC spectra, structure 130 was assigned to clauszoline-E. In 1997, Wu et al. described the isolation of clausine T (131) and clausine W (132) from the root bark of C. excavata (128) (Scheme 2.25). Both alkaloids were obtained from Nature in optically active form: [a]D –82.1 (c 0.0341, MeOH) for 131 and [a]D – 3.41 (c 1.002, MeOH) for 132. However, their absolute configuration is still unknown. The UV spectrum [lmax 242, 249, 274, 285 (sh), 302, and 345 nm] and the IR spectrum (nmax 1590, 1610, and 3400 cm1) of clausine T (131) indicated a 3-formylcarbazole. The 1H-NMR spectrum of clausine T was similar to that of clauszoline-E (130), but differed in the position of the hydroxy group. The aromatic region showed a deshielded singlet for H-4 at d 8.13, a doublet with an ortho coupling (J=8.4 Hz) for H-5 at d 7.88, a doublet of doublets with an ortho- and a meta-coupling (J=8.4, 2.1 Hz) for H-6 at d 6.76, and a doublet with a meta-coupling (J=2.1 Hz) for H-8 at d 6.91. Thus, the position of the hydroxy group was assigned at C-7. These spectroscopic data, additionally supported by the 13C-NMR spectrum and NOE experiments, led to structure 131 for clausine T (128). The UV and IR spectra of clausine W (132) resembled those of clausine T (131), indicating a 3-formyl-7-hydroxypyranocarbazole skeleton. The 1H-NMR spectrum confirmed the similarity to clausine T, except for the substitution pattern of the

Occurrence, Isolation, and Structure Elucidation

51

dihydropyran ring. The heteroaliphatic region exhibited signals of four, mutuallycoupled protons at d 3.81 (dd, J=7.5, 5.2 Hz), 4.58 (d, J=7.0 Hz), 4.86 (d, J=5.2 Hz), and 4.92 (dd, J=7.5, 7.0 Hz). Of these four signals, the two doublets at d 4.58 and 4.86 were exchangeable with D2O and the two other signals showed a vicinal diaxial coupling (J=7.5 Hz) indicating a –CH(OH)CH(OH)– moiety with a trans-diol configuration. The two singlets at d 1.31 and 1.55 were assigned to the geminal dimethyl group of the pyran ring. Based on these spectroscopic data and additional support by 13 C-NMR, NOESY, HSQC, and HMBC spectra, structure 132 was assigned to clausine W (128). In 1985, Furukawa et al. reported the isolation of dihydroxygirinimbine (133) from the root bark of M. euchrestifolia collected in Taiwan (129). Although this alkaloid was obtained in optically active form ([a]D –4, MeOH), the absolute configuration remains unknown. The UV spectrum (lmax 238, 254, 259, 303, and 332 nm) of dihydroxygirinimbine was typical of a 3-methylcarbazole, which was supported by the IR spectrum. The 1H-NMR spectrum indicated an aromatic methyl group at d 2.28, along with a trans-2u,2u-dimethyl-3u,4u-dihydroxydihydropyran ring similar to clausine W (132). In the aromatic region, H-4 appeared at d 7.72, suggesting C-3 as the position of the methyl substituent. Moreover, four, mutually-coupled protons at d 7.06, 7.24, 7.50, and 7.96 indicated an unsubstituted C-ring of the carbazole. Based on these spectroscopic data, structure 133 was assigned to dihydroxygirinimbine (Scheme 2.25). In 1996, Wu et al. described the isolation of murrayamine-I (134) and murrayamine-K (135) from the acetone extract of the leaves of M. euchrestifolia collected in November (130). The UV spectrum [lmax 222, 240, 281 (sh), 295, 324, 349, and 360 nm] of murrayamine-I (134) indicated a 2,7-dioxygenated carbazole framework. This assignment was supported by the IR spectrum. Except for the substitution pattern of the pyran ring, the 1H-NMR spectrum resembled that of murrayamine-A (120) (see Scheme 2.22), suggesting a similar structure. In the olefinic region, two doublets at d 5.64 and 6.75, with a mutual coupling of J=9.8 Hz, confirmed the annulated pyran ring with two geminal substituents. A singlet at d 1.50 indicated a quaternary methyl group. Two diasterotopic protons belonging to the same methylene group, which appeared as doublets (J=11.5 Hz) at d 4.17 and 4.26, and a singlet at d 2.02 for an acetate, showed that the other geminal substituent was an acetoxymethylene group. The mass fragmentation ion at m/z 264 (M+CH2OCOCH3) supported this assignment. These spectroscopic data led to structure 134 for murrayamine-I (130). The UV spectrum [lmax 237, 279 (sh), 288, 327, 344, and 359 nm] of murrayamine-K (135) indicated a 3-methylcarbazole, which was supported by the IR spectrum. The 1 H-NMR spectrum resembled that of murrayamine-I (134). The only difference was that murrayamine-K has an unsubstituted carbazole C-ring, as concluded from the four, mutually-coupled protons at d 7.18, 7.31, 7.37, and 7.91. Based on these spectroscopic data and additional support by the 13C-NMR data as well as NOE experiments, structure 135 was assigned to murrayamine-K (130). In 1986, Furukawa et al. reported the isolation of pyrayafoline A (136) from the stem bark of M. euchrestifolia (38,87). The UV spectrum [lmax 239, 286 (sh), 295, and 334 nm] and the IR spectrum (nmax 1590, 1605, and 1625 cm1) of pyrayafoline A (136) suggested a carbazole framework. The 1H-NMR spectrum showed signals for an aromatic methyl group, an aromatic methoxy group, and a 2,2-dimethyl-D3-pyran

52

Chemistry and Biology of Carbazole Alkaloids

ring. In the aromatic region, H-5 and H-6 appeared as ortho-coupled (J=8.0 Hz) doublets at d 7.63 and 6.67, indicating the position of the pyran ring at C-7 and C-8. Moreover, H-1 appeared as a shielded singlet at d 6.83 and H-4 as a deshielded singlet at d 7.62, indicating the position of the methoxy group at C-2 and of the methyl group at C-3. Based on the spectroscopic data and additional support by synthesis, structure 136 was assigned to pyrayafoline A (38). Five years later, the same group isolated from the same natural source further pyranocarbazole alkaloids, pyrayafoline C (137) and pyrayafoline D (138), which were obtained in racemic form (87). In 1992, Reisch et al. described the isolation of pyrayafoline D from the fruits of a different natural source, M. koenigii, and named it isomahanine (138). The absolute configuration of isomahanine is not known (71). In 2003, Nakatani et al. reported the isolation of isomahanine (138) from the leaves of M. koenigii in optically active form: ½a25 D  38:2 (c 0.22, CHCl3). However, the absolute configuration at the stereogenic center has not been assigned. Pyrayafoline D (isomahanine) (138) exhibited radical scavenging activity against the 1,1-diphenyl-2picrylhydrazyl (DPPH) radical (116) and significant cytotoxicity against HL-60 cells (131). The UV spectrum [lmax 238, 286 (sh), 296, and 323 nm] of pyrayafoline C (137) resembled that of pyrayafoline A (136) suggesting a similar chromophore. This conclusion was supported by the IR spectrum. The 1H-NMR spectrum was also very similar to that of pyrayafoline A (136), except for the presence of a hydroxy group instead of the methoxy group. The spectroscopic data led to structure 137 for pyrayafoline C. This assignment was additionally supported by methylation of pyrayafoline C with diazomethane to give pyrayafoline A (136) (Scheme 2.26) (38). The UV spectrum [lmax 238, 288 (sh), 296, and 331 nm] and the IR spectrum (nmax 3380, 3480, and 3600 cm1) of pyrayafoline D (138) resembled those of pyrayafoline C (137), indicating a similar carbazole framework. The 1H-NMR spectrum of pyrayafoline D (138) differs from that of pyrayafoline C (137) only by the presence of signals at d 1.75 (2H, m), 2.15 (2H, m), 5.10 (1H, t), 1.57 (3H, s), and 1.65 (3H, s), assignable to the side chain –CH2CH2CHQCMe2, instead of the signal for one of the methyl groups at the pyran ring of pyrayafoline C (137) The presence of this side chain was supported by the mass fragmentation ion at m/z 264 (M+CH2CH2CHQCMe2). Based on the spectroscopic data, structure 138 was

Me O

R N H

134 Murrayamine-I R = OH 135 Murrayamine-K R=H

R2 R3

Me

O N H

OAc

Me R1

136 Pyrayafoline A R1 = H; R2 = Me; R3 = OMe 137 Pyrayafoline C R1 = H; R2 = Me; R3 = OH 138 Pyrayafoline D (Isomahanine) R1 = prenyl; R2 = Me; R3 = OH

Scheme 2.26

Occurrence, Isolation, and Structure Elucidation

53

assigned to pyrayafoline D. Additional structural support was derived from NOE experiments with the methyl ether of pyrayafoline D, obtained by methylation using diazomethane (87) (Scheme 2.26). In 1966, Chakraborty et al. described the isolation of (+)-mahanimbine (139a) from M. koenigii (132). Two years later, Narasimhan et al. corrected the structural assignment of Chakraborty. Although alkaloid 139a was obtained in optically active form ([a]D +52), the absolute configuration is still unknown (111,133). Later, the racemic alkaloid, (7)-mahanimbine (139b), was isolated independently from two different Murraya species, M. euchrestifolia (29) and M. siamensis (85). The UV spectrum (lmax 277, 288, 328, 343, and 357 nm) and the IR spectrum (nmax 1600, 1650, and 3330 cm1) of (+)-mahanimbine (139a) resembled that of girinimbine (115) (see Scheme 2.22), indicating a 3-methylpyranocarbazole. The 1H-NMR spectrum differs from that of girinimbine (115) only by the presence of signals at d 1.67–1.87 (2H, m), 1.93–2.21 (2H, m), 5.13 (1H, m), 1.57 (3H, s), and 1.63 (3H, s), assignable to the –CH2CH2CHQCMe2 side chain, instead of one signal of a methyl group at the pyran ring. The presence of this side chain was supported by the mass fragmentation ion at m/z 258 (M+CH2CH2CHQCMe2). Based on these spectroscopic data, structure 139a was assigned to (+)-mahanimbine (111,133). Additional support for this assignment was derived from total synthesis and transformation into known carbazole derivatives (133) (Scheme 2.27). In 1991, Wu reported the isolation of murrayamine-C (141) and murrayamine-B (142) from the leaves of M. euchrestiolia collected in Taiwan. Both alkaloids were obtained from Nature in racemic form (115) (Scheme 2.28). One year later, the same group reported the isolation of a structurally different carbazole from the fruits of the same natural source and gave an identical name, murrayamine-C (140). This alkaloid was also obtained in racemic form (134) (Scheme 2.27). In 1979, Chakraborty et al. assigned the same structure to mahanimboline, which was isolated from the root bark of M. koenigii (135). A close comparison of the spectroscopic data of mahanimboline with those of murrayamine-C (140) showed that they were different alkaloids. Therefore, mahanimboline must have another structure, which is yet to be assigned (134). The UV spectrum (lmax 222, 238, 278, 288, 327, 342, and 358 nm) of murrayamine-C (140) resembled that of girinimbine (115) (see Scheme 2.22), indicating the presence of a similar 3-methylpyranocarbazole. The 1H-NMR spectrum differs from that of girinimbine (115) only in the presence of signals at d 1.70 as a singlet for an allylmethyl (3H), d 4.83 and 4.93 as singlets for the vinyl protons (2H),

Me O N H

Me O

Me Me Me

139a (+)-Mahanimbine 139b (±)-Mahanimbine

N H

Me Me HO

140 Murrayamine-C* (Mahanimboline)

Scheme 2.27

54

Chemistry and Biology of Carbazole Alkaloids

R2

R1

R1 O R3

N H

R2

Me

O N H

Me

Me

Me

Me 141 Murrayamine-C 1

145 Murrayamine-J

R = H; R = Me; R = OMe 142 Murrayamine-B

R1 = CHO; R2 = H 146 (−)-Isomahanimbine

R1 = Me; R2 = H; R3 = OMe 143 Murrayacinine

R1 = Me; R2 = H

1

2

3

2

Me

147 (+)-Mahanimbicine

3

R1 = Me; R2 = H

R = CHO; R ,R = H 144 Murrayamine-N R1 = H; R2 = CHO; R3 = OMe

Scheme 2.28

d 4.07 as a multiplet for a carbinol proton (1H), and d 1.79 as a multiplet for the vicinal methylene protons (4H) of the side chain –CH2CH2CH(OH)C(Me)QCH2. These signals replace the signal of one of the methyl groups on the pyran ring in the 1 H-NMR spectrum of girinimbine (115). The presence of this side chain was confirmed by proton decoupling experiments and the mass fragmentation ion at m/z 248 (M+CH2CH2CH(OH)C(Me)QCH2). Based on these spectral data, structure 140 was assigned to murrayamine-C. This structure was further supported by the difference NOE experiment (134) (Scheme 2.27). The UV spectrum (lmax 241, 274, 285, 340, and 353) of murrayamine-C (141) indicates the presence of a 1,7-dioxygenated carbazole chromophore. This was confirmed by the IR spectrum. The 1H-NMR spectrum showed a similar C-ring substitution pattern with that of pyrayafoline D (138) (see Scheme 2.26). However, the A-ring substitution pattern was completely different. Thus, the 1H-NMR spectrum showed the presence of an aromatic methyl at d 2.49, an aromatic methoxy at d 3.97, and two aromatic singlets at d 7.33 for a deshielded C-4 proton and at d 6.65 for a shielded C-2 proton. Based on these spectral data, and the similarity with the C-ring substitution pattern of pyrayafoline D, the structure 141 was assigned to murrayamine-C. This structure was further supported with the 13C-NMR data, as well as NOE experiments (115). The UV (lmax 272, 283, 330, 341, and 357 nm) and IR (nmax 1580, 1645, and 3433 cm1) spectra of murrayamine-B (142) resembled those of (+)-mahanimbine (139a) (see Scheme 2.27) indicating the presence of a similar 3-methylpyranocarbazole framework. The 1H-NMR spectrum differs from that of (+)-mahanimbine (139a) only in the C-ring substitution pattern of the carbazole nucleus. Thus, the 1H-NMR spectrum showed the presence of an aromatic methoxy group at d 4.0 and, in the aromatic region, three, mutually ortho-coupled (J=7.8 Hz) C-5, C-6, and C-7 protons at d 7.52, 7.10, and 6.81, respectively, suggesting the presence of a methoxy group at C-8. Based on these spectral data, and the structural similarity with that of (+)-mahanimbine, the structure 142 was assigned to murrayamine-B. This structure was further supported by NOE experiments (115).

Occurrence, Isolation, and Structure Elucidation

55

In 1974, Chakraborty et al. reported the isolation of murrayacinine (143), a formyl analog of (7)-mahanimbine (139b) from the stem bark of M. koenigii. The absolute configuration of this isolate is also not known (77). The UV (lmax 234, 280, 301, and 312 nm) and IR (nmax 1590, 1610, 1670, and 3360 cm1) spectra of murrayacinine (143) showed the presence of a 3-formylcarbazole framework. On borohydride reduction, murrayacinine gave the corresponding alcohol, the UV spectrum of which resembled that of (7)-mahanimbine (139b) (see Scheme 2.27) and confirmed it to be a formyl analog of (7)-mahanimbine (139b). This structure was also supported by the mass fragmentation ions at m/z 262 (M+CH2CH2CHQCMe2) and 234 (M+CH2CH2CHQCMe2CO). Based on these spectral data and comparison with the known UV data of (7)-mahanimbine (139b) and 3-formylcarbazole, structure 143 was assigned to murrayacinine. Further support for this structure comes from its synthesis (77). In 1996, Wu et al. reported the isolation of murrayamine-N (144) and murrayamine-J (145) from the leaves of M. euchrestifolia collected in November. The absolute configurations of these alkaloids are not assigned (130). The UV [lmax 248, 271 (sh), 289, 300, and 313 nm] and IR (nmax 1590, 1668, 1750, and 3333 cm1) spectra of murrayamine-N (144) were similar to those of murrayamine-C (141) indicating the presence of a similar pyranocarbazole chromophore. The 1H-NMR spectrum differs from that of murrayamine-C (141) only in the presence of a C-3 formyl group at d 10.03 instead of the aromatic methyl group. The presence of a formyl group at C-3 was unequivocally confirmed by the downfield shift of the C-4 (d 8.07) and C-2 (d 7.41) protons by about 0.75 ppm as compared to the C-4 (d 7.33) and C-2 (d 6.65) protons of murrayamine-C. Based on these spectral data, structure 144 was assigned to murrayamine-N. This structure was further supported by the NOE experiments (130). The UV (lmax 243, 267, 290, 311, and 346 (sh) nm) and IR (nmax 1575, 1646, 1667, 2856, and 3331 cm1) spectra of murrayamine-J (145) resembled those of murrayamine-N (144), indicating the presence of a similar 3-formylpyranocarbazole chromophore. The 1H-NMR spectrum differs from that of murrayamine-N (144) only in the A-ring substitution pattern of the carbazole nucleus. In the aromatic region, H-4 (d 8.46) and H-2 (d 7.89) were mutually meta-coupled (J=1.7 Hz), indicating the presence of a formyl group at C-3. This assignment was supported by the signal for H-1, which appeared as a doublet at d 7.44 with an ortho-coupling (J=8.4 Hz). Based on these spectroscopic data and the similarity to murrayamine-N, structure 145 was assigned to murrayamine-J (130). In 1970, Joshi et al. reported the isolation of ()-isomahanimbine (146), a methyl analog of murrayamine-J (145) from the leaves of M. koenigii. Although, murrayamine-J (145) was isolated from Nature in optically active form ([a]D –6, c 2.1, CHCl3), the absolute configuration is still not known (110). In the same year, Kapil et al. isolated the opposite enantiomer (½a30 D þ 18:6, c 0.86, CHCl3) from the same source and named it (+)-mahanimbicine (147). The absolute configuration of this alkaloid is also unknown (136). The UV (lmax 238, 281, 290, 335, and 354 nm) and IR (nmax 1580, 1600, 1638, 3410, and 3440 cm1) spectra of ()-isomahanimbine (146) were similar to those of murrayamine-C (141) (see Scheme 2.28) indicating the presence of a similar pyranocarbazole framework. The 1H-NMR spectrum indicated a similar C-ring substitution pattern with that of murrayamine-C (141) (see Scheme 2.28). However,

56

Chemistry and Biology of Carbazole Alkaloids

the A-ring substitution pattern was completely different. Thus, in the aromatic region, H-1 (d 7.15) and H-2 (d 7.05) were mutually ortho-coupled (J=8.0 Hz), and H-4 appeared as a broad singlet at d 7.68, indicating the presence of a methyl group at C-3. The position of the methyl group was supported by the meta-coupling (J=1.0 Hz) of H-2. Based on these spectroscopic data, structure 146 was assigned to ()-isomahanimbine. Additional support for this structure was derived from the transformation into known carbazole derivatives (110). In 1970, Narasimhan et al. described the isolation of ()-mahanine (148) in optically active form ([a]D 24.4) from the leaves of M. koenigii (113,133). Three decades later, Nakatani et al. isolated from the same natural source the opposite enantiomer, (+)-mahanine (149) (88). In 1999, Ramsewak et al. reported the isolation of mahanine from the leaves of the same natural source. However, its absolute configuration was not mentioned (137). In 1991, Wu reported the isolation of (+)-mahanine (149) from a different Murraya species, M. euchrestifolia (115). This alkaloid showed a specific rotation of [a]D +34 (c 2.0, CHCl3), and its CD spectrum displayed a positive Cotton effect in the region of 265–276 nm due to the styrene chromophore, indicating a negative chirality of the pyranocarbazole ring system. Therefore, the absolute configuration of (+)-mahanine (149) was S at C-3u. Consequently, ()-mahanine (148) has an R configuration (115). In 2002, (+)-mahanine (149) was also isolated by Nakahara et al. from the twigs of Micromelum minutum (138). This alkaloid showed a wide variety of biological activities, including cytotoxicity against the tumor cell line HL60 (131,138), antimutagenicity against heterocyclic amines such as 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1), and antimicrobial activity against Bacillus cereus and Staphylococcus aureus (138). The UV spectrum [lmax 221, 240, 285 (sh), 294, 342, and 357 nm] of (+)-mahanine (149) resembled that of murrayamine-A (120) (see Scheme 2.22), indicating the presence of a similar pyranocarbazole framework. This assignment was supported by the IR spectrum. The 1H-NMR spectrum differs from that of murrayamine-A only by the signals at d 1.73 (2H, t), 2.14 (2H, m), 5.10 (1H, t), 1.57 (3H, s), and 1.65 (3H, s) resulting from the side chain –CH2CH2CHQCMe2, which replaces one of the methyl groups on the pyran ring of murrayamine-A (120). The presence of this side chain was supported by the mass fragmentation ion at m/z 264 (M+CH2CH2CHQCMe2). Based on these spectral data, structure 149 was assigned to (+)-mahanine (115) (Scheme 2.29). In 2003, Nakatani et al. reported the isolation of O-methylmahanine (149a) from the leaves of M. koenigii (116). Although this alkaloid was isolated in optically active form (½a25 D þ 3:0, c 0.10, CHCl3), the absolute configuration is unknown. O-Methylmahanine (149a) showed radical scavenging activity against 1,1-diphenyl2-picrylhydrazyl (DPPH) radical (116). Prior to its isolation, the same compound was known synthetically in racemic form as DL-O-methylmahanine (139). The UV spectrum [lmax 221, 241, 285 (sh), 296, 343, and 358 (sh) nm] of O-methylmahanine (149a) resembled that of (+)-mahanine (149), indicating a similar pyranocarbazole framework. This conclusion was supported by the IR spectrum. The 1H-NMR spectrum differs from that of (+)-mahanine (149) only in the presence of an aromatic methoxy group at d 3.88 instead of the hydroxy group. This assignment was confirmed by the 13C-NMR signal at d 55.7. Based on these spectral data, structure 149a was assigned to O-methylmahanine (116) (Scheme 2.29).

Occurrence, Isolation, and Structure Elucidation

Me

Me HO

O N H

3′ 1′

57

O

HO N H

Me

2′

Me

3′ 1′

2′

Me Me Me

Me 148 (−)-Mahanine

149 (+)-Mahanine Me O

MeO N H

Me Me Me

149a O-Methylmahanine

Scheme 2.29

2 Cyclic Monoterpenoid Pyrano[3,2-a]carbazole Alkaloids In 1969, Dutta et al. reported the isolation of a pentacyclic pyrano[3,2-a]carbazole alkaloid (currayanin) from M. koenigii and assigned its structure as 150 (140,141). This alkaloid was obtained from Nature in racemic form (141). The name currayanin derives from the vernacular name of this plant: currypatta or curry-leaf tree. One year later, Chakraborty et al. described the isolation of the same alkaloid from the stem bark of the same source in optically active form (½a30 D þ 20, CHCl3) and named it murrayazolidine (142). In 1969, Kapil et al. isolated from the leaves of M. koenigii a pentacyclic pyrano[3,2-a]carbazole alkaloid cyclomahanimbine (151) in racemic form (143). In 1974, Bandaranayake et al. achieved the synthesis of cyclomahanimbine (151) by heating (7)-mahanimbine (139) (see Scheme 2.27) in benzene under reflux in the presence of an ion-exchange resin (Dowex-50W-X8, H+) (144). Independently, Bandaranayake and Narasimhan et al. examined the structure of optically active murrayazolidine and racemic currayanin and reassigned the structure as 151 (141,144). In 1983, Furukawa et al. reported the relative stereochemistry of cyclomahanimbine based on the X-ray structure of (7)-murrafoline (178) (see Scheme 2.38) which is a C–C dimer of girinimbine (115) (see Scheme 2.22) and cyclomahanimbine (145,146). Two years later, the same authors reported the isolation of racemic cyclomahanimbine from the root bark of M. euchrestifolia (29). In 1974, Chakraborty et al. revised the structure of optically active murrayazolidine to racemic cyclomahanimbine (151) (147) (Scheme 2.30). In 1992, Reisch et al. also reported the isolation of murrayazolidine (151), which was identical with cyclomahanimbine and curryanin, from the fruits of M. koenigii and confirmed the relative stereochemistry by X-ray analysis (71). The UV spectrum (lmax 246, 251, 257, 307, and 341 nm) of cyclomahanimbine (151) indicates the presence of a carbazole framework with an ether oxygen at C-2. This assignment was supported by the IR spectrum [nmax 1602, 1615 (aromatic system), and 3425 (NH) cm1]. On hydrogenation, cyclomahanimbine yielded the corresponding dihydro derivative, which did not show any shift of the absorption

58

Chemistry and Biology of Carbazole Alkaloids

O N H

Me

Me

Me Me

O Me

N H H

Me

Me 150

HO

H

Me Me

151 Cyclomahanimbine (Murrayazolidine,Curryanin) Me O Me

N H Me

153 Exozoline

152 Murrayazolinine

Me

H

N H Me

Me

O Me

N H

H

O

Me Me Me

3′

OH

154 Murrayamine-O

H

N H HO

H

O

Me Me

3′

Me

155 Murrayamine-P

Scheme 2.30

maxima, indicating that the double bond in the alkaloid is not conjugated with the carbazole system. The 1H-NMR spectrum resembled that of (+)-mahanimbine (139a) (see Scheme 2.27). However, cyclomahanimbine showed two additional vinylic protons at d 4.72, a vinylic methyl group at d 2.33, and a benzylic methine proton at d 3.11. These spectral data, and the characteristic mass fragmentation at m/z 248 (M+83), indicated the presence of a 2,2-substituted pyran system. Based on these spectroscopic data, structure 151 was assigned to cyclomahanimbine (143). This structural assignment was supported by two independent syntheses, starting from murrayazoline (163a) (see Scheme 2.32) and (+)-mahanimbine (139a) (see Scheme 2.27) (141,143,144,148), and by transformation into known carbazole derivatives (143), as well as X-ray analysis (71). In 1973, Chakraborty et al. reported the isolation of murrayazolinine (152) from the stem bark of M. koenigii. The absolute configuration of murrayazolinine is not known (148). The UV (lmax 240, 253, 258, and 304 nm) and IR [nmax 1610, 1630 (aromatic system), and 3400 (NH) cm1] spectra of murrayazolinine (152) resembled those of cyclomahanimbine (151), indicating a similar carbazole framework. The 1H-NMR spectrum differs from that of cyclomahanimbine only by the presence of a hydroxy isopropyl group instead of the vinylic methyl group. This conclusion was supported by the IR band at 3250 (OH) cm1, as well as by the isolation of acetone during the chromic acid oxidation of murrayazolinine. The presence of a –CH2CH2CHC(OH)(Me)2 group annulated at the dihydropyran ring was confirmed by the mass fragmentation ion at m/z 248 (M+CH2CH2 CHC(OH)(Me)2). Based on these spectral data, structure 152 was assigned to murrayazolinine. Direct support for this structure derived from dehydration of murrayazolinine (152) with phosphorous oxychloride to murrayazoline (163a) (see Scheme 2.32).

Occurrence, Isolation, and Structure Elucidation

59

In 1978, Ganguly and Sarkar reported the isolation of exozoline (153) from the leaves of M. exotica (149). The UV (lmax 242, 256, and 306 nm) and IR [nmax 1615, 1625 (aromatic system), and 3440 (NH) cm1] spectra of exozoline (153) resembled those of cyclomahanimbine (151), indicating a similar carbazole framework. The 1HNMR spectrum of exozoline is similar to that of cyclomahanimbine, but showed a six-proton doublet at d 0.62 instead of the signals for the isopropenyl group. Based on the spectral data, the structure of exozoline (153) was confirmed as dihydrocyclomahanimbine. This assignment was supported by the superimposable IR spectrum of dihydrocyclomahanimbine obtained by hydrogenation of cyclomahanimbine (151). In 1995, Wu et al. reported the isolation of two C-3u epimeric, cannabinol-skeletal carbazole alkaloids, murrayamine-O (154) and murrayamine-P (155) from the root bark of M. euchrestifolia (150). Although these two diasteromeric alkaloids were obtained in optically active form ([a]D –137.6, c 0.07, CHCl3) and [a]D +92, c 0.015, CHCl3), respectively, their absolute configuration is not known. However, the relative configuration was assigned based on 2D-NMR studies (150). In the same year, Wu et al. also reported the isolation of murrayamine-D (156) from the leaves of the same plant collected in winter (February). This alkaloid contains the same bicyclic terpenoid skeleton as murrayazolidine (151), but has a hydroxy group at C-7 of the carbazole nucleus. Therefore, murrayamine-D (156) is a 7-hydroxymurrayazolidine. The absolute configuration of murrayamine-D is not known (151). One year later in spring (May), the same group isolated from the leaves of M. euchrestifolia murrayamine-H (157), murrayamine-F (158), and murrayamine-G (159). The absolute configuration of these alkaloids is still not known (125). The plant shows strong seasonal variations of carbazole alkaloids. Therefore, the pharmacological activity of the extracts from this traditional Chinese medicinal plant is dependent on the collection time, which may be explained by the variation of the biologically active carbazole alkaloids (125) (Scheme 2.31). The UV spectrum [lmax 240, 254, 258 (sh), 304, 319 (sh), and 332 nm] of murrayamine-O (154) indicates a 2-oxygenated carbazole. This assignment was confirmed by the IR spectrum [nmax 1614 (aromatic system), 3200 (OH), and 3450 (NH) cm1]. The presence of a hydroxy group was supported by the mass fragmentation ion at m/z 248 (M+18)U The 1H-NMR spectrum showed the presence Me

Me R1 R2

N H Me

O Me R

156 Murrayamine-D (7-Hydroxymurrayazolidine) R1 = OH; R2 = H

N H Me

O Me

158 Murrayamine-F R = OMe 159 Murrayamine-G

157 Murrayamine-H

R=H

R1 = H; R2 = OMe

Scheme 2.31

60

Chemistry and Biology of Carbazole Alkaloids

of a broad singlet for an NH proton at d 8.61. In the aromatic region, a downfield singlet at d 7.59 for H-4, and four, mutually-coupled protons at d 7.07, 7.20, 7.33, and 7.84 for H-6, H-7, H-8, and H-5, respectively, indicated a 1,3-disubstituted-2oxygenated carbazole framework. The aromatic methyl group, supported by a characteristic signal at d 2.22, was located at C-3. Nine of the eleven double bond equivalents corresponded to the carbazole nucleus. The lack of olefinic protons indicated that the additional two double bond equivalents were due to two rings. Based on 13C-NMR, DEPT, and QUAT (unprotonated 13C-nuclear only) spectra of murrayamine-O (154), the remaining skeleton consisted of ten carbon atoms: three methyl groups, three methylene groups, two methine carbons, and two quaternary carbons, suggesting a 3u-hydroxy-3u,7u,7u-trimethyloxadecalin ring fused to C-1 and C-2 of ring A of the carbazole. This assignment was confirmed by HMBC and COSY spectra. The relative configurations were confirmed by the splitting patterns, coupling constants, and NOESY experiments. Based on the spectroscopic data, structure 154 was assigned to murrayamine-O (150) (Scheme 2.30). The UV [lmax 240, 254, 257 (sh), 304, 319 (sh), and 331 nm] and IR (nmax 1609, 3377, and 3522 cm1) spectra of 155 resembled those of murrayamine-O (154), indicating a similar carbazole framework. The 1H-NMR and 13C-NMR spectra of murrayamine-P were also similar to those of murrayamine-O (154), except for the NOESY correlations. This assignment was confirmed by an HMBC spectrum, which emphasized that murrayamine-P differed from murrayamine-O only by the relative configuration at C-3u. Therefore, structure 155 was assigned to murrayamine-P (150) (Scheme 2.30). The UV (lmax 239, 266, 315, and 324 nm) and IR [nmax 1620 (aromatic system), and 3429 (NH) cm1] spectra of murrayamine-D (156) resembled those of murrayazolidine (151) (see Scheme 2.30) indicating a similar carbazole framework. The 1H-NMR spectrum confirmed the same A-ring substitution pattern as that of murrayazolidine (151). However, the C-ring substitution pattern was completely different. Thus, in the aromatic region, H-5 (d 7.69) and H-6 (d 6.65) were mutually ortho-coupled (J=8.4 Hz), and H-8 (d 6.78) was only meta-coupled (J=2.2 Hz), indicating C-7 as the position of the hydroxy group. The location of the hydroxy group was confirmed by the meta-coupling (J=2.2 Hz) of H-5 with H-8. The presence of a hydroxy group was supported by a broad IR band between 3200 and 3600 cm1. Based on the spectral data, the structure of murrayamine-D (156) was assigned as 7-hydroxymurrayazolidine. This assignment was confirmed by NOE experiments (151) (Scheme 2.31). The UV (lmax 243, 255, 301, and 329 nm) and IR [nmax 1580, 1628 (aromatic system), and 3435 (NH) cm1] spectra of murrayamine-H (157) resembled those of murrayamine-D (156) indicating a similar carbazole framework. The 1H-NMR spectrum showed a close similarity to murrayamine-D, except for the carbazole C-ring substitution pattern which confirmed the presence of an aromatic methoxy group at d 3.99, instead of the aromatic hydroxy group. Thus, in the aromatic region, H-5, H-6, and H-7 were mutually ortho-coupled (J=7.8 Hz) at d 7.50, 7.06, and 6.78, respectively, indicating that the position of the methoxy group is at C-8. The downfield shift of H-5 at d 7.50, along with the meta-coupling (J=1.2 Hz) to H-7, confirmed the position of the methoxy group. Based on these spectral data, structure 157 was assigned to murrayamine-H. This structural assignment was supported by NOE experiments (125).

Occurrence, Isolation, and Structure Elucidation

61

The UV spectrum [lmax 244, 256 (sh), 303, and 328 (sh) nm] of murrayamine-F (158) is very similar to that of murrayamine-H (157) indicating a similar carbazole framework. This assignment was supported by the IR spectrum. The 1H-NMR spectrum showed similar substituents, including an aromatic methyl group at d 2.49, an aromatic methoxy group at d 3.97, and a bicyclic ring with isopropenyl and methyl substituents. However, the aromatic methyl and methoxy substituents were in different positions as compared to murrayamine-H (157). Besides these substituents, the aromatic region showed two, ortho-coupled (J=8.4 Hz) doublets at d 7.69 and 6.70, assigned to H-5 and H-6, respectively. Furthermore, two, metacoupled protons appeared as broad singlets at d 6.62 and 7.32, assigned to H-2 and H-4, respectively. The chemical shift and the coupling pattern of the signals for the aromatic protons confirmed structure 158 for murrayamine-F. This assignment was supported by an NOE difference spectrum (125). The UV (lmax 241, 262, and 307 nm) and IR [nmax 1617 (aromatic system), and 3465 (NH) cm1] spectra of murrayamine-G (159) resembled those of murrayamine-F (158), indicating a similar carbazole framework. The 1H-NMR spectrum was also similar to that of murrayamine-F, but the signal for the methoxy group was absent. In the aromatic region, H-4 (d 7.71) showed a meta-coupling (J=1.0 Hz) with H-2 (d 7.10), which had an additional ortho-coupling (J=8.3 Hz) with H-1 (d 7.22), indicating the position of the aromatic methyl group at C-3, as in murrayamine-F. Based on these spectroscopic data, structure 159 was assigned to murrayamine-G. This assignment was supported by NOE experiments (125) (Scheme 2.31). In 1969, Kapil et al. reported the isolation of bicyclomahanimbine (160) from the leaves of M. koenigii. Although, bicyclomahanimbine was isolated in optically active form ½a23 D  1:23 (CHCl3), the absolute configuration is not known (143). One year later, the same authors isolated from the same natural source bicyclomahanimbicine (161), an isomer of bicyclomahanimbine (160). The absolute configuration of this alkaloid is also not known (136). Four years after their isolation, Bandaranayake et al. revised the original structure of these alkaloids (144). In 1995, Wu et al. reported the isolation of bicyclomahanimbine (160) from the leaves of a different Murraya species, M. euchrestifolia (151) (Scheme 2.32). The UV spectrum (lmax 242, 255, 260, and 305 nm) of bicyclomahanimbine (160) shows the typical absorption of a 2-hydroxy-3-methylcarbazole skeleton. This assignment was supported by the IR spectrum [nmax 1605, 1625 (aromatic system), and 3455 (NH) cm1]. The aromatic region of the 1H-NMR spectrum resembled that of (7)-mahanimbine (139b) (see Scheme 2.27) and cyclomahanimbine (151) (see Scheme 2.30), indicating a similar aromatic substitution pattern on the carbazole framework. However, the monoterpene moiety fused at C-1 and C-2 was different. In consideration of the molecular formula, and the absence of two double bonds present in (7)-mahanimbine (139b), bicyclomahanimbine (160) was proposed as a hexacyclic base with a cyclobutane system. The presence of a cyclobutane ring was supported by the downfield shift (D 0.72) of the methyl group at d 0.71 in bicyclomahanimbine when compared to the methyl group of (7)-mahanimbine at d 1.43 (29). Based on these spectroscopic data and the structural similarity to cannabicyclol, which was determined by X-ray analysis, structure 160 was assigned to bicyclomahanimbine (143,144).

62

Chemistry and Biology of Carbazole Alkaloids

R2

R1 O Me

N H

Me O

R N Me

Me

Me

Me

160 Bicyclomahanimbine R1 = Me; R2 = H 161 Bicyclomahanimbicine R1 = H; R2 = Me 162 Murrayamine-M R1 = H; R2 = CHO

Me

163a Murrayazoline (Mahanimbidine,Curryangin) R=H 163b (+)-Murrayazoline R=H 164

Murrayamine-E (7-Hydroxymurrayazoline) R = OH

Scheme 2.32

The UV (lmax 243, 257, 263, and 305 nm) and IR [nmax 1610 (aromatic system), and 3445 (NH) cm1] spectra of bicyclomahanimbicine (161) resembled those of bicyclomahanimbine (160) indicating a similar carbazole framework. The 1H-NMR spectrum showed similar substituents, including an aromatic methyl group at d 2.51 and a dihydropyran ring. However, the position of the aromatic methyl group was different. The aromatic region showed the presence of two ortho-coupled (J=8.0 Hz) doublets at d 7.76 and 6.74, assigned to H-5 and H-6, respectively. Furthermore, a meta-coupled proton appeared as a broad singlet at d 7.76 and was assigned to H-4, and a two-proton multiplet at d 7.21 to H-1 and H-2. The chemical shifts and the coupling patterns of the signals in the aromatic region, as well as the similarity to bicyclomahanimbine, led to structure 161 for bicyclomahanimbicine (136,144). In 1996, Wu et al. reported the isolation of murrayamine-M (162), a formyl analog of bicyclomahanimbicine (161) from the leaves of M. euchrestifolia collected in November in Taiwan. The UV spectrum [lmax 243, 254 (sh), 292, and 325 nm] of murrayamine-M (162) indicated a 3-formylcarbazole. This assignment was supported by the IR spectrum [nmax 1605 (aromatic system), 1675 (CHO), and 3300 (NH) cm1]. The 1H-NMR spectrum resembled that of bicyclomahanimbicine (161), but exhibited a formyl group (d 10.08) at C-3 instead of the aromatic methyl group. The deshielded meta-coupled (J=1.7 Hz) H-4 at d 8.48 confirmed the position of the formyl group at C-3. Based on the spectral data, structure 162 was assigned to murrayamine-M (Scheme 2.32). The absolute configuration of 162 is not known (130). In 1969, Dutta et al. isolated curryangin (163a) from the stem bark of M. koenigii in racemic form (152). In the same year, Kapil et al. described the isolation of the same alkaloid, also as a racemate, from the leaves of M. koenigii and named it mahanimbidine (163a) (143). In 1972, Chakraborty et al. reported the third isolation of this structure from M. koenigii and named it murrayazoline (163a). From the X-ray structure determination it was clear that this isolation again provided the natural product in racemic form (153). In 1985, Furukawa et al. isolated this alkaloid in optically active form ([a]D +2.25, CHCl3) from the root bark of M. euchrestifolia and named it (+)-murrayazoline (163b). However, the absolute configuration has not been determined (29).

Occurrence, Isolation, and Structure Elucidation

63

The UV spectrum (lmax 239, 266, and 308 nm) of murrayazoline (163a) indicated a 2-oxygenated carbazole. The 1H-NMR spectrum showed the presence of three methyl singlets at d 1.26, 1.43, and 1.90, which are typical of methyl groups attached to carbon bearing an electronegative atom, and a fourth singlet at d 2.33 for an aromatic methyl group. Along with these four methyl groups, a benzylic methine proton appeared as a broad multiplet at d 3.33. The lack of an NH proton, and of olefinic protons, indicated the hexacyclic structure of this alkaloid with a carbazole N-atom common to two rings. Based on the spectral data and an X-ray analysis, structure 163a was assigned to murrayazoline (153). This assignment was additionally supported by the synthesis of murrayazoline (163a) starting from (7)-mahanimbine (139b) (see Scheme 2.27) (141,143,152). In 1995, Wu et al. reported the isolation of murrayamine-E (164) from the leaves of M. euchrestifolia collected in February in Taiwan. Murrayamine-E (164) was obtained in optically active form [a]D –39.68 (c 0.133, CHCl3). However, the absolute configuration was not determined. The relative stereochemistry was confirmed by a NOESY spectrum and an X-ray analysis (151). The UV spectrum [lmax 245, 273, 316, and 335 (sh) nm] of murrayamine-E (164) indicated a 1-substituted-3-methyl-2,7dioxygenated carbazole. This assignment was supported by the IR spectrum [nmax 1608, 1623 (aromatic system), and 3358 (OH) cm1]. The 1H-NMR spectrum differed from that of murrayazoline (163a) only in the substitution pattern of the carbazole C-ring by the presence of an additional aromatic hydroxy group at d 4.70. From the aromatic splitting pattern of the carbazole C-ring, the hydroxy group was located at C-7. The aromatic region showed signals for two ortho-coupled (J=9.0 Hz) protons at d 7.75 and 6.78, assigned to H-5 and H-6, respectively. Moreover, H-6 showed an additional meta-coupling (J=2.4 Hz) with H-8, which appeared at d 6.99. Based on the spectral data, the structure of murrayamine-E (164) was assigned as 7-hydroxymurrayazoline (Scheme 2.32). Additional support for this assignment was derived from a NOESY spectrum and an X-ray crystal structure analysis (151) (Scheme 2.31). In 1982, Chakraborty et al. reported the isolation of isomurrayazoline (165), a regioisomer of murrayazoline (163a) (see Scheme 2.32), from the stem bark of M. koenigii. This alkaloid was obtained from Nature in optically active form ([a]D 7.33, CHCl3). However, its absolute configuration is not known. The UV (lmax 240, 253, 258, 303, and 330 nm) and IR [nmax 1605 (aromatic system) cm1] spectra of isomurrayazoline (165) resembled those of murrayazoline (163a) (see Scheme 2.32), indicating a similar pyranocarbazole framework. The 1H-NMR spectrum confirmed the similarity with signals for an aromatic methyl group at d 2.35 and a hexacyclic carbazole ring. However, the methyl group was located at a different position on the carbazole framework. The aromatic region showed signals for five aromatic protons as a one-proton multiplet at d 7.95, an unresolved two-proton doublet at d 7.55, and a two-proton multiplet at d 7.13–7.33. The aromatic substitution pattern was very similar to that of ()-isomahanimbine (146) (see Scheme 2.28). Based on the spectroscopic data, structure 165 was assigned to isomurrayazoline. Additional proof for this assignment was obtained by the transformation of isomurrayazoline (165) to isomurrayazolinine by acid-catalyzed hydration (154) (Scheme 2.33). In 1989, the same authors reported the isolation of murrayazolinol (166) from the same natural source as a minor carbazole alkaloid (155). In 1995, this alkaloid was also obtained by Ahmad as a minor carbazole alkaloid from the benzene extract of

64

Chemistry and Biology of Carbazole Alkaloids

the root bark of Murraya exotica (156). The absolute configuration of murrayazolinol (166) has not been determined (155,156). The UV spectrum (lmax 245, 265, and 305 nm) of murrayazolinol (166) is similar to that of murrayazoline (163a) (see Scheme 2.32), indicating a similar pyranocarbazole framework. The IR spectrum [nmax 1350, 1380 (C-methyl), 1620, 1650 (aromatic system), 3360 (OH) cm1] confirmed the pyranocarbazole structure with an additional OH group. The 1H-NMR spectrum of murrayazolinol exhibited signals for an aromatic methyl group at d 2.34, and confirmed an aromatic substitution pattern similar to murrayazoline (163a). The difference was in the substitution of the monoterpenoid moiety. The 1H-NMR spectrum of the monoterpenoid moiety of murrayazoline showed a signal for the carbinyl hydrogen of a secondary alcohol, which appeared as a doublet of doublets (J=7.2 Hz) at d 3.80. The presence of a secondary hydroxy group was confirmed by the mass fragmentation ion at m/z 314 (M+CH3H2O). Based on the spectroscopic data, structure 166 was assigned to murrayazolinol (155) (Scheme 2.33).

3 Pyrano[2,3-a]carbazole Alkaloids In 1996, Ito et al. reported the isolation of clauszoline-A (167) and clauszoline-B (168) from the acetone extract of the stem bark of C. excavata collected in Singapore (74). These alkaloids represented the first, naturally occurring 2,8-dioxygenated-3formylcarbazole alkaloids with a dimethylpyran ring fused to C-7 and C-8 of the carbazole nucleus. The extracts of the leaves and bark of this tree have been used in traditional medicine for the treatment of snakebites and abdominal pain (74). One year later, the same group isolated another pyrano[2,3-a]carbazole alkaloid, clauszoline-H (169), from the roots of the same natural source in Japan (47) (Scheme 2.34). Me

Me O N

O N

Me

Me

Me OH

Me

Me

Me

165 Isomurrayazoline

166 Murrayazolinol

Scheme 2.33 OHC

3

4

5

Me

6 7

2

HO 1

R

N H

8

O 1′

2′

Me

4′

MeO N H

3′

Me

O Me

169 Clauszoline-H

167 Clauszoline-A R = prenyl 168 Clauszoline-B R=H

Scheme 2.34

Me

Occurrence, Isolation, and Structure Elucidation

65

The UV spectrum (lmax 240, 265, 306, and 375 nm) of clauszoline-A (167) indicated a carbazole framework. This assignment was supported by the IR spectrum [nmax 1630 (aromatic system), 3440 (br) (OH), and 3450 (NH) cm1]. The 1 H-NMR spectrum showed signals for an NH at d 8.31 (broad singlet), a strongly hydrogen-bonded hydroxy group at d 11.64, a formyl group at d 9.89, and a prenyl side chain (d 1.79, 1.94, 3.65, and 5.36). The prenyl side chain was confirmed by the mass fragmentation ion at m/z 306 (M+CHQCMe2). In the aromatic region, the deshielded singlet at d 7.98 was assigned to H-4 based on the deshielding caused by the C-3 carbonyl group. The singlet for H-4 suggested the position of the hydroxy group at C-2 and of the prenyl side chain at C-1. Moreover, two, mutually ortho-coupled (J=7.7 Hz) proton signals at d 7.44 and 6.90 were assigned to H-5 and H-6, indicating substitution at C-7 and C-8. The six-proton singlet at d 1.53, together with symmetrical doublets at d 5.63 and 6.48, suggested the presence of a 2,2-dimethyl-D3-pyran ring. The fusion of the pyran ring at C-7 and C-8 of the carbazole nucleus was confirmed by an NOE enhancement between H-6 (d 6.90) and H-4u (d 6.48). The 2,2-dimethyl-D3-pyran ring was confirmed by the mass fragmentation ion at m/z 346 (M+Me), which could represent the carbazolopyrrylium ion. On the basis of these spectral data, structure 167 was assigned to clauszoline-A (74). The UV [lmax 242, 252 (sh), 264, 291 (sh), 304, and 376 nm] and IR [nmax 1630 (aromatic system), 3300 (br) (OH), and 3450 (NH) cm1] spectra of clauszoline-B (168) resembled those of clauszoline-A (167), indicating a pyranocarbazole framework. The 1H-NMR spectrum also showed a signal pattern similar to that of clauszoline-A, except for the presence of a high-field, one-proton singlet at d 6.83, instead of signals for the prenyl side chain. Based on the spectroscopic data, structure 168, representing a deprenylated clauszoline-A, was assigned to clauszoline-B. This assignment was supported by NOE experiments (74). The UV spectrum [lmax 230, 258, 288, 310, and 363 nm] of clauszoline-H (169) was very similar to that of clauszoline-B (168), indicating a pyranocarbazole. This assignment was supported by the IR spectrum. The 1H-NMR spectrum of clauszoline-H (169) differs from that of clauszoline-B (168) only in the substituents at the A-ring of the carbazole nucleus. The 1H-NMR spectrum showed signals for an aromatic methyl group at d 2.34 and an aromatic methoxy group at d 3.90, instead of a formyl group and a strongly hydrogen-bonded hydroxy group, as in clauszoline-B. Based on these spectral data, and additional support by NOE experiments, structure 169 was assigned to clauszoline-H (47).

4 Pyrano[2,3-b]carbazole Alkaloids In 1991, Furukawa et al. reported the isolation of pyrayafoline B (170) from the stem bark of M. euchrestifolia collected in May in Taiwan (87). In the same year, the same group isolated a further pyrano[2,3-b]carbazole alkaloid, pyrayafoline E (171), from the stem bark of M. euchrestifolia. Pyrayafoline E was isolated from Nature in racemic form (70). These alkaloids are the first members of the naturally occurring 2,7-dioxygenated-3-methylcarbazole alkaloids having a dimethyl pyran ring fused to C-6 and C-7 of the carbazole nucleus (70,87) (Scheme 2.35). The UV spectrum [lmax 228, 252, 285, 296 (sh), 329, and 353 nm] of pyrayafoline B (170) indicated a carbazole framework. This assignment was supported by the IR spectrum. The 1H-NMR spectrum showed a singlet for an NH proton at d 7.70, a

66

Chemistry and Biology of Carbazole Alkaloids

Me

Me

HO N H

O Me

Me

Me

HO

O N H

170 Pyrayafoline B

171 Pyrayafoline E

Scheme 2.35

broad singlet for a hydroxy group at d 4.94, and a singlet for an aromatic methyl group at d 2.37. A six-proton singlet at d 1.46, assigned to the geminal dimethyl group at the pyran ring, and the symmetrical doublets at d 5.58 and 6.48 indicated a 2,2-dimethyl-D3-pyran ring. The presence of a 2,2-dimethyl-D3-pyran ring was supported by the mass fragmentation ion at m/z 264 (M+Me), which could be represented by the carbazolopyrylium ion. Furthermore, the aromatic region showed the presence of four, one-proton singlets at d 6.74, 7.62, 7.49, and 6.71. The two lowfield singlets at d 7.62 and 7.49 were assigned to H-4 and H-5, both deshielded by the carbazole nucleus. O-Methylation of pyrayafoline B with diazomethane gave the corresponding monomethyl ether, suggesting the presence of a phenolic group in pyrayafoline B. The spectral data of pyrayafoline B, supported by NOE experiments with the corresponding monomethyl ether, led to structure 170 for pyrayafoline B. This assignment was unequivocally confirmed by a spectroscopic comparison with the synthetic monomethyl ether of pyrayafoline B, obtained by a palladium(II)mediated synthesis starting from 7-acetylaminochromene and 4-bromo-2-methoxytoluene (87). The UV [lmax 233 (sh), 252, 284, 330 (sh), and 354 nm] and IR [nmax 1625 (aromatic system), 3380 (br) (OH), and 3470 (NH) cm1] spectra of pyrayafoline E (171) resembled those of pyrayafoline B (170), indicating a similar pyranocarbazole framework. The 1H-NMR spectrum differed from that of pyrayafoline B (170) only by the presence of signals at d 1.70 (2H, m), 2.13 (2H, m), 5.10 (1H, t), 1.57 (3H, s), and 1.65 (3H, s), assigned to the –CH2CH2CHQCMe2 side chain, instead of the signal for one of the methyl groups at the pyran ring of pyrayafoline B (170). The presence of this side chain was confirmed by the mass fragmentation ion at m/z 264 (M+CH2CH2CHQCMe2). Based on the spectral data, structure 171 was assigned to pyrayafoline E (70) (Scheme 2.35).

5 Pyrano[2,3-c]carbazole Alkaloids In 1989, Reisch et al. reported the isolation of glycomaurin (172) from the stem bark of G. mauritiana. This alkaloid represents the first example of a naturally occurring, 6-oxygenated-3-methylcarbazole having a dimethylpyran ring fused to the carbazole nucleus at C-5 and C-6 (100). In the following year, Ito and Furukawa isolated the same alkaloid from the root bark of M. euchrestifolia and named it eustifoline-A (101). Along with eustifoline-A (172), they also reported the isolation of the corresponding prenyl analog, eustifoline-B (173). The absolute configuration of this alkaloid is not known (101) (Scheme 2.36). The UV spectrum (lmax 232, 262, 273, 286, 314, 324, and 378 nm) of eustifoline-A (glycomaurin) (172) indicated a carbazole framework. This assignment was

Occurrence, Isolation, and Structure Elucidation

3′ 4′

Me

4

3

5

Me

Me R 2′

Me Me

O 1′ 7

N H

O

6

2 1

67

HO N H

8

172 Eustifoline-A (Glycomaurin) R=H

174 Glycoborinine

173 Eustifoline-B R = prenyl

Scheme 2.36

supported by the IR spectrum. The 1H-NMR spectrum showed a singlet for an NH proton at d 10.06 and an aromatic methyl group at d 2.48. In addition, a six-proton singlet at d 1.45, assignable to the geminal dimethyl group of the pyran ring, and the symmetrical doublets at d 5.90 and 7.36 indicated a 2,2-dimethyl-D3-pyran ring. The presence of a 2,2-dimethyl-D3-pyran ring was supported by the mass fragmentation ion at m/z 248 (M+Me). In the aromatic region, a deshielded, meta-coupled (J=0.7 Hz) doublet at d 7.99 for H-4, and the mutually ortho-coupled (J=8.4 Hz) H-1 and H-2 at d 7.36 and 7.19, respectively, suggested the position of the methyl group at C-3. Furthermore, H-2 at d 7.19 showed a meta-coupling (J=0.7 Hz) with H-4, confirming the position of methyl substituent at C-3. For the carbazole C-ring, two, mutually ortho-coupled (J=8.4 Hz) protons at d 6.84 and 7.25 indicated the fusion of the dimethylpyran ring at C-5 and C-6. The annulation of the pyran ring at C-5 and C-6 of the carbazole nucleus was confirmed by NOE experiments. Based on the spectroscopic data, structure 172 was assigned to eustifoline-A (101). This assignment was supported by the synthesis of 172 from glycozolinine (91), as well as glycomaurrol (92) (100) (see Scheme 2.17). The UV spectrum (lmax 230, 268, 304, 324, and 362 nm) of eustifoline-B (173) is very similar to that of eustifoline-A (glycomaurin) (172) indicating a similar pyranocarbazole. This assignment was supported by the IR spectrum. The 1H-NMR spectrum signal pattern of eustifoline-B (173) was also similar to that of eustifolineA, except for the presence of signals at d 1.78 (2H, m), 2.17 (2H, m), 5.11 (1H, t), 1.58 (3H, s), and 1.65 (3H, s), assignable to the side chain –CH2CH2CHQCMe2. The presence of this side chain was supported by the mass fragmentation ion at m/z 248 (M+CH2CH2CHQCMe2). Based on these spectral data, structure 173 was assigned to eustifoline-B (101). In 1999, Chakravarty et al. reported the isolation of glycoborinine (174) from the roots of G. arborea (62). The UV spectrum (lmax 262, 269, 293, and 335 nm) of glycoborinine (174) resembled that of eustifoline-A (glycomaurin) (172), indicating a similar carbazole framework. The 1H-NMR spectrum differed from that of eustifoline-A (172) only in the A-ring substitution pattern. In the aromatic region, H-4 (d 7.79) and H-1 (d 6.82) appeared as broad singlets, indicating the position of a methyl group at C-3 and a hydroxy group at C-2. Based on these spectral data, structure 174 was assigned to glycoborine. This assignment was supported by the 13 C-NMR, COSY, NOESY, HSQC, and HMBC spectra (62) (Scheme 2.36).

68

Chemistry and Biology of Carbazole Alkaloids

6 Pyranocarbazole-1,4-quinone Alkaloids In 1985, Furukawa et al. reported the isolation of pyrayaquinone-A (175) and pyrayaquinone-B (176) from the root bark of M. euchrestifolia (157). Three years later, the same authors reported a further pyranocarbazole-1,4-quinone alkaloid, pyrayaquinone-C (177) from the root bark of the same natural source. The absolute configuration of this isolate is not known (22) (Scheme 2.37). The UV [lmax 220 (sh), 252, 308 (sh), and 460 nm] and IR (nmax 1610, 1630, 1640, and 1660 cm1) spectra of pyrayaquinone-A (175) indicated the presence of a carbazole-1,4-quinone nucleus. The 1H-NMR spectrum showed signals for a vinylic methyl group as a doublet (J=1.5 Hz) at d 2.16, and an olefinic proton as a quartet (J=1.5 Hz) at d 6.46, both having a long-range coupling. In addition, a six-proton singlet at d 1.48, assigned to the geminal dimethyl group on the pyran ring, and the symmetrical doublets at d 5.72 and 6.48 indicated a 2,2-dimethyl-D3-pyran ring. The presence of a 2,2-dimethyl-D3-pyran ring was supported by the mass fragmentation ion at m/z 278 (M+Me). In the aromatic region, H-5 appeared downfield (d 7.79) as a singlet due to the deshielding effect of the C-4 carbonyl moiety. The upfield singlet at d 6.83 was assigned to H-8. The chemical shifts and the splitting pattern of the signals in the aromatic region indicated the fusion of the pyran ring at C-6 and C-7 of the carbazole nucleus. The spectral data, combined with biogenetic considerations, suggested structure 175 for pyrayaquinone-A (157). Additional support for this assignment was derived from synthesis (157). The UV [lmax 229 (sh), 248, 295 (sh), and 410 nm] and IR (nmax 1605, 1635, 1640, and 1650 cm1) spectra of pyrayaquinone-B (176) resembled those of pyrayaquinoneA (175) indicating a 3-methylcarbazole-1,4-quinone. The 1H-NMR spectrum indicated similar substituents as for pyrayaquinone-A, including an aromatic methyl group at d 2.14 and a 2,2-dimethyl-D3-pyran ring, which was annulated at a different position. The aromatic region showed the presence of two ortho-coupled (J=9.0 Hz) doublet protons at d 7.94 and 6.86, assigned to H-5 and H-6, respectively. The chemical shifts and the splitting pattern of the signals in the aromatic region, suggested structure 176 for pyrayaquinone-B (157). This assignment was supported by synthesis (157). The UV spectrum [lmax 248, 275 (sh), 294, and 392 nm] of pyrayaquinone-C (177) resembled that of pyrayaquinone-B (176) indicating a 3-methylcarbazole-1,4quinone. This assignment was supported by the IR spectrum. The 1H-NMR

O

O

Me

Me

Me Me

O N H

Me

O N H

O

O

R 175 Pyrayaquinone-A

176 Pyrayaquinone-B R=H 177 Pyrayaquinone-C R = prenyl

Scheme 2.37

Occurrence, Isolation, and Structure Elucidation

69

spectrum of pyrayaquinone-C (177) was also similar to that of pyrayaquinone-B, except for the presence of signals at d 1.76 (2H, m), 2.12 (2H, m), 5.09 (1H, t), 1.56 (3H, s), and 1.65 (3H, s), assignable to the side chain –CH2CH2CHQCMe2. The presence of this side chain attached to the pyran ring was confirmed by the mass fragmentation ion at m/z 278 (M+CH2CH2CHQCMe2). Based on the spectral data, structure 177 was assigned to pyrayaquinone-C (22) (Scheme 2.37).

C. Bis-Carbazole Alkaloids The bis-carbazole alkaloids contain previously known monomeric carbazoles as structural subunits. All bis-carbazole alkaloids were isolated only from plants of the genus Murraya, until 1996, when clausenamine-A (203) (see Scheme 2.48) was isolated from the stem bark of C. excavata. The plant M. euchrestifolia is one of the richest sources of carbazole alkaloids. The bis-carbazoles often co-occur with monomeric carbazoles in the root bark, stem bark, and leaves of this plant (3,5– 7,158,159). The aspect of atropisomerism for axially chiral, bis-carbazoles was considered only recently. Thus, in many cases it is not clear whether the isolated natural products are racemic or enantiomerically pure. Moreover, little attention has been paid to the relationship between their stereochemistry and biological activity. In 1983, Furukawa et al. isolated the first bis-carbazole alkaloid, murrafoline-A [(7)-murrafoline] (178) from the root bark of M. euchrestifolia. Murrafoline-A consists of a dihydrogirinimbine unit (cf. girinimbine (115) Scheme 2.22) attached at C-12 to the C-8 of cyclomahanimbine (151) (see Scheme 2.30). Both monomeric carbazole alkaloids co-occur with murrafoline-A (178). This alkaloid was isolated from nature in racemic form. The complete structure and relative stereochemistry of murrafolineA were confirmed by an X-ray analysis (145,146) (Scheme 2.38). The UV spectrum [lmax 243, 260 (sh), 307, and 332 (sh) nm] of murrafoline-A (178) indicated a carbazole framework. This assignment was supported by the IR spectrum. The 1H-NMR spectrum showed signals for two aromatic methyl groups at d 2.28 and 2.37, a vinylic methyl group at d 1.54, three tertiary methyl groups at a carbon linked to an oxygen, a triplet and a multiplet at d 4.58 and 3.24 due to benzylic protons, and overlapping unresolved signals for thirteen protons in the aromatic region between d 6.70 and 7.90 (two of which disappeared on treatment with deuterated water). The mass fragmentation showed a peak at m/z 297 along with the molecular ion peak at m/z 594, confirming the presence of a bis-carbazole 5

8′

Me

8 1′ 12′

4′ 2′

Me

O

O Me

9

N 1 H H H 11′ Me

10′

Me

3 9′ N

5′

H

2′

Me

178 Murrafoline-A [(±)-Murrafoline]

Scheme 2.38

9 1′ 12′

4′

H Me

Me

4

5

8′

3 9′ N

5′

4

H

O

8

N H Me

10′

Me

179 Murrafoline-B

1

OMe

70

Chemistry and Biology of Carbazole Alkaloids

framework. Based on these spectral data and an X-ray analysis, the structure for murrafoline-A [(7)-murrafoline] was assigned as 178 (145). From the same natural source, Furukawa et al. isolated in 1985 and 1993 further bis-carbazole alkaloids: murrafoline-B (179), -C (180a), -D (181) (146,160), -G (182), and -H (183) (146). In 2006, the same authors reported a further derivative of murrafoline, murrafoline-I (180b), from M. koenigii (131). Murrafoline-I (180b) induced apoptosis in HL-60 cells by activation of the caspase-9/caspase-3 pathway, through mitochondrial dysfunction (131). The common structural feature of all these murrafoline congeners is a dihydrogirinimbine attached at C-12 to a second carbazole moiety. All of these murrafolines were obtained from Nature as racemates (146,160) (Schemes 2.38–2.40). The UV spectrum [lmax 240, 292, 304, and 330 nm] of murrafoline-B (179) indicated the presence of a bis-carbazole framework. This assignment was supported by the IR spectrum, as well as the mass fragmentation which showed a peak at m/z 237 along with the molecular ion peak at m/z 474. The 1H-NMR spectrum showed signals for one aromatic methoxy group at d 3.87, two aromatic methyl groups at d 2.48 and 2.49, and a dimethyldihydropyran ring (d 2.30, 2.38, 4.69, 1.46, and 1.56). From decoupling experiments, it was concluded that the carbazole had one unsubstituted C-ring, and another C-ring with a substitution at C-8. NOE experiments supported the positions of the substituents. The spectral data and the mass fragmentations at m/z 263 and 211 indicated that the monomeric units of this alkaloid are murrayafoline-A and girinimbine. All of the spectral data led to structure 179 for murrafoline-B, which consists of a dihydrogirinimbine (cf. girinimbine (115) Scheme 2.22) attached at C-12 to C-8 of murrayafoline-A (7) (see Scheme 2.4) (146,160). This assignment was supported by 13C-NMR and COSY spectra (146) and finally by synthesis (reaction of murrayafoline-A and girinimbine with Nafion 117 in refluxing aqueous methanol) (160) (Scheme 2.38). The UV (lmax 242, 251, 291, 328, and 342 nm) and IR (nmax 1610, and 3460 cm1) spectra of murrafoline-C (180a) indicated a bis-carbazole framework. This assignment was supported by the mass fragmentation ion at m/z 256. The 1H-NMR spectrum showed signals for two aromatic methyl groups at d 2.24 and 2.47. The observation of ABX type signals at d 2.27, 2.31, and 4.63 and AB-type signals at d 5.56

R1

R2 8′

2 9 8

9 ′ NH 1′

5′

Me

4

R2

R1 5′

5

N H

12 ′

1 12

O Me 10

4′

9′

1′

N H5

8′ 4

Me

Me

12′ 6

Me 9

4′ 2′

Me

O

1

Me

MeO

10 ′

Me

180a Murrafoline-C R1,R2 = H

N H

8

181 Murrafoline-D

180b Murrafoline-I R1 = OMe; R2 = OH

Scheme 2.39

O Me 10 ′

Me

Occurrence, Isolation, and Structure Elucidation

71

and 6.07, and tertiary methyl groups at d 1.38, 1.41, 1.42, and 1.54, suggested the presence of a 4-substituted 2,2-dimethyldihydropyran ring and a 2,2-dimethylpyran ring. The similarity of the 1H-NMR spectra of murrafoline-C and murrafoline-B suggested that both alkaloids had the same linkage between C-12 and C-8 of the two carbazole units. Thus, the murrafoline-C structure 180a consists of a dihydrogirinimbine unit that is attached at C-12 to the C-8 of girinimbine (115) (160). This assignment was supported by NOESY and HMBC spectra (146) (Scheme 2.39). The UV spectrum [lmax 240, 256 (sh), 296, 332, and 345 nm] of murrafoline-D (181) indicated a bis-carbazole framework. This assignment was supported by the IR spectrum. The mass fragmentation showed a peak at m/z 237, along with the molecular ion peak at m/z 474. The 1H-NMR spectrum showed similar substituents as for murrafoline-B (179) (see Scheme 2.38), including two aromatic methyl groups at d 2.38 and 2.45, an aromatic methoxy group at d 3.97, and a 4-substituted 2,2-dimethyldihydropyran ring, indicating the presence of a dihydrogirinimbine and a murrayafoline-A (7) unit (see Scheme 2.4). However, the two monomeric carbazole units have different attachment points. The characteristic aromatic C-ring signals for murrayafoline-A confirmed the linkage of C-6 of murrayafoline-A to C-12 of dihydrogirinimbine, which was supported by HMBC and NOE experiments. Based on these spectral data, structure 181 was assigned to murrafoline-D (146). This assignment was confirmed by the 13C-NMR data (146), and finally by synthesis through the reaction of murrayafoline-A and girinimbine with Nafion 117 in refluxing aqueous methanol (146,160) (Scheme 2.39). The UV spectrum [lmax 243, 254 (sh), 293, 332, and 343 (sh) nm] of murrafoline-G (182) resembled that of murrafoline-D (181) (see Scheme 2.39), indicating a biscarbazole framework with similar monomeric units. The 1H-NMR spectrum showed signals for substituents similar to those of murrafoline-D (181) (see Scheme 2.39), including aromatic methyl groups at d 2.39 and 1.73, an aromatic methoxy group at d 3.96, and a 4-substituted 2,2-dimethyldihydropyran ring, indicating a dihydrogirinimbine unit and a murrayafoline-A (7) unit, with different attachments of the two monomeric carbazole units. The signal for the methyl group at C-3 of the murrayafoline-A unit of murrafoline-G exhibited an abnormal high-field shift (d 1.73) as compared to the corresponding methyl group (d 2.45) of murrafoline-D (181). The lack of a deshielded H-4 and signals of four, mutually ortho-coupled (J=8.6 Hz) protons at d 8.35, 7.21, 7.43, and 7.69 for H-5 to H-8 confirmed the linkage of C-4 of murrayafoline-A to C-12 of dihydrogirinimbine. Based on the spectroscopic

5

Me

4

O Me

9 8

N H Me 3′ 1′

MeO

5

1

12 5′

Me

9′

N H

8′

O Me

9

O

Me

182 Murrafoline-G

N H 5′

8 4′

Me

10

Me 4′

Me

4

1

12

6′

2′ 1′

9′

N H

8′

183 Murrafoline-H

Scheme 2.40

10

Me

72

Chemistry and Biology of Carbazole Alkaloids

data, structure 182 was assigned to murrafoline-G. The assignment was supported by 13C-NMR data, NOE experiments (146), and finally by synthesis through the reaction of murrayafoline-A and girinimbine with Nafion 117 in refluxing aqueous methanol (146) (Scheme 2.40). The UV spectrum [lmax 239, 256 (sh), 292, 331, and 345 nm] of murrafoline-H (183) resembled that of murrafoline-C (180a) (see Scheme 2.39) and indicated a dimeric carbazole with similar monomeric units. The 1H-NMR spectrum showed a similarity to murrafoline-C (180a) (see Scheme 2.39), with signals for two aromatic methyl groups at d 2.38 and 2.26, and a 4-substituted 2,2-dimethyldihydropyran ring. This indicated the presence of a dihydrogirinimbine unit and a girinimbine (115) unit (see Scheme 2.22), but with a different attachment of the monomeric carbazole units. Furthermore, the aromatic region of the girinimbine unit showed the presence of H-4 as a singlet at d 7.64, along with two ortho-coupled (J=8.1 Hz) protons at d 7.09 and 7.30, and a meta-coupled (J=1.8 Hz) doublet at d 7.93. This low-field meta-coupled doublet was assigned to C-5, and indicated the linkage of C-6 of girinimbine with C-12 of dihydrogirinimbine. The linkage at C-6 was supported by the presence of an additional meta-coupling (J=1.8 Hz) for H-7 (d 7.09). Based on the spectral data, structure 183 was assigned to murrafoline-H. This assignment was confirmed by 13C-NMR data, NOE experiments, and synthesis (146) (Scheme 2.40). In 1988, Furukawa et al. isolated murrafoline-E (184) and murrafoline-F (185) from the root bark of M. euchrestifolia. Murrafoline-E was the third example of an N-benzyl-linked bis-carbazole alkaloid from a Murraya plant, while murrafoline-F was the first N-methoxy-bis-carbazole alkaloid (22). The UV spectrum [lmax 238, 255 (sh), 263 (sh), 328, 340, and 352 (sh) nm] of murrafoline-E (184) indicated a carbazole. This assignment was supported by the IR spectrum. The mass fragmentation with two base peaks at m/z 262 and 211 suggested a bis-carbazole with girinimbine (115) and murrayafoline-A (7) units. The 1 H-NMR spectrum showed signals for an aromatic methyl group at d 2.51, an aromatic methoxy group at d 3.94, a 2,2-dimethyl-D3-pyran ring [d 1.41 (6H, s), 5.79 and 6.92 (each 1H, d, J=10.0 Hz)], and a benzylic methylene attached to a nitrogen atom at d 6.01. Moreover, the 1H–1H COSY spectrum showed two, four-spin systems in the aromatic region indicating the lack of substituents on the C-ring of both carbazole skeletons. Based on these spectral data and NOE experiments, structure 184 was assigned to murrafoline-E (22) (Scheme 2.41).

5′

8′

9 8

1′

1

N

OMe

4

5

Me

3′

9′

N H

4′

Me

4

5

1′

OMe N 9′

3′

O

9

Me

8

Me 184 Murrafoline-E

N H

2 1

OMe

185 Murrafoline-F

Scheme 2.41

5'

8′

Occurrence, Isolation, and Structure Elucidation

73

The UV spectrum [lmax 239, 252 (sh), 261 (sh), 285 (sh), 296, 326, and 340 nm] of murrafoline-F (185) indicated a carbazole. The 1H-NMR spectrum showed signals for an aromatic methyl at d 2.38 and two aromatic methoxy groups at d 3.93 and 4.14. The 1H–1H COSY spectrum showed two, four-spin and one, three-spin system, suggesting unsubstituted C-rings for both carbazole units and a 3-substituted A-ring in one of the carbazoles. The signals at dH 4.43 (2H) and dC 32.2 in the 1H- and 13 C-NMR spectra, and a mass fragment at m/z 223 (M+-196–H), indicated the methylene linkage between two carbazole moieties of this bis-carbazole. The strong mass fragment at m/z 390 (M+OMe), and the presence of 12 sp2 carbons as doublets in the 13C-NMR spectrum, indicated that one methoxy group was located on the nitrogen of the carbazole. Based on the spectral data and NOE experiments, structure 185 was assigned to murrafoline-F (22) (Scheme 2.41). In 1990, Furukawa et al. reported the isolation of murrastifoline-A (186), -B (187), -C (188), and -D (189) from the root bark of M. euchrestifolia (161). Later, the same authors isolated further murrastifoline derivatives, murrastifoline-E (190) (101) and murrastifoline-F (191) (82) from the same natural source. Their common substructure is a 1-methoxy-3-methylcarbazole [murrayafoline A (7)], which is attached at the N-atom to a second carbazole moiety. For murrastifoline A (186), murrastifoline-B (187), and murrastifoline-F (191) no optical rotations were mentioned. Murrastifoline-D (189) was isolated as a racemate and murrastifoline-E (190) in optically active form: [a]D 5.7 (c 0.035, CHCl3). However, the absolute configuration of murrastifoline-E (190) is still not known. In 2001, Bringmann et al. described the enantiomeric resolution and the chiroptical properties of murrastifoline-F (191) (162) (Schemes 2.42–2.44). The murrastifolines exhibited characteristic carbazole UV spectra. Their 1H-NMR spectra showed signals for aromatic methoxy (d 3.57–4.11) and methyl groups (d 2.52–2.56). In the aromatic region, signals of a four-spin system and two singlets for H-4 (d 7.56–7.63) and H-2 (d 6.85–7.00) were observed. The 1H-NMR spectra, NOE studies, and mass fragments at m/z 210 or 211 confirmed murrayafoline A (7) as the common structural unit for all murrastifolines (Schemes 2.42–2.44). The 1H-NMR spectrum of murrastifoline-A (186) showed, besides the signals for murrayafoline A, a broad singlet for an NH (d 10.45), and singlets for an aromatic methyl (d 2.48) and a methoxy (d 4.03) group. In the aromatic region, the two singlets at d 7.54 and 6.88 were assigned to H-4 and H-2, respectively. Furthermore, the

5′

5

1

6′

5′

8′

H MeO

9′

Me

N

OMe

3′

5′

4′ 9′

1

N

8

OMe

Me

4

9

9

N

8

Me

4

1′

OMe

N

8′

1′

186 Murrastifoline-A

H

187 Murrastifoline-B

Scheme 2.42

74

Chemistry and Biology of Carbazole Alkaloids

5

Me

4

Me 4

9

5′

N

8

OMe

3′ 8′

OMe OH 12 ′ Me

N H N

8

O

1′

1

9

2′

9′

N H

5

1

8′

Me

10 ′

1′

9′

2′

Me 5′

Me 188 Murrastifoline-C

4′

O

Me

Me

189 Murrastifoline-D

Scheme 2.43

Me 4′ 1′

OMe

9′

9

N

8′ H 8

11

N

1

9

5

Me

4

5

5′

12

10

O 4

8 5′

Me Me

8′

Me

190 Murrastifoline-E

N 4′

1

OMe Me

9′

N H

1′

OMe

191 Murrastifoline-F

Scheme 2.44

aromatic region showed an ortho-coupling (J=7.9 Hz) for H-7 (d 7.40) and H-8 (d 7.67), and a deshielded meta-coupled (J=2.0 Hz) H-5 (d 8.10), indicating the linkage of C-6 of one murrayafoline A unit to the N-atom of a second. This linkage was confirmed by the additional meta-coupling of H-7 (d 7.40) with H-5. The spectral data and NOE experiments led to structure 186 for murrastifoline-A (161) (Scheme 2.42). The 1H-NMR spectrum of murrastifoline-B (187) showed signals for an NH proton (broad singlet at d 10.59) and an aromatic methoxy group (d 4.03). The aromatic region exhibited a four-spin system, suggesting an unsubstituted C-ring and two meta-coupled (J=1.5 Hz) singlets at d 7.04 and 7.81 for H-2 and H-4, respectively, indicating a linkage between C-3 of one murrayafoline A unit with the N-atom of a second. Based on the spectral data and NOE experiments, structure 187 was assigned to murrastifoline-B (161) (Scheme 2.42). The mass fragmentation of murrastifoline-C (188) at m/z 330 and 211 indicated the presence of mahanimbine (139) (see Scheme 2.27) along with the murrayafoline A unit. In addition to the 1H-NMR spectral data of murrayafoline A, murrastifoline-C showed a four-spin system suggesting an unsubstituted C-ring. The symmetrical doublets at d 5.77 and 6.96, and a three-proton singlet at d 1.38, were assigned to olefinic protons and a tertiary methyl group at the pyran ring. The signals at d 1.70 (2H, m), 2.08 (2H, m), 5.14 (1H, t), 1.59 (3H, s), and 1.67 (3H, s) were assigned to the –CH2CH2CHQCMe2 side chain of the pyran ring. This side chain was

Occurrence, Isolation, and Structure Elucidation

75

confirmed by the mass fragmentation ion at m/z 457 (M+CH2CH2CHQCMe2). The 1H–1H COSY and NOESY spectra showed a correlation between the broad singlet at d 7.36 for H-4 and the two-proton singlet at d 6.03, assigned to the benzylic methylene protons linked to the N-atom of murrayafoline A. Based on the spectral data, structure 188 was assigned to murrastifoline-C (161) (Scheme 2.43). The mass spectrum of murrastifoline-D (189), with fragments at m/z 280 and 211, confirmed the murrayafoline A unit. The second carbazole unit was deduced from the 1H-NMR spectrum, which showed signals for geminal dimethyl groups at d 1.55 and 1.42, and a doublet of doublets (J=5.9, 9.2 Hz) at d 4.38, coupled with a hydroxy proton at d 4.48 (J=5.9 Hz). The doublet (J=9.2 Hz) at d 7.21 was assigned to H-12u of the benzylic carbon attached to the nitrogen of murrayafoline A. The spectral data indicated a 2,2-dimethyl-3-hydroxy-4-substituted dihydropyran ring. The trans relationship between substituents at C-11u and C-12u was confirmed by the coupling constant (J=9.2 Hz) of the methine protons and the absence of an NOE between them. The aromatic region showed a singlet at d 7.87 for H-4, and a four-spin system indicating an unsubstituted carbazole C-ring. Based on the spectral data and NOE experiments, structure 189 was assigned to murrastifoline-D (161) (Scheme 2.43). The UV spectrum (lmax 239, 255, 291, 331, and 348 nm) of murrastifoline-E (190) resembled that of murrastifoline-D (189) (see Scheme 2.43) indicating a bis-carbazole with similar monomeric carbazole units. The 1H-NMR spectrum confirmed the structural similarity to murrastifoline-D (189), but was lacking the signal for the hydroxy function of the 4-substituted 2,2-dimethyl dihydropyran ring, which was indicated by signals for the geminal dimethyl groups at d 1.50 and 1.48, a doublet of doublets (J=7.3, 11.0 Hz) at d 7.42, and a two-proton multiplet at d 2.23. The doublet of doublets at d 7.42 was assigned to H-12 of the benzylic carbon attached to the nitrogen of the murrayafoline A unit. The spectral data confirmed that murrastifoline-E (190) is a deoxygenated murrastifoline-D. This assignment was supported by 13 C-NMR data and NOE experiments (101) (Scheme 2.44). The 1H-NMR spectrum of murrastifoline-F (191) showed singlet signals for two aromatic methyl groups (d 2.05, 2.55), two methoxy groups (d 3.33, 4.10), three aromatic protons (d 6.67, 6.88, and 7.67), and an NH group (d 8.27). The 1H–1H COSY spectrum showed two, four-spin systems suggesting an unsubstituted C-ring in both carbazole units. The spectral data and the NOE experiments confirmed that the basic structural subunit of murrastifoline-F (191) is murrayafoline A (7), which co-occurs with 191 in the plant. The linkage of the two murrayafoline A molecules is between the N-atom of one unit and C-4 of the second unit. Therefore, structure 191 was assigned to murrastifoline-F (82) (Scheme 2.44). In 1990, Furukawa et al. described the isolation and structural elucidation of chrestifoline-A (192), -B (193), and -C (194) from the root bark of M. euchrestifolia. The chrestifolines contain 1-methoxy-3-methylcarbazole [murrayafoline A (7)] as the common structural subunit, which is linked to the second carbazole via the methyl group at C-3. Chrestifoline-C (194) was isolated from nature in optically active form: [a]D 5.6 (c 0.054, CHCl3). However, the absolute configuration is not known (161) (Schemes 2.45 and 2.46). All of the chrestifoline alkaloids have a UV spectrum characteristic of a carbazole chromophore. The 1H-NMR spectra of all these alkaloids showed signals for an NH proton at d 10.16 or 10.31, an aromatic methoxy group at d 3.84 or 3.85, and a 2H singlet at d 4.78–5.80 assigned to the benzylic methylene protons connected to

76

Chemistry and Biology of Carbazole Alkaloids

H N

MeO

1′

5

4′

2′ 5

5′

4

8′ 4

1′

N

8 1

N H

8

OMe

192 Chrestifoline-A

O Me 10 ′

12′ 11′

3 9

Me

9′

4′

Me

5′

8′

9′

Me

9

N H

1

OMe 193 Chrestifoline-B

Scheme 2.45

R1 N

8′ 4′

5′

Me 2′

9′ 8′ 4

5

8

1′

3

9

N H

N

1′

5′

O Me

3′

4′

O

Me 5

1

R2

9′

4

Me

3

OMe

9 8

194 Chrestifoline-C

N R1

1

R2

195 Oxydimurrayafoline R1 = H; R2 = OMe 196 3,3′-[Oxybis(methylene)]bis(9-methoxy-9H-carbazole) R1 = OMe; R2 = H

Scheme 2.46

the N-atom of the second carbazole nucleus. In the aromatic region, signals of a four-spin system and two singlets for H-2 at d 7.00 or 6.90 and H-4 at d 7.39 or 7.38 were observed. This aromatic splitting pattern, supported by NOE studies and the mass fragment at m/z 210, indicated the presence of a 1-methoxy-3(substituted methylene)carbazole nucleus as a common structural unit of the chrestifolines. The 1H-NMR spectrum of chrestifoline-A (192) showed additional signals of a four-spin system indicating an unsubstituted C-ring, a methoxy group at d 4.02, an aromatic methyl group at d 2.47, a singlet for an aromatic proton at d 6.94, and an NH singlet at d 10.28. The spectral data, supported by NOE studies, confirmed structure 192 for chrestifoline-A. This assignment was supported by the mass spectrum displaying m/z 420 as the base peak and a fragment at m/z 210 (161) (Scheme 2.45). The mass fragmentation of chrestifoline-B (193) at m/z 263 and 248, and a molecular ion at m/z 472 and a base peak at m/z 210, indicated the presence of girinimbine (115) (see Scheme 2.22) as the second, monomeric carbazole unit. The 1 H-NMR spectrum of this bis-carbazole alkaloid showed signals of a four-spin

Occurrence, Isolation, and Structure Elucidation

77

system indicating an unsubstituted C-ring, an aromatic methyl group at d 2.27, a deshielded H-4 at d 7.81, and signals for a 2,2-dimethyl-D3-pyran ring at d 1.36 (6H, s), and d 5.53 and 6.91 (each 1H, d, J=9.9 Hz). Based on the spectral data and NOE experiments, structure 193 was assigned to chrestifoline-B (161) (Scheme 2.45). The mass fragments of chrestifoline-C (194) at m/z 331 and 210 (base peak) indicated mahanimbine (139) (see Scheme 2.27) as the second carbazole unit. The 1HNMR spectra of chrestifoline-C showed signals for a deshielded H-4 at d 7.81 and a four-spin system indicating an unsubstituted C-ring. The symmetrical doublets at d 5.53 and 6.95 and the three-proton singlet at d 1.34 were assigned to the olefinic protons and the tertiary methyl group of the pyran ring. The signals at d 1.68 (2H, m), 2.04 (2H, m), 5.00 (1H, t), 1.45 (3H, s), and 1.54 (3H, s) confirmed the side chain – CH2CH2CHQCMe2, attached to the quaternary carbon of the pyran ring. The presence of this side chain was supported by the mass fragmentation ion at m/z 457 (M+CH2CH2CHQCMe2). Based on the spectroscopic data and NOE experiments, structure 194 was assigned to chrestifoline-C (161) (Scheme 2.46). In 1987, Furukawa et al. reported the isolation of oxydimurrayafoline (195) from the root bark of M. euchrestifolia. This alkaloid represented the first example of a dimeric carbazole alkaloid with an ether linkage (69). The UV spectrum (lmax 242, 253, 294, 324, and 337 nm) and the base peak at m/z 211 in the mass spectrum of oxydimurrayafoline (195) indicated a symmetrical dimeric carbazole with two murrayafoline A units. The 1H-NMR spectrum resembled that of murrayafoline A (7), except for the presence of a singlet at d 4.76 instead of the singlet for the aromatic methyl group in murrayafoline A at d 2.42. The singlet at d 4.76 suggested a benzylic oxymethylene moiety. The spectral data, supported by NOE experiments, led to structure 195 for oxydimurrayafoline (Scheme 2.46). In 2005, Rahman and Gray isolated 3,3u-[oxybis(methylene)]bis(9-methoxy-9Hcarbazole) (196) from the stem bark of M. koenigii (163). This alkaloid showed potent activity against Gram-negative bacteria and fungi. Alkaloid 196 represented the first example of an ether linked, symmetrical dimeric carbazole with N-methoxycarbazole units (163). The UV spectrum (lmax 237, 264, 293, and 329 nm) of 3,3u-[oxybis(methylene)]bis(9-methoxy-9H-carbazole) (196) resembled that of 3-hydroxymethyl-Nmethoxycarbazole (106) (see Scheme 2.20) indicating the presence of a similar monomeric carbazole unit. The 1H-NMR spectrum was also very similar and indicated the presence of two symmetrical 3-hydroxymethyl-N-methoxycarbazole (106) units linked via a methylene ether. The methylene protons at d 4.78 showed HMBC correlations to C-1, C-3, and C-4, as well as direct (1J) and long-range (3J) correlations to the methylene carbons at d 72.7. The latter correlation confirmed the bismethylene ether linkage of the dimer, similar to that of oxydimurrayafoline (195). Based on the spectroscopic data and the structural similarity to 3-hydroxymethyl-Nmethoxycarbazole (106), structure 196 was assigned to 3,3u-[oxybis(methylene)]bis (9-methoxy-9H-carbazole) (Scheme 2.46). In 1983, Furukawa et al. isolated bismurrayafoline-A (197) and -B (200) from M. euchrestifolia (164). The absolute configuration of bismurrayafoline-B is not known (164) (Scheme 2.47). The UV spectrum [lmax 228, 244, 253 (sh), 284 (sh), 293, and 340 nm] of bismurrayafoline-A (197) indicated a dimer of murrayafoline A (7) (see Scheme 2.4). This assignment was supported by the IR spectrum and the mass fragmentation which showed a peak at m/z 210 along with the molecular ion peak at m/z 420. The

78

Chemistry and Biology of Carbazole Alkaloids

5

R

4

3 5′

8′

Me

4

1

N

8 4′

OMe 3′

9′

N H

5

9

R1O 8

9

N H

2

R 1′

2 1

OH

HO

1′

R2 8′

9′

2′

Me

H N

4′

OR1

5′

OMe

197 Bismurrayafoline-A R = Me

200 Bismurrayafoline-B

198 Bismurrayafolinol

201 Bismurrayafoline-C

R = CH2OH

R1 = H; R2 = geranyl 202 Bismurrayafoline-D

199 Chrestifoline-D R = CHO

R1 = Me; R2 = prenyl

R1 = Me; R2 = geranyl

Scheme 2.47

1

H-NMR spectrum of bismurrayafoline-A (197) showed singlets for an aromatic methyl group (d 2.46), two methoxy (d 3.71, 3.82) groups, and four aromatic protons d 6.62 (2H), 7.32 (1H), and 7.36 (1H). Moreover, two, four-spin systems indicated that the C-rings of both carbazole units were unsubstituted. The two-proton singlet at d 5.83 and the base peak at m/z 210 confirmed the benzylic methylene group bound to the N-atom. Based on the spectral data, structure 197 was assigned to bismurrayafoline-A. Additional support for this assignment was derived from the transformation to murrayafoline A by hydrogenation (164) (Scheme 2.47). In 1987, Furukawa et al. described the isolation of bismurrayafolinol (198) from the root bark of M. euchrestifolia (69). The UV spectrum (lmax 225, 244, 252, 281, 292, and 340 nm) of bismurrayafolinol (198) resembled that of bismurrayafoline-A (197) indicating a similar dimeric carbazole framework. This assignment was supported by the IR spectrum and the mass fragmentation which showed a peak at m/z 210. Moreover, the 1H-NMR spectrum was also similar to that of bismurrayafoline-A (197), except for the presence of the signal for an aromatic hydroxymethylene group at d 4.86 instead of an aromatic methyl group at d 2.46. The spectroscopic data led to structure 198 for bismurrayafolinol. This structure was unequivocally confirmed by synthesis of the acetate of natural murrayafolinol starting from murrayanine (9) (see Scheme 2.4) (69) (Scheme 2.47). Two years after the isolation of the chrestifolines 192–194 (see Schemes 2.45 and 2.46), the same authors obtained chrestifoline-D (199) from the same natural source. Similar to the previous chrestifolines, this alkaloid had a 1-methoxy-3-methylenecarbazole unit. The UV spectrum (lmax 223, 241, 250, 275, 291, and 335 nm) of chrestifoline-D (199) resembled that of bismurrayafoline-A (197), indicating a similar dimeric carbazole framework. The 1H-NMR spectrum was also similar to that of bismurrayafoline-A (197), except for the presence of a low-field singlet at d 10.07 for a formyl group instead of the signal for an aromatic methyl group. This assignment was supported by the IR band at nmax 1680 cm1. The spectral data, supported by NOE experiments, led to structure 199 for chrestifoline-D. Additional

Occurrence, Isolation, and Structure Elucidation

79

support for this assignment derived from the synthesis of bismurrayafoline-A (197) by DDQ-oxidation (104) (Scheme 2.47). The UV spectrum [lmax 225 (sh), 240, 265 (sh), 285 (sh), 312, and 333 (sh) nm] of bismurrayafoline-B (200), and its bathochromic shift in alkali, indicated a phenolic carbazole. This conclusion was supported by the IR spectrum (nmax 3550, 3450, and 1615 cm1). The 19 carbon signals of the 13C-NMR spectrum, the molecular ion peak at m/z 588, and the peak at m/z 294 confirmed a symmetrical dimeric carbazole with two equivalent monomer units. The 1H-NMR spectrum of bismurrayafoline-B (200) was similar to that of murrayafoline B (27) (see Scheme 2.6), except for some differences in the chemical shifts and the lack of a signal for H-2 at d 6.56 (for murrayafoline B). The spectroscopic data and NOE experiments confirmed a 2,2ulinkage of the two murrayafoline B units and led to structure 200 for bismurrayafoline-B (164) (Scheme 2.47). In 1991, Furukawa et al. described the isolation of bismurrayafoline-C (201) and -D (202) from the stem bark of M. euchrestifolia. Bismurrayafoline-D represents the dimethyl ether of bismurrayafoline-C. The absolute configuration of both alkaloids is not known (70). The UV spectrum [lmax 226, 235, 260 (sh), 285, 311, and 335 (sh) nm] of bismurrayafoline-C (201) resembled that of bismurrayafoline-B (200), indicating a similar carbazole framework. The 1H-NMR spectrum of bismurrayafoline-C was also very similar to that of bismurrayafoline-B (200), except for the presence of signals for an aromatic hydroxy group and a geranyl moiety instead of the aromatic methoxy group and the prenyl moiety. The spectral data supported by NOE experiments led to structure 201 for bismurrayafoline-C. This assignment was supported by additional NOE studies with the corresponding tetra-O-methyl ether obtained by the treatment of bismurrayafoline-C (201) with diazomethane (70) (Scheme 2.47). The UV and IR spectra of bismurrayafoline-D (202) resembled those of bismurrayafoline-C (201), indicating a similar bis-carbazole framework. The 1 H-NMR spectrum was also similar to that of bismurrayafoline-C, except for an additional singlet at d 3.89 for a methoxy group. The geranyl side chain was supported by the mass fragmentation ion at m/z 239 (M2+CHQ CMeCH2CH2CHQCMe2), and a doubly charged molecular ion at m/z 362 (M2+). The spectroscopic data, supported by NOE experiments with bismurrayafoline-D and the corresponding di-O-methyl ether, led to structure 202 for bismurrayafolineD (70) (Scheme 2.47). In 1996, Wu et al. reported the isolation of clausenamine-A (203) from the methanol extract of the stem bark of C. excavata, which is used in traditional medicine in China for the treatment of poisonous snakebites (53). Four years later, Zhang and Lin reported the in vitro cytotoxic activity of clausenamine-A (203) and its synthetic analogs against a variety of human cancer cell lines (165). The UV spectrum (lmax 218, 235, 257, 307, and 343 nm) of clausenamine-A (203) and the 1H-NMR singlets at d 2.44 and 8.95, typical of an aromatic methyl group and a carbazole NH, indicated a 3-methylcarbazole framework. The 15 carbon signals in the 13C-NMR spectrum, the molecular ion peak at m/z 512, and the peak at m/z 256 confirmed it as a symmetrical dimeric carbazole. Moreover, The 1H-NMR spectrum showed a lowfield singlet at d 7.81 for H-4 and meta-coupled (J=2.0 Hz) doublets at d 6.45 and 7.13 for H-7 and H-5, supported by an NOE of the signal at d 7.81 (H-4) with the signal at d 7.13 (H-5). Additional NOEs of the methoxy group at d 3.77 with H-7, and of the other methoxy group at d 3.82 with H-5 and H-7, indicated the positions of the

80

Chemistry and Biology of Carbazole Alkaloids

R

Me

4

5

2 9 8

R

N H

HO 2′

1′

H N

R 8′

9′

Me

11

1 9a

10

1

OH

Me

4′

5′

R

12

Me O Me

4

HO H N 8a

4 ′′

5′′

R

9′′

8′′

9

5

8a′′ 8

N

H OH

9a′′ 12′′

Me 1′′

O Me 10 ′′

11′′

Me

R

203 Clausenamine-A R = OMe

205 8,8′′-Biskoenigine R = OMe

204 Bis(O-demethylmurrayafoline A)

206 Bis-7-hydroxygirinimbine-A R=H

R=H

Scheme 2.48

methoxy groups at C-8 and C-6. The hydroxy-substituted C-1 at d 152.2 showed in an HMBC experiment a correlation with the NH at d 8.95 confirming a C-2–C-2u carbon– carbon linkage of the dimeric carbazole. Based on these spectroscopic data, structure 203 was assigned to clausenamine-A (53) (Scheme 2.48). In 1995, Bringmann et al. reported the antiplasmodial activity of the non-natural bis(O-demethylmurrayafoline A) (204) against Plasmodium falciparum in vitro. Along with the antimalarial activity, an enantiomeric resolution and the chiroptical properties of this alkaloid were described (166). The 1H-NMR spectrum of bis(Odemethylmurrayafoline A) (204) resembled that of clausenamine-A (203), except for the lack of two aromatic methoxy group signals and the presence of two, four-spin systems, indicating a similar dimeric carbazole with unsubstituted C-rings in both carbazole units. Based on the spectroscopic data, structure 204 was assigned to bis(O-demethylmurrayafoline A) (166–168). In 2002, Hao et al. isolated 8,8v-biskoenigine (205) from M. koenigii (119,169). Although, this alkaloid was optically active and exhibited a specific rotation of ½a25 D þ 139:6 (c 1.0, CHCl3) (119), the absolute configuration is unknown. 8,8vbiskoenigine (205) showed antiosteoporotic activity in the cathepsin B (CAT-B) model (119). The UV spectrum [lmax 225, 301, and 343 nm] of 8,8v-biskoenigine (205) indicated a dimeric carbazole framework. This assignment was supported by the IR spectrum and the mass spectrum which showed a peak at m/z 308 and the molecular ion peak at m/z 616. Nineteen carbon signals in the 13C-NMR spectrum suggested a symmetrical dimeric carbazole. The 1H-NMR spectrum of 8,8v-biskoenigine was very similar to that of koenigine (119) (see Scheme 2.22), except for the absence of the C-8 methine proton indicating a linkage between C-8 and C-8v. This linkage was supported by the upfield shifts of C-7 (C-7v) and C-8a (C-8av). The spectroscopic data led to structure 205 for 8,8v-biskoenigine (119,169). This structural assignment was additionally confirmed by the 13C-NMR spectrum (119,169) and by synthesis via an oxidative coupling of koenigine with FeCl3 in the solid state (119) (Scheme 2.48). In 1991, Wang et al. reported the isolation of bis-7-hydroxygirinimbine-A (206) and -B (207) from the leaves of M. euchrestifolia. The absolute configuration of these alkaloids is not known (170). The UV spectrum (lmax 226, 295, and 343 nm) of bis-7hydroxygirinimbine-A (206) is very similar to that of 8,8v-biskoenigine (205),

Occurrence, Isolation, and Structure Elucidation

81

indicating a similar dimeric carbazole framework. The 1H-NMR spectrum of bis-7hydroxygirinimbine-A (206) also resembled that of 8,8v-biskoenigine (205), except for the absence of the singlet (d 4.05) for the two aromatic methoxy groups at C-6 and C-6u, and the presence of a doublet for H-6 (H-6u) at d 6.98 with an ortho-coupling (J=8.55 Hz) to H-5 (H-5u) at d 7.89. The molecular ion peak at m/z 556, along with the peak at m/z 263, confirmed the dimeric nature of this carbazole alkaloid. Based on the spectroscopic data, structure 206 was assigned to bis-7-hydroxygirinimbine-A. Additional support for this assignment was derived from an HMBC spectrum and NOE experiments with the di-O-methyl ether of bis-7-hydroxygirinimbine-A, prepared by the treatment of bis-7-hydroxygirinimbine-A (206) with diazomethane (170) (Scheme 2.48). The UV spectrum (lmax 224, 296, and 345 nm) of bis-7-hydroxygirinimbine-B (207) resembled that of bis-7-hydroxygirinimbine-A (206) suggesting a similar dimeric carbazole. The 1H- and 13C-NMR spectra indicated the presence of two 7-hydroxygirinimbine units. NOE experiments with the di-O-methyl ether of bis-7hydroxygirinimbine-B confirmed that the two 7-hydroxygirinimbine units, in contrast to bis-7-hydroxygirinimbine-A (206), had a linkage from C-6 of the first to C-8u of the second unit. On the basis of the spectroscopic data, structure 207 was assigned to bis-7-hydroxygirinimbine-B (170) (Scheme 2.49). In 1993, Furukawa et al. isolated bismahanine (208) from the acetone extract of the stem bark of M. koenigii (82). Ten years later, Nakatani et al. obtained the same alkaloid in optically active form (½a25 D þ 4:0, c 0.65, CHCl3) from the dichloromethane extract of the leaves of the same natural source (116). However, the absolute configuration was not determined. Bismahanine (208) showed radical scavenging activity against the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical (116). The UV spectrum (lmax 223, 245, 297, 331, 341, and 359 nm) of bismahanine (208) resembled that of (+)-mahanine (149) (see Scheme 2.29) indicating a similar pyranocarbazole unit. The 1H-NMR spectrum was also similar to that of bis-7-hydroxygirinimbine-B (207), except for the signals at d 1.71 (2H, m), 1.77 (2H, m), 2.15 (4H, m), 5.08 (1H, t), 5.12 (1H, t), 1.54 (3H, s), 1. 56 (3H, s), 1.60 (3H, s), and 1.63 (3H, s). These signals were assigned to the two side chain –CH2CH2CHQCMe2 units, replacing a methyl group on the pyran ring of bis-7-hydroxygirinimbine-B (207). The side chain was confirmed

4′

5′

HO Me

8′ 6

3

Me

O

9 1

10 11

12

N H

9′

N H OH

5

4

Me

12′

5'

3′

O Me

1′

4′

Me

3′

10′ 11′

11 10

R Me

8

HO H N

12 8

1′ 1

9

O

9′

N H OH

8′ 12 ′

3 5

4

Me

R 207 Bis-7-hydroxygirinimbine-B R=H 208 Bismahanine R = prenyl

Scheme 2.49

209 Bisisomahanine

O Me 10 ′ 11′

82

Chemistry and Biology of Carbazole Alkaloids

by the mass fragmentation ion at m/z 609 (M+CH2CH2CHQCMe2), 347 (M2++1), and 263 (M2+CH2CH2CHQCMe2). Based on the spectral data, structure 208 was assigned to bismahanine (82) (Scheme 2.49). In 2004, Cuong et al. reported the isolation of bisisomahanine (209) from the roots of G. stenocarpa (30). Bisisomahanine was obtained in optically active form (½a20 D  13:1, c 0.25, CHCl3). However, the absolute configuration is not known. This alkaloid represented the first dimeric prenylated pyranocarbazole alkaloid with a 1,1u-linkage (30). The UV spectrum (lmax 224, 245, 298, and 335 nm) of bisisomahanine (209) resembled that of isomahanine (pyrayafoline D) (138) (see Scheme 2.26) indicating a similar monomeric pyranocarbazole unit. This assignment was supported by the IR spectrum (nmax 1621, 3362, and 3470 cm1). The presence of 23 signals in the 13 C-NMR spectrum, and the molecular ion peak at m/z 692, confirmed a symmetrical dimeric carbazole alkaloid. The 1D- and 2D-NMR spectra of bisisomahanine (209) were also similar to those of isomahanine (pyrayafoline D), with the exception of an additional, non-hydrogen substituted, aromatic carbon signal at d 99.1, and the absence of the aromatic methine signal for H-1 (C-1) in the 1H- and 13C-NMR spectra. The spectroscopic data and the NOESY experiments suggested the C-1/C-1u-linkage of the two isomahanine (pyrayafoline D) monomers. Additional support by HMBC, HMQC, and 1H–1H COSY spectra confirmed structure 209 for bisisomahanine (30) (Scheme 2.49). In 1991, Ito and Furukawa reported the isolation of murranimbine (210) from the root bark of M. euchrestifolia collected in Taiwan. This alkaloid was isolated in racemic form (171). The UV spectrum (lmax 240, 260, 306, and 336 nm) of murranimbine (210) indicated a carbazole framework. This assignment was supported by the IR spectrum. The mass spectrum, which showed a peak at m/z 263 and the molecular ion peak at m/z 526, suggested a dimeric carbazole. The 1HNMR spectrum showed signals for two aromatic methyl groups at d 2.30 and 2.32, four geminal methyl groups at d 0.60, 1.54, 1.44, and 1.60, and a D2O-exchangeable NH signal at d 10.55. The 1H–1H COSY spectrum exhibited two sets of signals for four aromatic protons, including the characteristic H-5 and H-5u of the carbazole units, and two deshielded signals at d 7.65 and 8.00 with a long-range coupling to the aromatic methyl groups. The latter signals also showed NOEs with the aromatic methyl groups. The spectral data confirmed that the aromatic C-ring and H-4 of the carbazole nucleus were unsubstituted. A 1H–1H COSY spectrum showed the relationships of the signals at d 6.12 (H-12u, J=2.9 Hz), 2.74 (H-11u, J=2.9, 5.1 Hz), 4.07 (H-12), 2.21 (H-11, J=5.1, 12.8 Hz), and 2.08 (H-11), and suggested that murranimbine contained two girinimbine (115) (see Scheme 2.22) units. Analysis of the HMBC spectrum of murranimbine confirmed the connectivity of the two units, and thus the structure of murranimbine 210. The relative stereochemistry was assigned based on NOE experiments (171) (Scheme 2.50). In 2003, Nakatani et al. reported the isolation of bispyrayafoline (211) and 1,6u-[9,9u,10,10u-tetrahydro-2,7u-dihydroxy-3,7u,10,10u-tetramethyl-10,10u-bis(4-methyl3-pentenyl)]bipyrano[3,2-a]carbazole (212), both in optically active form: ½a25 D þ 55:0 (c 0.12, CHCl3) and ½a25 þ 22:2 (c 0.09, CHCl ), from the leaves of M. koenigii (116). The 3 D absolute configurations of 211 and 212 remain unknown. Both alkaloids showed radical scavenging activity against the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical (116). In 2006, Furukawa et al. reported the isolation of the alkaloid 212 from the same source

Occurrence, Isolation, and Structure Elucidation

5

3

Me

4′

5′ 8'

8

9

NH H N H

9′

1′

12′

1 1′

5′ 4′

3′

1 12

O Me

HO H N

10 11

Me

11

H Me

12

10

Me

10′ O Me

1

9′ 8′ 8

9

O

N H OH

1′ 1 2′

83

Me O Me 10′ 11′

3

Me

5

4

Me 210 Murranimbine

211 Bispyrayafoline

Me

3

4

5

6

4a 4 b

2

HO Me

5′

4′

O

2′′′

10′

4′′′

7′

9′ 1′ 12′

1′′′ 11′

9a

6′

3′

Me

7 9

1

N H

N H OH

8a

8

O Me 10

12

8′

11

2′′ 1′′ 3′′

4′′

3′′′

212 Mahabinine-A

Scheme 2.50

and named it mahabinine-A (131). Mahabinine-A (212) induced apoptosis in HL-60 cells by activation of the caspase-9/caspase-3 pathway, through mitochondrial dysfunction (131). The UV spectrum (lmax 224, 243, 298, and 327 nm) of bispyrayafoline (211) was similar to that of (+)-mahanine (149) (see Scheme 2.29) and indicated the monomeric pyranocarbazole unit. The presence of 23 signals in the 13C-NMR spectrum and a molecular ion peak at m/z 692 confirmed a symmetrical dimeric carbazole. The 1 H- and 13C-NMR spectra resembled those of (+)-mahanine (149), with the exception of an additional non-hydrogen substituted aromatic carbon signal at d 99.0 and the lack of the aromatic methine signal for H-1 (C-1) in the 1H- and 13C-NMR spectra. The spectroscopic data confirmed the C-8/C-8u linkage between the (+)-mahanine monomers and led to structure 211 for bispyrayafoline (116) (Scheme 2.50). The UV spectrum (lmax 224, 243, 298, and 327 nm) of mahabinine-A (212) resembled that of bismahanine (208) (see Scheme 2.49) indicating a similar dimeric carbazole framework. The 1H- and 13C-NMR spectra were also similar to those of bismahanine, except for the signal of one additional aromatic methyl group indicating the presence of an isomahanine (138) unit (see Scheme 2.26). The 1 H-NMR spectrum showed two, ortho-coupled (J=8.3 Hz) aromatic protons at d 6.71 and 7.70. The HMBC spectrum with cross-peaks between the aromatic proton at d 6.71 and C-8 at d 104.8, as well as C-4b at d 117.9, suggested that the aromatic proton was located at C-6. The HMBC correlation of the other ortho-coupled aromatic proton at d 7.70 and the aromatic carbon atoms at d 136.0 (C-8a) and at d 150.9 (C-7) indicated that the aromatic proton at d 7.70 was located at C-5. Moreover, HMBC

84

Chemistry and Biology of Carbazole Alkaloids

correlations between the aromatic methyl group (d 2.47) and d 121.4 (C-4), 117.5 (C-3), and 150.0 (C-2) indicated that the aromatic methyl group was located at C-3. The assignments of the aromatic proton at d 6.71 to C-6 and of the aromatic methyl group at d 2.47 to C-3 were confirmed by NOESY experiments. The spectroscopic data confirmed the presence of isomahanine (138) (see Scheme 2.26) linked at C-1 to the second carbazole unit. The HMBC spectrum of mahabinine-A (212) indicated the linkage to the mahanine (149) (see Scheme 2.29) unit: thus, H-5u (d 7.88) showed a correlation to C-1 (d 104.1) of the isomahanine unit, confirming the C-6u/C-1-linkage between mahanine and isomahanine. The linkage was supported by NOESY correlations between H-5u of the mahanine unit to both OH and NH of the isomahanine unit. Based on these spectroscopic data, structure 212 was assigned to mahabinine-A (212) (116) (Scheme 2.50). In 1993, Furukawa et al. reported the isolation of bis-2-hydroxy-3-methylcarbazole (213), bismurrayaquinone-A (215), and bikoeniquinone-A (216) from the acetone extract of the root bark of M. koenigii (82). Bismurrayaquinone-A and bikoeniquinone-A were the first examples of dimeric carbazolequinone alkaloids isolated from Nature. The absolute configurations of these alkaloids are not known (82). However, two years later, Bringmann et al. described the enantiomeric resolution and the chiroptical properties of bismurrayaquinone-A (215) (167) (Schemes 2.51 and 2.52). The UV spectrum [lmax 237, 260 (sh), 304, and 336 nm] of bis-2-hydroxy-3methylcarbazole (213) resembled that of 2-hydroxy-3-methylcarbazole (52) (see

Me

4

5

5

4

Me

3

2 9

1

N H HO

8

1′

Me

MeO

OH H N

N H HO

8′

9′

4′

9 8

1 1′

213 Bis-2-hydroxy-3-methylcarbazole 1,1′-Bis(2-hydroxy-3-methylcarbazole)

8′

9′

OMe

2′

Me

5′

OH H N

3′ 4′

5′

214 Bismurrayafoline E

Scheme 2.51

O 5

Me O

4

2 2′ 9 8

N H

H N

1′

O 5

8′

9′

2

1

O Me

4′

O

Me

4

9 8

5′

215 Bismurrayaquinone-A

N H

1

O Me

5′

8′ 9′N

H

1′

OMe

4′

216 Bikoeniquinone-A

Scheme 2.52

Occurrence, Isolation, and Structure Elucidation

85

Scheme 2.11) indicating a similar carbazole unit. The EI-MS spectrum showed a molecular ion peak at m/z 392, and a peak at m/z 196, suggesting a symmetrical dimeric carbazole with two, 2-hydroxy-3-methylcarbazole units. The 1H-NMR spectrum was also similar to that of 2-hydroxy-3-methylcarbazole (52), except for the lack of the signal for H-1 (H-1u), indicating a C-1/C-1u-linkage between the two 2-hydroxy-3-methylcarbazole units. Based on the spectroscopic data and additional support by NOE experiments, structure 213 was assigned to bis-2-hydroxy-3methylcarbazole (82). In 1999, Rashid et al. isolated bismurrayafoline E (214) from the leaves of M. koenigii (172). The FAB mass spectrum of bismurrayafoline E (214) showed a molecular ion peak at m/z 725 (M++H), identical to that of bismurrayafoline-D (202) (see Scheme 2.47), indicating a similar dimeric carbazole framework. The 1H-NMR spectrum was almost superimposable on that of bismurrayafoline-D (202). However, the HSQC and HMBC spectra confirmed the position of the methyl groups at C-3 (C-3u) and the hydroxy groups at C-2 (C-2u) in bismurrayafoline E, as compared to C-3 (C-3u) and C-1 (C-1u) in bismurrayafoline-D. Thus, a C-1/C-1u-linkage was suggested for bismurrayafoline E. Based on the spectroscopic data, structure 214 was assigned to bismurrayafoline E (172) (Scheme 2.51). The UV spectrum (lmax 225, 252, 291, and 392 nm) of bismurrayaquinone-A (215) resembled that of murrayaquinone A (107) (see Scheme 2.21) indicating a similar carbazole unit. The IR spectrum showed a strong band at nmax 1650 cm1. The 1 H-NMR spectrum was also similar to that of murrayaquinone A, except for the lack of a signal for H-2 (H-2u). The spectroscopic data confirmed structure 215 for bismurrayaquinone-A (82) (Scheme 2.52). The 1H-NMR and the 1H–1H COSY spectrum of bikoeniquinone-A (216) showed the presence of two sets of four mutually coupling aromatic proton signals, a oneproton singlet at d 6.94, two methyl groups attached to sp2-carbon atoms, a methoxy group at d 4.01, and two D2O-exchangeable protons at d 11.70 and 10.36, assigned to NH groups. The spectroscopic data suggested the presence of two different monomeric carbazole units in bikoeniquinone-A, which were assigned as murrayaquinone A (107) (see Scheme 2.21) and murrayafoline A (7) (see Scheme 2.4). The presence of these monomeric units was supported by a strong IR absorption at nmax 1645 cm1, typical UV bands at lmax 227, 240, 257, 289, and 331 nm, and a mass fragmentation at m/z 211. These spectroscopic data, and the NOEs between the two methyl singlets at d 1.81 and 2.26, indicated a C-2/C-4u–linkage between murrayaquinone A (107) and murrayafoline A (7). In conclusion, structure 216 was assigned to bikoeniquinone-A (82) (Scheme 2.52).

D. Carbazolelactone Alkaloids In 1998, Ito et al. isolated clausamine-A (217), -B (218), and -C (219), each in their racemic form from the branches of C. anisata (173). The clausamines have a 1-oxygenated carbazole framework with an annulated six-membered lactone in the 3,4-position. They represented the first examples of naturally occurring carbazole alkaloids with a lactone moiety (173). Later in the same year, Wu et al. reported four further carbazolelactone alkaloids, clausevatine-D (220), -E (221), -F (222), and -G (223), from the root bark of C. excavata (Rutaceae) (174). This plant is a wild shrub

86

Chemistry and Biology of Carbazole Alkaloids

HO O

O O

N H

O N H

OR

OR

217 Clausamine-A R=H

219 Clausamine-C R = Me

218 Clausamine-B R = Me

220 Clausevatine-D R=H

Scheme 2.53

HO HO

HO O

HO O

HO O

N H

OH

221 Clausevatine-E

O O

N H

OH

222 Clausevatine-F

O N H

OH

223 Clausevatine-G

Scheme 2.54

that is used in traditional medicine for the treatment of snakebites and abdominal pain. In nature, except clausevatine-G (223), clausevatine-D (220) [a]D 5.7 (c 0.932, MeOH), -E (221) [a]D –92.4 (c 0.0552, MeOH), and -F (222) [a]D –199.0 (c 0.0203, MeOH) were isolated in their optically active form. Although these isolates were available in nature in their enantiopure form, except for the relative stereochemistry of clausevatine-D and -E, their absolute stereochemistry is not known (174) (Schemes 2.53 and 2.54). The UV spectrum [lmax 248, 269, 278 (sh), 310 (sh), and 322 nm] of clausamine-A (217) was similar to that of clausine F (32) (see Scheme 2.7), indicating the presence of a 1-oxygenated-3-carboxy-4-substituted carbazole framework. The 1H- and 13C-NMR spectra of clausamine-A suggested the presence of an NH group at dH 10.94 and a lactone carbonyl group at dC 166.03. This assignment was supported by the IR data at nmax 3462 and 1697 cm1. In addition, the IR spectrum also showed the presence of a hydroxy group at nmax 3329 (br) cm1 and the 1H-NMR spectrum showed in the aromatic region, the presence of a set of four-spin protons, along with a lone singlet at d 7.55 for H-2. Furthermore, the 1H- and 13C-NMR spectra showed the signals assignable to a vinyl methyl group at dH 1.98 and dC 18.57, a vinyl methylene at dH 5.26, 5.07, and dC 113.58, a methine at dH 5.12 and dC 81.18 on a carbon bearing an oxygen atom, a methylene carbon at dH 3.71, 3.52, and dC 29.80, and a quaternary vinyl carbon at dC 144.82. Based on these spectral data, and HMBC

Occurrence, Isolation, and Structure Elucidation

87

and NOE experiments, the structure 217 was assigned to clausamine-A. This structure was further supported with the significant mass fragmentation ions at m/z 223 (M+OCMeCQCH2) and 195 (M+OCMeCQCH2CO) (173) (Scheme 2.53). The UV spectrum [lmax 248, 269, 278 (sh), 310 (sh), and 321 nm] of clausamine-B (218) was similar to that of clausamine-A (217), indicating a similar carbazole framework. The 1H-NMR spectrum also showed a similar signal pattern to that of clausamine-A, except for an additional aromatic methoxy group at d 4.07. This assignment was supported by the 13C-NMR signal at d 55.94. In NOE experiments, irradiation of the methoxy group at d 4.07 resulted in a 20% area increase of the signal at d 7.66 (H-2). Based on these spectral data, structure 218 was assigned to clausamine-B. This structure was further supported with the HMBC spectrum, as well as the significant mass fragmentation pattern at m/z 237 (M+OCMeCQCH2) and 209 (M+OCMeCQCH2CO) (173) (Scheme 2.53). The UV spectrum [lmax 249, 270, 278 (sh), 312 (sh), and 322 nm] of clausamine-C (219) was similar to that of clausamine-B (218) indicating the presence of a similar carbazole framework. This was also discernible for its IR spectrum with the presence of bands at nmax 3464, 3400 (br), and 1703 cm1 for the NH, OH, and lactone carbonyl groups, respectively. The 1H-NMR spectrum also showed a similar signal pattern to that of clausamine-B, except for the difference on the substitution pattern of the lactone nucleus. Further, the 1H-NMR spectrum showed ABC-type signals at d 3.67 (1H, dd, J=3.3, 16.1 Hz), 3.47 (1H, dd, J=12.8, 16.1 Hz), and 4.47 (1H, dd, J=3.7, 12.8 Hz), and two aliphatic methyl singlets at d 1.50 and 1.47 attached to a carbon atom bearing an oxygen function. The spectral data indicate a 1-hydroxy-1-methylethyl substitution at the lactone nucleus. This assignment was additionally supported by the mass fragment ion at m/z 267 (M+CMe2OH+H) in the EI-MS. Based on these spectral data, structure 219 was assigned to clausamine-C. This structure was confirmed by HMBC experiments (173) (Scheme 2.53). The UV spectrum [lmax 241, 251, 272, 278 (sh), and 325 nm] of clausevatine-D (220) was similar to that of clausamine-A (217), indicating a similar 1-oxygenated-3carbonyloxycarbazole framework. The 1H-NMR spectrum resembled that of clausamine-C (219), except for the presence of a downfield, D2O-exchangeable aromatic hydroxy group at C-1 (d 9.14), instead of the aromatic methoxy group of clausamine-C. Based on these spectral data, structure 220 was assigned to clausevatine-D. This assignment was additionally supported by HMQC, HMBC, and NOESY spectra (174) (Scheme 2.53). The UV spectrum [lmax 240, 251, 271, 282, 315 (sh), and 325 nm] of clausevatine-E (221) resembled that of clausevatine-D (220), indicating a similar 1-oxygenated-3carbonyloxycarbazole. The 1H-NMR spectrum was also similar to that of clausevatine-D with an aliphatic hydroxy group at d 5.45 replacing one of the benzylic protons. Based on the chemical shifts, coupling constants, and NOE analysis of the benzylic and homobenzylic protons, the relative stereochemistry of the benzylic hydroxy and 1-hydroxy-1-methyl-ethyl group was assigned to be cis. Based on the spectroscopic data, structure 221 was assigned to clausevatine-E (174) (Scheme 2.54). The UV, IR, and 1H-NMR spectra of clausevatine-F (222) were very similar to those of clausevatine-E (221) indicating that the two alkaloids are diastereoisomers. The differences between these two alkaloids were only in the chemical shifts and coupling constants of the benzylic and homobenzylic protons, and indicated a trans

88

Chemistry and Biology of Carbazole Alkaloids

stereochemistry of both substituents. Based on these spectral data, structure 222 was assigned to clausevatine-F. This structural assignment was supported by 13C-NMR and NOE spectra (174) (Scheme 2.54). The UV spectrum [lmax 223, 264 (sh), 274, 287, and 338 nm] of clausevatine-G (223) was similar to that of clausevatine-D (220), indicating a similar 1-oxygenated-3carbonyloxycarbazole. The 1H-NMR spectrum also resembled that of clausevatine-D, except for the lack of benzylic protons and the presence of an olefinic singlet at d 7.65, indicating a double bond at the lactone ring conjugated to the carbazole. Based on these spectral data, and additional support from the 13C-NMR and NOE spectra, structure 223 was assigned to clausevatine-G (174) (Scheme 2.54).

E. Furocarbazole Alkaloids In 1990, Ito and Furukawa reported the isolation of furostifoline (224) and the isomeric eustifoline-D (227) from the root bark of M. euchrestifolia. These were the first furocarbazole alkaloids obtained from a natural source (101). Seven years later, Wu et al. reported the isolation of further furocarbazole alkaloids, furoclausine-A (225) and furoclausine-B (226) from the root bark of a different plant source, C. excavata (128). Furoclausine-B (226) was isolated from nature in optically active form [a]D –32.73 (c 0.022, MeOH), however, the absolute stereochemistry is not known (128,175,176) (Scheme 2.55). The UV spectrum (lmax 238, 274, and 334 nm) of furostifoline (224) indicates the presence of a 2-oxygenated carbazole framework. The 1H-NMR spectrum showed the presence of a NH at d 8.28 and an aromatic methyl group at d 2.67. The aromatic region showed signals for a low-field H-4 at d 7.79, a four-spin system indicating the presence of an unsubstituted C-ring, and two doublets with a vicinal-coupling (J=2.0 Hz) at d 7.73 and 7.00 for H-2u and H-3u on the furan ring, respectively. The spectral data, supported by NOE results, led to structure 224 for furostifoline (101) (Scheme 2.55). Me

4

5

5

2 9 8

2′

3′

5

CHO

4

2′ 1′ O

3′

2′

1

3′

Me

4

5

O1′

9

N H

1

225 Furoclausine-A

2 8

O1′

9

N H

8

1

224 Furostifoline

HO

2

HO

O1′

N H

CHO

4

3

2′ 3'

8

OH 226 Furoclausine-B

N H

1

227 Eustifoline-D

Scheme 2.55

Occurrence, Isolation, and Structure Elucidation

89

The UV spectrum of [lmax 239, 288 (sh), 301, and 345 nm] of furoclausine-A (225) resembled that of clausine T (131) (see Scheme 2.25) indicating a similar 2,7dioxygenated-3-formylcarbazole. The 1H-NMR spectrum of furoclausine-A was also very similar to that of clausine T (131), except for the absence of all aliphatic signals and the presence of two extra aromatic doublets at d 7.27 and 7.99 with a characteristic small vicinal coupling (J=2.3 Hz) suggesting the presence of a furan ring instead of the dihydropyran ring of clausine T. This assignment was confirmed by NOE and HMBC experiments. Based on the spectroscopic data, structure 225 was assigned to furoclausine-A. This assignment was supported by 13C-NMR and HMQC spectra (128) (Scheme 2.55). The UV spectrum of [lmax 231 (sh), 286 (sh), 301, and 339 nm] of furoclausine-B (226) resembled that of furoclausine-A (225) indicating a similar carbazole nucleus. The 1H-NMR spectrum was also very similar to that of furoclausine-A, except for the absence of two aromatic protons of the furan ring and the presence of two diastereotopic protons for a methylene group at d 3.40 (d, J=8.3 Hz) and 3.41 (d, J=8.0 Hz) coupled with a tertiary proton at d 4.92 (1H, dd, J=8.3, 8.0 Hz), two methyl singlets at d 1.21, and a singlet for a hydroxy group at d 3.60, indicating the presence of a (2-hydroxyisopropyl)dihydrofuran ring. Based on these spectral data, and the structural similarity with furoclausine-A, the structure 226 was assigned for furoclausine-B (128) (Scheme 2.55). The UV spectrum (lmax 224, 268, 298, 310, and 340 nm) of eustifoline-D (227) indicated the presence of a carbazole framework. The 1H-NMR spectrum showed signals for an NH at d 8.10 and an aromatic methyl group at d 2.58. The aromatic region exhibited signals for a low-field H-4 at d 7.97, mutually ortho-coupled H-1 and H-2 at d 7.40 and 7.26, and H-7 and H-8 at d 7.58 and 7.35, indicating the presence of substitutions at C-3, C-5, and C-6 of the carbazole moiety. Two, vicinally-coupled (J=2.0 Hz) 1H signals at d 7.81 (doublet) and 7.32 (double doublet) were assigned to H-2u and H-3u on the furan ring system, respectively. The C-3u proton showed an additional coupling (J=0.7 Hz) with H-7 at d 7.58 (1H, doublet of doublets, J=8.7, 0.7 Hz). Based on these data, and an NOE of H-3u on the furan ring (d 7.32) and H-4 (d 7.97), structure 227 was assigned to eustifoline-D (101) (Scheme 2.55).

F. Pyrido[4,3-b]carbazole Alkaloids In 1959, Goodwin et al. reported the isolation of the fully aromatized pyrido[4,3b]carbazole alkaloids ellipticine (228) and 9-methoxyellipticine (229) from the leaves of Ochrosia elliptica Labill. and Ochrosia sandwicensis A.DC. of the Apocynaceae family (177). In the following years, different groups reported the isolation of the same alkaloids from several different plants in the Apocynaceae family namely, Aspidosperma subincanum Mart. (178), Ochrosia maculata Jacq. (Ochrosia borbonica J.F. Gmel.) (179), Bleekeria vitiensis (Markgr.) A.C. Sm. (180), Ochrosia moorei F. Muell. ex Benth. (181), Ochrosia acuminata Trimen (182), as well as the Loganiaceae family, Strychnos dinklagei Gilg. (183). Two years later, from the stem bark of S. dinklagei Gilg., the same authors reported further ellipticine congeners, 9-hydroxyellipticine (230), 13-oxoellipticine (231), and 12-hydroxyellipticine (232) (184) (Scheme 2.56). Since the isolation of ellipticine and its congeners from natural sources, and the initial discovery of their anticancer activity in various experimental and human

90

Chemistry and Biology of Carbazole Alkaloids

12

R

Me

10

1

11

N

9 A

8 7

B

N6 H

D

C 5

R2

2

N

3

4

N H

Me 13

R1

228 Ellipticine R=H

231 13-Oxoellipticine

229 9-Methoxyellipticine R = OMe

232 12-Hydroxyellipticine

R1 = CHO; R2 = Me R1 = Me; R2 = CH2OH

230 9-Hydroxyellipticine R = OH

Scheme 2.56

tumor systems, a widespread interest in the chemistry and biology of these alkaloids has emerged (185–196). This development resulted in the commercialization of ellipticine derivatives for clinical use in the treatment of myleoblastic leukemia, advanced breast cancer, and other solid tumors (197–201). The UV spectrum (lmax 224, 237, 245, 275, 285, 293, 331, 346, 380, and 400 nm) of ellipticine (228) indicated a pyrido[4,3-b]carbazole framework. The 1H-NMR spectrum showed signals for two aromatic methyl groups at d 2.50 and 2.97 and a D2O-exchangeable NH at d 11.10. The aromatic region showed a deshielded orthocoupled (J=8.5 Hz) doublet at d 8.10, a three-proton multiplet at d 6.98–7.25, indicating an unsubstituted A-ring of the pyrido[4,3-b]carbazole nucleus, two, mutually ortho-coupled (J=6.0 Hz) protons at d 7.65 and 8.15, and a deshielded singlet at d 9.42. These data indicated the pyrido[4,3-b]carbazole framework. The assignment of the 13C-NMR data was achieved through INEPT experiments (202). Based on these spectral data, structure 228 was assigned to ellipticine (183). This assignment was unambiguously confirmed by total synthesis (178), as well as transformation into further ellipticine derivatives (177). The UV spectrum (lmax 246, 277, 294, 337, 353, and 403 nm) of 9-methoxyellipticine (229) resembled that of ellipticine (228) indicating a similar pyrido[4,3b]carbazole framework (177). The 1H-NMR spectrum was also very similar to that of ellipticine, except for the presence of an additional aromatic methoxy group at d 3.97 and the difference in the A-ring substitution pattern of the pyrido[4,3b]carbazole nucleus. The aromatic region showed signals for the mutually orthocoupled (J=8.7 Hz) H-8 and H-7 at d 7.17 and 7.42, respectively, a deshielded H-10 at d 7.91 as a doublet with a meta-coupling (J=2.4 Hz) to H-8 at d 7.17, indicating the position of the aromatic methoxy group at C-9. Based on the spectral data, structure 229 was assigned to 9-methoxyellipticine (182). This assignment was unambiguously confirmed by synthesis (203) and transformation into 9-methoxyellipticine derivatives (177). The UV spectrum (lmax 245, 277, 294, 338, 352, and 400 nm) of 9-hydroxyellipticine (230) resembled that of 9-methoxyellipticine (229) indicating the presence of a similar pyrido[4,3-b]carbazole framework. The 1H-NMR spectrum was also very similar to that of 9-methoxyellipticine (229), except for the presence of a hydroxy

Occurrence, Isolation, and Structure Elucidation

91

group at d 9.06 instead of the aromatic methoxy group at d 3.97. The presence of the hydroxy group was confirmed by the characteristic mass fragmentation at m/z 245 (M+OH). Based on these spectral data, structure 230 was assigned to 9-hydroxyellipticine (184). This structure was unambiguously confirmed by synthesis (204). The UV spectrum [lmax 239 (sh), 261, 291, 335, 358, and 404 nm] of 13oxoellipticine (231) resembled that of ellipticine (228), indicating a similar pyrido[4,3b]carbazole framework. The 1H-NMR spectrum was also very similar to that of ellipticine (228), except for the presence of an aldehyde group at d 11.05 instead of the aromatic methyl group at C-5 (d 2.71) of ellipticine. The aldehyde functionality was confirmed by characteristic IR bands at nmax 1655 (CQO) and 2820 (aldehyde CH) cm1, and a mass fragmentation at m/z 231 (M+CHO). Based on these spectral data, structure 231 was assigned to 13-oxoellipticine. This assignment was supported by transformation into 13-oxoellipticine derivatives (205). The UV spectrum [lmax 278 (sh), 289, 295, and 315 (sh) nm] of 12-hydroxyellipticine (232) resembled that of ellipticine (228) indicating a similar pyrido[4,3b]carbazole framework. The 1H-NMR spectrum was also similar to that of ellipticine (228), except for the presence of a hydroxymethylene group instead of one of the aromatic methyl groups, which was supported by a two-proton singlet at d 5.48, assigned to the methylene group, and a signal for a D2O-exchangeable aliphatic hydroxy group at d 5.44. The hydroxymethylene function at C-11 was confirmed by transformation of 12-hydroxyellipticine to the corresponding O-acetyl derivative (184). Based on these spectroscopic data, structure 232 was assigned to 12-hydroxyellipticine (184) (Scheme 2.56). In 1957, Schmutz et al. reported the isolation of (+)-guatambuine (u-alkaloid C) (233), a tetrahydro-derivative of olivacine, from Aspidosperma ulei Markgr. (206,207). In the following year, Carvalho-Ferreira et al. reported the same alkaloid from a different Aspidosperma species, Aspidosperma longipetiolatum Kuhlm. In Brazil, this plant is known as guatambu amarelo (208,209). In 1961, Ondetti and Deulofeu reported the isolation of (+)-guatambuine (233) from the root bark of Aspidosperma australe Mu¨ll. Arg., along with ()-guatambuine (233), and from the stem bark, (7)-guatambuine (233) and olivacine (238a) (210,211). It is interesting to note that two optical isomers and the racemic form of guatambuine have been obtained from the same natural source. Although, (+)-guatambuine (233) ½a25 D þ 112:0 (c 0.990, 29 pyridine) (207), ½a25 þ 106 (pyridine) (208), ½a þ 112:0  3:0 (c 0.485, pyridine), D D and ()-guatambuine (233) ½a26  106:0  2:0 (pyridine) were isolated in optically D active form, the absolute stereochemistry is not known (210,211). In 1959, Woodward et al. reported the isolation of N-methyltetrahydroellipticine (234) from A. subincanum Mart. (178). In 1967, Burnell and Casa reported the isolation of (7)-guatambuine (233) from the bark of a different Aspidosperma species, Aspidosperma vargasii A.DC., together with N-methyltetrahydroellipticine (234) and 9-methoxyolivacine (238b) (212). The UV spectrum (lmax 240, 250, 262, 299, and 330 nm) of (7)-guatambuine (233) indicated a carbazole framework (210,211). The 1H-NMR spectrum showed signals for an aromatic methyl group at d 2.41 and an N-methyl group at d 2.54 as singlets, along with a doublet (J=6.3 Hz) for an aliphatic methyl group at d 1.52. The 1H-NMR spectrum also showed two ddd-signals (J=5.7, 6.0, and 11.7 Hz) at d 2.79 and 3.19 for the protons at two C-3, a two-proton multiplet at d 2.94 for H-4, and a one-proton

92

Chemistry and Biology of Carbazole Alkaloids

quartet (J=6.3 Hz) at d 3.89 for H-1. The aromatic region showed signals for a downfield H-11 as a singlet at d 7.70, a four-spin system, indicating an unsubstituted tetrahydropyrido[4,3-b]carbazole A-ring. Based on these spectral data, and additional support by 13C-NMR, HMBC, and HMQC spectra, structure 233 was assigned to (7)-guatambuine (213). This assignment was unambiguously confirmed by synthesis from olivacine (238a) (see Scheme 2.58) (210,211). The UV spectrum (lmax 239, 260, 290, 319, and 330 nm) of N-methyltetrahydroellipticine (234) resembled that of (7)-guatambuine (233) indicating a similar tetrahydropyrido[4,3-b]carbazole framework. The 1H-NMR spectrum was also very similar to that of (7)-guatambuine (233), except for the presence of a singlet at d 2.68 for an aromatic methyl group instead of the doublet at d 1.52 for the aliphatic methyl group of (7)-guatambuine, and two equivalent C-1 protons as singlet at d 3.70, along with a four-proton multiplet at d 2.92 for H-3 and H-4. These spectral data led to structure 234 for N-methyltetrahydroellipticine (212). In 1995, Moreti et al. reported the isolation of janetine (235), 3,4-dihydroolivacine (237), olivacine (238a), and 3-hydroxytetrahydroolivacine (239) from the stem bark of Peschiera buchtienii (H. Winkl.) Markgr. (syn. Tabernaemontana buchtienii H. Winkl.) (214). This tree is common in the Chapare region of Bolivia, and is locally used for the treatment of leishmaniasis (214). Although, janetine (235) was isolated from Nature in its optically active form [a]D +8 (c 0.95, EtOH), the absolute stereochemistry is not known (214). In 1958, Schmutz and Hunziker reported the isolation of 3,4-dihydroellipticine (u-alkaloid D) (236) from A. ulei (207). Three years later, the same authors reported the isolation of the same alkaloid, 3,4-dihydroellipticine (236) along with 3,4-dihydroolivacine (237) as an inseparable mixture (215). In 1961, Bu¨chi et al. reported the isolation of 3,4-dihydroellipticine (236), together with N-methyl-tetrahydroellipticine (234) and ellipticine (228) (see Scheme 2.56) from a different Aspidosperma species, A. subincanum (216). In 1982, Michel et al. reported the isolation of 3,4-dihydroellipticine (236) from the stem bark of S. dinklagei (Loganiaceae) (184). In 1958, Schmutz and Hunziker reported the isolation of olivacine (238a), an isomeric structure of ellipticine (228) (see Scheme 2.56) from Aspidosperma olivaceum Mu¨ll. Arg. (217). In the following years, olivacine (238a) was also isolated from other species of the genera Aspidosperma, namely, A. longepetiolatum (209), A. australe (218), and of the genus Tabernaemontana, Tabernaemontana psychotrifolia H.B. & K. (219) (Schemes 2.57 and 2.58). The UV spectrum (lmax 240, 250, 262, 298, and 328 nm) of janetine (235) resembled that of (7)-guatambuine (233), indicating a similar tetrahydropyrido[4,3-b]carbazole framework. The 1H-NMR spectrum was similar to that of (7)-guatambuine, except for the lack of the N-methyl group at d 2.54. The assignment was supported by the mass fragment at m/z 250 (M+). Based on these spectral data and additional support by 13C-NMR, COSY, HMBC, and HMQC spectra, structure 235 was assigned to janetine (214). The UV spectrum (lmax 235, 270 (sh), 279, 301, 312, and 378 nm) of 236 indicated a dihydropyrido[4,3-b]carbazole framework. This assignment was supported by the IR spectrum (nmax 843, 1028, 1167, 1410, 1595, and 1615 cm1). The structure for 3,4dihydroellipticine was confirmed by synthesis from ellipticine and comparison of the IR and UV spectra, melting points and Rf values. Additional support for this assignment derived from the transformation into derivatives of 3,4-dihydroellipticine (216).

Occurrence, Isolation, and Structure Elucidation

R1

R3

R2

R2

R1 N

N N H

93

N H

Me

Me

236 3,4-Dihydroellipticine

233 Guatambuine R1,R2 = Me; R3 = H

R1 = H; R2 = Me 237 3,4-Dihydroolivacine R1 = Me; R2 = H

234 N-Methyltetrahydroellipticine R1 = H; R2,R3 = Me 235 Janetine R1 = Me; R2,R3 = H

Scheme 2.57 Me R

Me N

NH OH

N H

N H

Me

238a Olivacine R=H

Me

239 3-Hydroxytetrahydroolivacine

238b 9-Methoxyolivacine R = OMe

Scheme 2.58

The UV spectrum (lmax 235, 274, 282, 298, 310, and 370 nm) of 3,4-dihydroolivacine (237) indicated a dihydropyrido[4,3-b]carbazole framework. The 1H-NMR spectrum showed signals for an NH proton at d 8.25, two aromatic methyl groups at d 2.40 and 2.55, and two triplets (J=7.0 Hz) at d 2.80 and 3.70 for the C-4 and C-3 protons. The aromatic region showed signals for H-11 as a downfield singlet at d 8.10, a four-spin system indicating an unsubstituted A-ring of the dihydropyrido [4,3-b]carbazole. Based on these spectroscopic data, structure 237 was assigned to 3,4-dihydroolivacine (214). The UV spectrum (lmax 218, 235, 265, 289, and 324 nm) of olivacine (238a) indicated a pyrido[4,3-b]carbazole framework (220). The 1H-NMR spectrum showed signals for two aromatic methyl groups at d 2.90 and 3.20. The aromatic region showed signals for H-11 as a deshielded singlet at d 8.70, a four-spin system indicating an unsubstituted pyrido[4,3-b]carbazole A-ring, and two mutually orthocoupled (J=6.3 Hz) protons at d 7.80 and 8.17, indicating a methyl-substituted pyrido[4,3-b]carbazole framework. Based on these spectral data, structure 238a was assigned for olivacine (214). This assignment was unambiguously confirmed by synthesis (220), as well as transformation into known derivatives (210,211). The UV spectrum (lmax 222, 239, 269, 290, and 323 nm) of 9-methoxyolivacine (238b) resembled that of olivacine (238a), indicating a similar pyrido[4,3-b]carbazole framework. The 1H-NMR spectrum was also similar to that of olivacine, except for

94

Chemistry and Biology of Carbazole Alkaloids

the presence of an additional aromatic methoxy group and the difference in the A ring substitution pattern of the pyrido[4,3-b]carbazole nucleus. The aromatic region showed, instead of the four-spin proton system, a three-spin proton system in which H-10 at d 7.50 was only meta-coupled to H-8 at d 7.00. The ortho-coupling of H-8 to H-7 at d 7.31 confirmed the position of the aromatic methoxy group at C-9. Based on these spectroscopic data, structure 238b was assigned to 9-methoxyolivacine. The assignment was additionally supported by transformation into derivatives and comparison of their spectral data (212). The UV spectrum (lmax 242, 251, 261, 297, and 329 nm) of 3-hydroxytetrahydroolivacine (239) resembled that of janetine (235) (see Scheme 2.57), indicating a similar tetrahydropyrido[4,3-b]carbazole framework. The 1H-NMR spectrum was also similar to that of janetine, except for the presence of an additional aliphatic hydroxy group. The spectral data indicated a hydroxylated janetine. This assignment was by the mass fragment at m/z 266 (M+), which is 16 more than for janetine. The position of the hydroxy group was assigned to C-3 based on the presence of a triplet (1H, J=2.0 Hz) at d 4.90, which suggested a hemiaminal group. Based on these spectral data, structure 239 was assigned to 3-hydroxytetrahydroolivacine (214). In 1981, Potier et al. reported the isolation of N-oxyellipticine (240) from O. moorei (181). In the following year, Michel et al. reported the isolation of another N-oxyellipticine derivative, N-oxy-13-oxoellipticine (241), from the stem bark of S. dinklagei (184). Five years later, the same authors isolated from the bark of the same natural source, a novel, natural, bis-ellipticine alkaloid, strellidimine (242), in racemic form (221). Strellidimine represented the first example of a natural bisellipticine alkaloid, containing a 9-hydroxyellipticine (230) unit (see Scheme 2.56) linked to a 3,4-dihydroellipticine (236) unit (see Scheme 2.57) (221) (Scheme 2.59). The UV spectrum (lmax 240, 268, 278, 288, 295, and 330 nm) of N-oxyellipticine (240) resembled that of ellipticine (228) (see Scheme 2.56), indicating a similar pyrido[4,3-b]carbazole framework (222). Comparison of the mass spectrum of N-oxyellipticine at m/z 262 (M+), with that of ellipticine (228) showed only the presence of an additional oxygen as an N-oxy function. This conclusion was supported by comparison with the spectral data of synthetic N-oxyellipticine, obtained by oxidation of ellipticine (228) with H2O2 in dichloromethane, and by reduction of N-oxyellipticine with zinc to ellipticine. Based on these comparisons,

Me

O

H 6′ N

7′

N

Me 5′

8′

N H

9′

2

1

4′ 3′

10′

11′

Me

R

1′

Me

N2 ′

11

O 8

7

242 Strellidimine

241 N-Oxy-13-oxoellipticine R = CHO

Scheme 2.59

3 4

5

10

9

240 N-Oxyellipticine R = Me

N

Me N6 H

Occurrence, Isolation, and Structure Elucidation

95

structure 240 was assigned to N-oxyellipticine (222). This assignment was unequivocally confirmed by an X-ray crystal structure analysis (223) (Scheme 2.59). The UV spectrum [lmax 233 (sh), 287 (sh), 296, 323 (sh), and 354 nm] of N-oxy-13oxoellipticine (241) indicated a pyrido[4,3-b]carbazole framework. The 1H-NMR spectrum was very similar to that of 13-oxoellipticine (231) (see Scheme 2.56), except for the upfield shift of H-1 and H-3 at d 9.28 and 8.48, when compared to the corresponding signals for 13-oxoellipticine for H-1 at d 10.0 and for H-3 at d 9.15. The N-oxy function was supported by the mass fragment at m/z 276 (M+). Based on these spectral data, structure 241 was assigned to N-oxy-13-oxoellipticine. This assignment was unequivocally confirmed by transformation of N-oxy-13-oxoellipticine to 13-oxoellipticine (231) (see Scheme 2.56) (184). The UV spectrum [lmax 244, 253, 265, 279, 298, 327 (sh), 340, and 410 nm] of strellidimine (242) indicated a highly conjugated, polyaromatic system with at least one pyridine ring. The chemical ionization mass spectrum (CI-MS) (NH3) showed a molecular ion at m/z 509 (M++H), along with two fragment ions at m/z 263 and 247, typical of hydroxyellipticine and dihydroellipticine units. The 1H-NMR spectrum of strellidimine showed most of the characteristic signals of these two monomeric units, although there were differences in the aromatic region, when compared to the spectra of 9-hydroxyellipticine (230) (see Scheme 2.56) and 3,4-dihydroellipticine (236) (see Scheme 2.57). The two signals typical for H-10 of 9-hydroxyellipticine and for H-1 of 3,4-dihydroellipticine were absent, whereas the two signals of H-7 and H-8 of the hydroxyellipticine moiety appeared as a simple AB system at d 7.34 and 7.29, respectively. A singlet typical of an isolated proton at C-2 of a 2,3-dihydrooxazole ring appeared at d 6.55. Based on these spectral data, structure 242 was assigned to strellidimine. This assignment was confirmed by synthesis via oxidative coupling of 9-hydroxyellipticine (230) and 3,4-dihydroellipticine (236) in phosphate buffer with horseradish peroxidase-H2O2 (221) (Scheme 2.59).

G. Miscellaneous Carbazole Alkaloids In 1993, Kusano et al. isolated 2-hydroxy-7-methyl-9H-carbazole (243) from the aerial parts of Cimicifuga simplex Wormsk. ex DC. (224). Six years later, Wu et al. reported the isolation of clausine V (244) from the root bark of C. excavata (43) (Scheme 2.60). The UV spectrum (lmax 236, 261, and 305 nm) of 2-hydroxy-7-methyl-9H-carbazole (243) indicated a 2-hydroxycarbazole. This assignment was supported by the IR spectrum [nmax 1611 (aromatic system), 2700–3000 (OH), and 3400 (NH) cm1]. The presence of a hydroxy function was confirmed by transformation into the corresponding O-acetate and comparison with 2-hydroxy-7-methyl-9H-carbazole. 4

5

2

7

Me

N H

7

OH

9 8

4

5

2

MeO 8

1

243 2-Hydroxy-7-methyl-9H-carbazole

Scheme 2.60

OMe

9

N H

1

244 Clausine V

96

Chemistry and Biology of Carbazole Alkaloids

The 1H-NMR spectrum showed signals for an aromatic methoxy group at d 2.45 and two sets of three-spin systems in the aromatic region. The first set appeared at d 6.79 (d, J=2.1 Hz), 6.68 (dd, J=8.3, 2.1 Hz), and 7.80 (d, J=8.3 Hz), and was assigned to H-1, H-3, and a deshielded H-4, respectively. The signals of the second set appeared at d 6.89 (dd, J=8.8, 1.7 Hz), 7.13 (br s), and 7.77 (d, J=8.8 Hz), and were assigned to H-6, H-8, and a deshielded H-5, respectively. Based on these spectral data and additional support by 13C-NMR, COSY, NOESY, HMBC, and HMQC spectra, structure 243 was assigned to 2-hydroxy-7-methyl-9H-carbazole (224). The UV spectrum (lmax 208, 236, 261, 311, and 319 nm) of clausine V (244) indicated a 2,7-dioxygenated carbazole framework. This assignment was supported by the IR spectrum [nmax 1615 (aromatic system), and 3380 (NH) cm1]. The 1H-NMR spectrum showed a signal for an NH proton at d 10.13 and a singlet for two aromatic methoxy groups at d 3.84. In the aromatic region, a set of mutually ortho-coupled (J=8.4 Hz) protons at d 7.84 and 6.76 for H-4, H-5, H-3, and H-6, appeared together with a set of meta-coupled (J=2.3 Hz) protons at d 6.98 for H-1 and H-8, indicating the presence of methoxy groups at C-2 and C-7. These spectral data confirmed a symmetrical carbazole and led to structure 244 for clausine V (43).

II. CARBAZOLE ALKALOIDS FROM OTHER SOURCES While 1- and 2-oxygenated tricyclic carbazole alkaloids were isolated primarily from higher plants, various tricyclic carbazole alkaloids, which are 3-oxygenated or 3,4dioxygenated, were obtained from alternative natural sources, such as microbial, marine, and mammalian sources.

A. Tricyclic Carbazole Alkaloids 1 3-Oxygenated Tricyclic Carbazole Alkaloids Since the late 1960s, several carbazole alkaloids oxygenated in the 3-position were isolated from diverse natural sources, the majority of which were isolated from different plant sources. However, in 1979, Moore et al. reported the isolation of two unusual, non-basic, 3-oxygenated carbazole alkaloids, hyellazole (245) and chlorohyellazole (246), from the blue-green marine algae Hyella caespitosa (225). These alkaloids have structures entirely different from those of the carbazole alkaloids isolated from terrestrial plants. The UV spectrum [lmax 226, 232, 238 (sh), 250 (sh), 260 (sh), 292 (sh), 304, 338, and 352 nm] of hyellazole (245) indicated a carbazole framework. This assignment was supported by the IR band at nmax 3490 (NH) cm1. The 1H-NMR spectrum of hyellazole (245) showed signals for an aromatic methyl group at d 2.14, an aromatic methoxy group at d 3.99, and an NH group at d 9.52. In the aromatic region at d 7.357.60 appeared a complex multiplet for 6H, indicating the presence of a phenyl group along with H-8 of the carbazole nucleus at d 7.50. Additionally, the aromatic region showed the presence of a deshielded H-4 at d 7.70 as a singlet, indicating substitution at C-1, C-2, and C-3, along with three, mutually ortho-coupled protons at d 8.08, 7.28, and 7.11 for deshielded H-5, H-7, and H-6, respectively. Based on these

Occurrence, Isolation, and Structure Elucidation

97

spectral data and additional support from the 13C-NMR spectrum, structure 245 was assigned to hyellazole (225). The UV [lmax 220, 235, 242, 255 (sh), 272 (sh), 300 (sh), 310, 348, and 360 nm] spectrum of chlorohyellazole (246) resembled that of hyellazole (245). The 1H-NMR spectrum was also similar to that of hyellazole (245), except for the absence of H-6, as shown by two, mutually meta-coupled protons at d 8.13 and 7.27, assigned to a deshielded H-5 and H-7, respectively, indicating the position of the chlorine atom to be at C-6. These spectral data led to structure 246 for chlorohyellazole. This assignment was unequivocally confirmed by an X-ray crystal structure analysis (225). In 1989, Kato et al. reported the isolation of carazostatin (247) from Streptomyces chromofuscus. Carazostatin represents a novel radical scavenger more active than butylated hydroxytoluene (BHT) (226). Moreover, it exhibits strong inhibitory activity against the free radical-induced, lipid peroxidation in liposomal membranes, and shows stronger antioxidant activity than a-tocopherol (227). The UV spectrum (lmax 218, 235, 254, 266, 303, and 342 nm) of carazostatin (247) indicated a 3-hydroxycarbazole framework. This assignment was supported by the IR spectrum [nmax 1590 (aromatic system), 3360 (OH), and 3460 (NH) cm1]. The presence of OH and NH functions were confirmed by transformation of carazostatin into N,O-dimethylcarazostatin, and comparison of the data. The 1H-NMR spectrum of carazostatin (247) showed an aromatic methyl (d 2.38) and two broad singlet protons for NH (d 7.77) and OH (d 4.72) groups. The presence of an n-heptyl group was indicated by 1H-NMR signals at d 2.87 (2H, t, J=7.9 Hz), 1.65 (2H, m), 1.30–1.46 (8H, m), and 0.91 (3H, t, J=7.0 Hz). The aromatic region showed signals for a low-field H-4 at d 7.31, and a four-spin system indicating an unsubstituted C-ring of the carbazole. The NOE studies with N,O-dimethylcarazostatin confirmed the position of the hydroxy, aromatic methyl, and n-heptyl groups at C-3, C-2, and C-1, respectively. On the basis of these spectral data, and additional support from the 13 C-NMR, COSY, and HMBC spectra, structure 247 was assigned to carazostatin (226) (Scheme 2.61). In 1990, Seto et al. described the isolation of antiostatin A1 (248), A2 (249), A3 (250), A4 (251), B2 (252), B3 (253), B4 (254), and B5 (255) from Streptomyces cyaneus 2007-SV1. The antiostatins represent the first carbazole derivatives with an acetamido group or a substituted urea chain, and exhibited strong inhibitory activity against free radicalinduced lipid peroxidation (228) (Scheme 2.62). The UV spectrum (lmax 220, 238, 301, 338, and 350 nm) of antiostatin A1 (248) indicated the presence of a carbazole framework. This was also discernible from its IR spectrum. The 1H-NMR spectrum of antiostatin A1 (248) showed an N-acetyl group (d 2.47, 3H, s and 9.68, 1H, br s), an aromatic methyl group (d 2.40), a phenolic

OMe

OMe

Cl

Me N H

Ph

245 Hyellazole

OH

Me N H

Ph

246 Chlorohyellazole

Scheme 2.61

Me N H

C7H15

247 Carazostatin

98

Chemistry and Biology of Carbazole Alkaloids

O

O H N

Ac

N H

OH

N H

NH

Me N H

OH Me

N H

R

R

248 Antiostatin A1 R = (CH2)4Me

252 Antiostatin B2 R = (CH2)5Me

249 Antiostatin A2 R = (CH2)2CHMeCH2Me

253 Antiostatin B3 R = (CH2)4CHMe2

250 Antiostatin A3

254 Antiostatin B4

R = (CH2)4CHMe2

R = (CH2)6Me 255 Antiostatin B5 R = (CH2)5CHMe2

251 Antiostatin A4 R = (CH2 )6 Me

Scheme 2.62

hydroxy group (d 8.05), and an NH group (d 10.16). The presence of an n-pentyl group was indicated by 1H-NMR signals at d 2.97 (2H, t), 1.65 (2H, m), 1.45 (2H, m), 1.37 (2H, m), and 0.89 (3H, t). The aromatic region showed signals for a four-spin system indicating an unsubstituted C-ring of the carbazole nucleus. From the HMBC spectra, and comparison of the 13C-NMR spectra with those of carazostatin (247) (see Scheme 2.61), the n-pentyl, aromatic methyl, aromatic hydroxy, and N-acetyl groups were located at C-1, C-2, C-3, and C-4 of the carbazole nucleus. Based on the spectral data, structure 248 was assigned to antiostatin A1 (228). Comparison of the 1H-NMR and mass spectral data of antiostatin A1 (248) with those of the antiostatins A2, A3, and A4 confirmed the structures for 249, 250, and 251. The UV spectrum (lmax 218, 238, 301, 338, and 352 nm) of antiostatin B4 (254) resembled that of antiostatin A1 (248), indicating a similar carbazole framework. This was also supported from its IR spectrum. The 1H-NMR spectrum of antiostatin B4 (252) was also very similar to that of antiostatin A1 (248), except for the presence of an isobutylurea group instead of the acetyl group. Moreover, C-1 was substituted by an n-heptyl side chain, as supported by peaks at d 2.98 (2H, t), 1.66 (2H, m), 1.47 (2H, m), 1.36 (2H, m), 1.30 (2H, m), 1.28 (2H, m), and 0.89 (3H, t). Based on these spectroscopic data, and additional support from the 13C-NMR and HMBC spectra, structure 254 was assigned to antiostatin B4 (228). Comparison of the 1H-NMR and mass spectral data of antiostatin B4 (254) with those of the antiostatins B2, B3, and B5 confirmed the structures for 252, 253, and 255 (228) (Scheme 2.62). In 1997, Seto et al. reported the isolation of the novel neuronal protecting substances, carbazomadurin A (256) and carbazomadurin B (257) from Actinomadura madurae 2808-SV1. Carbazomadurin B (257) was isolated from Nature in optically active form ½a24 D þ 4:0 (c 0.05, MeOH). However, the absolute configuration was not determined (229) (Scheme 2.63). The UV spectrum [lmax 237, 249 (sh), 289 (sh), 299, 347, and 357 nm] of carbazomadurin B (257) indicated a carbazole framework. The 1H-NMR spectrum showed an aromatic methyl at d 2.26, a hydroxymethyl at d 5.01, and an NH group at

Occurrence, Isolation, and Structure Elucidation

HO

99

HO OH

5

4

3

OH 9'

HO

N H

Me Me Me

9

8

R

Me

HO

N H

1 1'

Me

3'

O

2'

4'

7'

R

5' 6'

Me 8'

256 Carbazomadurin A R=H

258 Epocarbazolin A R=H

257 Carbazomadurin B R = Me

259 Epocarbazolin B R = Me

Scheme 2.63

d 8.89. The DQF-COSY and HMBC spectra revealed the presence of alkyl, aromatic methyl, and hydroxy groups at C-1, C-2, and C-3 of the A-ring of the carbazole, which was also supported by the presence of a deshielded H-4 at d 7.59. Based on the 2D-NMR DQF-COSY and HMBC spectra, the structure of the alkyl side chain was confirmed as 2,5-dimethylhept-1-ene. The stereochemistry of the double bond in the 2,5-dimethylhept-1-ene side chain was assigned as E based on NOE spectra. Moreover, the HMBC spectrum indicated the presence of a hydroxymethyl group at C-5, and a second hydroxy group at C-8, which was supported by two aromatic protons at d 6.92 and 6.72 for H-6 and H-7, respectively. Based on these spectroscopic data, structure 257 was assigned to carbazomadurin B (229). The UV spectrum [lmax 237, 250 (sh), 289 (sh), 299, 345, and 357 nm] of carbazomadurin A (256) resembled that of carbazomadurin B (257), indicating a similar carbazole framework. The 1H-NMR spectrum was also similar to that of carbazomadurin B (257), except for the signals of the alkyl side chain. Detailed analysis of the DQF-COSY and HMBC spectra confirmed a 2,5-dimethylhex-1-ene side chain at C-1 with the same configuration of the double bond. Based on the spectral data, structure 256 was assigned to carbazomadurin A (229). In 1993, Oki et al. isolated the novel carbazole antibiotics epocarbazolin A (258) and B (259) from the culture broth of Streptomyces anulatus T688-8 (230). They represent the first carbazole alkaloids with an epoxide moiety in a side chain, and are the epoxides corresponding to carbazomadurin A (256) and B (257). Epocarbazolin A 26 (258) ½a26 D þ 75:0 (c 0.5, MeOH) and B (259) ½aD þ 78:0 (c 0.5, MeOH) were obtained from Nature in optically active form. However, their absolute configuration is not known. These alkaloids showed potent 5-lipoxygenase inhibitory activity and weak antibacterial activity (230) (Scheme 2.63). The UV spectrum [lmax 233, 250 (sh), 289 (sh), 300, 344, and 358 nm] of epocarbazolin B (259) resembled that of carbazomadurin B (257) indicating the presence of a similar carbazole framework. The 1H-NMR spectrum was also similar to that of carbazomadurin B (257), except for the presence of an epoxide instead of the double bond in the side chain. This epoxide was confirmed by the chemical shifts of C-1u and C-2u (d 64.7 and 63.9), and the C–H coupling constant of C-1u and H-1u (J=175 Hz). Additional support for this assignment was derived from COSY experiments. The structure was unequivocally supported by COSY and NOESY

100

Chemistry and Biology of Carbazole Alkaloids

studies of N,O-tetramethylepocarbazolin B, prepared by the permethylation of epocarbazolin B with MeI in the presence of NaH in DMF (230). The UV spectrum [lmax 234, 250 (sh), 289 (sh), 299, 345, and 359 nm] of epocarbazolin A (258) resembled that of epocarbazolin B (259), indicating a similar carbazole framework. The 1H-NMR spectrum was also similar to that of epocarbazolin B (259), but lacked the signal for one methylene group in the alkyl side chain, indicating a 3-methylbutyl group instead of the 3-methylpentyl group. This assignment was supported by the FAB-mass spectrum with a molecular ion at m/z 369 (M+). Based on the spectral data, and additional support from the 13C-NMR spectrum, structure 258 was assigned to epocarbazolin A (230).

2 3,4-Dioxygenated Tricyclic Carbazole Alkaloids A broad range of structurally diverse 3,4-dioxygenated carbazole alkaloids, such as the carbazomycins A–F (260-265) and the neocarazostatins A–C (266-268) were isolated from different Streptomyces species. In 1980, Nakamura et al. reported the isolation of carbazomycin A (260) and B (261) from Streptomyces ehimense H 1051-MY 10 (231). These structurally unique alkaloids (232,233), biogenetically derived from tryptophan (234), were the first antibiotics with a carbazole framework. Six years later, Marumo et al. reported the isolation of carbazomycin E (carbazomycinal) (264) and F (6-methoxycarbazomycinal) (265) from a different Streptoverticillium species of the strain KCC U-0166 (235). Subsequently, these alkaloids were isolated by Nakamura et al. from S. ehimense H 1051-MY 10, along with further members of the carbazomycin family, carbazomycin C (262) and D (263) (236). Carbazomycin A and B inhibit the growth of phytopathogenic fungi and have antibacterial and antiyeast activities (231). Carbazomycin B (261) and C were shown to inhibit 5-lipoxygenase (237). The UV spectrum (lmax 223, 242, 293, 327, and 340 nm) of carbazomycin A (260) indicates the presence of a carbazole framework (231). The 1H-NMR spectrum showed a signal for an NH proton at d 7.89, two aromatic methyl groups at d 2.40, and two aromatic methoxy groups at d 3.92 and 4.13. The aromatic region showed overlapping of three proton signals at d 7.137.42 and a deshielded ortho- and metacoupled (J=7.0, 2.0 Hz) dd-signal for H-5 at d 8.25 suggesting the lack of substituents on ring C of the carbazole nucleus. Based on the 13C-NMR decoupling technique and their chemical shift positions, two aromatic methyl and two aromatic methoxy groups were assigned to the C-1, C-2, C-3, and C-4 positions of the carbazole nucleus, respectively. Moreover, this assignment was supported by the presence of two aromatic methyl carbons at higher field (dC 12.6 and 13.6) than the usual values (dC 15B25) and two methoxy carbons at lower field (dC 60.5 and 61.1) than the usual values (dC 53B57). Additionally, the position of the aromatic methoxy group at C-3 was supported by the mass fragment at m/z 212 (M+CH3–CO) in the EI-MS. Based on these spectroscopic data, structure 260 was assigned to carbazomycin A (232) (Scheme 2.64). The UV spectrum (lmax 224, 245, 289, 330, and 340 nm) of carbazomycin B (261) resembled that of carbazomycin A (260), indicating a similar carbazole framework (231). The 1H-NMR spectrum was similar to that of carbazomycin A, except for the presence of a phenolic hydroxy group at d 6.21 instead of the C-4 methoxy group at d 4.13. The presence of a hydroxy group at C-4 was confirmed by the transformation of carbazomycin B into 4-deoxycarbazomycin B (reduction of O-tosylcarbazomycin B

Occurrence, Isolation, and Structure Elucidation

R1O

R2

OMe

R

HO

Me N H

OMe Me

N H

Me

260 Carbazomycin A 1

101

CHO

264 Carbazomycin E R=H

2

R = Me; R = H 261 Carbazomycin B

265 Carbazomycin F R = OMe

R1,R2 = H 262 Carbazomycin C R1 = H; R2 = OMe 263 Carbazomycin D R1 = Me; R2 = OMe

Scheme 2.64

over Raney nickel) and transformation into carbazomycin A by O-methylation with diazomethane (231,232). Based on the spectral data, structure 261 was assigned to carbazomycin B. This assignment was unequivocally confirmed by an X-ray crystallographic analysis (233). The UV spectrum [lmax 227, 245, 287 (sh), 341, and 354 nm] of carbazomycin C (262) resembled that of carbazomycin B (261) indicating a similar carbazole framework. The 1H-NMR spectrum was also similar to that of carbazomycin B, except for the difference in the C-ring aromatic substitution pattern and the presence of an additional aromatic methoxy group at d 3.84. In the aromatic region, the deshielded H-5 showed a meta-coupling (J=2.4 Hz) at d 7.7 indicating a methoxy group at C-6. This assignment was supported by the mutually ortho-coupled (J=8.8 Hz) aromatic protons at d 6.91 and 7.31, assigned to H-7 and H-8. Moreover, H-7 at d 6.91 showed a meta-coupling (J=2.4 Hz) with H-5 (d 7.7). The 13C-NMR spectrum also supported these assignments. Due to the shifts induced by the presence of the methoxy groups, the signals for C-5, C-6, C-7, and C-8 appeared at d 106.2, 154.0, 113.9, and 111.5, respectively. Based on these spectral data, structure 262 was assigned to carbazomycin C. Additional structural support derived from transformation into carbazomycin D (263) by O-methylation of 262 with dimethyl sulfate and potassium carbonate in boiling acetone (236). The assignment was unequivocally confirmed by X-ray crystallographic analysis (238). The UV spectrum [lmax 229, 247, 291 (sh), 340, and 356 nm] of carbazomycin D (263) resembled that of carbazomycin C (262) indicating a similar carbazole framework. The 1H-NMR spectrum was also similar to that of carbazomycin C, except for the presence of an additional aromatic methoxy group at d 4.06 instead of the aromatic hydroxy group (d 8.06). These data suggested an O-methyl ether of carbazomycin C for carbazomycin D. Based on the spectral data, structure 263 was assigned to carbazomycin D. This structure was unambiguously confirmed by O-methylation of carbazomycin C (262) using dimethyl sulfate and potassium carbonate in boiling acetone (236). The UV spectrum (lmax 227, 263, 295, 320, and 372 nm) of carbazomycin E (264) indicated a carbazole framework. The 1H-NMR spectrum showed the signal of an

102

Chemistry and Biology of Carbazole Alkaloids

aldehyde group (dH 10.41, dC 189.4). The aldehyde group was confirmed by characteristic IR bands at nmax 1660 (CQO) and 2860 (aldehyde CH) cm1. Moreover, the 1H-NMR spectrum showed signals for an aromatic methyl, a methoxy, and a hydroxy group at d 2.77, 3.81, and 9.57, respectively. The aromatic region showed the signals of a four-spin system, indicating an unsubstituted C-ring of the carbazole. This assignment was confirmed by four aromatic CH-signals in the 13 C-NMR spectrum. Based on NOE experiments, the positions of the aromatic methyl and aldehyde groups were assigned to C-2 and C-1, respectively. The position of the aromatic methoxy group at C-3 was supported by the mass fragmentation ion at m/z 212 (M+CH3–CO) in the EI-MS. Based on these spectral data, structure 264 was assigned to carbazomycin E (235). The UV spectrum (lmax 227, 268, 295, 310, and 382 nm) of carbazomycin F (265) resembled that of carbazomycin E (264) indicating the presence of a similar carbazole framework. The 1H-NMR spectrum was also similar to that of carbazomycin E, except for an additional aromatic methoxy group at d 3.93, and the difference in the aromatic substitution pattern. The aromatic region showed an ortho- and metacoupled (J=8.5, 2.7 Hz) doublet of doublets at d 7.05, a doublet with an ortho-coupling (J=8.5 Hz) at d 7.38, and another broad doublet proton with a meta-coupling (J=2.7) at d 7.72. The most deshielded proton at d 7.72 was assigned to H-5. The chemical shifts and the splitting pattern in the aromatic region suggested C-6 as the position for the second aromatic methoxy group. This assignment was confirmed by a long-range selective proton decoupling (LSPD) experiment. Based on these spectral data, structure 265 was assigned to carbazomycin F. This structure was unambiguously confirmed by O-methylation of carbazomycin E (264) (235). In 1991, Kato et al. reported the isolation of the neocarazostatins A (266), B (268), and C (267) from the culture of Streptomyces species strain GP 38 (239). Although, the 25 neocarazostatins A (266) ½a25 D  36:0 (c 0.1, MeOH), B (268) ½aD  24:0 (c 0.1, MeOH), 25 and C (267) ½aD  92:0 (c 0.1, MeOH) were optically active, their absolute configuration was not determined. The neocarazostatins exhibited strong inhibitory activity against the free radical-induced lipid peroxidation (239) (Scheme 2.65). The UV spectrum (lmax 230, 250, 271, 292, 331, and 345 nm) of neocarazostatin A (266) resembled that of carbazomycin B (261) (see Scheme 2.64), indicating a similar carbazole framework. In the 13C-NMR spectrum, 12 signals due to the carbazole nucleus in neocarazostatin A were almost identical to those of the analogous carbons 4′′ 3′′

1′′

5′′ 2′′

6

HO 5

HO

OMe

4

OMe

4b 4a 2

7

Me OH

9 8 8a

N 9a 1 H RO 5′

1′

4′

2′

N H

Me OH

3′

266 Neocarazostatin A R=H

268 Neocarazostatin B

267 Neocarazostatin C R = Me

Scheme 2.65

Occurrence, Isolation, and Structure Elucidation

103

in the spectrum of carbazomycin B, except for the signals assigned to C-1 and C-6, indicating a 1,6-disubstituted carbazomycin B-type chromophore for neocarazostatin A. Moreover, the 1H-, 13C-NMR, and 1H–1H COSY spectra of neocarazostatin A indicated the existence of the partial structures –CHOHCHOHMe and –CH2CH=CMe2. Furthermore, the HMBC spectrum showed long-range couplings of H-1u (CH) to C-1, C-2, and C-9a, and of H-1uu (CH2) to C-5, C-6, and C-7, indicating the attachment of partial structure –CHOHCHOHMe to C-1 and of CH2CH=CMe2 to C-6. Based on these spectral data, structure 266 was assigned to neocarazostatin A (239). The UV spectrum (lmax 231, 250, 271, 292, 331, and 345 nm) of neocarazostatin C (267) resembled that of neocarazostatin A (266), indicating a similar carbazole framework. The 1H-NMR and 13C-NMR spectra of neocarazostatin C were also similar to those of neocarazostatin A, except for the presence of one methoxy group (dH 3.25, dC 56.9). The HMBC spectrum showed the long-range coupling of the O-methyl protons to C-1u. Based on the spectral data, structure 267 was assigned to neocarazostatin C (239). The UV spectrum (lmax 228, 249, 270, 292, 331, and 344 nm) of neocarazostatin B (268) resembled that of neocarazostatin A (266), indicating a similar carbazole. Comparison of the mass fragmentation (m/z 353, M+) in the EI-MS spectrum of neocarazostatin B (268) with that of neocarazostatin A (266) confirmed a deoxyderivative of neocarazostatin A. The 1H-NMR and 13C-NMR spectra of neocarazostatin B also resembled those of neocarazostatin A, except for the signals of H-1u (dH 2.93 and 3.03, instead of 4.92) and C-1u (dC 38.6, instead of 76.5). Based on the spectroscopic data, structure 268 was assigned to neocarazostatin B (239).

3 Tricyclic Carbazole-1,4-quinol Alkaloids In 1988, Nakamura et al. reported the isolation of carbazomycins G (269) and H (270) from the culture broth of Streptoverticillium ehimense. These alkaloids have a structurally unique carbazole-1,4-quinol framework and were obtained from Nature in racemic form. Carbazomycin G showed moderate antifungal activity against Trichophyton species (238). The UV spectrum [lmax 214, 253, 272 (sh), 278, and 340 nm] of carbazomycin G (269) indicated a carbazole. The 1H-NMR spectrum showed signals for an NH at d 12.27, an aromatic methoxy group at d 3.71, and two methyl groups. However, the signals for the methyl groups appeared at higher field than aromatic methyl signals, such as those of carbazomycin B (251) (d 2.35 and 2.39) (see Scheme 2.64). The signal at d 2.01 was assigned to an olefinic methyl group, and the other signal at d 1.60 to a tertiary methyl group at an oxy-substituted carbon. This assignment was confirmed by the 13C-NMR methyl signals at d 10.1 and 27.9, assigned to the vinylic methyl group and the tertiary methyl group, respectively. Moreover, the 13C-NMR spectrum showed signals for a quaternary carbon at d 67.3 and a carbonyl carbon at d 177.5. The 1 H-NMR spectrum showed a three-proton multiplet at d 7.21–7.50 and a deshielded signal for H-5 at d 8.05, indicating an unsubstituted C-ring. The spectral data, and biogenetic considerations, of the carabazomycins led to structure 269 for carbazomycin G. The assignment was confirmed by an X-ray crystallographic analysis (238). The UV spectrum (lmax 214, 253, 261 (sh), 292, and 340 nm) of carbazomycin H (270) resembled that of carbazomycin G (269), indicating a similar carbazole framework. The 1H-NMR spectrum was also similar to that of carbazomycin G,

104

Chemistry and Biology of Carbazole Alkaloids

R

O

O

OMe

5

Me Me N HO H

4

9 8

MeO

269 Carbazomycin G R=H

N O OH

1

HO

CHO

271 Coproverdine

270 Carbazomycin H R = OMe

Scheme 2.66

except for an additional aromatic methoxy group at d 3.84, and the difference in the C-ring aromatic substitution pattern. The aromatic region showed an ortho- and metacoupled (J=8.8, 2.4 Hz) dd at d 6.85, a doublet with an ortho-coupling (J=8.8 Hz) at d 7.39, and another deshielded broad doublet with a meta-coupling (J=2.4) at d 7.66, assigned to H-5. The chemicals shifts in the aromatic region, and the coupling constants, confirmed the position of the aromatic methoxy group at C-6. Based on the spectroscopic data, structure 270 was assigned to carbazomycin H. This assignment was supported by the 13C-NMR spectrum (238) (Scheme 2.66). In 2002, Munro et al. reported the isolation of coproverdine (271) from a New Zealand Ascidian. The name of this isolate was derived from the descriptor attached to the voucher specimen (green sheep-shit-like in appearance), hence coproverdine (copro Greek dung, ovis Latin sheep, verde Latin green). This alkaloid was isolated from Nature in optically active form ½a20 D  8:0 (c 0.36, EtOH). However, the absolute configuration was not assigned. Coproverdine showed cytotoxic activity against a variety of murine and human tumor cell lines (240). The UV spectrum (lmax 208, 270, 302, and 382 nm) of coproverdine (271) indicated a carbazole framework. The NMR spectrum showed the presence of an aldehyde group (dH 10.13, dC 192.7), and a methyl ester (dH 4.06, dC 53.4 and 168.2), along with a carbonyl carbon at d 186.6. The aldehyde group was confirmed by the characteristic IR band at nmax 1665 (CQO). The 1H-NMR spectrum showed the presence of three, mutually ortho-coupled (J=8.0 Hz) protons at d 7.84, 7.39, and 7.28, indicating the presence of a 1,2,3-trisubstituted aromatic ring, and a cis-double bond (J=10.2 Hz) at d 6.25 and 7.01. The HMBC spectrum confirmed the methyl ester functionality at C-8, the oxo group at C-4, and the formyl group at C-1 of the carbazole nucleus. The UV data and carbon chemical shift calculations suggested C-1 and N-9 as the positions for the remaining two hydroxy groups. This assignment was confirmed by the characteristic IR bands at nmax 3500 cm1 (broad) and 3690 cm1 (sharp), for both hydrogen-bonded and free hydroxy groups. Based on the spectroscopic data, and additional support from COSY, HSQC, and HMBC spectra, structure 271 was assigned to coproverdine (240) (Scheme 2.66).

4 Tricyclic Carbazole-3,4-quinone Alkaloids In the past decade, Seto et al. reported the isolation of a series of unprecedented carbazole-3,4-quinone alkaloids from various Streptomyces species. In 1993, the first example of a carbazole-3,4-quinone alkaloid, carquinostatin A (278) was isolated

Occurrence, Isolation, and Structure Elucidation

105

from Streptomyces exfoliatus 2419-SVT2. This alkaloid was shown to be a potent neuronal cell protecting substance that also exhibited free radical scavenging activity. Carquinostatin A was isolated from Nature in enantiopure form, and the absolute stereochemistry at C-2u was determined by the Mosher method to be R. Although this alkaloid was available in enantiopure form, the optical rotation could not be measured due to strong absorption in the visible range (241). One year later, another 6-prenyl-carbazole-3,4-quinone alkaloid, carquinostatin B (279), was isolated from the same source. Carquinostatin B presented as a hydroxycarquinostatin A, was a potent neuronal cell protecting substance, and was isolated from Nature in optically active form. However, the optical rotation could not be determined due to strong visible region absorption. By analogy with carquinostatin A, the absolute configuration at C-2u was assigned as R. Based on NOE studies with the dimethylketal of carquinostatin B, the absolute configuration at C-1u was assigned as S (242,243). In 1998, Grammel et al. reported the isolation of the carquinostatins A (278) and B (CS-79B) (279) from a Streptomyces tendae bald mutant, created by acriflavine treatment. These carbazole alkaloids showed antibacterial activity (244). In 1995, lavanduquinocin (280), a structurally intriguing carbazole-3,4-quinone alkaloid, with a monoterpenoidal b-cyclolavandulyl side chain in the 6-position, was isolated from Streptomyces viridochromogenes 2942-SVS3. Lavanduquinocin exhibited strong neuronal cell protecting activity. Using Mosher’s method, the absolute configuration at C-2u was determined as R (245). In the same year, a series of carbazole-3,4-quinones, named carbazoquinocin A (272), B (273), C (274), D (275), E (276), and F (277), were isolated from Streptomyces violaceus 2448-SVT2. The carbazoquinocins exhibited strong inhibitory activity against lipid peroxidation. Among the various carbazoquinocins, carbazoquinocin A (272) and D (275) have a secondary stereogenic center at the 1-alkyl side chain. Although they were optically active, their absolute configuration was not assigned (246) (Schemes 2.67 and 2.68). O 5

O

4 4b 4a

8 8a

9

N H

9a

3 1

2

Me

R

272 Carbazoquinocin A R = (CH2)2CHMeCH2Me 273 Carbazoquinocin B R = (CH2)4CHMe2 274 Carbazoquinocin C R = (CH2)6Me 275 Carbazoquinocin D R = (CH2)4CHMeCH2Me 276 Carbazoquinocin E R = (CH2)5CHMe2 277 Carbazoquinocin F R = (CH2)6CHMe2

Scheme 2.67

106

Chemistry and Biology of Carbazole Alkaloids

8′′

4′′ 5′′ 3′′ 2′′

3′′

O

1′′

5

O

4

6

3

9 8

N H

9′′

1 1′

R

Me OH

10′′

5′′ 6′′

O

2′′ 1′′

5

6 7′′

3′

3

Me OH

9 8

2′

O

4

N H

1 1′

2′ 3′

280 Lavanduquinocin

278 Carquinostatin A R=H 279 Carquinostatin B R = OH

Scheme 2.68

The UV (lmax 228, 264, and 398 nm) and IR (nmax 1625, 1640 (sh), and 3440 cm1) spectral data of carbazoquinocin C (274) indicated a carbazole-3,4-quinone. This assignment was confirmed in the 13C-NMR spectrum by two carbonyl carbon signals at d 183.5 and 172.7, and by typical carbazole-3,4-quinone bands in the IR spectrum at nmax 1625 and 1640 cm1. The 1H-NMR spectrum of carbazoquinocin C (274) showed an aromatic methyl group at d 1.90 and an n-heptyl group at d 2.67 (2H, t, J=7.5 Hz), 1.55 (2H, m), 1.45 (2H, m), 1.31 (2H, m), 1.27 (2H, m), 1.25 (2H, m), and 0.85 (3H, t, J=8.0 Hz). The aromatic region showed signals for a low-field H-5 at d 7.85, a three-proton multiplet at d 7.23 (2H) and 7.50 (1H) assigned to H-6, H-7 and H-8, respectively, indicating an unsubstituted C-ring. In the 1H-13C long-range HMBC spectrum, the terminal methylene protons (C-1u) of the n-heptyl group showed coupling to C-1 (dC 142.2), C-2 (dC 133.1), and C-9a (dC 145.7). Moreover, the aromatic methyl group coupled to C-1 (dC 142.2), C-2 (dC 133.1), and C-3 (dC 183.5), indicated the position of the n-heptyl group at C-1, and the aromatic methyl group at C-2. Based on the spectroscopic data, structure 274 was assigned to carbazoquinocin C (246) (Scheme 2.67). The UV (lmax 228, 264, and 398 nm) and IR [nmax 1625, 1640 (sh), and 3440 cm1] spectral data of carbazoquinocin D (275) were identical to those of carbazoquinocin C (274), indicating the presence of a similar carbazole-3,4-quinone framework. Chemically, the presence of a carbazole-3,4-quinone function was established by formation of an o-phenylenediamine adduct. The 1H- and 13C-NMR spectra of carbazoquinocin D were also very similar to those of carbazoquinocin C, except for the presence of a 5-methylheptyl residue in place of the n-heptyl group. Thus, the 1 H-NMR spectrum of carbazoquinocin D showed a doublet (3H, J=7.0 Hz), and a triplet (3H, J=6.5 Hz) for the aliphatic methyl groups, and the chemical shifts of the corresponding aliphatic methyl carbons in the 13C-NMR spectrum were shifted to higher fields (d 19.1 and 11.2, respectively) due to a g-effect. Based on these spectral data, and the structural similarity to carbazoquinocin C, the structure 275 was assigned to carbazoquinocin D (246) (Scheme 2.67). A close comparison of the HRFAB-MS and 1H-NMR spectral data of the carbazoquinocins A (272), B (273), E (276), and F (277) with those of the carbazoquinocins C (274) and D (275) indicated the presence of a 3-methylpentyl, 5-methylhexyl, 6-methylheptyl, and 7-methyloctyl residue, respectively, in place of the

Occurrence, Isolation, and Structure Elucidation

107

carbazoquinocin C (274) C-1 n-heptyl and carbazoquinocin D (275) 5-methylheptyl group. Based on these spectral data, and the structural similarities to the carbazoquinocins C (274) and D (275), the structures 272, 273, 276, and 277 were assigned to carbazoquinocins A, B, E, and F, respectively (246) (Scheme 2.67). The UV (lmax 230, 267, and 425 nm) and IR [nmax 1615, 1640 (sh), 1660 (sh), 3220, and 3450 cm1] spectral data of carquinostatin A (278) were similar to those of carbazoquinocin C (274) (see Scheme 2.67), indicating the presence of a similar carbazole-2-methyl-3,4-quinone framework. This was substantiated by the 13C-NMR showing two carbonyl carbon signals at d 183.5 and 172.6, as well as typical carbazole-3,4-quinone bands in the IR spectrum at nmax 1615 and 1640 cm1. Chemically, the presence of a carbazole-3,4-quinone function was established by the formation of an o-phenylenediamine adduct. A close comparison of the 1H- and 13 C-NMR spectra of carquinostatin A (278) with those of neocarazostatin B (268) (see Scheme 2.65) indicated that carquinostatin A is structurally related to neocarazostatin B with a masked carbazole-3,4-hydroquinone (ortho-hydroquinone) unit. This was further supported by the 1H–13C long-range HMBC spectrum, as well as NOE experiments. Based on this spectroscopic analysis, the structure 278 was assigned for carquinostatin A (241) (Scheme 2.68). The UV (lmax 230, 267, and 425 nm) and IR [nmax 1615, 1640 (sh), 1660 (sh), 3220, and 3450 cm1] spectra of carquinostatin B (279) were similar to those of carquinostatin A (278), indicating the presence of a similar carbazole-3,4-quinone framework. The comparison of the mass fragmentation ion m/z 354 (M++1) in the HRFAB-MS spectrum of carquinostatin B (279) with carquinostatin A (278) showed it to be a hydroxy derivative of carquinostatin A. The 1H- and 13C-NMR spectra of carquinostatin B were also very similar to those of carquinostatin A, except for the signals due to H-1u (dH 4.70 in place of 2.75) and C-1u (dC 73.9 in place of 37.7). Based on these spectral data, and the structural similarity to carquinostatin A, structure 279 was assigned to carquinostatin B. This structure was further supported by DQF-COSY and HMBC spectra (243) (Scheme 2.68). The UV (lmax 232, 269, and 429 nm) and IR [nmax 1615, 1640 (sh), 1660 (sh), 3220, and 3450 cm1] spectra of lavanduquinocin (280) were similar to those of carquinostatin A (278), indicating the presence of a similar carbazole-3,4-quinone framework. The 1H- and 13C-NMR spectra of lavanduquinocin (280) were also very similar to those of carquinostatin A, except for the presence of a cyclolavandulyl moiety in place of a prenyl side chain at C-6 of the carbazole nucleus. Thus, the DQF-COSY spectrum showed the coupling between the C-6uu methylene protons at d 1.24 with the C-7v methylene protons at d 1.84, which also showed long-range coupling with the C-4v (d 1.78) and C-1v (d 3.41) methylene protons. Further, the HMBC spectrum showed coupling between the C-5v methyl protons at d 0.84 to C-4v (dC 45.6), C-5v (dC 28.9), and C-6v (dC 35.4). In addition, the C-3v allylic methyl proton at d 1.73 showed coupling to C-2uu (dC 127.3), C-3uu (dC 125.6), and C-4uu (dC 45.6). Furthermore, the C-1v protons at d 3.41 showed coupling to C-2v (dC 127.3), C-3v (dC 125.6), and C-7v (dC 26.8), establishing the connectivity between C-1v (dC 38.4) and C-2v (dC 127.3). These results indicated the presence of a cyclolavandulyl moiety at C-6 of the carbazole nucleus. These spectral data, together with the similarities to the data of carquinostatin A, established the structure 280 for lavanduquinocin (245) (Scheme 2.68).

108

Chemistry and Biology of Carbazole Alkaloids

B. Benzocarbazole Alkaloids In the past decade, a few examples of benzoannulated carbazole ring systems were found in nature as marine products. In 1993, Chan et al. reported a novel marine benzocarbazole alkaloid, purpurone (281) from the marine sponge Iotrochota sp. in its racemic form. Purpurone, as indicated by its name, is purple in color. This represents the first example of a benzocarbazole alkaloid with a biphenylene quinone methide functionality. The isolate showed ATP-citrate lyase (ACL) inhibitory activity (247). The UV spectrum (lmax 216, 296, and 500 nm) of purpurone (281) showed a bathochromic shift on addition of base, indicating the presence of phenolic groups. The IR spectrum showed a strong hydroxy band at nmax 3100–3600 cm1 and a carbonyl band at 1680 cm1 which was assigned to a highly conjugated carbonyl group. This was substantiated by the 13C-NMR carbonyl carbon signal at d 185.4. The HRFAB mass spectrum, in combination with the NMR spectral data, established a molecular formula of C40H27NO11. The 1H- and 13C-NMR spectra showed only 22 carbon signals and 9 proton signals, indicating purpurone to be a highly symmetrical molecule in which the nitrogen atom, one oxygen atom, and four carbon atoms lie in a plane of symmetry. Permethylation of purpurone with diazomethane gave an unstable nonamethyl derivative with five methyl signals in a ratio of 2:2:2:2:1 indicating the presence of nine phenolic groups, one of which lies in the plane of symmetry, and four phenolic groups in each symmetrical unit, along with one carbonyl function. The presence of a tyramine unit in the plane of symmetry is evident from the NMR spectra. The HMBC correlations from the C-1v proton signal at d 2.95 to the 6a and 7a carbon signals at d 156.1 indicated that the tyramine nitrogen was attached to the symmetrical units, each C16H9O5, through this aromatic carbon atom. The downfield shift for this carbon shows conjugation to a carbonyl carbon. Further, the 1H-NMR spectral data and the HMBC correlations indicated the presence of two, symmetrically located, 4-substituted, 1,2-dihydroxyphenyl rings at C-6 and C-8 of the benzocarbazole nucleus. Additional support came from NOE experiments. The remaining signals in the 1H-NMR spectrum were at d 7.45 (s, 2H) and 7.80 (s, 2H). The HETCOR spectrum indicated the dC values for these carbons as 115.1 and 114.1, respectively. The HMBC spectrum showed that both of these proton signals were correlated with the 13C-NMR signals at d 149.0 and 150.1, which were assigned to the phenolic carbons C-3, C-11 and C-2, C-12, respectively. These proton signals were therefore on two, symmetrically located, 1,2-disubstituted 4,5-dihydroxyphenyl rings. The HMBC spectrum showed a strong correlation between the 1H-NMR signal at d 7.45 and the 13C-NMR signal at d 185.4, the carbonyl groups must be adjacent to the 1,2-disubstituted 4,5-dihydroxyphenyl rings. This experiment led to the assignment of dH 7.45 for the C-4 and C-10 protons, and dC 185.4 for the C-5 and C-9 carbonyl carbons. Based on this spectroscopic analysis, the structure 281 was assigned for purpurone (247) (Scheme 2.69). Four years later, Kang and Fenical reported the isolation of ningalin D (282) from a marine ascidian of the genus Didemnum collected in Western Australia, near Ningaloo Reef. On the basis of the restricted rotation and also because of the apparent helicity, 282 could be chiral. However, from the marine source, it was available only in racemic form (248).

Occurrence, Isolation, and Structure Elucidation

HO

OH

HO

12

11 9a

O

3′′′

13b

9 8

6′′′

HO

6a

1′′ 2′′ 3′′

4′′′

4''

6′ 5′

5

O

N 2′

1′

3′

OH

OH

HO

4′

OH 6′′

O

O

6

HO 7′′

OH

4

13c

N

HO

OH

4a

7 7a 1′′′

HO

3

13 1 13a 13d

10

OH

2

109

OH

HO

5′′

OH

OH

OH

281 Purpurone

282 Ningalin D

Scheme 2.69

The UV (lmax 206, 294, and 508 nm) and IR (nmax 1665, 3000–3700 cm1) spectra of ningalin D (282) were very similar to those of purpurone (281), indicating the presence of a similar benzocarbazole framework with a biphenylene quinone methide functionality. Comparison of the HRFAB mass spectrum of ningalin D with that of purpurone showed it to be a hydroxy-derivative of purpurone. The 1H- and 13 C-NMR spectra of ningalin D were also very similar to those of purpurone, except for the presence of an additional hydroxy group at C-5v of the phenethyl aromatic ring, showing the presence of a dopamine unit in place of a tyramine unit in the plane of the symmetry of ningalin D. Thus, the 1H-NMR spectrum showed two, mutually coupled (J=6.5 Hz) triplet methylene protons at d 2.13 and 2.95 for C-2v and C-1v, respectively. Further, in the aromatic region, two, mutually ortho-coupled (J=7.5 Hz) C-8v and C-7v protons at d 5.95 and 6.30, respectively, and one metacoupled (J=1.5 Hz) C-4v proton at d 6.12, indicated the presence of a dopamine moiety. Based on these spectral data, and the structural similarity to those of purpurone, the structure 282 was assigned for ningalin D. This structure was further supported by the HMBC and NOESY spectra (248) (Scheme 2.69).

C. Pyrrolo[2,3-c]carbazole Alkaloids Since the late eighties, pyrrolocarbazole alkaloids began to emerge as a new class of condensed heteroarylcarbazoles. Until the early nineties, these compounds were known from their synthetic origin due to their broad spectrum of bioactivities, such as anticancer, antidiabetic, neurotropic, and protein kinase C (PKC) inhibitory properties (249). In 1993, Sato et al. isolated the novel pyrrolo[2,3-c]carbazole alkaloids, 289, 290, and 291 from a dark green marine sponge, Dictyodendrilla sp. These compounds showed inhibitory activities against bovine lens aldose reductase. Although, 290 and 291 have a stereogenic center, they were obtained in optically inactive form (no Cotton effect) (250). A decade later, Fusetani et al. reported the isolation of further pyrrolo[2,3-c]carbazole alkaloids, the dictyodendrins A (283), B (284), C (286), D (287), and E (288), along with the previously known carbazole alkaloid 290 from the same Japanese marine invertebrate, the marine sponge Dictyodendrilla verongiformis. Dictyodendrins A–E were the first telomerase-inhibitory marine natural products.

110

Chemistry and Biology of Carbazole Alkaloids

Despite the presence of a stereogenic center, the CD spectrum of dictyodendrin A (283) exhibited no Cotton effect, indicating its racemic nature. This was proven by chiral reverse phase HPLC (251). Dictyodendrin A (283) showed UV maxima at lmax 208, 227, 328, and 480 nm. The IR spectrum indicated the presence of a strong hydroxy band at nmax 3408 cm1, and an ester carbonyl band at 1724 cm1. The 1H-NMR spectrum showed the presence of a signal for an NH proton at d 9.96, 13 methine signals between d 5.9 and 7.5, along with two methylenes at d 2.19, 3.73, and an ester methoxy group at d 3.52. The presence of an ester function was supported by the 13C-NMR signal at d 174.1 for the ester carbonyl carbon. Interpretation of the COSY spectral data, together with HMBC correlations, led to the establishment of four, 4-substituted phenols in which ring H was connected to the C-4 carbon of the pyrrolo[2,3-c]carbazole nucleus, and ring E was connected to the C-1 carbon of the pyrrolo[2,3-c]carbazole nucleus. However, ring G was linked to a methylene carbon C-2vu (dH 2.19, dC 36.2). Furthermore, HMBC cross peaks were observed between H-3v (H-8v) and C-1v, between H-1v and C-8v, and between H-1v and C-2, connecting ring F to the C-1v methine (dH 5.28, dC 48.9), which was linked to a methoxycarbonyl functionality and C-2v of ring F. The three, contiguous, aromatic protons at d 5.94, 6.56, and 7.17 for C10, C-9, and C-8, respectively, indicated the further substitution on C-7 of the A ring of the pyrrolo[2,3-c]carbazole nucleus. The HMBC cross peaks (H-10/C-10b, C-6a; H-9/C-10a, C-7; H-8/C-6a; N-6/C-10b, C-10a, C-6a, C-5a) indicated the fusion of ring A with a pyrrole, leading to a 2,3,7-trisubstituted indole. Based on this spectral analysis, the structure 283 was assigned to dictyodendrin A. This structure was further supported by the transformation of dictyodendrin A to the 7-O-sodium sulfate salt of 289 (see Scheme 2.72) (251) (Scheme 2.70).

OMe HO

8′′

4′

O

OH F

1′′

OH

O

HO

5′′

2′′

E 1

2

1′′′ 1′ 3′′′ G 6′′′ OH 10 10a 10c D N3 3a 2′′′ 10b 4 A C 8 4′′′′ B 1′′′′ H OH 7 6a N 5a 5 6

N

OH

9

NaO3SO

H

OH

NaO3SO

283 Dictyodendrin A

OH

N H

OH

284 Dictyodendrin B

HO

O N

HO

N H

OH OH

O 285

Scheme 2.70

111

Occurrence, Isolation, and Structure Elucidation

Dictyodendrin B (284) showed UV maxima at lmax 228, 305, and 397 nm. The IR spectrum indicated the presence of a strong hydroxy band at nmax 3381 cm1 and a conjugated ketone band at 1608 cm1. Comparison of the HRFAB mass spectrum of dictyodendrin B with that of dictyodendrin A showed it to be an oxidative decarboxylation product of dictyodendrin A. This was supported by the presence of a conjugated ketone carbon signal at d 191.8 in its 13C-NMR spectrum, as well as the absence of an ester methoxy group and the C-1v methine signals in its NMR spectra. Furthermore, similar to dictyodendrin A, the NMR spectra showed the presence of four, 4-substituted phenols, an isolated ethylene unit, and a 2,3,7-trisubstituted indole, indicating the presence of the similar common core. Based on these spectral data, and the structural similarity to dictyodendrin A, the structure 284 was assigned to dictyodendrin B. This structure was unequivocally established by transformation of dictyodendrin B into pyrrolidinone 285 by treament with acid, the same pyrrolidinone was also obtained by acid treatment of the 7-O-sodium sulfate salt of 289 (see Scheme 2.72) (251) (Scheme 2.70). The UV (lmax 238, 277, 302, and 415 nm) and IR (nmax 1602, 3362 cm1) spectra of dictyodendrin C (286) were similar to those of dictyodendrins A (283) and B (284), indicating the presence of a similar carbazole framework. The 1H-NMR spectrum showed the absence of C-1v and ring F, which was substantiated by the 13C-NMR data. The C-9 unit attached at C-2 in dictyodendrin A was replaced by an oxygen atom, which was in agreement with HR-FABMS and NMR data, indicating dictyodendrin C to be the 10-sulfate of pyrrolidinone. Based on this spectral analysis, the structure 286 was assigned to dictyodendrin C. This structure was unequivocally established by the transformation of dictyodendrin C to pyrrolidinone 285 (see Scheme 2.70) by acid hydrolysis (251) (Scheme 2.71). The UV (lmax 243, 276, 305, and 416 nm) and IR (nmax 1602, 3454 cm1) spectra of dictyodendrin D (287) were very similar to those of dictyodendrin C (286), indicating the presence of a similar carbazole framework. The FABMS data, showed that the molecular ion peak is 80 units larger than that of dictyodendrin C. Furthermore, sequential loss of SO3 and NaSO3 suggested the presence of two sulfate groups. The NMR spectra of dictyodendrin D were also very similar to those of dictyodendrin C, except that in the 1H-NMR spectrum, a downfield shift

7′′

HO

O

HO

4′

1′′ 2

1′

N

OR 10

9

2′′ 3

1

N 4

NaO3SO

N H

OH 7

O

NaO3SO

286 Dictyodendrin C R=H

6

N H

5′′ OH

3′′ 1′′′

5 1′′′′

O

288 Dictyodendrin E

287 Dictyodendrin D R = SO3H

Scheme 2.71

6′′′

3′′′

2′′′ 4′′′′

OH

OH

112

Chemistry and Biology of Carbazole Alkaloids

of 0.5 ppm was observed for H-5vu and H-7vu, assigning dictyodendrin D as the 7vu-O-sulfate of dictyodendrin C. Based on these spectral data and the structural similarity to dictyodendrin C, the structure 287 was assigned to dictyodendrin D. This structure was unequivocally established by the transformation of dictyodendrin D into pyrrolidinone 285 (see Scheme 2.70) by acid hydrolysis (251) (Scheme 2.71). Dictyodendrin E (288) showed UV maxima at lmax 230, 280, and 464 nm. Similar to dictyodendrin C (286), the 1H-NMR spectrum of dictyodendrin E showed the presence of four, 4-substituted phenols, an isolated ethylene unit, and a 2,3,7trisubstituted indole, indicating the presence of a similar common core. Furthermore, in place of a keto group at C-2, the isolate showed the presence of a vinyl proton connected to a 4-substituted phenol. This was established with the HMBC spectrum in which a vinyl proton at d 5.99 (H-1u) showed long-range coupling to C-1 and C-3v (C-7v). Further, from the ROESY spectrum, the geometry of this double bond (D2,1v) was established to be Z. Based on these spectral data, and the structural similarity to dictyodendrin C, the structure 288 was assigned to dictyodendrin E. This structure was unequivocally established by the transformation of dictyodendrin E into pyrrolidinone 285 (see Scheme 2.70) through acid treatment (251) (Scheme 2.71). The UV spectrum (lmax 231, 281, and 482 nm) of pyrrolo[2,3-c]carbazole alkaloid 289 was very similar to that of dictyodendrin E (288), indicating the presence of a similar carbazole framework. The NMR spectra of 289 were also very similar to those of dictyodendrin E (288), except for the presence of an O-sulfate group at C-7 and a methoxycarbonyl group instead of the C-1v vinyl proton. The presence of a methoxycarbonyl group was supported by the presence of an IR band at nmax 1691 cm1, as well as long-range coupling between the methoxy protons (d 3.17) and the carbonyl carbon (d 171.3) in the HMBC spectrum. Further, the presence of a 7-Osulfate group was supported from its HRFAB-MS. Based on these spectral data and the structural similarity to those of dictyodendrin E, the structure 289 was assigned for this isolate (250) (Scheme 2.72). The UV spectrum (lmax 229, 288, 324, 391, and 475 nm) of the pyrrolo[2,3c]carbazole alkaloid 290 showed the presence of a pyrrolo[2,3-c]carbazole framework with a spirolactone structure. The 1H-NMR spectrum indicated the presence of two

OMe HO

OH

O

O

HO

4′ 4′′O

N

OH

10 10a

HO3SO

N H

OH O

7

RO3SO

289

6a

1 1′ 10c 10b 6

N H

5a

2′′ OH 3′′

1′′ 3 1′′′ 2 N 1′′′′2′′′′ 3a 4 5 1′′′′′

O 290 R = Na 291 R = H

Scheme 2.72

OH 4′′′ 6′′′′

OH

4′′′′′

OH

Occurrence, Isolation, and Structure Elucidation

113

methylene protons at d 2.37 and 2.97, assignable to an isolated ethylene group and unresolved broad signals for 22 protons as multiplets. In the aromatic region, the three contiguous aromatic protons at d 5.74, 6.61, and 7.15 for C-10, C-9, and C-8, respectively, indicated further substitution at C-7 of the A ring of a pyrrolo[2,3c]carbazole nucleus. The 13C-NMR spectrum indicated the presence of two methylene carbon atoms at d 36.8 and 47.5, and a carbonyl carbon atom at d 181.6, along with many unassignable aromatic carbon atoms. The isolate was hydrolyzed chemically with trifluoroacetic acid, and enzymatically with sulfatase to the corresponding hydroxy derivative, indicating the presence of a sulfate group. The 1 H-NMR spectrum of this hydroxy derivative showed an upfield shift for the C-10 (d 5.43) and C-8 protons (d 6.54) compared with 290, while the other protons did not shift as much. This established the position of the sulfate group at C-7. Transformation of this hydroxy derivative to the corresponding acetate, and the X-ray crystallographic analysis of this acetate, led unequivocally to the structure 290 for the pyrrolo[2,3-c]carbazole alkaloid (250) (Scheme 2.72). The UV spectrum (lmax 229, 289, 324, 391, and 475 nm) of the pyrrolo[2,3c]carbazole alkaloid 291 was identical to that of 290, indicating the presence of a similar pyrrolo[2,3-c]carbazole spirolactone framework. Comparison of the spectral data of this isolate with those of the pyrrolo[2,3-c]carbazole alkaloid 290 indicated it to be an acid form of 290. This was further established by the chemical conversion of 291 to the corresponding 7-hydroxy derivative. Based on these spectral data, and the close structural similarity to 290, the structure 291 was assigned to this compound (250) (Scheme 2.72).

D. Indolo[2,3-a]carbazole Alkaloids The indolocarbazole family is comprised of five different isomeric ring systems based on the fusion and orientation of the indole ring and the C-ring of the carbazole nucleus (8). Among these, the most interesting structural class are the indolo[2,3a]carbazoles, since many natural products bear this basic framework, and show a wide range of potent biological activities (252–260). The other structural classes of indolocarbazoles and their derivatives have been studied in much less detail due to the fact that they are not present in natural products, and there is a lack of knowledge of their biological activities. However, several aza analogs of indolo[3,2a]carbazoles were shown to be powerful benzodiazepine receptor ligands (261,262). Moreover, in the mid-1990s derivatives of the indolo[3,2-b]carbazole attracted interest due to their affinity to the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) receptor [also referred to as the aryl hydrocarbons (Ah) receptor protein] (263–266) which plays an important physiological role. Previously in the literature, for simplicity, under indolo[2,3-a]carbazole natural products, only the indolo[2,3-a]carbazoles with and without the pyrrolo[3,4-c]ring were considered. The recent past has witnessed an explosive growth of these natural products. Due to this, and the difference in the aglycon framework, in this article we have classified the indolo[2,3-a]carbazoles with a pyrrolo[3,4-c]ring as indolo[2,3a]pyrrolo[3,4-c]carbazole alkaloids, and the indolo[2,3-a]carbazoles without a pyrrolo[3,4-c]ring as simple indolo[2,3-a]carbazole alkaloids.

114

Chemistry and Biology of Carbazole Alkaloids

1 Indolo[2,3-a]pyrrolo[3,4-c]carbazole Alkaloids The majority of indolocarbazole alkaloids, isolated so far from nature, are derivatives of the indolo[2,3-a]pyrrolo[3,4-c]carbazole ring system 292. They have been isolated from soil organisms, slime molds, and marine sources (3,7,8,252–255), and have shown a broad range of potent biological activities, such as antifungal, antimicrobial, antitumor, and antihypertensive activity (3,7,256–260,267–270). Their activity as potent inhibitors of protein kinase C (PKC) has received special attention, and was the focus of several investigations (8,257,258,271–280). The history of these natural products dates back about 30 years (Scheme 2.73). ¯ mura et al. isolated the first indolo[2,3-a]pyrrolo[3,4-c]carbazole In 1977, O alkaloid from Streptomyces staurosporeus Awaya (281), and subsequently from several other actinomycetes (267,268). Initially, this alkaloid was called AM-2282, but later it was named staurosporine (295) (282,283). From Nature, this isolate was obtained in its optically active form ½a25 D þ 35:0 (c 1.0, MeOH) (281). The absolute configuration of this isolate was initially assigned from circular dichroism (CD) measurements (284). However, this assignment was revised based on anomalous dispersion measurements performed on crystalline 4u-N-methylstaurosporine methiodide, which was prepared from staurosporine (295). Based on this X-ray crystallographic analysis, the absolute stereochemistry of staurosporine (295) was revised to be 2uS, 3uR, 4uR, and 6uR (285). Staurosporine has very interesting biological activities (280), including antimicrobial (281,286,287), antihypertensive (286,287), cytotoxic (271), inhibition of PKC (271,288), and platelet aggregation inhibition (268). Since 1997, the number of isolated and structurally elucidated indolo[2,3a]pyrrolo[3,4-c]carbazole alkaloids has grown considerably (8,255,258). Almost 10 years later, Kase et al. reported the isolation of K-252c (293) from the culture broth of Nocardiopsis sp. K-290. The structure of K-252c represents the aglycon of staurosporine (295), therefore, 293 is named staurosporinone (273,274). In 1994, Horton et al. reported the isolation of the staurosporine aglycon (K-252c) from a different source, the marine ascidian Eudistoma sp., collected off the coast of West Africa (275). Staurosporine aglycone (K-252c) showed strong inhibition of PKC isoenzymes (273,275), and also potent in vitro cytotoxicity against the human lung cancer A549 and P388 murine leukemia cell lines (275). In 1996, Cai et al. reported the isolation of a 6-alkylated derivative of staurosporine aglycon, 6-isopropoxymethylK-252c (294) from S. longisporoflavus strain R-19 (289).

7

O

H N 6

5

O 4

8 9

3 12

10 11

N H

13

N H

2 1

292 Indolo[2,3-a]pyrrolo [3,4-c]carbazole

Scheme 2.73

Occurrence, Isolation, and Structure Elucidation

115

The UV spectrum [lmax 230, 238 (sh), 246 (sh), 257 (sh), 287, 320 (sh), 331, 341, and 358 nm] of staurosporinone (K-252c) (293) showed the presence of an indolo[2,3a]pyrrolo[3,4-c]carbazole framework. The IR spectrum indicated the presence of an NH band at nmax 3440 cm1 and an amide band at 1648 cm1. The presence of NH groups at d 11.38 and 11.56, and a secondary amide at d 8.49, were also established from its 1H-NMR spectrum. Further, the NMR spectra of this isolate were very similar to those of K-252a (330) (see Scheme 2.85), except for the absence of the sugar moiety. This was also in agreement with the HR-MS. Hydrolysis of K-252a (330) gave staurosporinone (K-252c) (293), establishing it to be the aglycon of K-252a. Based on these spectral data, and the structural similarity to K-252a, the structure 293 was established for K-252c (274) (Scheme 2.74). The 1H-NMR spectrum of 6-isopropoxymethyl-K-252c (294) was very similar to that of staurosporinone (K-252c) (293), except for the presence of isopropoxy signals at d 1.17 as a doublet and a multiplet at d 3.80 along with a singlet at d 5.14, assignable to methylene protons attached to a nitrogen atom. The 13C-NMR spectrum also showed the presence of isopropoxymethyl signals, together with those attributed to staurosporinone. The location of the additional isopropoxymethyl group at the lactam nitrogen was supported by the shifts of the 4c, 5, 7, and 7a carbon signals by more than 2 ppm in comparison to staurosporinone. Based on these spectral data, and the structural similarity to staurosporinone, the structure 294 was assigned to 6-isopropoxymethyl-K-252c (289). The UV spectrum [lmax 243, 267 (sh), 292, 322 (sh), 335, 356, and 372 nm] of (+)-staurosporine (AM-2282) (295) was very similar to that of staurosporinone (293), indicating the presence of a similar indolo[2,3-a]pyrrolo[3,4-c]carbazole framework. The IR spectrum indicated the presence of an NH band at nmax 3500 cm1 and an amide band at 1675 cm1. The structure and relative stereochemistry of this isolate were established by X-ray crystallographic analysis of the methanol solvate (282,283). The structure 295, indicating the presence of an indolocarbazole subunit, wherein two

7 8

7a 7c 7b

R N 6

5

O

4c 4 4b 4a

12b 12a 11a N12 13 N 13a 11 1

H

7

H N

5

O

6

4

8

R1

H

12 11

N 2'

Me R2O

1'

O 4'

3'

13

N 6'

1

H 5'

NHMe 293 Staurosporinone (K-252c) Staurosporine Aglycone R=H 294 6-Isopropoxymethyl-K-252c R = CH2OCHMe2

295 (+)-Staurosporine (AM-2282) R1 = H; R2 = Me 296 TAN-999 R1 = OMe; R2 = Me 297 O -Demethylstaurosporine (3'-O-Demethylstaurosporine) R1,R2 = H

Scheme 2.74

116

Chemistry and Biology of Carbazole Alkaloids

indole nitrogens are bridged by glycosyl linkages, was unambiguously confirmed by its 1H-, 13C-NMR, COSY, NOESY, selective INEPT, HMBC, and HMQC spectra (290). Furthermore, in addition to the relative stereochemistry, the absolute stereochemistry of staurosporine was assigned to be 2uS, 3uR, 4uR, and 6uR based on X-ray crystallographic analysis of 4u-N-methylstaurosporine methiodide (285). Based on these data, the structure 295 was assigned to (+)-staurosporine (AM-2282). In 1989, Tanida et al. reported the isolation of a 10-methoxy derivative of staurosporine, TAN-999 (296) from the culture broths of Nocardiopsis dassonvillei C-71425 in its optically active form [a]D +42.0 (c 0.50, DMF). This isolate functions as a macrophage activator, useful for the treatment of mycosis, bacterial infection, and cancer (291,292). The UV spectrum [lmax 245, 296, 341, 352 (sh), and 368 nm] of TAN-999 (296) was very similar to that of (+)-staurosporine (295), indicating the presence of a similar indolo[2,3-a]carbazole framework with a lactam function. This was also discernible from its IR spectrum with the presence of an NH band at nmax 3430 cm1 and an amide band at 1680 cm1. The 1H-NMR spectrum of TAN-999 was also very similar to that of (+)-staurosporine, except for the presence of an additional methoxy group at d 3.95, resulting in the presence of a 1,2,4-trisubstituted aromatic ring instead of a 1,2-disubstituted aromatic ring. The location of this additional methoxy group was assigned to C-10, based on 1H–1H COSY, 1H–13C COSY, refocused INEPT, and COLOC experiments. In the COLOC spectrum (J=4.2 Hz), a C-10 quaternary carbon (d 157.49) was correlated with the methoxy protons (d 3.95) and the C-8 aromatic proton (d 7.75). The NOE experiment showed a cross-peak between the methoxy protons (d 3.95) and two aromatic protons (H-9 and H-11). Furthermore, an NOE was observed between the aromatic (H-11) and methyl protons (Hu-6, d 2.33). These data establish the presence of this additional methoxy group (d 3.95) at C-10. Based on these spectral data, and the structural similarity to (+)-staurosporine, the structure 296 was assigned to TAN-999 (293) (Scheme 2.74). In 1995, Hoehn et al. reported the isolation of O-demethylstaurosporine (3u-O-demethylstaurosporine) (297) from a blocked mutant of S. longisporoflavus R 19 (294). In nature, this was isolated in its optically active form ½a20 D þ 82:0  1:1 (c 1%, DMSO), and was less potent than (+)-staurosporine (295), but showed more selective inhibition of PKC subtypes a, b-2, and g (294). The UV (lmax 244, 293, 335, 355, and 372 nm) and IR (nmax 1660 and 3420 cm1) spectra of O-demethylstaurosporine (3u-O-demethylstaurosporine) (297) were very similar to those of (+)-staurosporine (295), indicating the presence of a similar indolo[2,3-a]carbazole framework with a lactam function. The 1H- and 13C-NMR spectra of O-demethylstaurosporine (3u-O-demethylstaurosporine) (297) were also very similar to those of (+)-staurosporine, except for the absence of a methoxy group at dH 3.32 and dC 57.2. In addition, the carbon signal for C-3u was significantly shifted from d 82.7 to 68.9. Based on these data, and the structural similarity to (+)-staurosporine, the structure 297 was assigned to O-demethylstaurosporine (3u-O-demethylstaurosporine). This structure was unambiguously established by a bioconversion experiment with a blocked mutant of S. longisporoflavus M 13 transforming O-demethylstaurosporine (3u-O-demethylstaurosporine) quantitatively into (+)-staurosporine (294) (Scheme 2.74). In 1992, Kinnel and Scheuer reported the isolation of 11-hydroxystaurosporine (298) and 3,11-dihydroxystaurosporine (299a) from the Pohnpei brown tunicate,

Occurrence, Isolation, and Structure Elucidation

117

Eudistoma sp. (295). These were the first examples of naturally occurring, enantiopure indolo[2,3-a]carbazole alkaloids from a marine organism. Based on the specific rotation, [a]D +10.3 (c 0.30, MeOH), of 11-hydroxystaurosporine (298) and the CD spectrum of 3,11-dihydroxystaurosporine (299a), the absolute configurations of these isolates were presumed to be similar to that of (+)-staurosporine (295) (see Scheme 2.74). These isolates were active against human nasopharyngeal cancer cells, and 3,11-dihydroxystaurosporine (299a) was more potent than (+)-staurosporine (295) in PKC inhibition (295). In 1999, 3,11-dihydroxystaurosporine (299a) was also isolated by Boyd et al. from a different natural source, the prosobranch mollusk Coriocella nigra collected in the Philippines (296). The UV [lmax 246, 256, 292, 300, 334 (sh), 356, and 374 nm] and IR (nmax 1660 and 3400 cm1) spectra of 11-hydroxystaurosporine (298) were very similar to those of (+)-staurosporine (295) (see Scheme 2.74), indicating the presence of a similar indolo[2,3-a]carbazole framework with a lactam function. The 1H- and 13C-NMR spectra of 11-hydroxystaurosporine (298) were also very similar to those of (+)staurosporine, except for the absence of the C-11 proton. But there was an exchangeable proton, indicating the presence of a phenolic group, at d 10.6. The presence of a phenolic hydroxy group was supported from its HRFAB-MS. In addition, this isolate formed a diacetate, indicating the presence of the secondary amine and the phenol. Based on these data, and the structural similarity to (+)staurosporine, the structure 298 was assigned to 11-hydroxystaurosporine. This structure was further supported by the HMBC and NOE spectra (295) (Scheme 2.75). The 1H-NMR spectrum of 3,11-dihydroxystaurosporine (299a) was very similar to that of 11-hydroxystaurosporine (298), except for the absence of one proton in the aromatic region. Decoupling experiments showed that the second aromatic ring is 1,2,4-trisubstituted, and the C-4 proton is shifted to d 8.69 with meta-coupling (J=2.7 Hz). This shielding effect of the C-4 proton, together with HRFAB-MS, indicated the presence of an additional oxygen atom ortho to the C-4 carbon. Based

H N 7

6

H N

O

O

5

8

4

R1 3

12

N

11

R2

2′

Me MeO

1′

O

13

N 6′

4′

N

1

NHMe

R1 = H; R2 = OH 299a 3,11-Dihydroxystaurosporine 1

2

R ,R = OH

N

Me MeO

H

298 11-Hydroxystaurosporine

O

Me

H OH N

R

300 4′-N-Methyl-5′-hydroxystaurosporine R = Me 301 5′-Hydroxystaurosporine R=H

299b 3-Hydroxystaurosporine R1 = OH, R2 = H

Scheme 2.75

118

Chemistry and Biology of Carbazole Alkaloids

H N

H N

O

O R1

OH N

O

Me R1O Me

N

N R2

304 3-Hydroxy-4′-N-demethylstaurosporine R1 = OH; R2 = H

= Me

303 3-Hydroxy-3′-O-demethylstaurosporine R1,R2 = H

H NH2

R2

302 3-Hydroxy-4′-N-methylstaurosporine R1,R2

N

Me MeO

H N

O

305 11-Hydroxy-4′-N-demethylstaurosporine R1 = H; R2 = OH 306 4′-N-Demethylstaurosporine R1,R2 = H

Scheme 2.76

on these spectral data, and the structural similarity to 11-hydroxystaurosporine (298), the structure 299a was assigned to 3,11-dihydroxystaurosporine (295). In 1999, Schupp et al. reported the isolation of 3-hydroxystaurosporine (299b) (Scheme 2.75), 3-hydroxy-3u-O-demethylstaurosporine (303), 11-hydroxy-4u-Ndemethylstaurosporine (305), and 4u-N-demethylstaurosporine (306) (see Scheme 2.76), along with the previously known staurosporinone (293), (+)-staurosporine (295), and O-demethylstaurosporine (3u-O-demethylstaurosporine) (297) (see Scheme 2.74) from the marine ascidian Eudistoma toealensis and its predatory flatworm Pseudoceros sp. (Pseudocerotidae). Except for 3-hydroxy-3u-O-demethylstaurosporine (303) and 11-hydroxy-4u-N-demethylstaurosporine (305), the remaining staurosporine derivatives were isolated in their protonated form (297). In the same year, prior to Schupp’s report Boyd et al. already reported the isolation of 11-hydroxy-4u-Ndemethylstaurosporine (305), along with the previously known 3,11-dihydroxystaurosporine (299a) (see Scheme 2.75), from a different natural source, the prosobranch mollusk Coriocella nigra collected in the Philippines (296). The 1H-NMR spectrum of 3-hydroxystaurosporine (299b) was very similar to that of (+)-staurosporine (295) (see Scheme 2.74), except for the absence of one proton in the aromatic region. Decoupling experiments showed that the second aromatic ring is 1,2,4-trisubstituted, and the C-4 proton is shifted to d 8.71 with meta-coupling (J=1.8 Hz). This shielding effect of the C-4 proton indicated the presence of an additional oxygen atom ortho to the C-4 carbon. Based on these spectral data, and the structural similarity to (+)-staurosporine (295), the structure 299b was assigned to 3hydroxystaurosporine. This structure was further supported by the COSY, HMBC, and HMQC spectra (297) (Scheme 2.75). In 2000, Baz et al. reported the isolation of 4u-N-methyl-5u-hydroxystaurosporine (300) and 5u-hydroxystaurosporine (301), along with (+)-staurosporine (295) (see Scheme 2.74), from the culture broth of a marine Micromonospora sp. strain L-31CLCO-002. In nature, these isolates were available in their enantiopure form with a

Occurrence, Isolation, and Structure Elucidation

119

specific rotation of [a]D +30.0 (c 0.11, CHCl3) for 4u-N-methyl-5-hydroxystaurosporine and [a]D +53.0 (c 0.10, CHCl3) for 5u-hydroxystaurosporine. The relative configurations of these staurosporine analogs were determined by NMR analysis (298). The UV (lmax 242, 291, 320, 334, 354, and 370 nm) and IR (nmax 1670 and 3400 cm1) spectra of 4u-N-methyl-5u-hydroxystaurosporine (300) were very similar to those of (+)-staurosporine (295) (see Scheme 2.74), indicating the presence of a similar indolo[2,3-a]carbazole framework with a lactam function. The NMR spectra of 4u-N-methyl-5u-hydroxystaurosporine (300) were also very similar to those of (+)staurosporine (295) (see Scheme 2.74), except for the difference in the substitution pattern of the sugar moiety. Thus, the 1H-NMR spectrum showed two shielded N-methyl singlets at d 2.37 and a doublet (J=9.9 Hz) for the C-5u proton at d 4.43 and the C-3u singlet at d 3.95, and a shielded doublet (J=9.9 Hz) for the C-4u proton at d 3.02, indicating the presence of additional methyl and hydroxy groups at the C-4u Nmethyl and the C-5u carbon, respectively. Based on these spectral data, and the structural similarity to (+)-staurosporine (295), the structure 300 was assigned to 4uN-methyl-5u-hydroxystaurosporine. This structure was further supported by the 13CNMR and NOESY spectra (298) (Scheme 2.75). The UV (lmax 242, 291, 320, 334, 354, and 370 nm) and IR (nmax 1670 and 3400 cm1) spectra of 5u-hydroxystaurosporine (301) were identical to those of 4u-N-methyl5u-hydroxystaurosporine (300), indicating the presence of a similar carbazole framework. The 1H-NMR spectrum of 5u-hydroxystaurosporine (301) also closely resembled that of 4u-N-methyl-5u-hydroxystaurosporine, except for the presence of a three-proton singlet at d 2.17 in place of a six-proton singlet at d 2.37, indicating the addition of one C-4u-N-methyl group. This was also in agreement with the FAB-MS data. Based on these spectral data, and the close structural similarity to 4u-N-methyl-5u-hydroxystaurosporine (300), the structure 301 was assigned to 5uhydroxystaurosporine. This structure was unambiguously established by the transformation of 5u-hydroxystaurosporine (301) to 4u-N-methyl-5u-hydroxystaurosporine (300) by N-methylation with methyl iodide in acetone with potassium carbonate (298) (Scheme 2.75). In 2002, Schupp et al. reported the isolation of 3-hydroxy-4u-N-methylstaurosporine (302), 3-hydroxy-4u-N-demethylstaurosporine (304) (see Scheme 2.76) and 3u-O-demethyl-4u-N-demethylstaurosporine (307) (see Scheme 2.77), along with the H N

N

O

H N

O

N

Me HO

H NH2

307 3′-O-Demethyl-4′-N-demethylstaurosporine

N

O

Me MeO Me

O

N H

N

H N

Me

N

O

Me MeO OHC

O

N H

N

Me

308 N-Methylstaurosporine 309 N-Formylstaurosporine

Scheme 2.77

120

Chemistry and Biology of Carbazole Alkaloids

previously known 11-hydroxystaurosporine (298) (see Scheme 2.75) and N-methylstaurosporine (308) (see Scheme 2.77), from the marine ascidian E. toealensis and its predatory flatworm Pseudoceros sp. (Pseudocerotidae). The CD measurements of all these staurosporine derivatives confirmed that they have a similar 2uS, 3uR, 4uR, and 6uR absolute configuration as (+)-staurosporine (295) (see Scheme 2.74) (299). Prior to Schupp’s isolation, N-methylstaurosporine (308) was already known by Cai et al. at Ciba-Geigy from S. longisporoflavus (300). The UV spectrum (lmax 287, 297, 308, 324, 342, 366, and 385 nm) of 3-hydroxy4u-N-methylstaurosporine (302) was similar to that of (+)-staurosporine (295) (see Scheme 2.74), indicating the presence of a similar indolocarbazole framework with a lactam function. The ESI-MS spectrum showed a molecular ion at m/z 497 (M++H), together with the daughter ion at m/z 354, characteristic of the oxygenated indolocarbazole moiety in 3-hydroxy-4u-N-methylstaurosporine (302). The 1H-NMR spectrum was similar to that of (+)-staurosporine (295), except for a broad methyl signal at d 2.94 corresponding to two N-methyl groups. Based on the HMQC and HMBC experiments, the two other methyl groups at d 2.35 and 2.59 were assignable to the C-3u methoxy and C-2u methyl groups, respectively. Furthermore, the aromatic region showed a characteristic, three-proton coupling pattern, in which there was an upfield shift for the meta-coupled (J=2.5 Hz) C-4 proton (d 8.77). The absence of the C-3 proton, and the corresponding upfield shifts of the C-4 (d 8.77) and C-2 (d 7.07) protons, indicated the presence of an additional hydroxy group at C-3. Based on these spectral data, and the structural similarity to (+)staurosporine, the structure 302 was assigned to 3-hydroxy-4u-N-methylstaurosporine. This structure was further supported by the 13C-NMR and COSY spectra (299) (Scheme 2.76). The UV (lmax 237, 251, 270, 297, 342, 366, and 384 nm) spectrum of 3-hydroxy-3uO-demethylstaurosporine (303) was very similar to that of O-demethylstaurosporine (3u-O-demethylstaurosporine) (297) (see Scheme 2.74), indicating the presence of a similar indolo[2,3-a]carbazole framework with a lactam function. The 1H- and 13 C-NMR spectra of 3-hydroxy-3u-demethylstaurosporine (303) were also very similar to those of O-demethylstaurosporine (3u-O-demethylstaurosporine) (297), except for the absence of one proton in the aromatic region. The 1H–1H COSY spectrum showed a characteristic three-proton aromatic coupling pattern in which the C-4 proton was shifted to d 8.74 with meta-coupling (J=2.4 Hz), indicating the presence of an additional oxygen atom ortho to the C-4 carbon. This 1,2,4trisubstituted aromatic pattern was also supported by the absence of the C-3 proton and the upfield shifts of the C-4 and C-2 protons compared to O-demethylstaurosporine (3u-O-demethylstaurosporine). Based on these spectral data, and the structural similarity to O-demethylstaurosporine (3u-O-demethylstaurosporine) (297), the structure 303 was assigned to 3-hydroxy-3u-O-demethylstaurosporine. This structure was further supported by the COSY, HMBC, and HMQC spectra (297) (Scheme 2.76). The UV spectrum (lmax 287, 297, 342, 366, and 384 nm) of 3-hydroxy-4u-Ndemethylstaurosporine (304) was very similar to that of 3-hydroxy-4u-N-methylstaurosporine (302), indicating the presence of a similar indolocarbazole framework with a lactam function. The ESI-MS spectrum showed a molecular ion at m/z 469 (M++H), together with a daughter ion at m/z 354, indicating the presence of an oxygenated indolocarbazole moiety, together with the absence of two methyl groups in the sugar

Occurrence, Isolation, and Structure Elucidation

121

moiety. The 1H-NMR spectrum was also similar to that of 3-hydroxy-4u-Nmethylstaurosporine (302), except for the absence of a broad methyl signal at d 2.94 corresponding to two N-methyl groups. Furthermore, the C-4u proton showed a downfield shift (d 4.12) when compared to the C-4u proton (d 3.92) of 3-hydroxy-4u-Nmethylstaurosporine (302), establishing the absence of methyl groups at C-4u-nitrogen. Based on these spectral data, and the structural similarity to 3-hydroxy-4u-Nmethylstaurosporine, the structure 304 was assigned to 3-hydroxy-4u-N-demethylstaurosporine. This structure was further supported by the COSY spectrum (299) (Scheme 2.76). The UV spectrum (lmax 290, 354, and 371 nm) of 11-hydroxy-4u-N-demethylstaurosporine (305) was similar to that of 11-hydroxystaurosporine (298) (see Scheme 2.75), indicating the presence of a similar indolocarbazole framework (296). The ESIMS spectrum of 11-hydroxy-4u-N-demethylstaurosporine was identical to that of 3-hydroxy-4u-N-demethylstaurosporine (304) with a molecular ion at m/z 469 (M++H) and a daughter ion at m/z 354, establishing that these two are regioisomeric, oxygenated, indolocarbazole alkaloids (299). The 1H-NMR spectrum of 11-hydroxy4u-N-demethylstaurosporine was also very similar to that of 11-hydroxystaurosporine (298) (see Scheme 2.75), except for the presence of the NH2 protons at d 8.45 as a broad singlet in place of the N-methyl protons at d 2.55. The absence of a CH2 group was supported from its HRFAB-MS. Based on these spectral data, and the structural similarity to 11-hydroxystaurosporine, the structure 305 was assigned to 11-hydroxy-4u-N-demethylstaurosporine. This structure was further supported by the HMBC and NOE spectra (296) (Scheme 2.76). The 1H- and 13C-NMR spectra of 4u-N-demethylstaurosporine (306) were very similar to those of (+)-staurosporine (295) (see Scheme 2.74), except for the absence of the C-4u-N-methyl at dH 2.83 and dC 31.3, indicating the presence of an NH2 group at C-4u. Based on these spectral data, and the close structural similarity to (+)-staurosporine, the structure 306 was assigned to 4u-N-demethylstaurosporine (297) (Scheme 2.76). The UV spectrum (lmax 291, 322, 334, 355, and 372 nm) of 3u-O-demethyl-4u-Ndemethylstaurosporine (307) was very similar to that of (+)-staurosporine (295) (see Scheme 2.74), indicating the presence of a similar indolo[2,3-a]pyrrolo[3,4-c]carbazole framework. The NMR spectra of 3u-O-demethyl-4u-N-demethylstaurosporine were also very similar to those of (+)-staurosporine (295), except for the difference in the substitution pattern of the sugar moiety. Thus, the 1H-NMR spectrum showed only one methyl signal at d 2.41. From the HMBC experiments this methyl group was correlated with C-2u, indicating the location of this methyl at C-2u, and there were no methyl signals representing the 3u-OMe and 4u-NMe, as in (+)-staurosporine. Further, the presence of a (+)-staurosporine indolocarbazole moiety was supported by the mass fragmentation ion at m/z 338 in the EI-MS. Based on these spectral data, and the close structural similarity to (+)-staurosporine, the structure 307 was assigned to 3u-O-demethyl-4u-N-demethylstaurosporine (299) (Scheme 2.77). The IR (nmax 1685 and 3450 cm1) spectrum of N-methylstaurosporine (308) was similar to that of 4u-N-methyl-5u-hydroxystaurosporine (300) (see Scheme 2.75), indicating the presence of a similar indolo[2,3-a]carbazole framework with a lactam function (300). The 1H-NMR spectrum of N-methylstaurosporine (308) was very similar to that of (+)-staurosporine (295), except for a broad methyl signal at d 2.94 corresponding to two N-methyl groups. Based on these spectral data, and the

122

Chemistry and Biology of Carbazole Alkaloids

close structural similarity to (+)-staurosporine, the structure 308 was assigned to Nmethylstaurosporine. This structure was further supported by the 13C-NMR, HMBC, and HMQC spectra (299) (Scheme 2.77). In 1995, Cai et al. reported the isolation of several metabolites related to staurosporine, N-formylstaurosporine (309) (see Scheme 2.77), N-acetoxymethoxystaurosporine (310), 4u-N-demethyl-N-formyl-N-hydroxystaurosporine (311), and 4u-demethylamino-4u-nitrostaurosporine (312) (see Scheme 2.78) from S. longisporoflavus R19 strain (301). Prior to this report, N-formylstaurosporine (309) had been described in the patent literature (302). Comparison of the HREI-MS of N-formylstaurosporine (309) with (+)-staurosporine (295) (see Scheme 2.74) indicated the presence of an additional carbonyl group. The EI-MS spectrum mass fragmentation ion at m/z 466 (M+–CO) indicated the presence of a formyl group. Additionally, the presence of an aldehyde functionality was confirmed by the characteristic IR bands at nmax 1670 (CQO), 2840 (aldehyde CH) cm1. The 1H- and 13C-NMR spectra of N-formylstaurosporine (308) were also very similar to those of (+)-staurosporine (295), except for the presence of an additional aldehyde group (dH 8.18 and dC 162.8). The position of this formyl group was established at the 4u-N atom by recording a high temperature 1 H-NMR spectrum. The 4u-N-methyl group at 301C split into two separate signals due to the syn and anti conformations of the formyl group. However, at 1501C only one signal was observed due to the rapid conformational interchange of the formyl group. Based on these spectral analyses and the close structural similarity to (+)-staurosporine, the structure 309 was assigned to N-formylstaurosporine (301) (Scheme 2.77). Comparison of the HREI-MS of N-acetoxymethoxystaurosporine (310) with (+)-staurosporine (295) (see Scheme 2.74) indicated the presence of an additional C3H4O3 residue. The 1H- and 13C-NMR spectra of N-acetoxymethoxystaurosporine (309) were also very similar to those of (+)-staurosporine (295), except for the presence of a singlet methyl group at d 1.76 and the doublets at d 4.55 and 4.46 of a methylene group. From the two 13C-NMR signals at d 20.3 and 169.0, the methyl group (dH 1.76) was indicated to be part of an acetate function. The position of the CH2O at the 4u-N atom was established by basic hydrolysis of N-acetoxymethoxystaurosporine (310) to N-hydroxystaurosporine. Based on these spectral analyses, chemical correlation to N-hydroxystaurosporine, and the close structural similarity to (+)-staurosporine, the structure 310 was assigned to N-acetoxymethoxystaurosporine (301) (Scheme 2.78). The 1H-NMR spectrum of 4u-N-demethyl-N-formyl-N-hydroxystaurosporine (311) was very similar to that of (+)-staurosporine (295), except for the absence of the N-methyl group in the sugar moiety and the presence of two, rather broad, signals at d 8.1 and 9.4 assignable to N-formyl and N-hydroxy groups, respectively. The presence of a formyl group was confirmed by the observation of a 13C-NMR signal at d 160.0. Furthermore, the characteristic IR bands at nmax 1665 (CQO), 2860 (aldehyde CH), and 3400 (OH) cm1 indicated the presence of N-formyl and N-hydroxy groups. Based on these spectral data, and the close structural similarity to (+)-staurosporine, the structure 311 was assigned to 4u-N-demethyl-N-formyl-Nhydroxystaurosporine (301) (Scheme 2.78). The 1H-NMR spectrum of 4u-demethylamino-4u-nitrostaurosporine (312) was very similar to that of (+)-staurosporine (295) (see Scheme 2.74), except for the absence of the N-methyl group and the strong, downfield shift of the C-4u proton from d 3.33 to

Occurrence, Isolation, and Structure Elucidation

H N

N

O

Me O MeO Me

O

O

N

N

N H

O

H N

Me

O

Me MeO OHC

N H

N

H N

O

OH

310 N-Acetoxymethoxy- 311 4′-N-Demethyl-N-formyl-Nstaurosporine hydroxystaurosporine

N

O

123

O

N

Me MeO

H NO2

312 4′-Demethylamino-4′nitrostaurosporine

Scheme 2.78

4.53 in the sugar moiety. Comparison of the HREI-MS of 312 with (+)-staurosporine (295) (see Scheme 2.74) indicated the presence of two additional oxygen atoms. These data, together with the 1H-NMR data, indicated the presence of a nitro group in position C-4u. Further, the presence of a nitro group was supported by a characteristic, very strong absorption band in the IR spectrum at nmax 1590 cm1, as well as the expected 13C-NMR shifts for the C-3u, C-4u, and C-5u signals. Based on these spectral data, and the close structural similarity to (+)-staurosporine, the structure 312 was assigned to 4u-demethylamino-4u-nitrostaurosporine. This structure was further supported by NOE experiments (301) (Scheme 2.78). In 1989, Tanida et al. reported the isolation of the oxime analog of staurosporine, TAN-1030A (313) from culture broth of Streptomyces sp. C-71799, along with previously known (+)-staurosporine (295) (see Scheme 2.74) (291). In 1995, Cai et al. also reported TAN-1030A (313) from a different Streptomyces sp., S. longisporoflavus R19 strain (301). TAN-1030A (313) was shown to activate macrophage function in mice (291). The UV [lmax 244 (sh), 263 (sh), 275 (sh), 289, 319 (sh), 333, 352, and 369 nm] and IR (nmax 1680 and 3430 cm1) spectra of TAN-1030A (313) were very similar to those of (+)-staurosporine (295) (see Scheme 2.74), indicating the presence of a similar indolo[2,3-a]pyrrolo[3,4-c]carbazole framework. The 1H-NMR spectrum of TAN1030A (313) was also very similar to that of (+)-staurosporine (295), except for the presence of a D2O-exchangeable proton at d 10.45 in place of the N-methyl group at d 1.44 in the sugar moiety. Further, in the 13C-NMR spectrum, a quaternary carbon at d 145.1 appeared in place of the staurosporine C-4u methine signal (d 50.0). These NMR data indicated the presence of an oxime function at the C-4u position. Hydrogenation of ()-TAN-1030A with Pt-black afforded the corresponding C-4u amino derivative, which, on acetylation with Ac2O-pyridine, gave the corresponding N-acetyl derivative. These chemical reactions confirmed the presence of an oxime function. Furthermore, the oxime proton at d 10.45 showed NOE enhancement with the C-3u methoxy (d 3.43) and the C-2u methyl (d 2.47), indicating the syn stereochemistry of the oxime function at C-4u relative to the methoxy group. Based on these spectral data and the structural similarities to (+)-staurosporine the structure 313, was assigned to TAN-1030A. This structure was further supported by the COSY, NOESY, and COLOC spectra (291,293) (Scheme 2.79).

124

Chemistry and Biology of Carbazole Alkaloids

O

H N

N

O

Me MeO HO

N

O

N H

N

313 TAN-1030A

O

N

O

Me MeO HO

N

O

N H

N

314 6-MethoxymethylTAN-1030A

N

O

Me MeO HO

O

N H

N

315 6-IsopropoxymethylTAN-1030A

Scheme 2.79

In 1996, Cai et al. reported the isolation of several metabolites related to TAN1030A, 6-methoxymethyl-TAN-1030A (314), 6-isopropoxymethyl-TAN-1030A (315), 4u-deoxime-4u-oxo-TAN-1030A (316), and 4u-deoxime-4u-oxo-3u-epi-TAN-1030A (317) from S. longisporoflavus strain R-19 (289). The 1H-NMR spectrum of 6-methoxymethyl-TAN-1030A (314) was very similar to that of TAN-1030A (313), except for the absence of a lactam proton at nitrogen 6, suggesting a substitution at this center. Further, the 1H-NMR spectrum showed a singlet for methylene protons at d 5.12 and a methoxy group at d 3.29, indicating the presence of a methoxymethyl (CH2OMe) group at the lactam nitrogen. The presence of this additional methoxymethyl group was also supported by the comparison of the HREI-MS with that of TAN-1030A (313). Based on these spectral data, and the structural similarities to TAN-1030A (313), the structure 314 was assigned to 6-methoxymethyl-TAN-1030A. This structure was further supported by the 13C-NMR spectrum (289) (Scheme 2.79). The 1H-NMR spectrum of 6-isopropoxymethyl-TAN-1030A (315) was very similar to that of 6-methoxymethyl-TAN-1030A (314), except for the difference in the substitution pattern on the lactam nitrogen 6. Comparison of the HREI-MS with that of 6-methoxymethyl-TAN-1030A indicated the presence of an isopropyl group instead of a methyl group. The presence of this additional isopropoxy group was also established from the 1H-NMR spectrum by the presence of a six-proton doublet at d 1.17 assignable to two methyl groups, and a one-proton multiplet at d 3.80, assignable to an isopropoxy methine proton. Based on these spectral data, and the structural similarities to 6-methoxymethyl-TAN-1030A (314), the structure 315 was assigned to 6-isopropoxymethyl-TAN-1030A. This structure was further supported by the 13C-NMR spectrum (289) (Scheme 2.79). The 1H-NMR spectrum of 4u-deoxime-4u-oxo-TAN-1030A (316) was very similar to that of TAN-1030A (313) (see Scheme 2.79), except for the downfield shift of the C-3u and C-5u signals. Comparison of the HRFAB-MS of 316 with TAN-1030A (313) (see Scheme 2.79), indicated the lack of nitrogen and hydrogen atoms. These data, together with the 1H-NMR data, indicated the presence of a ketone function at position C-4u. Furthermore, the presence of a keto group was supported by a typical ketone band in the IR spectrum at nmax 1730 cm1, as well as a carbonyl carbon signal at d 200.6 in the 13C-NMR spectrum. Based on these spectral data, and the structural

Occurrence, Isolation, and Structure Elucidation

H N 7

6

5

8

N 2′

Me 3′ MeO

O

13

O 1′ 4′

N 6′

1

H 5′

O 316

H N

O

4 12

11

H N

O

125

4′-Deoxime-4′-oxoTAN-1030A

N Me MeO

O 3′

N H

O 317 4′-Deoxime-4′-oxo-3′-epiTAN-1030A

N

O

Me MeO

N H

OH 318 RK-286C

Scheme 2.80

similarities to TAN-1030A (313), the structure 316 was assigned to 4u-deoxime-4u-oxoTAN-1030A (289) (Scheme 2.80). The 1H-NMR spectrum of 4u-deoxime-4u-oxo-3u-epi-TAN-1030A (317) was quite similar to that of 4u-deoxime-4u-oxo-TAN-1030A (316), except for the differences in the position of the 2u-methyl group, and the C-3u and C-5u signals. Furthermore, the 13 C-NMR spectrum showed shifts of about 4 ppm for the 2u-methyl group, and the C-3u and C-5u signals. The NOE difference experiments indicated that these two indolocarbazoles are C-3u epimeric compounds. 4u-Deoxime-4u-oxo-3u-epi-TAN1030A (317) showed no pronounced NOE (3%) as compared to the 13% NOE for 4u-deoxime-4u-oxo-TAN-1030A (316), on the proton at C-3u by irradiation at the equatorial 2-methyl group, indicating a cis-relationship between the C-2u methyl and the C-3u methoxy groups of 317. Structural support came from the observed long-range effects in the 13C-NMR spectrum. Based on these spectral data, and the structural similarities to 4u-deoxime-4u-oxo-TAN-1030A (316), the structure 317 was assigned to 4u-deoxime-4u-oxo-3u-epi-TAN-1030A (289) (Scheme 2.80). In 1990, Isono et al. reported the isolation of RK-286C (318) from the culture filtrate and the mycelium extract of Streptomyces sp. RK-286 (303). In nature, this isolate was obtained in its optically active form ½a20 D þ 45:3 (c 0.22, EtOAc). Based on similar CD curves, the absolute configuration of this isolate was assigned to be similar to that of (+)-staurosporine (295) (see Scheme 2.74) (284). RK-286C has shown PKC inhibitory activity and platelet aggregation in vitro, as well as weak antifungal activity (303). The UV spectrum [lmax 245, 266 (sh), 292, 322 (sh), 335, 356, and 372 nm] of RK286C (318) was identical to that of (+)-staurosporine (295) (see Scheme 2.74), indicating the presence of a similar indolo[2,3-a]pyrrolo[3,4-c]carbazole framework. This was also discernible from its IR spectrum. The 1H- and 13C-NMR spectra of RK286C were also very similar to those of (+)-staurosporine (295), except for the presence of a D2O-exchangeable proton at d 4.17, in place of the corresponding C-4u methylamino protons at d 1.44 and 3.33. Besides these spectral differences, the C-4u proton and carbon also showed a downfield shift, further supporting the presence of a hydroxy group. Based on these spectral data, and the structural similarity to (+)-staurosporine, the structure 318 was assigned to RK-286C. This structure was further supported by the COSY spectrum (284) (Scheme 2.80).

126

Chemistry and Biology of Carbazole Alkaloids

Two years later, the same authors also reported the 3u-epimer of RK-286C, RK-1409B (319), from the culture broth of Streptomyces platensis subsp. malvinus RK1409. In nature, this isolate was obtained in its optically active form ½a22 D þ 147:0 (c 0.2, DMSO). RK-1409B showed inhibition of PKC and weak antifungal activity (304). The UV spectrum [lmax 245, 267 (sh), 293, 320 (sh), 336, 357, and 374 nm] of RK-1409B (319) was identical to that of RK-286C (318) (see Scheme 2.80), indicating the presence of a similar indolo[2,3-a]pyrrolo[3,4-c]carbazole framework. This was also discernible from its IR spectrum. The 1H- and 13C-NMR spectra of RK-1409B (319) were also very similar to those of RK-286C (318), except for some differences in the chemical shifts for the sugar moiety, indicating that RK-1409B is a stereoisomer of RK-286C. The relative stereochemistry of the hydroxy group at C-4u was determined to be axial by the small coupling constants of 4u-H (J3u,4u=4.3 Hz, J4u,5ua=5.5 Hz, and J4u,5ub=4.3 Hz), and the axial orientation of the methoxy group at C-3u was supported by an NOE between 11-H and 3u-H, indicating that RK-1409B and RK-286C were epimers at the C-3u position. The CD spectra of RK-1409B and RK-286C exhibited quite similar curves, showing that the absolute stereochemistry at C-2u and C-6u were the same in RK-286C. Based on these spectral data, and the structural similarity to RK-286C, the structure 319 was assigned to RK-1409B. This structure was further supported by the COSY and HMBC spectra (304) (Scheme 2.81). In 1994, McAlpine et al. reported the isolation of MLR-52 (320), along with (+)-staurosporine (295) (see Scheme 2.74), from the fermentation broth and mycelia of Streptomyces sp. AB 1869R-359. In nature, this isolate was obtained in its optically active form [a]D +68.0 (c 0.093, MeOH). This isolate has shown inhibition of PKC and potent in vitro immunosuppressive activity (305). The UV spectrum (lmax 234, 286, 317, 332, 351, and 368 nm) of MLR-52 (320) was similar to that of RK-286C (318) (see Scheme 2.80), indicating the presence of a similar indolo[2,3-a]pyrrolo[3,4-c]carbazole framework. This was also discernible from its IR spectrum. The 1H- and 13C-NMR spectra of MLR-52 (320) were similar to those of RK-286C (318) (see Scheme 2.80), except for the different substitution pattern of the sugar moiety. Thus, the 1H-NMR spectrum showed a one-proton doublet at d 4.16 for the C-5u proton, in place of a two-proton multiplet at d 2.41 and 2.61, indicating a hydroxy group at this carbon. Furthermore, the presence of an additional oxygen atom was supported from the HRFAB-MS. An axial–axial

H N

H N

O

H N

O

7

6

O 5

8

4 12b

N

O

Me MeO

N H

OH

N

O

Me MeO

N H OH

11

12 12a 11a N O 2′ 1′ Me 3′ 4′

O

OH O

319 RK-1409B

320 MLR-52

Scheme 2.81

1′′

13

N

13a

6′

H 5′

N Me

321 ZHD-0501

1

Occurrence, Isolation, and Structure Elucidation

127

coupling constant (J=10.3 Hz) between the proton signals for H-3u and H-4u at d 4.14 and 3.57, respectively, indicated that the 3u-methoxy and the 4u-hydroxy groups are equatorial to each other. Further, the proton at C-5u showed a small coupling constant (J=2.6 Hz) with the C-4u hydrogen indicating an axial hydroxy group at C-5u. Based on these spectral data, and the structural similarity to RK-286C, the structure 320 was assigned to MLR-52. This structure was further supported by the COSY and HMBC spectra (305) (Scheme 2.81). In 2005, Han et al. reported the isolation of a novel, naturally occurring, staurosporine analog, ZHD-0501 (321) from the fermentation broth of a marinederived Actinomadura sp. 007. This was the first example of a staurosporine analog carrying a heterocycle fused to the pyran ring, and it has shown in vitro anticancer activity against mammalian cancer cells. In nature, this isolate was obtained in its optically active form ½a20 D þ 83:2 (c 0.10, MeOH) (306). The UV spectrum [lmax 243 (sh), 275 (sh), 290, 318, 332, 351, and 369 nm] of ZHD0501 (321) was very similar to that of (+)-staurosporine (295) (see Scheme 2.74), indicating the presence of a similar indolo[2,3-a]pyrrolo[3,4-c]carbazole framework. This was also discernible from its IR spectrum. The 1H- and 13C-NMR spectra of ZHD-0501 (321) were also very similar to those of (+)-staurosporine (295), except for the difference in the sugar moiety, establishing the presence of a similar aglycon. Analysis of the PFG COSY and PFG HMQC spectra indicated the structural units related to the proton spin system in the sugar moiety. The HMBC correlations of 2u-Me/C-2u, 2u-Me/C-3u, and H-6u/C-2u showed the presence of a methyl pyranose ring system. Further, the HMBC correlations of H-3u/C-1v, H-4u/C-1v, N-Me/C-1v, and N-Me/C-4u confirmed the N-methyl oxazolone ring fused to C-3u and C-4u in the sugar moiety. Additionally, the presence of an oxazolone was also established by its IR spectrum, with the oxazolone carbonyl band at nmax 1680 cm1. Based on the aglycon chemical shifts, and the HMBC correlations between H-6u and the carbons C-12b and C-13a, the carbons C-2u and C-6u in the sugar ring could be connected to N-12 and N-13 in the aglycon. The stereochemistry of ZHD-0501 was established on the basis of the coupling constants of the protons on the pyran ring and the results of difference NOE experiments. Based on these spectral analyses, and the structural similarities to (+)-staurosporine, the structure 321 was assigned to ZHD-0501 (306) (Scheme 2.81). In 1990, researchers at Bristol-Myers Squibb reported the isolation of Bmy-41950 (322) from S. staurosporeus strain R10069 (ATCC 55006). This isolate showed in vitro activity against human colon cancer cells (HCT-116) (307). Two years later, Isono et al. reported the isolation of the same natural product from a different Streptomyces sp., S. platensis subsp. malvinus RK-1409 and named it RK-1409 (7-oxostaurosporine) (322) (308,309). In nature, this isolate was obtained in its optically active form ½a20 D þ 38:3 (c 0.06, CHCl3) (309). The PKC inhibitor RK-1409 (7-oxostaurosporine) inhibited the morphological change of a human erythroleukemia cell line, K-562, induced by phorbol 12,13-dibutyrate (PDBu), and also showed a weak antimicrobial activity against Chlorella vulgaris and Pyricularia oryzae (308). The UV spectrum [lmax 238, 260, 287, 305 (sh), 317, 340, and 410 nm] of Bmy-41950 (RK-1409, 7-oxostaurosporine) (322) indicated the presence of an indolo[2,3a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione framework. This was also discernible from its IR spectrum. The 1H-NMR spectrum of Bmy-41950 (RK-1409, 7-oxostaurosporine) (322) was very similar to that of (+)-staurosporine (295) (see Scheme 2.74), except for

128

Chemistry and Biology of Carbazole Alkaloids

H N

O

O

H N

O

O

7 5

4

8

N Me MeO

O

13

12

N

N

11

Me MeO

H NHMe

HO

322 Bmy-41950 (RK-1409, 7-Oxostaurosporine)

O 1′ 4′

N

1

H

N

323 7-Oxo-TAN-1030A

Scheme 2.82

the difference in the aglycon moiety. Thus, the 1H-NMR spectrum indicated the absence of the C-7 methylene protons at d 4.97 and 5.03. Further, a strong downfield shift of the C-8 proton from d 7.87 to 9.35 indicated the presence of an oxo group at C7. The presence of this additional oxygen atom in place of two hydrogen atoms was also supported by the HREI-MS. Furthermore, oxidation of (+)-staurosporine (295) with tert-butyl hydroperoxide and Mn(III)acetylacetonate gave 7-oxostaurosporine, whose spectral data were identical with those of RK-1409 (7-oxostaurosporine) and having the same absolute stereochemistry as that of (+)-staurosporine, and establishing unambiguously the structure and absolute stereochemistry of natural Bmy-41950 (RK-1409, 7-oxostaurosporine) as 322. Based on these spectroscopic data, the structural similarity to (+)-staurosporine (295), and the chemical evidence, the structure 322 was assigned to Bmy-41950 (RK-1409, 7-oxostaurosporine) (309) (Scheme 2.82). In 1996, Cai et al. reported the isolation of the 7-oxygenated TAN-1030A derivatives, 7-oxo-TAN-1030A (323), and 7-hydroxy-TAN-1030A (324), along with the 7-hydroxy derivative of (+)-staurosporine, UCN-01 (325a) from S. longisporoflavus strain R-19 (289). Prior to Cai’s report, in 1987, Takahashi et al. isolated UCN-01 (325a) from a different strain of the genus Streptomyces, N-71. UCN-01 was shown to inhibit PKC, protein kinase A (PKA), had antitumor activity against murine lymphotic leukemia P388 in vivo, and cytotoxic effects on the growth of HeLa S3 cells (310,311). In nature, UCN-01 was isolated in its optically active form ½a22 D þ 132:0 (c 0.3, MeOH) (311). Based on the CD spectral results, UCN-01 was assigned to be a b-7-hydroxy isomer (289). Two years later, the same authors also reported the isolation of UCN-01 (325a), together with its C-7-epimer, UCN-02 (325b), from a different strain of the genus Streptomyces, N-126. In nature, UCN-02 was also isolated in its optically active form ½a22 D  38:6 (c 0.35, MeOH) (279,312). Based on the known b-configuration at C-7 for UCN-01 (289), UCN-02 was assigned to be the 7a-hydroxy isomer. In acid or alkaline media, UCN-01 and UCN-02 are in equilibrium. UCN-02 was shown to inhibit PKC and protein kinase A (PKA) and showed cytotoxic effects on the growth of HeLa S3 cells (279). Comparison of the HREI-MS of 7-oxo-TAN-1030A (323) with TAN-1030A (313) (see Scheme 2.79) indicated the presence of one additional oxygen in place of two hydrogens. The 1H-NMR spectrum of 7-oxo-TAN-1030A (323) was very similar to

Occurrence, Isolation, and Structure Elucidation

129

that of TAN-1030A (313), except for the absence of the C-7 methylene protons at d 4.95, and a strong downfield shift of the C-8 proton signal from d 7.96 to 9.08, indicating the presence of an oxo group at C-7. Based on these spectral data, and structural similarity to TAN-1030A (313), the structure 323 was assigned to 7-oxo-TAN-1030A (289) (Scheme 2.82). Comparison of the HRFAB-MS of 7-hydroxy-TAN-1030A (324) with TAN-1030A (313) (see Scheme 2.79), indicated the presence of one additional oxygen atom. The 1 H-NMR spectrum of 7-hydroxy-TAN-1030A (324) was also very similar to that of TAN-1030A (313), except for the presence of two, one-proton doublets (J=11.0 Hz) at d 6.41 and 6.53, indicating the presence of a proton and a hydroxy group at C-7, respectively, in place of the two-proton singlet (d 4.95) for the protons at C-7 in TAN1030A (313). The presence of a hydroxy group at C-7 was further supported by the downfield shift of the C-8 proton signal from d 7.96 to 8.42. Based on these spectral data, and the structural similarity to TAN-1030A (313), the structure 324 was assigned for 7-hydroxy-TAN-1030A (289) (Scheme 2.83). The UV spectrum [lmax 240, 264 (sh), 274 (sh), 300, 326 (sh), 338 (sh), 358, and 374 nm] of UCN-01 (325a) resembles closely that of (+)-staurosporine (295) (see Scheme 2.74), indicating the presence of a similar indolo[2,3-a]pyrrolo[3,4-c]carbazole framework. This was also discernible from its IR spectrum. The 1H-NMR spectrum of UCN-01 (325a) was very similar to that of (+)-staurosporine (295), except for the presence of signals at d 6.39 (1H, dd, J=9.8, 1.1 Hz) and 6.44 (1H, d, J=9.8 Hz). On D2O addition, the signal at d 6.39 changed to a singlet and the signal at d 6.44 collapsed, indicating the 7-methine proton and the 7-hydroxy proton, respectively. Furthermore, in a proton decoupling experiment, the signal at d 6.39 was changed to a doublet (J=9.8 Hz) on irradiation of the 6-imino proton at d 8.72 (1H, d, J=1.1 Hz). In the 13C-NMR spectrum, the C-7 carbon appeared as a doublet at d 78.4 in place of a triplet at d 45.3 in (+)-staurosporine (311). The NOE studies indicated a similar absolute stereochemistry as (+)-staurosporine, except for the configuration of the 7-hydroxy group (279). CD spectral analysis indicated a b-configuration at the 7-hydroxy group (289). Based on these spectroscopic analyses, and the structural similarity to (+)-staurosporine, the structure 325a was assigned to UCN-01 (279,289,311) (Scheme 2.83). The UV, IR, and EI-MS spectral data of UCN-02 (325b) were identical to those of UCN-01 (325a), except for the optical rotation and the Rf value on TLC. The 1H- and H N

HO

O

H N

HO

O

7 5

13

12

O

Me MeO HO

N H

N

324 7-Hydroxy-TAN-1030A

O

7

4

8

N

H N

HO

N

11

Me MeO

O 1′ 4′

N H

NHMe 325a UCN-01

Scheme 2.83

N

1

Me MeO

O

N H

NHMe 325b UCN-02

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Chemistry and Biology of Carbazole Alkaloids

H N 7

6

5

O

O

4

8 13

12 11

H N

N N H O 6′ H 1′ 5′ Me

2′

N N H H O HO 2′

1

4′ 3′

Me

NH2

HO

HO

NH2

326 Holyrine A

327 Holyrine B

H N

H N

O

N N H H O OH

O

N N H H O

Me

Me HO

OH

HO

328 K-252d

OH

329 RK-286D

Scheme 2.84 13

C-NMR spectra were also very similar to those of UCN-01 (325a), except for the chemical shift difference of H-7, indicating that UCN-02 (325b) is a diastereomer of UCN-01 (325a) at the C-7 position, with an a-configuration of the 7-hydroxy group. Based on these data, and the close structural similarity to UCN-01 (325a), the structure 325b was assigned to UCN-02 (279) (Scheme 2.83). In 1999, Andersen et al. reported the isolation of holyrine A (326) and holyrine B (327), along with the previously known K-252d (328) (Scheme 2.84), (+)-staurosporine (295), and O-demethylstaurosporine (297) (see Scheme 2.74) from the cultures of an Actinomycete st. N96C-47, isolated from the North Atlantic Ocean near Holyrood. Holyrine A (326) and holyrine B (327) have only a single attachment of their sugar moiety to the aromatic aglycon, similar to K-252d (328) (Scheme 2.84) and rebeccamycin (337) (see Scheme 2.86) (313). Prior to Andersen’s report, Kase et al. had already reported the isolation of K-252d (328), along with K-252b (331) (see Scheme 2.85) and K-252c (293) (see Scheme 2.74), from the culture broth of Nocardiopsis sp. K-290 (273). All these isolates were shown to be potent inhibitors of PKC (273). In nature, K-252d (328) ½a20 D þ 35:0 (c 0.4, MeOH) and K-252b (331) ½a20 þ 97:0 (c 0.6, DMF) were isolated in their D optically active forms (273,274). In the same year, the same authors also reported the isolation of K-252a (330) (see Scheme 2.85) from a different Nocardiopsis sp., K-252a (272). Prior to the isolation of K-252a (330), Sezaki et al. reported the same natural product as SF-2370 (330) from a different natural source, Actinomadura sp. SF-2370 in its optically active form ½a25 D  57:0 (c 0.1, MeOH) (314). The antibiotic K-252a

Occurrence, Isolation, and Structure Elucidation

131

(SF-2370) (330) showed extremely potent inhibitory activity on PKC (272), as well as weak antibacterial and antifungal activities (314). In 1992, Isono et al. isolated a novel indolocarbazole antibiotic, RK-286D (329), along with the previously known (+)-staurosporine (295) (see Scheme 2.74) and RK-286C (318) (see Scheme 2.80), from the mycelial cake of Streptomyces sp. RK-286. In nature, RK-286D was isolated in optically active form ½a20 D  60:0 (c 0.13, MeOH), showing the structural relation to RK-286C (318) (315) (see Scheme 2.80). The 1H-NMR spectrum of holyrine A (326) was very similar to that of 3u-Odemethyl-4u-N-demethylstaurosporine (307) (see Scheme 2.77), except for the presence of a mutually coupled (J=7.2 Hz) one-proton quartet at d 4.61 and a three-proton doublet at d 1.60 in place of the C-2u methyl singlet proton at d 2.41 of 3uO-demethyl-4u-N-demethylstaurosporine (307), indicating the presence of a proton and a methyl group at C-2u of the glycon. Further, a detailed analysis of the COSY, HMQC, and HMBC revealed that the aglycon in 326 was different from the aglycon in 307 by the presence of a proton at N-12 (d 11.75). Strong anisotropic neighboring group deshielding of the C-4 proton at d 9.47 by the C-5 lactam carbonyl differentiated the two, four-spin aromatic systems in the aglycon. These data, in conjunction with the HMBC correlation between the N-12 proton (d 11.75) and C-11 (d 111.6), showed that the glycon was attached to the aglycon at N-13. Furthermore, NOE experiments and coupling constant analysis established the same relative stereochemistry as for the glycon substituents in 3u-O-demethyl-4u-N-demethylstaurosporine (307). Based on these spectral data, and the close structural similarity to 3u-Odemethyl-4u-N-demethylstaurosporine, the structure 326 was assigned to holyrine A (313) (Scheme 2.84). Comparison of the HRFAB-MS of holyrine B (327) with holyrine A (326) indicated the presence of one additional oxygen atom. The 1H-NMR spectrum of holyrine B (327) was very similar to that of holyrine A (326), except for the presence of a methyl singlet at d 1.59 in place of the methyl doublet at d 1.60 and the absence of the resonance assigned to the C-2u proton at d 4.61. These 1H-NMR changes, together with the additional oxygen atom in the molecular formula of 327, indicated the presence of a hydroxy functionality at C-2u. The HMBC correlations observed between the C-2u methyl (d 1.59) and the C-2u and C-3u carbons at d 99.0 and 67.6, respectively, confirmed the presence of a hemiketal functionality at C-2u. The close similarity of the chemical shifts and multiplicities of the C-3u, C-4u, C-5u, and C-6u resonances in the 1H-NMR spectra of the holyrines A and B indicated the identical relative stereochemistries at C-3u to C-6u. However, the relative configuration at C-2u was not assigned. Based on these spectral data and the close structural similarity to holyrine A, the structure 327 was assigned to holyrine B (313) (Scheme 2.84). The UV spectrum [lmax 242 (sh), 248 (sh), 260 (sh), 280 (sh), 322, 335, 347, and 364 nm] of K-252d (328) was similar to that of staurosporinone (K-252c) (293) (see Scheme 2.74), indicating the presence of a similar indolo[2,3-a]pyrrolo[3,4-c]carbazole framework. Comparison of the 1H-NMR spectrum of K-252d (328) with that of staurosporinone (K-252c) (293) suggested it to be an N-glycoside of K-252c. The HREI-MS spectrum of this isolate revealed the composition of the sugar moiety as C6H11O4. Hydrolysis of K-252d (328) gave a water soluble substance which was identical with rhamnose. The optical rotation and CD spectral data of the 4-nitrobenzoate of methyl-a-rhamnopyranoside obtained from K-252d (328) were

132

Chemistry and Biology of Carbazole Alkaloids

H N

9

7 6 7a 8 7c 7b 11a 11

12

N

Me R1O

5

4c 4 4b 4a

12a 1′

O

O

R2

HO

3

N13 5′

N

1

H

O

N

Me

4'

HO R2O

O 330 K-252a (SF-2370) 1

O

12b

2′ 3′

R1

H N

O

H O

333 (+)-Indocarbazostatin

2

R1 = H; R2 = Et

R = Me; R = OH

334 (−)-Indocarbazostatin B

331 K-252b

R1 = NH2; R2 = Et

R1 = H; R2 = OH 332 3′-Methylamino-3'-deoxy-K-252a R1 = Me; R2 = NHMe

335 (+)-Indocarbazostatin C R1 = H; R2 = Me 336 (−)-Indocarbazostatin D R1 = NH2; R2 = Me

Scheme 2.85

identical with those of an authentic sample synthesized from l-rhamnose. Further, 1 H- and 13C-NMR long-range 1H–1H and 1H–13C-couplings constants showed that the glycon was attached at N-13 to the a-L-rhamnopyranosyl, indicating K-252d as 13-N-(a-L-rhamnopyranosyl)-252c. Based on these spectral data, and the structural similarity to K-252c and methyl-a-rhamnopyranoside, the structure 328 was established for K-252d (274) (Scheme 2.84). The UV spectrum [lmax 233, 278 (sh), 290, 320 (sh), 335, 347, and 364 nm] of RK-286D (329) was similar to that of K-286C (318) (see Scheme 2.80), indicating the presence of a similar indolo[2,3-a]pyrrolo[3,4-c]carbazole framework. The 1H-NMR spectrum of RK-286D (329) was also similar to that of K-286C (318), except for the difference in the sugar moiety, establishing the presence of a similar aglycon. Analysis of the decoupling experiments and NOE difference spectrum revealed that the sugar moiety of RK-286D is digitoxose, attached to N-13 of the aglycon. The digitoxosepyranosyl moiety is in the 1C4 conformation with the relative stereochemistry as shown in the structure 329. However, the absolute stereochemistry remains to be determined. Based on these spectral data, and the structural similarity to K-286C (318), the structure 329 was assigned to RK-286D (315) (Scheme 2.84). The UV spectrum [lmax 248, 264 (sh), 280 (sh), 320 (sh), 333, 350, and 367 nm] of K 252a (SF-2370) (330) was very similar to that of (+)-staurosporine (295) (see Scheme 2.74), showing the presence of a similar indolo[2,3-a]pyrrolo[3,4-c]carbazole framework. The IR spectrum indicated the presence of an NH and OH band at nmax 3420 cm1, an ester band at 1730 cm1, and an amide band at 1663 cm1. The 1H-NMR spectrum of K 252a (330) was similar to that of (+)-staurosporine (295), except for the difference in the sugar moiety, establishing the presence of a similar aglycon. The presence of a similar aglycon as in (+)-staurosporine (295) was also supported by the NOE spectrum. Further, the long-range coupling pattern of the sugar moiety determined from the COLOC spectrum between the 4u-methylene protons to the

Occurrence, Isolation, and Structure Elucidation

133

C-3u, C-2u, and the carbonyl carbons, the methyl protons to the C-3u and C-2u carbons, and the C-5u proton to the C-2u carbon, indicated the location of the methoxycarbonyl group at the C-3u position and the methyl group at the C-2u position. Furthermore, proton homo decoupling experiments showed the presence of methine and methylene protons at the C-5u and C-4u positions. These spectral data indicated the presence of a 2-deoxyfuranoside. Additionally, the observation of a long-range coupling between H-5u and C-12b, and the NOE (9.1%) between the C-2u methyl and C-11 protons, indicated that C-5u is bonded to N-13 and C-2u to N-12. Based on these spectroscopic analyses, and the structural similarity to (+)-staurosporine, the structure 330 was assigned to K-252a (SF-2370). This structure and the configuration at C-3u was unambiguously established from its X-ray analysis (274) (Scheme 2.85). The UV spectrum [lmax 246, 268 (sh), 280 (sh), 323, 337, 353, and 371 nm] of K-252b (331) was very similar to that of K 252a (330), indicating the presence of a similar indolo[2,3-a]pyrrolo[3,4-c]carbazole framework. The 1H- and 13C-NMR spectra of K-252b (331) were also very similar to those of K-252a (SF-2370) (330), except for the absence of the methoxycarbonyl methyl signal at dH 3.94 and dC 52.6. The compound obtained by hydrolysis of K-252a was identical with 331, which on methylation with diazomethane gave K-252a, indicating K-252b as the 3u-carboxylic acid of K-252a. Based on these spectral data, and the structural similarity to K-252a (330), the structure 331 was assigned to K-252b (274) (Scheme 2.85). In 1996, Cai et al. from Ciba-Geigy reported the isolation of 3u-methylamino-3udeoxy-K-252a (332), along with the previously known K-252c (293) (see Scheme 2.74) and K-252a (330), from S. longisporoflavus (276). The IR spectrum of 3u-methylamino-3udeoxy-K-252a (332) was very similar to that of K-252a (330), showing the presence of similar functional groups. The 1H-NMR spectrum of 3u-methylamino-3u-deoxy-K-252a (332) was also very similar to that of K-252a (330), except for the difference in the sugar moiety, indicating the presence of a similar aglycon. In addition to the peaks of K-252a, the 1H-NMR spectrum also showed the presence of a three-proton doublet at d 1.92, and a one-proton quartet at d 2.44 assignable to an NHMe in place of the C-3uhydroxy group of K-252a. Further, comparison of the 13C-NMR data of 330 and 332 showed that the alkaloids are identical, except for the upfield shift of the C-3u carbon from d 84.9 to 78.0, and the quartet methyl carbon at d 32.2, assignable to the NHMe group. Based on these spectral data, and the structural similarity to K-252a, the structure 332 was assigned to 3u-methylamino-3u-deoxy-K-252a (300) (Scheme 2.85). In 2002, Ubukata et al. reported the isolation of (+)-indocarbazostatin (333) and ()-indocarbazostatin B (334) from a culture broth of Streptomyces sp. TA-0403 (316,317). Two years later, the same authors reported the isolation of two further indocarbazostatin derivatives, (+)-indocarbazostatin C (335) and ()-indocarbazostatin D (336), along with the previously known (+)-indocarbazostatin (333) and ()-indocarbazostatin B (334) from a different mutant strain, Streptomyces sp. MUV-683 (318). These isolates function as novel inhibitors of nerve growth factor (NGF)induced neuronal differentiation in PC12 cells in the nanomolar range (316,318). In nature, (+)-indocarbazostatin (333) ½a26 D þ 51:3 (c 0.05, MeOH) and ()-indocarbazostatin B (334) ½a26  48:7 (c 0.05, MeOH) (317), (+)-indocarbazostatin C (335) D ½a26 þ 50:0 (c 0.05, MeOH), and ()-indocarbazostatin D (336) ½a26 D D  44:0 (c 0.05, MeOH) (318), were isolated in their optically active form, and their relative and absolute configurations were assigned as shown in their respective structures based on MM2, MOPAC, and CONFLEX calculations, and CD analyses (317,318).

134

Chemistry and Biology of Carbazole Alkaloids

The UV spectrum (lmax 236, 283, 290, and 326 nm) of (+)-indocarbazostatin (333) indicated the presence of a hetero-substituted indolo[2,3-a]pyrrolo[3,4-c]carbazole5,7(6H)-dione framework. This was also discernible from its IR spectrum. The 1 H- and 13C-NMR, 1H–1H-COSY, PFG HMQC, and PFG HMBC spectral data revealed the presence of a hydroxy group at C-9 of the indolo[2,3-a]pyrrolo[3,4c]carbazole-5,7(6H)-dione framework and the 2-deoxyfuranoside sugar moiety. The observed long-range coupling between H-5u and C-12b, and the NOE between the C-2u methyl and C-11 protons, indicated that C-5u and C-2u of the 2-deoxyfuranoside are bonded to N-13 and N-12 of the aglycon, respectively. Further, the 1H-NMR spectrum showed the presence of a hydroxy signal, along with ethyl ester signals with unusually low d values due to the anisotropic affect of the aglycon chromophore. Based on these spectral data, the structure 333 was assigned to (+)indocarbazostatin (317) (Scheme 2.85). The UV spectrum (lmax 236, 270, 292, and 327 nm) of ()-indocarbazostatin B (334) was very similar to that of (+)-indocarbazostatin (333) indicating the presence of a similar indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione framework. This was also discernible from its IR spectrum. The 1H-NMR spectrum of ()-indocarbazostatin B (334) was very similar to that of (+)-indocarbazostatin (333), except for the difference in the aglycon moiety. Thus, the 1H-NMR spectrum showed the absence of a meta-coupled (J=2.7 Hz) C-8 aromatic proton at d 8.97. This was further supported by the 13C-NMR spectrum with the presence of a C-8 singlet carbon at d 134.0 in place of the doublet carbon at d 111.5 in (+)-indocarbazostatin (333). Further, a 10 ppm high field shift of the 7c carbon indicated the presence of an amino group at C-8. The presence of this additional NH2 group in place of one hydrogen atom was supported from the FAB-MS. Based on the differential NOE, COSY, PFG HMQC, PFG HMBC, 13C-NMR chemical shift calculations and biosynthetic considerations, the relative and absolute configurations of ()-indocarbazostatin B (334) were similar to those of (+)-indocarbazostatin (333). However, an opposite optical rotation and the totally different CD spectrum from that of (+)-indocarbazostatin (333) could be explained by the CONFLEX calculations of the molecule. The results showed a negative atropisomeric chirality (left handed twist) in the 7bB7c axis, because of repulsion from steric hindrance between the C-8 amino group and the C-7 carbonyl group. Based on these spectroscopic analyses, and the structural similarity to (+)-indocarbazostatin (333), the structure 334 was assigned to ()-indocarbazostatin B (317) (Scheme 2.85). The UV and IR spectra of (+)-indocarbazostatin C (335) were very similar to those of (+)-indocarbazostatin (333), indicating the presence of a similar indolo[2,3a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione framework. The 1H- and 13C-NMR spectra were also very similar to those of (+)-indocarbazostatin (333), except for the methyl ester function at d 3.05 in place of an ethyl ester. Further, 1H- and 13C-NMR analyses including NOE experiments established that (+)-indocarbazostatin C (335) is the C-3u methyl ester analog of (+)-indocarbazostatin (333). Analysis of the NMR and CD spectral data of the (+)-indocarbazostatin C (335) revealed the same absolute configuration as for (+)-indocarbazostatin (333). Based on these spectral data, and the structural similarity to (+)-indocarbazostatin (333), the structure 335 was assigned to (+)-indocarbazostatin C (318) (Scheme 2.85). The UV and IR spectra of ()-indocarbazostatin D (336) were very similar to those of ()-indocarbazostatin B (334), indicating the presence of a similar

Occurrence, Isolation, and Structure Elucidation

135

indolo[2,3-a]carbazole framework. The 1H- and 13C-NMR spectra were also very similar to those of ()-indocarbazostatin B (334), except for the presence of a C-3u methyl ester function at d 3.13 in place of an ethyl ester. The presence of a methyl ester function at C-3u was established from the differential NOE experiments and the C–H long-range coupling pattern of ()-indocarbazostatin D (336). The comparable UV and CD spectra of ()-indocarbazostatin B (334) and ()-indocarbazostatin D (336) showed the presence of similar absolute configurations in these alkaloids. Further, similar to ()-indocarbazostatin B (334), the unusual CD spectrum was explained by the negative atropisomeric chirality in the 7bB7c axis. Based on these spectral data, and the structural similarity to ()-indocarbazostatin B (334), the structure 336 was assigned to ()-indocarbazostatin D (318) (Scheme 2.85). Independently, in 1985, researchers at Bristol-Myers reported the isolation of rebeccamycin (337) (269,319,320) and 1-dechlororebeccamycin (338) (321) from the fermentation of Saccharothrix aerocolonigenes (formerly Nocardia aerocoligenes), strain C38383-RK-2 (ATCC 39243). Recently, the genus name for strain ATCC 39243 was changed from Saccharothrix to Lechevalieria (322). In nature, rebeccamycin (337) 20 ½a20 D þ 143:0 (c 1.02, THF) and 1-dechlororebeccamycin (338) ½aD þ 128:1 (c 1.01, THF) were isolated in their optically active forms (323). Rebeccamycin has shown a broad spectrum of in vivo activity in tumor-bearing murine models such as P-388 leukemia, L1210 leukemia, and B16 melanoma. It inhibits the growth of human lung adenocarcinoma cells in vitro and produces single-strand breaks in the DNA of these cells (269,324). 1-Dechlororebeccamycin (338) inhibits Gram-positive and Gramnegative bacteria, as well as mammalian neoplasms, such as the murine leukemia P-388 (321) (Scheme 2.86). The UV spectrum [lmax 238, 256 (sh), 293 (sh), 314, 362 (sh), and 390 (sh) nm] of rebeccamycin (337) indicated the presence of an indolo[2,3-a]pyrrolo[3,4-c]carbazole5,7(6H)-dione framework. This was also discernible from its IR spectrum. The 1 H-NMR spectrum indicated the presence of an amide NH at d 11.37 and an indole NH at d 10.30, in addition to signals for aromatic protons and a sugar moiety. Unlike (+)-staurosporine (295) (see Scheme 2.74), where the lactam function deshielded only the ortho C-4 proton, the C-4 and C-8 aromatic protons in rebeccamycin are both deshielded due to the anisotropic deshielding effect of the phthalimide function.

H N

7

O

5

6

O

4

8 12

13

N

11

Cl

H N

O

O

6'

1'

O

N H

N

1

Cl

N H

Cl

OH

O

OH

5'

HO

2' 3'

HO

4'

OH OMe

OH OMe

337 Rebeccamycin

338 1-Dechlororebeccamycin

Scheme 2.86

136

Chemistry and Biology of Carbazole Alkaloids

In consideration of the 1H-NMR signals of the glycosidic and aglycon signals, a 4-O-methylglycosidic linkage with the aglycon was indicated. From the chemical shifts of the C-6u proton of rebeccamycin and its tetraacetate (obtained from rebeccamycin and acetic anhydride/pyridine) the sugar residue was either a C- or N-glycoside attached to the aglycon. Finally, the structure was deduced from X-ray crystallographic analysis (319) and its absolute configuration from the total synthesis (325). Based on these spectral data and X-ray analysis, the structure 337 was assigned to rebeccamycin (Scheme 2.86). Comparison of the HREI-MS of 1-dechlororebeccamycin (338) with that of rebeccamycin (337), indicated the presence of one hydrogen atom in place of a chlorine atom. The 1H-NMR spectrum of 1-dechlororebeccamycin (338) was similar to that of rebeccamycin (337), except for the difference in the aromatic pattern of the aglycon. Thus, in place of a one-proton doublet at d 7.69 for the C-2 proton, a twoproton multiplet at d 7.63 was apparent, assignable to the C-1 and C-2 protons. Further, the 13C-NMR spectrum indicated the presence of only one singlet carbon signal at d 116.4 assignable to C-11 in place of the two singlet carbon signals at d 116.0 and 116.5 in rebeccamycin, assignable to the C-1 and C-11 carbon atoms, respectively, establishing the absence of the chlorine atom at C-1. Based on these spectral data, and the structural similarity to rebeccamycin, the structure 338 was assigned to 1dechlororebeccamycin (323) (Scheme 2.86). In 1986, researchers at Bristol-Myers and Schering Plough reported the isolation of AT2433-A1 (339), AT2433-A2 (340), AT2433-B1 (341), and AT2433-B2 (342) from the cultured broth of Actinomadura melliaura ATCC 39691 [previously known as A. melliaura sp. nov. (SCC 1655)] (326–328). Structurally, these isolates were closely related to rebeccamycin (337) (see Scheme 2.86) and were active against Grampositive bacteria, such as Micrococcus luteus (ATCC 9341), Bacillus subtilis (ATCC 6633), Staphylococcus aureus (A 9537), Streptococcus faecalis (A 20688), and Streptococcus faecium (ATCC 9790). Further, AT2433-B2 (342) has shown activity against the Gramnegative bacterium Escherichia coli SS 1431. In addition, AT2433-A1 (339), and AT2433-B1 (340) showed antitumor activity against the transplantable murine P-388 leukemia (326,327). The UV spectrum [lmax 235, 283, 316, and 395 nm] of AT2433-A1 (339) was similar to that of rebeccamycin (337) (see Scheme 2.86), indicating the presence of a similar indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione framework. This was also discernible from its IR spectrum. The 1H-NMR spectrum of AT2433-A1 (339) showed the absence of a phthalimide NH signal at d 11.37 of rebeccamycin (337) (see Scheme 2.86), and the presence of a methyl singlet at d 3.25, indicating a methyl substitution on this nitrogen. Also, the aromatic region showed an additional aromatic proton at d 7.88, suggesting that one of the chlorine atoms of rebeccamycin was absent. This was confirmed from its CI-MS and IR spectrum, by the presence of strongly split absorption bands at nmax 759 and 768 cm1 due to the asymmetric substitution by a chlorine atom in the aromatic ring. Further, the crucial information regarding the carbohydrate units, and their mutual relationship, was obtained from the EI-MS spectrum of the more volatile tetraacetate derivative of AT2433-A1 (339). Similar to rebeccamycin, the N-glycosidic linkage of the 4-O-methylglucopyranoside was readily apparent for AT2433-A1 (339) by inspection of the 1H- and 13C-NMR data. In the 13C-NMR, the signals for the C-2u methylene were shifted downfield to 66.0 ppm, indicating the position of further substitution. In addition, the triplet for the hydroxy

Occurrence, Isolation, and Structure Elucidation

137

proton of the C-6u methylene hydroxy was absent in AT2433-A1, showing the linkage of the amino sugar at this position. The structure, methyl 2,4-dideoxy-4-Nmethylaminopentapyranoside, of the amino sugar was elucidated by additional MS, NMR, and CD studies of the methanolytic degradation product of AT2433-A1. The high temperature 1H-NMR spectrum of 3,4-di-p-bromobenzoate, obtained from the degradation product of AT2433-A1, showed the a-configuration at C-6v and an equatorial substitution of the pyranose ring at C-3v and C-4v. Further, the CD spectrum was negative, indicating the chirality of the 3,4-di-p-bromobenzoate as a-dthreo. In addition, the CD spectra of AT2433-A1 (339) and rebeccamycin were superimposable, indicating an identical chirality for the two alkaloids thereby establishing both the relative and absolute structure of AT2433-A1 as 339. Based on these spectroscopic analyses, and the close structural similarity to rebeccamycin, the structure 339 was assigned to AT2433-A1 (328) (Scheme 2.87). The UV spectrum [lmax 234, 286, 314, and 394 nm] of AT2433-A2 (340) was similar to that of AT2433-A1 (339) indicating the presence of a similar indolo[2,3a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione framework. The 1H-NMR spectrum of AT2433-A2 (340) was also similar to that of AT2433-A1 (339), except for the absence of a methyl group at d 2.22, indicating AT2433-A2 as the 3v-N-demethyl derivative of AT2433-A1. The absence of a CH2 group was also supported by its field desorption (FD)-MS. Further, the CD spectrum was identical to that of AT2433-A1, indicating the similar relative and absolute structure of AT2433-A2. Based on these spectral data, and the close structural similarity to AT2433-A1, the structure 340 was assigned to AT2433-A2 (328) (Scheme 2.87). The UV spectrum [lmax 234, 284, 316, and 400 nm] of AT2433-B1 (341) was very similar to that of AT2433-A1 (339), indicating the presence of a similar indolo[2,3a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione framework. The 1H-NMR spectrum of AT2433-B1 (341) was also very similar to that of AT2433-A1 (339), except for the Me N 5 O 6

7

O 8 12

1′′

1′

6′

N H

N

1

OH

O

N H OH

5′

O

O

O

13

N O

6′′

O 4

11

Cl

Me N

2′

4′

O

O

5′′ 3′

2′′ 4′′ 3′′

OH OMe

OH OMe

OH

OH

NHR

NHR 339 AT2433-A1 R = Me

341 AT2433-B1 R = Me

340 AT2433-A2 R=H

342 AT2433-B2 R=H

Scheme 2.87

138

Chemistry and Biology of Carbazole Alkaloids

presence of a proton at d 8.14, indicating the absence of a chlorine atom at C-11. The presence of this additional hydrogen atom in place of a chlorine atom was also supported from its FD-MS. Further, the CD spectrum was identical to that of AT2433A1, indicating a similar relative and absolute structure of AT2433-B1. Based on these spectral data, and the close structural similarity to AT2433-A1, the structure 341 was assigned for AT2433-B1 (328) (Scheme 2.87). The UV spectrum [lmax 233, 282, 315, and 400 nm] of AT2433-B2 (342) was very similar to that of AT2433-B1 (341), indicating the presence of a similar indolo[2,3a]pyrrolo[3,4-c]carbazole-5,7(6H)-dione framework. The 1H-NMR spectrum of AT2433-B2 (342) was also very similar to that of AT2433-B1 (341), except for the absence of a methyl group at d 2.19, indicating AT2433-B2 as the 3v-N-demethyl derivative of AT2433-B1. The absence of a CH2 group was also supported from its FD-MS. Further, the CD spectrum was identical to that of AT2433-B1, indicating a similar relative and absolute structure of AT2433-B2. Based on these spectral data, and the close structural similarity to AT2433-B1, the structure 342 was assigned to AT2433-B2 (328) (Scheme 2.87). In 1991, Bonjouklian et al. reported the isolation of 15 different tjipanazoles from an extract of the blue-green alga Tolypothrix tjipanasensis (strain DB-1-1). Among these 15 different tjipanazoles only tjipanazole J (343) has the indolo[2,3a]pyrrolo[3,4-c]carbazole framework analogous to 7-hydroxy-TAN-1030A (324), UCN-01 (325a), and UCN-02 (325b) (see Scheme 2.83), while the others have a simple indolo[2,3-a]carbazole framework (329). The UV spectrum [lmax 238, 259, 303, 339, 338, and 369 nm] of tjipanazole J (343) was similar to that of UCN-01 (325a) (see Scheme 2.83), indicating the presence of a similar indolo[2,3-a]pyrrolo[3,4-c]carbazole framework. Comparison of the 1H-NMR spectrum of tjipanazole J (343) with UCN-01 (325a), showed the absence of a sugar moiety, along with the disubstituted aglycon. Thus, in the aromatic region, deshielded, two-proton doublets with meta-coupling (J=2.4 Hz) at d 8.34 and 9.17 together with two sets of mutually ortho-coupled (J=8.3 Hz) protons at d 7.44, 7.47, 7.76, and 7.79, indicating the presence of two chlorine atoms ortho to the deshielded protons were observed. The locations (C-3 and C-9) of these chlorine atoms were established by an additional meta-coupling (J=2.4 Hz) for the protons at d 7.44 and 7.47. The presence of two chlorine atoms was evident from the FD-MS. Based on these spectral data and the structural similarity to UCN-01 (325a), the structure 343 was assigned to tjipanazole J. This structure was further supported by the 13C-NMR spectrum (329) (Scheme 2.88).

H N

HO 7

5

6

O

O

8

Cl

H N

4

9

O

Cl 3

12 11

N H

13

N H

1

HO

343 Tjipanazole J

N H

N H

344 BE-13793C

Scheme 2.88

OH

Occurrence, Isolation, and Structure Elucidation

139

In 1991, Kojiri et al. reported the isolation of BE-13793C (344), an alkaloid isomeric with the arcyriaflavins C (347) and D (348) (see Scheme 2.89), from the culture broth of Streptoverticillium mobaraense strain BA 13793 collected in Seto, Aichi Perfecture, Japan. BE-13793C (344) showed strong inhibitory activity against topoisomerases I and II and inhibited the growth of doxorubicin-resistant or vincristine-resistant P-388 murine leukemia cell lines, as well as their parent P-388 cell line (330). Comparison of the 1H- and 13C-NMR spectra with those of rebeccamycin (337) (see Scheme 2.86), and LSPD experiments on BE-13793C (344), indicated the absence of a sugar moiety and the presence of hydroxy groups in place of chlorine atoms in the aglycon. The presence of hydroxy functions was further established by the transformation of this isolate into the corresponding diacetyl derivative, whose 1 H-NMR spectrum showed the presence of a six-proton singlet at d 2.52 in place of a two-proton hydroxy signal at d 10.20. The UV spectrum [lmax 236, 255 (sh), 283, 311, and 395 (sh) nm] of this diacetyl derivative was very similar to that of rebeccamycin (337), indicating the presence of a similar indolo[2,3-a]pyrrolo[3,4-c]carbazole5,7(6H)-dione framework. Further, the integration of the 1H-NMR spectrum and the number of carbon atoms in the 13C-NMR spectrum were half those observed in the HRFAB-MS, indicating the symmetrical nature of BE-13793C. Based on these spectral data and the structural similarity to rebeccamycin (337), the structure 344 was assigned to BE-13793C (330) (Scheme 2.88). In 1980, Steglich et al. reported the isolation of arcyriaflavins B (346) and C (347) from the fruiting bodies of the slime mold Arcyria denudata (Myxomycetes) (254,331,332). Two years later, the same authors reported the isolation of the same natural products from a different slime mold, Metatrichia vesparium (Myxomycetes) (333). In the following years, arcyriaflavin A (345) was isolated from a different Arcyria species, Arcyria nutans (252,254), and arcyriaflavin D (348) was isolated from a different slime mold, Dictydiaethalium plumbeum (254). Except for arcyriaflavin D, which has a 2,9-dihydroxylation pattern, the other arcyriaflavin derivatives were classified according to the number of hydroxy groups present in the 2- and 10positions. The arcyriaflavins exhibit moderate antibiotic and antifungal activities (254). In 1994, McConnell et al. reported the isolation of arcyriaflavin A (345) from a different natural source, the marine ascidian Eudistoma sp., collected off the coast of West Africa (275). Recently, Ishibasi et al. isolated arcyriaflavin C (347) from a different species of Arcyria, Arcyria ferruginea. Further, arcyriaflavin C (347) was isolated, along with arcyriaflavin B (346), from the fruiting bodies of the slime mold, Tubifera casparyi. Arcyriaflavin C exhibited nanomolar range cell-cycle inhibition effects at the G1 and G2/M stages (334). The UV spectrum [lmax 235, 257, 272, 281, 300 (sh), 314, and 402 nm] of arcyriaflavin A (345) was similar to that of Bmy-41950 (RK-1409, 7-oxostaurosporine) (322), indicating the presence of an indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)dione framework (252). The 1H-NMR spectrum of arcyriaflavin A (345) was similar to that of Bmy-41950 (RK-1409, 7-oxostaurosporine) (322), except for the absence of a sugar moiety, and the presence of two NH protons at d 10.01 and 11.72. This was also supported from its HRFAB-MS. Based on these data, and the structural similarity to Bmy-41950 (RK-1409, 7-oxostaurosporine) (322), the structure 345 was assigned to arcyriaflavin A (275). This structure was unequivocally established from spectrometric comparison with synthetic arcyriaflavin A (335,336) (Scheme 2.89).

140

Chemistry and Biology of Carbazole Alkaloids

H N

O

O

H N

O

O

R1 N H

N H

R

R2

N H

N H

345 Arcyriaflavin A R=H

347 Arcyriaflavin C

346 Arcyriaflavin B

348 Arcyriaflavin D

OH

R1 = H; R2 = OH R1 = OH; R2 = H

R = OH

Scheme 2.89

The UV spectrum (lmax 229, 271, 280, 323, and 414 nm) of arcyriaflavin B (346) was similar to that of arcyriaflavin A (345), indicating the presence of a similar indolo[2,3-a]carbazole framework. The 1H-NMR spectrum of arcyriaflavin B (346) was also similar to that of arcyriaflavin A (345), except for the differences in the splitting pattern of one of the aromatic rings. Thus, the 1H-NMR spectrum showed the presence of two, deshielded, aromatic protons at d 8.96 and 9.15 as doublets and a broad doublet assignable to the C-4 and C-8 protons, respectively, in place of a twoproton signal at d 8.99. Further, in place of three, one-proton signals at d 7.80, 7.55, and 7.35 in arcyriaflavin A (345), arcyriaflavin B (346) showed the presence of a three-proton multiplet at d 7.24–7.80 assignable to the C-9, C-10, and C-11 protons, and mutually meta-coupled (J=2.1 Hz) signals at d 7.16 and 6.27 assignable to the C-1 and C-3 protons, respectively. In addition, the C-3 proton at d 6.27 showed a further ortho-coupling (J=8.6 Hz) with a deshielded C-4 proton at d 8.96, indicating the location of the hydroxy group at C-2 position. Furthermore, the position of the hydroxy group at the C-2 carbon was supported by the presence of a singlet carbon signal at d 157.5 in the 13C-NMR spectrum. Based on these spectral data, and the structural similarity to arcyriaflavin A (345), the structure 346 was assigned to arcyriaflavin B (331) (Scheme 2.89). The UV spectrum [lmax 229, 255 (sh), 270, 280, 318 (sh), 330.5 (sh), and 422 nm] of arcyriaflavin C (347) was similar to that of arcyriaflavin A (345), indicating the presence of a similar indolo[2,3-a]carbazole framework. The 1H-NMR spectrum showed the presence of a broad two-proton singlet at d 11.92, assignable to two NH protons, and a further broad one-proton singlet at d 9.56, which was assignable to the phthalimide NH proton. Additionally, the aromatic region showed the presence of three sets of two-proton signals, in which one set appeared in a deshielded region as an ortho-coupled (J=8.4 Hz) doublet at d 8.93, a second set appeared as a doublet with meta-coupling (J=2.2 Hz) at d 7.13, and a third set appeared in a shielded environment at d 6.89 as a double doublet with ortho- and meta-coupling (J=8.4, 2.2 Hz), indicating the location of two hydroxy groups at the C-2 and C-10 positions. Based on these spectral data, the structure 347 was assigned for arcyriaflavin C. This structure was unequivocally established by spectrometric comparison with synthetic arcyriaflavin C obtained by the acid-mediated cyclization of arcyriarubin C (351) (see Scheme 2.90) (331) (Scheme 2.89).

141

Occurrence, Isolation, and Structure Elucidation

O

9

H 10 N 9′ O 8′ 3′

8 3

4 5 6

N1 H

7

2

O

O

H N

O

O

4′ 5′

2′

6′

1′ N

HO

7′

H

349 Arcyriarubin A

H

N H

N H

HO

N H

350 Arcyriarubin B

H N

O

HO

H N

O

H N

H HO

N H

352 Dihydroarcyriarubin B

N H

OH

351 Arcyriarubin C

O

H

N H

N H

O H

N H

OH

353 Dihydroarcyriarubin C

Scheme 2.90

The UV spectrum (lmax 229, 327, and 418 nm) of arcyriaflavin D (348) was similar to that of arcyriaflavin C (347), indicating the presence of a similar indolo[2,3a]carbazole framework. The 1H-NMR spectrum of arcyriaflavin D (348) was similar to that of arcyriaflavin C (347), except for the differences in the splitting pattern of one of the aromatic rings. Thus, the aromatic region of the 1H-NMR spectrum indicated the presence of a deshielded, meta-coupled (J=2.2 Hz) proton at d 8.37, together with two, mutually ortho-coupled (J=8.5 Hz) protons at d 7.00 and 7.55. Further, a high-field proton signal (d 7.00) showed a meta-coupling (J=2.2 Hz) with the low-field proton signal (d 8.37), establishing the location of a second hydroxy group at C-9. Based on these spectral data, and the structural similarity to arcyriaflavin C (347), the structure 348 was assigned to arcyriaflavin D (337) (Scheme 2.89).

2 2,3-Bis(indol-3-yl)maleimide Alkaloids In the early 1980s, Steglich et al. reported the isolation of a series of biogenetically closely related bisindolylmaleimides, arcyriarubins B (350) and C (351) (254,331,332), dihydroarcyriarubin B (352) (252,254), (Scheme 2.90), arcyroxepin A (354) (254,331,332), and arcyriaverdin C (355) (254,255) (see Scheme 2.91), along with the indolo[2,3-a]pyrrolo[3,4-c]carbazole alkaloids, arcyriaflavins B (346) and C (347) (331) (see Scheme 2.89), from the red sporangia of the slime mold A. denudata. Arcyriarubin A (349) was present in this organism in only small amounts (252,254). Similar to the arcyriaflavins, the arcyriarubins also exhibit moderate antibiotic and antifungal activities (254). In 2003, Ishibasi et al. reported the isolation of a further, biogenetically closely related, bisindolylmaleimide, dihydroarcyriarubin C (353), along with the previously known, arcyriarubin C (351) (Scheme 2.90) and arcyriaflavin C (347) (see Scheme 2.89), from the fruit bodies of a different Arcyria species, A. ferrugine. The CD spectral data of dihydroarcyriarubin C (353) indicated it to be racemic. However, the

142

1

Chemistry and Biology of Carbazole Alkaloids

H-NMR spectral data showed the trans-relative stereochemistry for the protons of the dihydromaleimide ring (334). The UV spectrum [lmax 248 (sh), 276, 284 (sh), 371, and 465 nm] of arcyriarubin A (349) indicated the presence of a bisindolylmaleimide framework (252). This was also discernible from its IR spectrum with the presence of carbonyl bands at nmax 1710 and 1750 cm1 for the maleimide function. The 1H-NMR spectrum of arcyriarubin A (349) showed only half of the full set of signals, indicating a symmetrical structure for this alkaloid. The splitting and position of the aromatic signals, and the two indolic NH protons at d 11.59 in the 1H-NMR spectrum, indicated that the maleimide is substituted by two indol-3-yl groups. Based on these spectral data, the structure 349 was assigned to arcyriarubin A (338). This structure was unequivocally established by spectrometric comparison with synthetic arcyriarubin A, obtained by the reaction of indolylmagnesium bromide with 2,3-dibromo-Nmethylmaleimide as the crucial step (252,338) (Scheme 2.90). The UV spectrum [lmax 281, 392 (sh), and 465 nm] of arcyriarubin B (350) was similar to that of arcyriarubin A (349), indicating the presence of a similar bisindolylmaleimide framework. This was also discernible from its IR spectrum. The 1H-NMR spectrum of arcyriarubin B (350) was also similar to that of arcyriarubin A (349), except for the differences in the splitting pattern of one of the aromatic rings of the indole nucleus. Thus, the 1H-NMR spectrum showed the presence of two mutually ortho-coupled (J=8.7 Hz) protons at d 6.72 and 6.24 assignable to the C-4 and C-5 protons, respectively. The C-5 proton signal at d 6.24 showed a meta-coupling (J=2.1 Hz) with the C-7 proton signal at d 6.85, indicating the location of the OH function at C-6. The location of this hydroxy group at C-6 was further supported by the shift of the C-7 carbon signal at d 97.7 in the 13C-NMR spectrum. Further, in the 1H-NMR spectrum, two indolic NH protons appeared at different chemical shift values (d 10.78 and 10.52) indicating the unsymmetrical nature of the alkaloid, in which the maleimide unit is substituted by two, different indol-3-yl groups. Based on these spectral data, and the structural similarity to arcyriarubin A (349), the structure 350 was assigned to arcyriarubin B (252,331). This structure was unequivocally established by spectrometric comparison with synthetic arcyriarubin B (338) (Scheme 2.90). The UV spectrum (lmax 283 and 474 nm) of arcyriarubin C (351) was similar to that of arcyriarubin B (350), indicating the presence of a similar bisindolylmaleimide framework. This was also discernible from its IR spectrum. The 1H-NMR spectrum of arcyriarubin C (351) showed only half of the full set of signals, indicating the symmetrical structure of this alkaloid. The position and splitting pattern in the aromatic region of the 1H-NMR spectrum, and the two indolic NH protons at d 10.42, indicated that the maleimide unit is substituted by two (6-hydroxy)indol-3-yl groups. Further, the position of the C-7 and C-7u signals at d 97.7 in the 13C-NMR spectrum, indicated the location of the hydroxy groups at C-6 and C-6u of the indole nucleus. Based on these spectral data, and the structural similarity to arcyriarubin B (350), the structure 351 was assigned to arcyriarubin C (331). The IR spectrum of dihydroarcyriarubin B (352) showed the presence of carbonyl bands at nmax 1710 and 1770 cm1, indicating the presence of a dihydromaleimide function. The 1H-NMR spectrum showed the presence of an AB quartet at d 4.48 and 4.53 assignable to the methylene protons of the dihydromaleimide ring.

Occurrence, Isolation, and Structure Elucidation

143

The structure, and the trans-relative stereochemistry, of dihydroarcyriarubin B (352) was confirmed by comparison of the product obtained from arcyriarubin B (350) by palladium-catalyzed hydrogen transfer from cyclohexene in boiling xylene. Under these conditions, only the thermodynamically more stable trans-diastereomer was formed. Based on these data, and the spectroscopic comparison with the hydrogenation product of arcyriarubin B (350), the structure 352 was assigned to dihydroarcyriarubin B (252) (Scheme 2.90). The 1H- and 13C-NMR spectra of dihydroarcyriarubin C (353) were very similar to those of arcyriarubin C (351), except for the presence of one sp3 methine proton at d 4.44, which was assignable to the C-8 proton. The HMBC spectrum showed a cross peak from H-8 to C-8 (dC 48.2), and this HMBC correlation may be assigned to H-8 to C-8u (or H-8u to C-8), indicating the symmetrical structure of this alkaloid. This structure was further supported by its 1H–1H COSY and HMQC spectra (334). Comparison of the 1H-NMR spectral data of synthetic cis- and trans-dihydroarcyriarubin A (339) indicated the trans-relative stereochemistry for the natural dihydroarcyriarubin C (353). Based on these spectral data, and comparison with arcyriarubin C (351), as well as with synthetic trans-dihydroarcyriarubin A, the structure 353 was assigned to dihydroarcyriarubin C (334,339) (Scheme 2.90). The UV spectrum [lmax 226 (sh), 273, 283 (sh), 362, and 471 nm] of arcyroxepin A (354) indicated the presence of a bisindolylmaleimide framework. This was also discernible from its IR spectrum with the presence of carbonyl bands at nmax 1710 and 1760 cm1 for the maleimide function. The 1H-NMR spectrum of arcyroxepin A (354) showed three, mutually ortho-coupled (J=8.0 Hz) protons at d 7.18, 7.32, and 7.38 in the aromatic region, along with a fourth proton whose shape and position depended very strongly on the measuring conditions. The indole NH protons appeared as singlet at d 9.82, and no signal was observed for the C-2 and C-2u protons, indicating the presence of a third oxygen between these two carbons. Based on these spectral data, the structure 354 was assigned to arcyroxepin A (331) (Scheme 2.91). The UV spectrum [lmax 256 (sh), 336, 433, and 634 nm] of arcyriaverdin C (355) indicated the presence of a bisindolylmaleimide framework with an extended conjugation (252). The structure of arcyriaverdin C (355) was confirmed by chemical correlation of arcyriaverdin C (355) with arcyriarubin C (351) (see Scheme 2.90) by oxidation of the latter with lead tetraacetate in chloroform. Based on these data, and spectroscopic comparison with the oxidation product of arcyriarubin C (351), the structure 355 was assigned to arcyriaverdin C (252) (Scheme 2.91).

O

H N

O

O

H N

O

HO N H

O

OH N H

N H

O O

N H

355 Arcyriaverdin C

354 Arcyroxepin A

Scheme 2.91

144

Chemistry and Biology of Carbazole Alkaloids

3 Simple Indolo[2,3-a]carbazole Alkaloids In 1990, Moore et al. reported the isolation of 5-cyano-6-methoxy-11-methylindolo[2,3-a]carbazole (357), along with a minor component, 6-cyano-5-methoxyindolo[2,3-a]carbazole (358), from the blue-green alga Nostoc sphaericum EX-5-1 (340). These were the first, naturally occurring, indolo[2,3-a]carbazole alkaloids with a simple indolo[2,3-a]carbazole (356) framework (Scheme 2.92). These alkaloids are moderately active against herpes simplex virus type 2 and are weakly cytotoxic against murine and human cancer cell lines (340). The UV spectrum (lmax 234, 252, 290, 338, 354, and 372 nm) of 5-cyano-6-methoxy11-methylindolo[2,3-a]carbazole (357) indicated the presence of an indolo[2,3a]carbazole framework. The IR spectrum indicated the presence of a sharp band at nmax 2200 cm1 for a nitrile group. The 1H- and 13C-NMR spectral data indicated the presence of an aromatic methoxy group (dH 4.21 and dC 62.0) and an N-methyl group (dH 4.34 and dC 31.8). Further, a 1H–1H COSY experiment suggested the presence of an indolic NH and two, independent, ortho-disubstituted benzenoid rings. The HMQC and HMBC spectral data, including NOE experiments, established the presence of an indolo[2,3-a]carbazole system. The relative positions of the methoxy and N-methyl groups were established at C-6 and N-11, respectively, by the detection of a NOE between the signals for the OMe protons and H-4 and the correlation of H-4 and the protons of the N-methyl group with C-11a in the HMBC experiment. The position of the cyano group at C-6 was established by one-dimensional 13C–13C decoupling experiments. The downfield chemical shift for the C-5 carbon showed the presence of the cyano group at this position, and the location of the methoxy group at the adjacent carbon, C-6. Based on these spectral data, the structure 357 was assigned to 5-cyano-6methoxy-11-methylindolo[2,3-a]carbazole (340) (Scheme 2.93). 6

5

7

4 3

8 11

9 10

N H

12

N H

2 1

356 Indolo[2,3-a]carbazole

Scheme 2.92 MeO 7

6

CN 5

R

4

Cl

3

8 11

9 10

N R

12

N H

2

N H

1

357 5-Cyano-6-methoxy-11-methylindolo[2,3-a]carbazole R = Me 358 5-Cyano-6-methoxyindolo[2,3-a]carbazole R=H

Scheme 2.93

N H

359 Tjipanazole D R = Cl 360 Tjipanazole I R=H

Occurrence, Isolation, and Structure Elucidation

145

The 1H- and 13C-NMR spectra of 5-cyano-6-methoxyindolo[2,3-a]carbazole (358) were very similar to those of 5-cyano-6-methoxy-11-methylindolo[2,3-a]carbazole (357), except for the absence of the signals for the N-methyl group at dH 4.34 and dC 31.8, and the presence of an additional NH proton signal at dH 11.41. Based on these spectral data, and the structural similarity to 5-cyano-6-methoxy-11-methylindolo[2,3-a]carbazole (357), the structure 358 was assigned to 5-cyano-6-methoxy11-methylindolo[2,3-a]carbazole (340) (Scheme 2.93). In 1991, Bonjouklian et al. reported, from a bioactivity-directed isolation of the blue-green alga T. tjipanasensis (strain DB-1-1), an extraordinary array of indolo[2,3a]carbazoles, the tjipanazoles (343 and 359-372). Of these, only tjipanazole J (343) (see Scheme 2.88) has the characteristic pyrrolo[3,4-c]ring. Whereas tjipanazoles D (359) and I (360) are simple chlorinated indolo[2,3-a]carbazoles, tjipanazoles G1 (363) and G2 (366) are non-chlorinated indolo[2,3-a]carbazole N-glycosides, whereas tjipanazoles A1 (361), A2 (364), B (369), C1 (362), C2 (367), C3 (365), C4 (368), E (370), F1 (371), and F2 (372) are chlorinated indolo[2,3-a]carbazole N-glycosides (329) (Schemes 2.93–2.97). The UV spectrum (lmax 259, 291, 331, and 366 nm) of tjipanazole D (359) indicated the presence of an indolo[2,3-a]carbazole framework. The 1H-NMR spectrum

R2

6

7

8

5

N

10

OH 5′

1′ O 6′ 2′

3′ 4′

Me

3

12

11

9

4

R2

R1

R1

2

N H

N

1

OH

N H

O 2′

OH

Me

OH

OH

OH

361 Tjipanazole A1

364 Tjipanazole A2

R1,R2 = Cl

R1,R2 = Cl

362 Tjipanazole C1

365 Tjipanazole C3

R = Cl; R = H

R1 = Cl; R2 = H

363 Tjipanazole G1

366 Tjipanazole G2

1

1

2

2

R1,R2 = H

R ,R = H

Scheme 2.94

5

6

7

4

3

8 9 10

11

12

N H

N

Me

1′

O

N H

OH

N O

OH

2′

Me

4′ 3′

HO

2 1

6′ 5′

2′

Cl

Cl

OH

OH HO

367 Tjipanazole C2

368 Tjipanazole C4

Scheme 2.95

146

Chemistry and Biology of Carbazole Alkaloids

6

Cl

5 4

7

8

Cl

Cl

Cl

3 11

9

12

N

10 1′

O

OH 5′

6′ 3′

4′

2′

2

N H

N

1

OH

N H

O 2′

OH

OH

HO

OH

OH

369 Tjipanazole B

370 Tjipanazole E

Scheme 2.96

6 8

5

7

4 11

9

12

N

10 1′

O 2′

OH 5′

6'

N H

3

5 3

8

2

11

9

1

10

4′ 3′

6

7

Cl

12

N H 1′

N O

OH

6′ 5′ 4′

2′

OH

Cl

3′

OH

HO

OH 371 Tjipanazole F1

372 Tjipanazole F2

Scheme 2.97

showed the presence of a deshielded, two-proton singlet at d 8.20, assignable to the C-4 and C-7 protons, indicating the presence of chlorine atoms at the C-3 and C-8 carbons. The positions of the chlorine atoms were additionally supported by the three, two-proton doublet signals at d 7.35, 7.60, and 8.00, assignable to the C-2, and C-9, C-1, and C-10, and C-5 and C-6 protons, respectively. This was also supported by the HRFAB-MS. Based on these spectral data, the structure 359 was assigned for tjipanazole D. This structure was unequivocally established by spectrometric comparison of synthetic tjipanazole D, obtained by the coupling of two equivalents of 4-chlorophenylhydrazine with 1,2-cyclohexanedione under Fischer–Borsche conditions (329) (Scheme 2.93). The UV spectrum (lmax 259, 289, 329, and 361 nm) of tjipanazole I (360) was very similar to that of tjipanazole D (359), indicating the presence of a similar indolo[2,3a]carbazole framework. The 1H-NMR spectrum of tjipanazole I (360) was also very similar to that of tjipanazole D (359), except for the difference in the splitting pattern of one of the aromatic rings. Thus, the 1H-NMR spectrum indicated the presence of four, mutually coupled signals at d 7.20, 7.36, 7.59, and 8.15, assignable to the C-8, C-9, C-10, and C-7 protons, respectively, and establishing the absence of substitution on this aromatic ring. Comparison of the HRFAB-MS of tjipanazole I with that of tjipanazole D, indicated the absence of one chlorine atom. Based on these spectral data, and the structural similarity to tjipanazole D (359), the structure 360 was assigned to tjipanazole I (329) (Scheme 2.93). The UV spectrum (lmax 261, 294, 333, 354, and 371 nm) of tjipanazole A1 (361) was very similar to that of tjipanazole D (359) (see Scheme 2.93), indicating the presence of a similar indolo[2,3-a]carbazole framework. Comparison of the 1H-NMR spectral

Occurrence, Isolation, and Structure Elucidation

147

data of tjipanazole A1 (361) with those of tjipanazole D (359) (see Scheme 2.93) indicated the presence of similar aromatic peaks to those of tjipanazole D, except for an absent indole nitrogen proton and a new hexopyranose ring where the anomeric carbon was attached to the indole nitrogen. Proton decoupling and NOE experiments indicated that the sugar moiety was a b-6-deoxygulosyl unit which was attached to one of the nitrogens of a 3,8-dichloroindole[2,3-a]carbazole (tjipanazole D). The b-configuration at the 6-deoxygulosyl unit was also supported from its CD spectrum. Based on these spectral data, and the structural similarity to tjipanazole D (359), the structure 361 was assigned to tjipanazole A1. This structure was unequivocally established by spectrometric comparison of tjipanazole D and 6-deoxy-D-gulose obtained by acidic solvolysis of tjipanazole A1 (329) (Scheme 2.94). The 1H-NMR spectrum of tjipanazole C1 (362) was very similar to that of tjipanazole A1 (361), except for the difference in the splitting pattern of one of the aromatic rings. Thus, the 1H-NMR spectrum indicated the presence of four, mutually coupled protons at d 7.24, 7.42, 7.69, and 8.16 assignable to the C-8, C-9, C-10, and C-7 protons, respectively, indicating no substitution on this aromatic ring. Proton decoupling and NOE experiments indicated that the b-6-deoxygulosyl sugar unit was attached to N-11 of a 3-chloroindole[2,3-a]carbazole. Based on these spectral data and the structural similarity to tjipanazole A1 (361), the structure 362 was assigned to tjipanazole C1. Comparison of the 1H-NMR spectrum of tjipanazole G1 (363) with that of tjipanazole C1 (362) indicated the absence of a chlorine atom at C-3 of the aglycon. This was also clear from the 1H-NMR spectrum by the presence of an additional, mutually ortho-coupled (J=8.4 Hz), triplet proton signal at d 7.22, assignable to the C3 proton. Based on these spectral data and the close structural similarity to tjipanazole C1 (362), the structure 363 was assigned to tjipanazole G1 (329) (Scheme 2.94). The UV spectrum (lmax 261, 294, 333, 354, and 371 nm) of tjipanazole A2 (364) was identical to that of tjipanazole A1 (361), indicating the presence of a similar indolo[2,3-a]carbazole framework. The 1H-NMR spectrum of tjipanazole A2 (364) also showed the presence of a similar structure, except for the difference in the configuration of the 2u-methyl group of the sugar moiety, indicating that tjipanazole A2 is a stereoisomer of tjipanazole A1. Comparison of the proton and carbon chemical shifts with the values for K-252d (328) (see Scheme 2.84) indicated that the sugar unit is a b-rhamnosyl. This was supported by comparison with the Lrhamnose that was obtained by acid hydrolysis of tjipanazole A2. Based on these spectral data and the structural similarity to tjipanazole A1 (361), the structure 364 was assigned to tjipanazole A2 (329) (Scheme 2.94). Comparison of the 1H-NMR spectrum of tjipanazole C3 (365) with that of tjipanazole C1 (362) indicated that these two alkaloids are C-2u-epimers. Proton decoupling and NOE experiments indicated that the sugar moiety was a b-rhamnosyl unit which was attached to N-11 of 3-chloroindolo[2,3-a]carbazole. Based on these spectral data and the structural similarity to tjipanazole C1 (362), the structure 365 was assigned to tjipanazole C3 (329) (Scheme 2.94). Comparison of the 1H-NMR spectrum of tjipanazole G2 (366) with that of tjipanazole G1 (363) showed the presence of a similar structure, except for the difference in the configuration of the 2u-methyl group of the sugar moiety, showing

148

Chemistry and Biology of Carbazole Alkaloids

that these two alkaloids are C-2u-epimers, with a b-rhamnosyl sugar unit. Thus, in the 1 H-NMR spectrum, the C-2u-methyl showed a downfield shift (d 1.76, d, J=7.2 Hz), indicating the presence of an a-C-2u methyl group, and the C-2u hydrogen showed an upfield shift (d 4.58, q, J=7.2 Hz), indicating a b-C-2u hydrogen. Based on these spectral data and the structural similarity to tjipanazole G1 (363), the structure 366 was assigned to tjipanazole G1 (329) (Scheme 2.94). The 1H-NMR spectrum of tjipanazole C2 (367) was very similar to that of tjipanazole C1 (362), except for the attachment of a b-6-deoxygulosyl sugar unit at N-12 of a 3-chloroindolo[2,3-a]carbazole. The nature of this sugar unit, and its regiochemistry with respect to the chloro substituent, was established with proton decoupling and NOE experiments. Based on these spectral data and the structural similarity to tjipanazole C1 (362), the structure 367 was assigned to tjipanazole C2 (329) (Scheme 2.95). Comparison of the 1H-NMR spectrum of tjipanazole C4 (368) with that of tjipanazole C2 (367) indicated that these two alkaloids are C-2u-epimers. Proton decoupling and NOE experiments indicated that the sugar moiety was a b-rhamnosyl unit which was attached to N-12 of a 3-chloroindolo[2,3-a]carbazole. Based on these spectral data and the structural similarity to tjipanazole C2 (367), the structure 368 was assigned to tjipanazole C4 (329) (Scheme 2.95). The UV spectrum (lmax 259, 292, 330, 349, and 366 nm) of tjipanazole B (369) was similar to that of tjipanazole A1 (361) (see Scheme 2.94), indicating the presence of a similar 3,8-dichloroindolo[2,3-a]carbazole framework. Comparison of the 1H- and 13 C-NMR spectral data of tjipanazole B (369) with those of tjipanazole A1 (361) (see Scheme 2.94) indicated the presence of similar aromatic peaks to those of tjipanazole A1, but differed in the nature of the sugar moiety. Proton decoupling experiments suggested that the sugar moiety was a b-xylosyl unit, which was attached to one of the nitrogens of a 3,8-dichloroindole[2,3-a]carbazole (tjipanazole D). The b-configuration of the xylosyl unit was also supported by comparison of the optical rotation of the a- and b-methyl-D-xyloside triacetates obtained from xylose. Based on these spectral data and the structural similarity to tjipanazole A1, the structure 369 was assigned to tjipanazole B. This structure was unequivocally established by spectrometric comparison of tjipanazole D and D-xylose obtained by acidic solvolysis of tjipanazole B (329) (Scheme 2.96). The UV spectrum (lmax 259, 23, 332, 350, and 368 nm) of tjipanazole E (370) was very similar to that of tjipanazole B (369), indicating the presence of a similar 3,8dichloroindolo[2,3-a]carbazole framework. Comparison of the 1H- and 13C-NMR spectral data of tjipanazole E (370) with those of tjipanazole B (369) indicated the presence of a similar structure to tjipanazole B, except for the nature of the sugar moiety which was shown to be a b-glucosyl unit, and was attached to one of the nitrogens of a 3,8-dichloroindole[2,3-a]carbazole (tjipanazole D). The structure 370 was confirmed by spectrometric comparison of tjipanazole D and D-glucose obtained by acidic hydrolysis of tjipanazole E. The absolute stereochemistry of the sugar was unequivocally established by the synthesis of tjipanazole E by Nglycosidation of tjipanazole D using the procedure described by Robins et al. (341). Based on these data and the structural similarity to tjipanazole B (369), the structure 370 was assigned to tjipanazole E (329) (Scheme 2.96). The 1H-NMR spectrum of tjipanazole F1 (371) was very similar to that of tjipanazole C1 (362) (see Scheme 2.94), except for the nature of the sugar unit

Occurrence, Isolation, and Structure Elucidation

149

attached at N-11 of a 3-chloroindolo[2,3-a]carbazole. The nature of this sugar unit, which was assigned to be a b-xylosyl unit, and its regiochemistry with respect to the chloro substituents, was established with proton decoupling and NOE experiments. Based on these spectral data and the structural similarity to tjipanazole C1 (362), the structure 371 was assigned for tjipanazole F1 (329) (Scheme 2.97). Comparison of the 1H-NMR spectrum of tjipanazole F2 (372) with that of tjipanazole F1 (371) indicated that these two are regioisomeric 3-chloroindolo[2,3a]carbazole derivatives. Proton decoupling and NOE experiments, indicated that the b-xylosyl sugar moiety was attached to N-12 of a 3-chloroindolo[2,3-a]carbazole. Based on these spectral data and the structural similarity to tjipanazole F1 (371), the structure 372 was assigned to tjipanazole F2 (329) (Scheme 2.97).

E. Imidazo[4,5-a]pyrrolo[3,4-c]carbazole Alkaloids In 1998, Berlinck et al. reported on the bioassay-guided fractionation of the crude methanol extract of the Brazilian ascidian Didemnum granulatum to afford two novel imidazo[4,5-a]pyrrolo[3,4-c]carbazole alkaloids, granulatimide (374) and isogranulatimide (375) (342), along with previously known (343) didemnimide A (373). From a biogenetic perspective, it appears that the co-occurring didemnimide A (373) represents the precursor for the two pentacyclic alkaloids granulatimide (374) and isogranulatimide (375). These two alkaloids are the first examples of a new class of G2-specific cell-cycle check point inhibitors, and they were identified through a rational screening program (342). Three years later, from the same natural source, the same authors reported 6-bromogranulatimide (376), and the previously known (342) granulatimide (374) (344). The UV spectrum of didemnimide A (373) with lmax 430 nm indicates the presence of an indole ring with additional conjugation at the C-3 position through the maleimide ring. This was also discernible from its IR spectrum with the presence of asymmetric and symmetric stretching of the imide carbonyl groups at nmax 1702 and 1755 cm1, respectively. The mass fragmentation pattern observed in the HREIMS at m/z 207 (M+-71) for the imide unit, m/z 140 [(M+-71)-67] for the imidazole unit, and m/z 91 [(M+-71)-115] for the indole unit, showed the presence of a novel indole–maleimide–imidazole carbon skeleton. The 1H-NMR spectrum of didemnimide A (373) indicated the presence of a 3-substituted indole with four mutually ortho-coupled (J=7.8 Hz) protons at d 7.64, 7.18, 7.27, and 7.55, assignable to the C-4, C-5, C-6, and C-7 protons, respectively, along with a singlet proton signal at d 8.48 for C-2, and a broad singlet NH proton at d 12.90. The remaining singlets at d 8.18 and 8.12 were assignable to the imidazole ring protons. The connectivities of the indole and imidazole rings were established by HMBC experiments. Based on these spectral data, the structure 373 was assigned to didemnimide A. This structure was unequivocally established from its X-ray crystallographic analysis (343) (Scheme 2.98). The UV spectrum (lmax 210, 231, 280, and 470 nm) of granulatimide (374), indicated the presence of a polycyclic aromatic framework. The IR spectrum indicated the presence of NH and amide carbonyl groups at nmax 3246 and 1698 cm1, respectively. Comparison of the HRFABMS of didemnimide A (373) with that of granulatimide (374) indicated a difference of two hydrogen atoms. The 1H-NMR

150

Chemistry and Biology of Carbazole Alkaloids

O 4

5

H N10

9

7

7a

N1 H

O

11

8

5

12 13

3a 3

6

O

H N17

2 14

N

373 Didemnimide A O 5

9

H N10

3a 3

6

1 7 7a

N H

8

2

17 16

N H

8

O

12 13

2 14

H N17

N

16

15

374 Granulatimide H N

O

12 13

N

1

O

11

4

3a 3 7 7a

16

H N10 11

4

6

15

9

Br

14

N N H

N 15

375 Isogranulatimide

O H

N

376 6-Bromogranulatimide

Scheme 2.98

data showed that the two alkaloids were closely related, except for the absence of an aromatic proton signal corresponding to C-14 (one of the imidazole ring protons) at d 7.71 and the indole C-2 proton at d 8.05 (a singlet in didemnimide A), indicating a bond between the C-2 carbon of the indole fragment and the C-14 carbon of the imidazole fragment. This was also shown by the 13C-NMR singlet carbon signals at d 135.4 and 133.4, instead of doublet carbon signals at d 130.7 and 119.6 for the C-2 and C-14 carbons in didemnimide A, respectively. A planar, polycyclic, aromatic structure for granulatimide could be explained by the large chemical shifts observed for the C-4 proton (d 8.89) relative to the chemical shift observed for the C-4 proton in didemnimide A (d 7.07) and was attributed to a neighboring group effect of the C-9 maleimide carbonyl in granulatimide. Based on these spectral data, the structure 374 was assigned to granulatimide. In addition to COSY and NOE spectra, this structure was unequivocally established by spectrometric comparison of synthetic granulatimide obtained by the photocyclization of didemnimide A (342) (Scheme 2.98). The UV spectrum (lmax 210, 231, 280, and 470 nm) of isogranulatimide (375) was identical to that of granulatimide (374), indicating a similar polycyclic aromatic framework. This was also discernible from its IR spectrum by the presence of an NH and an imide carbonyl band at nmax 3294 and 1678 cm1, respectively. Comparison of the NMR spectral data of isogranulatimide (375) with those of granulatimide (374) showed the presence of two imidazole protons at d 8.10 and 9.12 in place of one imidazole proton (d 8.50) in granulatimide (374). These signals did not show any HMBC/HMQC correlations or NOEs. The NH proton (N-17) at d 13.57, corresponding to granulatimide (374) was absent, indicating a bond between this nitrogen of the imidazole fragment and the C-2 carbon of the indole fragment. Based on these spectral data and the structural similarity to granulatimide (374), the structure 375 was assigned to isogranulatimide. In addition to the COSY spectrum, this structure was unequivocally established by spectrometric comparison with synthetic isogranulatimide obtained as a minor product by the photolytic cyclization of didemnimide A (342) (Scheme 2.98).

Occurrence, Isolation, and Structure Elucidation

151

The UV spectrum (lmax 236, 282, 308, and 386 nm) of 6-bromogranulatimide (376) was similar to that of granulatimide (374), indicating the presence of a similar pentacyclic imidazo[4,5-a]pyrrolo[3,4-c]carbazole framework. The 1H- and 13C-NMR spectral data of 6-bromogranulatimide (376) were also very similar to those of granulatimide (374), except for the presence of a bromine atom in place of the C-6 proton. This was also discernible from its HREIMS. Based on these spectral data and the structural similarity to granulatimide (374), the structure 376 was assigned to 6bromogranulatimide. This structure was further supported by the HMQC and HMBC spectra (344) (Scheme 2.98).

F. Quinolino[4,3-b]carbazole-1,4-quinone Alkaloids In 1999, Rickards et al. reported the isolation of calothrixins A (377) and B (378) from photoautrophic cultures of Calothrix cyanobacteria (345). These two, novel, pentacyclic carbazole alkaloids contain a quinolino[4,3-b]carbazole-1,4-quinone framework. Calothrixins A and B inhibit the growth of a chloroquin-resistant strain of the malaria parasite P. falciparum and human HeLa cancer cells (345). The UV spectrum (lmax 292, 362, and 413 nm) of calothrixin A (377) was unaffected by acid, but shifted reversibly to longer wavelengths on the addition of aqueous sodium hydroxide, indicating the presence of an ionizable acid group on the pentacyclic quinolino[4,3-b]carbazole-1,4-quinone chromophore. The 1H-NMR spectrum showed the presence of an isolated proton singlet at d 8.88, and two-spin systems, each containing four adjacent aromatic protons, indicating the presence of two, ortho-disubstituted benzenoid rings, each with only one carbon substituent. The second substituent on each ring was nitrogen, as indicated by the deshielding (d 138.4 and 143.1) of the N-substituted ring carbons. The 1H and 13C shifts of these spin systems closely resembled those of the indole rings of 5-cyano-6-methoxyindolo[2,3a]carbazole (358) (see Scheme 2.93) indicating a similar indole system. The 1H and 13C resonances of another spin system were shifted downfield, indicating a different environment. The isolated singlet proton at d 8.88 showed three-bond correlation between N-5 and C-4a, in addition to correlations to the carbonyl carbon at d 178.4, and to the resonances at d 130.0 and 122.1, indicating a quinoline structure. These data indicated a fused pentacyclic ring system with indole and quinoline systems as the terminal rings. The presence of an N-oxide group was supported with the weak, variable intensity ion at m/z 314, carrying an extra oxygen atom relative to m/z 298 in its EIMS spectrum, which could be explained by the variable loss of an oxygen atom in the EIMS, due to thermal decomposition in the ion source before ionization. The EIMS spectrum fragmentation ions at m/z 297 (M+–OH), 286 (M+–CO), 258 [(M+-28)– CO] also indicated the presence of an N-oxide and two carbonyl carbons in the molecule. Based on these spectral data, the structure 377 was assigned to calothrixin A. This structure was unequivocally supported by the absence of any NOEs between the indole and quinoline systems, and the absence of long-range 1H and 13C correlations, as well as by X-ray crystallographic analysis (345) (Scheme 2.99). The UV spectrum (lmax 283, 352, and 405 nm) of calothrixin B (378) was similar to that of calothrixin A (377) indicating the presence of a similar pentacyclic quinolino[4,3-b]carbazole-1,4-quinone chromophore. Close comparison of the HREIMS of calothrixin B (378) with that of calothrixin A (377) indicated that

152

Chemistry and Biology of Carbazole Alkaloids

O 8 7b7a 7 11 11a

12

N H

6 6a

O N5

4a

O

N

4

13 13a 13b 12a 1

N H

O

377 Calothrixin A

O

378 Calothrixin B

Scheme 2.99

calothrixin B (378) was the N-5-deoxy analog of calothrixin A. The 1H- and 13C-NMR spectral data of calothrixin B showed significant differences in their chemical shifts only near N-5. Thus, the C-4, C-4a, and C-6 resonances of calothrixin B were 8–15 ppm downfield of those in calothrixin A, and the H-4 and H-6 resonances of calothrixin B were respectively 0.44 upfield and 0.73 ppm downfield of those in calothrixin A, paralleling the shifts observed for the corresponding nuclei in quinoline and quinoline N-oxide. Based on these spectral data and the structural similarity to calothrixin A (377), the structure 378 was assigned for calothrixin B (345) (Scheme 2.99).

G. Sesquiterpenoid Carbazole Alkaloids In 1989, Gloer et al. reported the isolation of tubingensin A (379) from the hexane extract of the sclerotia of the fungus Aspergillus tubingensis. Tubingensin A has a unique 9H-octahydronaphtho[3,4-b]carbazole pentacyclic framework. Moreover, tubingensin A is active against the widespread crop pest Heliothis zea and displays in vitro antiviral activity against herpes simplex virus type 1 (346). In the same year, the same authors isolated the cytotoxic hexacyclic carbazole alkaloid, tubingensin B (380) from the same source. Tubingensin B exhibited similar biological activity as found for tubingensin A, but was more cytotoxic to HeLa cells (IC50 4 mg/mL for 380 vs. 23 mg/mL for 379) (347). One year later, the same group reported the isolation of aflavazole 381, a new anti-insectan carbazole metabolite from a different Aspergillus sp., Aspergillus flavus sclerotia. Aflavazole showed strong antifeedant activity against the fungivorous beetle Carpophilus hemipterus (348). In nature, tubingensin A (379) ½a20 D þ 13:6 (c 1.0, CHCl3) (322,324), tubingensin B (380) [a]D –6.7 (c 0.80, CHCl3) (322), and aflavazole (381) [a]D +2.8 (c 0.35, MeOH) (348) were isolated in their optically active form. In 2001, Sings et al. isolated two indole diterpene alkaloids, dihydrotubingensins A (382) and B (383) (349), together with the previously known tubingensins A (379) (346) and B (380) (347). Dihydrotubingensins A and B were the first dihydrocarbazole-containing alkaloids isolated from a living system. Dihydrotubingensin B (380) was obtained in its optically active ½a20 D  50:0 (c 0.1, MeOH) form (349). The UV spectrum (lmax 218, 239, 262, 302, 326, and 340 nm) of tubingensin A (379) shows the presence of a carbazole framework. The 1H-NMR spectrum of tubingensin A (379) indicated the presence of a 2,3-disubstituted carbazole substructure. The selective INEPT spectrum showed correlations of H-5 with C-3, C-4, C-7, and C-9, the correlations of H-10 with C-2, C-4, C-12, and C-20, and the correlations of H-27 with

153

Occurrence, Isolation, and Structure Elucidation

C-3, C-10, C-11, and C-13. Among these, C-10 represents a four-bond correlation, and the absence of measurable coupling between H-10 and H-27 is in agreement with the observed correlation and their para-orientation. The partial structure assigned with these selective INEPT correlations supports the long-range correlation of the three protons at C-29 with C-14, C-15, C-16, and C-20, and the correlation of the three protons at C-28 with C-15, C-16, and C-17. The protons at C-13 were significantly downfield shifted, suggesting the attachment of C-13 to a sp2 center. The presence of a 4-methyl-3-pentenyl group was clearly shown by the 1H-NMR decoupling experiments and 13C-NMR data. The connectivity of these partial structures was established by selective INEPT experiments, in which the downfield C-13 protons of the C-13–C-14 ethylene unit were long-range coupled to two aromatic C-11 and C-12 quaternary carbons, the C-27 aromatic methine, and the C-15 aliphatic quaternary carbon. The upfield C-14 protons of the C-13–C-14 ethylene unit correlated with both the C-15 and C-20 aliphatic quaternary carbons and the C-12 aromatic quaternary carbon. Finally, the C-10 downfield aromatic proton correlated with the C-20 aliphatic quaternary carbon which has the 4-methyl-3-pentenyl substituent. The relative stereochemistry of tubingensin A, as shown in structure 379, was based on biogenetic considerations, NOESY correlation, and Dreiding models. Based on these spectroscopic analyses, structure 379 was assigned to tubingensin A (346) (Scheme 2.100). The UV spectrum (lmax 218, 237, 260, 299, 325, and 338 nm) of tubingensin B (380) was very similar to that of tubingensin A (379), indicating the presence of a similar carbazole framework. Comparison of the 1H-NMR spectrum of tubingensin B (380) with that of tubingensin A (379) indicated that these two alkaloids are structural isomers with a similar 2,3-disubstituted carbazole substructure. This was also supported with homonuclear decoupling and 1H–1H COSY experiments. In addition, the selective INEPT and COSY data indicated the presence of a second isolated ethylene moiety, and an isopropyl group attached to a third quaternary carbon. In the selective INEPT experiments, the isopropyl C-24 methine proton and the C-13 methylene protons both correlated with C-12 and C-23. The C–H proton of the hydroxylated methine (H-19) correlated with C-11, and the aromatic proton singlets (H-10 and H-27) correlated with C-20 and C-23, respectively. The relative stereochemistry of tubingensin B, as shown in structure 380, was based on NOESY correlation and Dreiding models. Based on these spectroscopic analyses, structure 380 was assigned to tubingensin B (347) (Scheme 2.100). 28

Me HO 28

25 24

17

HO

26 10

5

21

4 3 8

9

N1 2 H

19 20

11

15

16 19 15

16

Me28 Me 29

12 13 27

379 Tubingensin A

14 20 21 4 3 11 10 23 13 12 24 9 N 2 27 1 26 H 25

5

14 8

Me Me 29

HO

380 Tubingensin B

Scheme 2.100

13 27

Me

17

19 OH 15 11 20 21

H

4 3

5

29

Me

10

23

Me 8

9

N1 2 H

25

381 Aflavazole

26

154

Chemistry and Biology of Carbazole Alkaloids

The UV spectrum (lmax 219, 243, 263, 297, 327, and 341 nm) of aflavazole (381) indicated the presence of a carbazole framework. The 13C-NMR spectrum of aflavazole (381) showed the presence of 12 aromatic carbons similar to those of tubingensins A (379) and B (380), without any other multiple bonds, indicating the presence of three additional rings and a similar carbazole moiety. The 1H-NMR decoupling and COSY experiments and selective INEPT data, indicated the presence of a 2,3,4-trisubstituted carbazole substructure, and the presence of an isolated ethylene unit and an aromatic methyl group showing a benzylic coupling to a broad singlet at d 7.12 assignable to the C-25 proton. The selective INEPT correlations of H-11 with C-3, C-10, and C-23, indicated the direct attachment of C-11 to C-10 of the carbazole nucleus. The three protons of C-26 showed correlations to aromatic C-23, C-24, and C-25, thereby locating the aromatic methyl group meta to C-11, and confirming its position ortho to C-25. Irradiation of the isolated ethylene protons of C-22 at d 2.89 showed the polarization transfer to C-10, C-23, and C-24, thus establishing the linkage of C-22 to C-23. Similarly, the H-21 ethylene protons showed the polarization transfer to C-19 and C-20, indicating the linkage of C-20 to C-21. The relative stereochemistry of aflavazole, as shown in structure 381, was based on NOESY correlations. Based on these spectroscopic analyses, the structure 381 was assigned to aflavazole (348) (Scheme 2.100). Comparison of the 1H-NMR spectrum of dihydrotubingensin A (382) with that of tubingensin A (379) indicated the absence of the C-10 and C-27 aromatic singlets at d 7.92 and 7.11, respectively, and the presence of two additional methylene signals at d 3.26–3.41. This was also established from the HRESIMS spectrum. Based on these spectral data, and the close structural similarity to tubingensin A (379), the structure 382 was assigned to dihydrotubingensin A. This structure was unequivocally established by transformation of dihydrotubingensin A (382) into tubingensin A (379) (see Scheme 2.100) by mild air oxidation (349) (Scheme 2.101). The UV spectrum (lmax 227 and 281 nm) of dihydrotubingensin B (383) indicated the presence of a substituted indole framework, rather than a carbazole framework. Close comparison of the 1H-NMR spectrum of dihydrotubingensin B (383) with that of tubingensin B (380) indicated the absence of two aromatic signals corresponding to H-10 and H-27 at d 8.05 and 7.32, respectively, with the presence of two additional downfield-shifted methylene signals at d 3.34 and 3.53 for the C-10 protons, and at d 3.66 for the C-27 protons. This was also deduced from the HRESIMS and 13C-NMR spectral data. The presence of a dihydrocarbazole unit was also established through long-range 1H–13C-NMR correlations obtained from the HMBC experiment. Based

28

25 24 26 5

8

9

HO

19

21 20 4 3 10 11 15

N1 2 H

16

17 16

Me Me 29

28

19 15

14

27

382 Dihydrotubingensin A

8

HO

14 20 4 3 10 11 21 13 23 12 24 9 N 2 27 1 26 H 25

5

12 13

Me Me29

383 Dihydrotubingensin B

Scheme 2.101

155

Occurrence, Isolation, and Structure Elucidation

on these spectral data and the close structural similarity to tubingensin B (380), structure 383 was assigned to dihydrotubingensin B. This structure was unequivocally established by transformation of dihydrotubingensin B (383) into tubingensin B (380) (see Scheme 2.100) by mild air oxidation (349) (Scheme 2.101).

H. Miscellaneous Carbazole Alkaloids In 1991, Dillman and Cardellina reported the isolation of 1-methylcarbazole (384) from extracts of the sponge Tedania ignis collected in the shallow waters of Bermuda (350). This was the first report on the isolation of 1-methylcarbazole from a marine invertebrate (350). Prior to this isolation, 1-methylcarbazole was detected, along with other methylcarbazole derivatives as major components of cigarette smoke condensate (351). This isolate showed insecticidal and antimicrobial activity (352), but was shown to be non-mutagenic (353). In 1983, Luk et al. reported the isolation of 3-chlorocarbazole (385) from female bovine urine using a benzodiazepine receptor binding assay. This was the first example of a carbazole alkaloid isolated from mammalian tissues (354). The UV spectrum [lmax 215, 223, 229, 236, 246, 260, 291 (sh), 297, 319 (sh), 330, and 343 nm] of 3-chlorocarbazole (385) showed the presence of a carbazole framework, which was supported by its IR spectrum. The 1H-NMR spectrum showed the presence of two sets of multiplets at d 7.18–7.50 and 7.90–8.15 assignable to five and three protons, respectively, indicating the absence of one proton of 9H-carbazole. These spectral data, coupled with a characteristic mass fragmentation at m/z 166 (M+Cl), indicated the presence of a chlorine at C-3 of the carbazole nucleus. Based on these spectral data, structure 385 was assigned to 3-chlorocarbazole (354). This structure was unequivocally established by comparison with a synthetic sample (355) (Scheme 2.102). In 1999, Brown et al. reported the isolation of two regioisomeric dibromocarbazole alkaloids, 3,6-dibromocarbazole (386) and 2,7-dibromocarbazole (388), along with 3,6-diiodocarbazole (387) from one colony of the epilithic encrusting cyanobacterium Kyrtuthrix maculans on Hong Kong shores. Although all these Cl

N H

N H

Me

384 1-Methylcarbazole Br

Br

385 3-Chlorocarbazole

I

I Br

N H

N H

386 3,6-Dibromocarbazole

387 3,6-Diiodocarbazole

Scheme 2.102

Br N H

388 2,7-Dibromocarbazole

156

Chemistry and Biology of Carbazole Alkaloids

alkaloids were known previously through organic synthesis, this was the first report of their occurrence as natural products (356). Recently, Zhu and Hites isolated a further polybrominated carbazole, 1,3,6,8-tetrabromocarbazole, from the sediment cores of Lake Michigan. This was the first report of the isolation of a tetrabromocarbazole from the environment (357). The 1H- and 13C-NMR spectra of 3,6-dibromocarbazole (386) showed only half of the full set of signals, indicating the symmetrical structure for this alkaloid. The presence of two bromine atoms was clearly established by the HREIMS. The position and splitting pattern in the aromatic region of the 1H-NMR spectrum, along with one broad singlet at d 8.11 assignable to the NH proton indicated the location of the two bromine atoms at C-3 and C-6 on the carbazole nucleus. In addition, the 13C-NMR chemical shifts also supported the position of these bromine atoms. Based on these spetral data, the structure 386 was assigned to 3,6-dibromocarbazole. This structure was unequivocally established by comparison with a commercially available sample of 3,6-dibromocarbazole (356) (Scheme 2.102). The 1H-NMR spectrum of 3,6-diiodocarbazole (387) showed the same set of protons as 3,6-dibromocarbazole (386), except for their downfield shift. These spectral data, together with the HREIMS, indicated the presence of two iodine atoms in place of two bromine atoms. In addition, the 13C-NMR chemical shifts also supported the presence of iodine atoms. Based on these spectral analyses, and the close structural similarity to 3,6-dibromocarbazole, the structure 387 was assigned to 3,6-diiodocarbazole (356). The HREIMS of 2,7-dibromocarbazole (388) was identical to that of 3,6dibromocarbazole (386). Differences were identified in the chemical shifts and splitting pattern of the 1H-NMR spectrum. Thus, a deshielded, two-proton doublet at d 7.87 with ortho-coupling (J=8.3 Hz), assignable to the C-4 and C-5 protons, indicated the location of two bromine atoms at the C-2 and C-7 positions of the carbazole nucleus. This was also evident from the shielded ortho- and meta-coupled (J=8.3, 1.5 Hz) two-proton double doublet at d 7.36, assignable to the C-3 and C-6 protons. Further, a mutually meta-coupled (J=1.5 Hz) two-proton doublet at d 7.57, assignable to the C-1 and C-9 protons, supported the location of the two bromine atoms ortho to these carbons. Based on these spectral analyses and the HREIMS identical to that of 3,6-dibromocarbazole (386), the regioisomeric dibromocarbazole structure 388 was assigned to 2,7-dibromocarbazole (Scheme 2.102) (356). Recently, Steglich et al. isolated pityriazole (389), along with malasseziazoles A (390), B (391), and C (392), from cultures of the human pathogenic yeast Malassezia furfur. Malasseziazoles A–C (390–392) were the first natural products with an indolo[3,2-b]carbazole framework (358). The UV spectrum [lmax 221, 279, and 336 (sh) nm] of pityriazole (389) showed the presence of a carbazole framework. This was supported by the IR spectrum. The 1H-NMR spectrum of pityriazole (389) showed the presence of a broad OH peak at d 17.10 assignable to an aromatic hydroxy group, and a singlet at d 10.16 assignable to a NH. In the aromatic region, a deshielded C-4 proton appeared as a singlet at d 8.40, indicating substitution at C-1, C-2, and C-3 of the carbazole nucleus. Four, mutually coupled protons at d 7.89, 7.02, 7.13, and 7.30 assignable to the C-5, C-6, C-7, and C-8 protons, respectively, established the absence of substitution on the C-ring of the carbazole nucleus. In addition to these peaks, the 1 H-NMR also showed the protons corresponding to a 1H-indol-3-yl group, which was also supported by 1H–1H COSY experiments. Along with these spectral data,

Occurrence, Isolation, and Structure Elucidation

157

11 5

4

3

COOH 2

9 8

N H

1

3′

7

OH

12

H N

R1 6

4

N

8

1 7

5

11

N1′ H

10 7′

389 Pityriazole

N H

12

R2

OH 2

5

4′

2′

H

1

390 Malasseziazole A

6

3

OSO3Na

N 4 SO3Na

393 Ancorinazole

R1 = COCOOH; R2 = H 391 Malasseziazole B R1 = COCOOH; R2 = CHO 392 Malasseziazole C R1 = COOH; R2 = CHO

Scheme 2.103

HMBC and HMQC correlations indicated the presence of a 1H-indol-3-yl group at C-1, a hydroxy group at C-2, and a carboxylic group at C-3 of the carbazole nucleus. Based on these spectral data, the structure 389 was assigned to pityriazole (358) (Scheme 2.103). The UV spectrum (lmax 211, 225, 255, 305, 375, and 447 nm) of malasseziazole A (390) showed the presence of an indolo[3,2-b]carbazole framework. The 1H-NMR spectrum of malasseziazole A (390) showed signals for two, 2,3-disubstituted, 1Hindole moieties interconnected by a C4H2O3 unit containing a –C(QO)COOH group. This was supported by 1H–1H COSY experiments. Further structural support came from the HMBC and HMQC correlations. Based on these spectral analyses, the structure 390 was assigned to malasseziazole A (358) (Scheme 2.103). The UV spectrum [lmax 209, 230 (sh), 242 (sh), 275 (sh), 306, 409, and 482 nm] of malasseziazole B (391) was similar to that of malasseziazole A (390), indicating the presence of a similar indolo[3,2-b]carbazole framework. The 1H-NMR spectrum of malasseziazole B (391) was also very similar to that of malasseziazole A (390), except for the absence of the C-12 singlet proton at d 8.40, along with the presence of an aldehyde proton at d 11.55. This aldehyde proton showed correlations with the C-11a, C-12, and C-12a carbons in the HMBC experiment. Based on these spectral analyses and the structural similarity to malasseziazole A (390), the structure 391 was assigned to malasseziazole B (358) (Scheme 2.103). The UV spectrum [lmax 214, 226 (sh), 247, 268, 308, 391, and 462 nm] of malasseziazole C (392) was similar to that of malasseziazole B (391), indicating the presence of a similar indolo[3,2-b]carbazole framework. The 1H-NMR spectrum of malasseziazole C (392) was also very similar to that of malasseziazole B (391), except for the presence of a carboxylic group in place of an a-ketocarboxylic group. This was evident from its 13C-NMR spectrum, by the absence of an a-ketocarboxylic carbonyl carbon at d 198.6, as well as a downfield shift (d 126.5) of the carboxylic group attached to the C-6 carbon. The structure was also supported by the HMBC and HMQC correlations. Based on these spectral analyses and the structural similarity to malasseziazole B (391), the structure 392 was assigned to malasseziazole C (358) (Scheme 2.103).

158

Chemistry and Biology of Carbazole Alkaloids

In 2002, Boyd et al. reported the isolation of ancorinazole (393) from the aqueous extract of the sponge Ancorina sp., collected in New Zealand. This was the first natural product with an indolo[3,2-a]carbazole framework (359). The UV spectrum [lmax 243, 280, 296 (sh), 308, 341, and 357 nm] of ancorinazole (393) indicated the presence of a polycyclic aromatic framework. The HRFAB-MS of the pseudomolecular ion of ancorinazole (393) at m/z 469 (M+–Na), indicated the molecular formula C18H10O8N2S2Na2. The FAB-MS peaks at m/z 427 (M+–H–Na–SO2) and 413 (M++H– Na–SO3), indicated the loss of SO2 and SO3 from (M+–H) and (M++H), respectively. In addition to these mass spectral data, IR spectral bands at nmax 1053, 1232, and 1262 cm1 supported the presence of sulfate and sulfamate groups. Additional support for the sulfate functionality was obtained chemically with the formation of a white precipitate (BaSO4) by acid hydrolysis in the presence of BaCl2. The 1H-NMR spectrum showed three singlets at d 7.92, 8.09, and 8.67 in which the signal at d 8.67 was an exchangeable proton assignable to a hydroxy group. These data indicated substitutions at the C-2 and C-3 positions of the indolo[3,2-a]carbazole framework. The aromatic region showed four, mutually-coupled protons at d 8.07, 7.16, 7.32, and 7.58 assignable to the C-8, C-9, C-10, and C-11 protons, respectively, indicating an ortho-disubstituted aromatic ring. Two ortho-coupled (J=9.0 Hz) protons, which were assignable to C-6 and C-7 of the indolocarbazole framework, appeared at d 8.00 and 8.02. A series of 1D-TOCSY-experiments, as well as HMBC correlations, supported this assignment. Additionally, the [3,2-a]fusion geometry of the indolocarbazole, the position of the sulfate group at C-3 and a sulfonate at N-5, were supported by NOE experiments. Based on these spectral analyses, the structure 393 was assigned to ancorinazole. Further evidence for this structure comes from its transformation into the corresponding hydrolysis product 2,3-dihydroxy-indolo[3,2-a]carbazole by treatment with mild acid (359) (Scheme 2.103).

CH A PT ER

3 Biogenesis of Carbazole Alkaloids

A closer examination of all the carbazole alkaloids isolated and studied so far presents several interesting biogenetic features of these molecules. The most important one is the origin of the indole nucleus and of the ring A. With some rare exceptions, the alkaloids having an extra methyl group (or its equivalent) at the 3-position are isolated from higher plants, whereas the others are obtained from several different sources. Based on their natural occurrence, the carbazole alkaloids isolated to date were classified under these two main categories, and their biosyntheses is discussed consequently. Some of the biosynthetic pathways discussed below are lacking clear experimental support, and are based on rational, delineated proposals.

I. CARBAZOLE ALKALOIDS FROM HIGHER PLANTS The occurrence of 3-methylcarbazole (2) and its oxidative congeners 3-formylcarbazole (3) and methyl carbazole-3-carboxylate (4), from the taxonomically related genera Murraya, Clausena, and Glycosmis of the family Rutaceae, sub-family Aurantoidae, of higher plants, provides clear evidence for the in vivo oxidation of the methyl group in 3-methylcarbazole. This was supported by the photochemical oxidation of the 3-methyl group of carbazole alkaloids (360). Further support derives from the co-occurrence of a diverse range of 1- and 2-oxygenated 3-methylcarbazoles and their oxidative variants from the genus Murraya, and the closely allied genera Clausena and Glycosmis of the family Rutaceae (see Scheme 3.4) (8,361). Whatever may be the progenitor of the carbazole nucleus in nature, it is clear from these findings that 3-methylcarbazole (2) is the key precursor for the carbazoles isolated from higher plants. The route of formation of the carbazole nucleus is still far from understood, and has been variously considered to arise from 3-prenylquinolone via a pathway involving shikimic acid (394) and mevalonic acid (MVA) (400) (Scheme 3.1) (1,112,362–366), anthranilic acid (397) and prephenic acid (404) via a pathway involving shikimic acid (394) (Scheme 3.2) (367), and also tryptophan (408) involving the mevalonate (400) pathway (Scheme 3.3) (133). All of these pathways lack experimental proof. However, based on the occurrence of the diverse carbazole alkaloids derived from anthranilic acid (397) in the family Rutaceae, the pathway 159

160

Chemistry and Biology of Carbazole Alkaloids

HO

O

HO

O

HO

O NH2

L-Gln HO

OH

O

OH 394 Shikimic acid HO

CO2H

O

CO2H

OH 396 2-Amino-2-deoxyisochorismic acid

395 Chorismic acid

O

OH NH2

malonyl-CoA N O H 398 Quinolone

397 Anthranilic acid O 3

OH HO2C

SCoA 399 acetyl-CoA

400 Mevalonic acid

Me

N H 2 3-Methylcarbazole

OH

OPP

OH

401 Prenyl PP OH

−CO N H

N H 403 2-Prenylindole

O

402 3-Prenylquinolone

Scheme 3.1

described in Scheme 3.1 is regarded as more rational, and is the most widely accepted among these biogenetic pathways to carbazole alkaloids in higher plants. In the biogenetic pathway depicted in Scheme 3.1 (362–366), the formation of 3-methylcarbazole (2) it is considered to arise from 3-prenylquinolone (402) through 2-prenylindole (403). Although 2-prenylindole alkaloids are rare in nature, there is another major source in the Rutaceae in the form of the dimeric indoles of Flindersia fournieri, such as isoborreverine, which could arise from the monomeric units of 2-prenyltryptamines by Diels–Alder type condensation (368). For the synthesis of 3-prenylquinolone (402), the required quinolone (398) would be obtained from anthranilic acid (397), which has greatest abundance in plants from the family Rutaceae. Anthranilic acid (397) is obtained from chorismic acid (395), a very important branch point compound in the shikimate pathway. A central intermediate in the shikimate pathway is shikimic acid (394), a compound which was isolated from plants of Illicium species (Japanese shikimi) many years before its role in metabolism had been discovered (366). The shikimate pathway begins with a coupling of phosphoenolpyruvate (PEP) and D-erythrose 4-phosphate to give the seven-carbon 3-deoxy-D-arabino-heptulosonic acid 7-phosphate (DAHP) through an aldol-type condensation. Elimination of phosphoric acid from DAHP, followed by an intramolecular aldol reaction, generates the first carbocyclic intermediate, 3-dehydroquinic acid. Shikimic acid (394) is

Biogenesis of Carbazole Alkaloids

HO

HO

O

161

O HO

O NH2

O

HO

OH OH 394 Shikimic acid

CO2H

OH 395 Chorismic acid HO

397 Anthranilic acid O

O

CO2H

HO

O O

CO2H OH

OH

404 Prephenic acid

395 Chorismic acid O OH

HO

CO2H − C3 unit

O

O

OH O O NH

NH2

O

OH 404 Prephenic acid

397 Anthranilic acid

H

405 OH OH − CO2 − H2O

− CO2

O

Cyclization

N H 406

N H 1 Carbazole

Me C-3 Methylation [CH3]Methionine

N H 2 3-Methylcarbazole

Scheme 3.2

formed from 3-dehydroquinic acid via 3-dehydroshikimic acid through a series of dehydration and reduction steps. Shikimic acid 3-phosphate, which is obtained by ATP-dependent phosphorylation of shikimic acid (394), combines with PEP via an addition–elimination reaction giving 3-enolpyruvylshikimic acid 3-phosphate (EPSP). This reaction is catalyzed by the enzyme EPSP synthase. Then, 1,4-elimination of phosphoric acid from EPSP leads to chorismic acid (395). Amination of chorismic acid (395) at C-2 from L-glutamine (Gln) with the elimination of water leads to 2-amino-2-deoxyisochorismic acid (396), and then 2-aminobenzoic acid (anthranilic acid) (397). Anthraniloyl-coenzyme A (CoA), obtained from anthranilic acid and acetyl-coenzyme A (CoA), undergoes a chain extension to afford quinoline (398) via the addition of one molecule of malonyl-CoA through amide formation. Alkylation

162

Chemistry and Biology of Carbazole Alkaloids

O 3

OH HO2C

SCoA

399 acetyl-CoA

2 ATP −ATP −CO2

OH

400 Mevalonic acid

OPP 407 Isopentenyl PP Isomerase

OPP 401 Prenyl PP O

O OH

HO

NH2

NH2 Me

OPP

N H 408 L-Tryptophan

407 Isopentenyl PP

N H

O HO

N H

O HO

N H

N H 409

N Me

Me

Pyridoxal N H H NAD 411

N H 410

NADH

Me

Me

NAD

Aromatization N H

N H

412

2 3-Methylcarbazole

Scheme 3.3

of quinoline (398) at the nucleophilic C-3 position with prenyl diphosphate (DMAPP) affords 3-prenylquinolone (402). DMAPP is obtained from three molecules of acetyl-coenzyme A (399) via MVA (400) involving a series of reactions using b-hydroxy-b-methylglutaryl-CoA (HMG-CoA) reductase and ATP-dependent enzymes. The route for the transformation of 3-prenylquinolone (402) to 3-methylcarbazole lacks experimental support and is presumed to proceed through the 2-prenylindole 403 via elimination of carbon monoxide (CO) from 3-prenylquinolone (402) followed by oxidative cyclization of the 2-prenylindole 403 (362–366) (Scheme 3.1). The biogenetic pathway proposed by Chakraborty for the formation of carbazole (1) and 3-methylcarbazole (2) proceeds through N-phenylated anthranilic acid (406). This hypothesis is based on aromatic C-methylation of aniline with methionine, and originates from anthranilic acid (397) and prephenic acid (404). Until now, there are no N-phenylated anthranilic acid derivatives known naturally, therefore, this hypothesis is lacking substantial biogenetic evidence. However, the isolation of carbazole (1), 3-methylcarbazole (2), and several derivatives of 3-methylcarbazole

Biogenesis of Carbazole Alkaloids

163

from taxonomically related higher plants of the genera Glycosmis, Clausena, and Murraya (Rutaceae) supports this hypothesis. Based on this biogenetic pathway, Nphenylated anthranilic acid (406) could derive from anthranilic acid (397) and prephenic acid (404) with the elimination of a C3 unit, followed by CO2 and H2O. NPhenylated anthranilic acid (406) could be transformed to carbazole with the elimination of CO2. The methyl group (or its equivalent) at the C-3 position, the most active center of electrophilic attack at the carbazole nucleus, could originate from C-methylation with methionine on carbazole (1). This could also happen prior to the formation of the carbazole nucleus (367) (Scheme 3.2). In 1975, Narasimhan et al. described a biogenetic hypothesis for 3-methylcarbazole (2) starting from L-tryptophan (408). According to these authors, the A-ring of carbazole which shows an isopentane carbon skeleton could be of mevalonate origin. This was supported by the experiments of Kapil (1) by feeding 2-14C- and 2-3H-MVA lactone to M. koenigii, which resulted in the isolation of labeled koenimbin (116), koenigicine (118) (see Scheme 2.22), and mahanimbine (139) (see Schemes 2.27 and 3.7); though experiments establishing the location of the radioactivity are lacking. This experiment rules out Chakraborty’s proposal that the methyl group at C-3 is part of a one-carbon unit (see Scheme 3.2). Based on Narasimhan’s approach, an initial introduction of the isopentenyl chain (407) at the 3-position of L-tryptophan (408), followed by the preferential migration of the isopentenyl chain to the 2-position, and subsequent cyclization, would give the tetrahydrocarbazole derivative (409). Loss of serine from 409 in the presence of pyridoxal co-enzyme, followed by dehydrogenation, would lead to 3-methylcarbazole (2) (133) (Scheme 3.3). The isolation of murrayanine (9), the first member of the carbazole alkaloids, together with several members of this group, murrayafoline A (7), koenoline (8), mukoeic acid (10), mukonine (11), 1-hydroxy-3-methylcarbazole (23), O-demethylmurrayanine (24), clausine E (clauszoline-I) (25), 3-formylcarbazole (3), methyl carbazole-3-carboxylate (4), 2-methoxy-3-methylcarbazole (37), O-methylmukonal (glycosinine) (38), clausine L (O-methylmukonidine, methyl 2-methoxycarbazole-3-carboxylate) (39), 2-hydroxy-3methylcarbazole (52), mukonal (53), mukonidine (54), and 3-methylcarbazole (2) from the taxonomically related genera Murraya, Glycosmis, and Clausena (Rutaceae) indicates the in vivo oxygenation and oxidation of 3-methylcarbazole (2). The in vivo oxygenation of 3-methylcarbazole to hydroxy-3-methylcarbazoles is supported by biomimetic hydroxylation of 3-methylcarbazole with Fenton’s reagent (Fe+2/H2O2) under Udenfriend conditions (Fe+2/EDTA/ascorbic acid/oxygen), a reaction prototype of mixed function oxidases. Under these conditions, 1-hydroxy-3methylcarbazole and 2-hydroxy-3-methylcarbazole were isolated as the major products, along with other compounds (369). The in vivo oxidation of the C-3 methyl group to its oxidized functional variants, i.e., CH2OH, CHO, and COOH, which have been found in various alkaloids was supported by the photochemical oxidation of the 3-methyl group of carbazole alkaloids (360) (Scheme 3.4). The 3-methylcarbazole origin of the carbazole alkaloids of higher plants and the wider participation of 2-hydroxy-3-methylcarbazole in the formation of pyranocarbazoles, as well as furocarbazoles, has been further substantiated by the isolation of several derivatives of 3-methylcarbazoles, such as mukoenine-A (girinimbilol) (55), heptaphylline (76), furostifoline (224), furoclausine A (225), girinimbine (115), and murrayacine (124). Girinimbilol (55) could be considered the

164

Chemistry and Biology of Carbazole Alkaloids

Me

R

R

1-oxygenation N H 2 3-Methylcarbazole

oxidation

7 8 9 10 11

N N OH OMe H H Murrayafoline A R = Me 23 1-Hydroxy-3-methylcarbazole R = Me R = CH2OH Koenoline 24 O-Demethylmurrayanine Murrayanine R = CHO R = CHO Mukoeic acid R = COOH Mukonine R = COOMe 25 Clausine E (Clauszoline-I) R = COOMe R

oxidation 2-oxygenation oxidation R

N H 3 3-Formylcabazole R = CHO 4 Methyl carbazole-3-carboxylate R = COOMe R

OMe N H 37 2-Methoxy-3-methylcarbazole R = Me 38 O-Methylmukonal (Glycosinine) R = CHO 39 Clausine L (O-Methylmukonidine, Methyl 2-methoxycarbazole-3-carboxylate) R = COOMe

OH N H 52 2-Hydroxy-3-methylcarbazole R = Me 53 Mukonal R = CHO 54 Mukonidine R = COOMe

Scheme 3.4

precursor for furo- and pyrano[3,2-a]carbazole alkaloids. Moreover, the isolation of girinimbilol (55) and furostifoline (224) from Murraya species indicate the origin of the furan ring as shown through the cyclization pathway ‘‘a’’ from the prenylated congener. The occurrence of girinimbilol (55) and girinimbine (115) from M. koenigii, and heptaphylline (76) and murrayacine (124) in Clausena heptaphylla, may be considered circumstantial evidence in favor of the origin of the pyran ring as shown through the cyclization pathway ‘‘b’’ from the prenylated congeners (370) (Scheme 3.5). 2-Hydroxy-3-methylcarbazole (52) could also function as a precursor for the formation of carbazole alkaloids with a C23 skeleton as depicted in Scheme 3.6 (370). Insertion of a C10 unit, viz., geraniol at C-1 of 2-hydroxy-3-methylcarbazole (52) would yield mahanimbinol (mahanimbilol) (56). The geranyl monoterpene unit could undergo various transformations, thus giving rise to isomeric carbazole alkaloids with a C23 skeleton, such as mahanimbine (139), cyclomahanimbine (murrayazolidine, curryanin) (151), and bicyclomahanimbine (160). Therefore, mahanimbinol (mahanimbilol) could be considered as the representative member of the carbazoles with a C23 skeleton. The occurrence of 2-hydroxy-3-methylcarbazole (52),

Biogenesis of Carbazole Alkaloids

R1

R1 Prenylation R2

R2

OH

OH a

N H

N H

b

52 2-Hydroxy-3-methylcarbazole R1 = Me; R2 = H

55 Mukoenine-A R1 = Me; R2 = H (Girinimbilol)

53 Mukonal

76 Heptaphylline R1 = CHO; R2 = H

R1 = CHO; R2 = H R2 = H, OH

Cyclization via

Cyclization via

pathway a

pathway b

R2 = H

R1 R2 N H

R1 R2

O

O N H

224 Furostifoline R1 = Me; R2 = H

115 Girinimbine R1 = Me; R2 = H

225 Furoclausine A R1 = CHO; R2 = OH

124 Murrayacine R1 CHO; R2 = H

Scheme 3.5

Me

Me Geranylation

OH N H 52 2-Hydroxy-3-methylcarbazole

OH N H

56 Mahanimbinol (Mahanimbilol) Cyclization

Me O N H

Me

Me O Me

N H H

O Me

N H Me

Me 139 Mahanimbine

H

151 Cyclomahanimbine (Murrayazolidine, Curryanin)

Scheme 3.6

Me 160 Bicyclomahanimbine

165

166

Chemistry and Biology of Carbazole Alkaloids

mahanimbinol (mahanimbilol) (56), mahanimbine (139), cyclomahanimbine (murrayazolidine, curryanin) (151), and bicyclomahanimbine (160) in M. koenigii may be considered circumstantial evidence in favor of the origin of the carbazole C23 skeleton from the geranylated congener, mahanimbinol (mahanimbilol) (56) (370) (Scheme 3.6). Mukonal (53), an oxidation product of 2-hydroxy-3-methylcarbazole, could be further hydroxylated at the C-ring of the carbazole nucleus to give clauszoline-M (73), which could undergo insertion of a C5 prenyl unit on either ring of the carbazole nucleus, to give the C-ring prenylated carbazole derivative 413 and heptazoline (77), which on cyclization would lead to clauszoline-B (168) and clauszoline-G (126), respectively. The isolation of mukonal (53), clauszoline-M (73), heptazoline (77), clauszoline-B (168), and clauszoline-G (126) from the taxonomically related genera Murraya and Clausena (Rutaceae) is in favor of the origin of the pyran ring from the prenylated congeners (76) (Scheme 3.7). Chakraborty’s biomimetic hydroxylation studies of 3-methylcarbazole (2) using Udenfriend conditions (Fe+2/EDTA/ascorbic acid/oxygen) furnished a bis-carbazole, as a result of biomimetic dimerization of 3-methylcarbazole. This reaction, which is a prototype of hydroxylation followed by dimerization, provides circumstantial evidence for the existence of bis-carbazole alkaloids in higher plants (369,371). Murrayafoline A (7) could undergo various oxidative dimerizations to give murrastifoline-A (186), murrastifoline-F (191), and bismurrayafoline-A (197) as CHO

CHO Oxygenation

OH

OH

N H 53 Mukonal

N HO H 73 Clauszoline-M Prenylation

CHO

CHO

OH

OH HO

N H

HO

N H

413 77 Heptazoline Cyclization

Cyclization CHO

CHO

OH O

N H

O HO

168 Clauszoline-B

Scheme 3.7

N H

126 Clauszoline-G

167

Biogenesis of Carbazole Alkaloids

depicted in Scheme 3.8. The occurrence of murrayafoline A (7), murrastifoline-A (186), murrastifoline-F (191), and bismurrayafoline-A (197) in Murraya euchrestifolia may be considered circumstantial evidence in favor of the oxidative dimerization of murrayafoline A (7) (Scheme 3.8). Similarly, 1-hydroxy-3-methylcarbazole (23) and 2-hydroxy-3-methylcarbazole (52) could lead to bis(O-demethylmurrayafoline A) (204) and bis-2-hydroxy-3-methylcarbazole [1,1-bis(2-hydroxy-3-methylcarbazole)] (213), respectively, as shown in Scheme 3.9. Although bis(O-demethylmurrayafoline A) (204) is a non-natural carbazole derivative, the isolation of 2-hydroxy-3-methylcarbazole (52) and bis-2-hydroxy-3-methylcarbazole [1,1-bis(2-hydroxy-3-methylcarbazole)] (213) from M. koenigii supports the oxidative dimerization of 2-hydroxy-3-methylcarbazole (52) (Scheme 3.9). Me Oxidative coupling N H

OMe

7 Murrayafoline A Me Me Me

9

N

9

OMe

6′

9

N

OMe Me

4′

OMe

3′

Me

N

N

N H

H MeO 186 Murrastifoline-A

N H

OMe

OMe

197 Bismurrayafoline-A

191 Murrastifoline-F

Scheme 3.8

Me

Me Oxidative coupling N H

N H

OH

23 1-Hydroxy-3-methylcarbazole

OH

H N

HO

2

2′

Me

204 Bis(O-demethylmurrayafoline A) Me

Me Oxidative coupling OH N H 52 2-Hydroxy-3-methylcarbazole

N H HO

1 1′

OH H N

Me 213 Bis-2-hydroxy-3-methylcarbazole 1,1′-Bis(2-hydroxy-3-methylcarbazole)

Scheme 3.9

168

Chemistry and Biology of Carbazole Alkaloids

The biogenesis of ellipticine (228), as a representative member of the pyrido[4,3-b]carbazole alkaloids, lacks experimental support (372,373). However, for these alkaloids elegant and rational biogenetic pathways have been proposed (189,374–376). Because of this, their biosynthetic pathways remain an interesting enigma to be solved. Ellipticine (228) and its natural isomer olivacine (238a) are frequently present in the same plant, along with uleine. It is presumed, therefore, that all these Aspidosperma alkaloids have the same progenitor. Prior to the first detailed biogenetic proposal of Wenkert for ellipticine (228) and related alkaloids (374), Woodward et al. had already mentioned a common biosynthetic relationship of ellipticine and uleine, two structurally different Aspidosperma alkaloids (178). Wenkert’s non-tryptophan pathway was based on a common precursor 417, derived from glycosylideneanthranilic acid (414), a tryptophan progenitor, and a seco-prephenate formaldehyde (SPF) unit or secologanin, as possible biogenetic intermediates for the Aspidosperma alkaloids. The a-oxidation of glycosylideneanthranilic acid (414) and Mannich condensation of the product with SPF or secologanin would be expected to produce the a-alkyl-b-glycosylindole 418, an immediate precursor for the Aspidosperma alkaloids. This intermediate could undergo two modes of imine formation through the depicted pathways a and b to afford compounds, 419a and 419b, respectively. Finally, cyclization of 419a and 419b through the indolic b-position and extrusion (via retro-aldolization) of the b-glycosyl function would lead to the Aspidosperma alkaloids, ellipticine (228), and olivacine (238a) (374) (Scheme 3.10). The biosynthetic pathway proposed by Potier and Janot involves both L-tryptophan (408) and stemmadenine (420) (375). Labeling experiments with both L-tryptophan (408) and stemmadenine (420) indicated a weak incorporation into uleine, and none at all for both ellipticine (228) and olivacine (238a) (373). In the light of these observations, this hypothesis needs further experimental support to show its validity, although, using this biogenetic model, Besselie`vre and Husson achieved the syntheses of ellipticine (228) and olivacine (238a) (376). The conjugated iminium salt 426, which is often invoked for the biogenesis of indole alkaloids (376), functions as a key intermediate in this hypothesis. Stemmadenine (420), which is formed from L-tryptophan (408), undergoes a whole series of transformations (377) as shown in Scheme 3.11 to afford the conjugated iminium salt 426. Intramolecular Mannich type reaction of the conjugated iminium salt 426 should lead to ellipticine (228) via an intermediate 427. Alternatively, the conjugated iminium salt 426 could hydrolyze to afford the 2-vinylsubstituted indole 428, which, on cyclization through an intermediate 429, would lead to guatambuine (233). This alkaloid, on demethylation and dehydrogenation, should afford olivacine (238a) (375) (Scheme 3.11).

II. CARBAZOLE ALKALOIDS FROM OTHER SOURCES Biogenetic considerations of the carbazole alkaloids isolated from other sources have led to a different view about the genesis of these alkaloids. Without exception, to date, all of the biogenetic proposals of the carbazole alkaloids isolated from other sources have indicated L-tryptophan has a progenitor.

Biogenesis of Carbazole Alkaloids

CO2H

CO2H

OH

169

1. Oxidation

2. Mannich with SPF or N OH Secologanin 397 Anthranilic acid 414 Glycosylideneanthranilic acid (Tryptophan progenitor) R

NH2

HO2C

O

OH

CHO

O HO2C

H HO2C

CHO

415 Secoprephenateformaldehyde (SPF) CO2H HO R O

H O

416 Secologanin b

OH O R

CHO O

O-Glu

a NH2Me O a b

Cyclization

O

CHO

N H

N H

CHO

HO2C 417

418 Imine formation via pathway b

Imine formation via pathway a R

CHO CO2H

OH O R

N

N H 419a

OH O N

N CHO H CO2H 419b Cyclization

CHO CO2H

Cyclization

Me

Me N

N

N Me H 228 Ellipticine

N Me H 238a Olivacine

Scheme 3.10

In 1990, Nakamura et al. reported for the first time the complete biosynthetic origin of the whole carbon skeleton of carbazomycin B isolated from lower plants (378). Based on feeding experiments with 14C- and 13C-labeled compounds, followed by measurement of radioactivity and 13C-NMR spectroscopy, it was shown that L-tryptophan (408) contributes to C-3 and C-4 of the hexasubstituted aromatic ring, in addition to the indole ring, indicating tryptophan as the progenitor of carbazomycin B (261), in contrast to Chakraborty’s proposal of 2-methylcarbazole. The indole part of L-tryptophan (408) is formed by incorporation of two carbons from phosphoribosyl diphosphate (430), with loss of the anthranilic acid (397) carboxyl. The

170

Chemistry and Biology of Carbazole Alkaloids

O N

N

CO2H NH2

OH

OH N CO2Me H 420 Stemmadenine

N H 408 L-Tryptophan

N H 421

H

N

N

H

H2O

OH

N H

N H 423

CO2Me 422

H O

CO2Me

N

N

N

− CH2O

N H

N H 426

N H 425

424 O H

CHO HN

HN

Me N

N H

N H 429

N Me H 427

428

Me

Me N

N Me H 233 Guatambuine

Me N

N

N Me H 238a Olivacine

N Me H 228 Ellipticine

Scheme 3.11

remaining ribosyl carbons are removed by a reverse aldol reaction and replaced by L-serine (434), which becomes the side chain of L-tryptophan (408) (366). Further feeding experiments with 13C-labeled alanine, which is known to be a biosynthetic equivalent for the two-carbon unit of pyruvate, followed by measurement of the 13C-NMR spectra, indicated the origin of the C-1 and C-2 carbons and their methyl groups in the A-ring of the carbazole framework. Finally, a 13C-labeled methionine experiment indicated the origin of the methyl of the methoxy group. All these experiments established that tryptophan (408), after decarboxylation and deamination, reacts with two molecules of sodium pyruvate (436), before methylation with methionine, to give the complete carbon skeleton of carbazomycin B (261) (234,378) (Scheme 3.12).

171

Biogenesis of Carbazole Alkaloids

H O

O O

OP

CO2H O PPO OH OH

NH2

Δ

H O OH

− C3 unit

N H 432 Indole-3-glycerol P

− H2O

OH

O Δ

O

OH NH2 434 L-Serine

HO

OP

− CO2

OP

N H 431

430 Phosphoribosyl PP

397 Anthranilic acid

OH

Δ

Δ

Δ

OH

NH2 N H 408 L-Tryptophan

N H 433 Indole O 2 Δ

−

NH3

− CO 2

O Δ

OH N H 435

*

*

ONa

O 436 Sodiumpyruvate 

[CH3]Methionine − 2CO2



HO Δ

Δ

OMe *

*

Me

* N Me* H 261 Carbazomycin B

Scheme 3.12

Independently, in 1998, the Cordell (290,379,380) and Pearce (381) groups published some preliminary biosynthetic results on staurosporine and rebeccamycin, typical representative members of the indolo[2,3-a]pyrrolo[3,4-c]carbazole alkaloids. Cordell’s biosynthetic studies on staurosporine were based on feeding experiments with L-tryptophan. These studies showed that two units of L-tryptophan, with the two carbon side-chains intact, were responsible for the biosynthesis of staurosporine aglycone. Further experimental studies are necessary to establish the nature of the intermediate in the biotransformation of L-tryptophan to staurosporine. Although these studies are not complete, they gave for the first time insight into the biosynthesis of staurosporine (379,380). Pearce’s biosynthetic model study for rebeccamycin, a halogenated natural product of the indolocarbazole family, demonstrated that this alkaloid is biosynthesized by Lechevalieria aerocolonigenes (322) (formerly Saccharothrix aerocolonigenes) from one unit of glucose, one unit of methionine, and two units of tryptophan. It was also shown that the a-amino group of neither tryptophan unit provides the nitrogen of the phthalimide function. From these studies it is presumed that D-glucose and L-methionine are probably incorporated via UDP-glucose and S-adenosylmethionine, respectively. Tryptophan is probably incorporated following deamination to yield indolepyruvic acid. In order to understand the complete biosynthetic pathway to rebeccamycin it is necessary to have experimental studies based on a corresponding chloro analogue of L-tryptophan (381). Until the mid-1990s, knowledge on the biosynthesis of staurosporine (295), a pharmacologically interesting molecule was limited to the early steps, especially the

172

Chemistry and Biology of Carbazole Alkaloids

incorporation of tryptophan (290,379). In 1995, Hoehn et al. for the first time used a blocked mutant of Streptomyces longisporoflavus R19 for the demonstration of the biosynthetic path of staurosporine (295) by the isolation of O-demethylstaurosporine (3u-O-demethylstaurosporine) (297) in the last step of the biosynthetic pathway. In their studies, the staurosporine-producing strain S. longisporoflavus selected colony R 19/col 15 was taken as the parental strain, blocked mutant M13, responsible for the production of staurosporine aglycone (K-252c) (293) and M14, responsible for the production of O-demethylstaurosporine (297) from the staurosporine producer strain S. longisporoflavus R 19/col 15 were used for the mutation studies. The mutagenic treatment was performed by irradiation with a UV lamp (254 nm; 500 mW/cm2). These studies led to the isolation of O-demethylstaurosporine (3u-O-demethylstaurosporine) (297), a direct precursor for staurosporine by blocked mutants of the staurosporine producer strain M14. By cofermentation and bioconversion experiments, the possibility that O-demethylstaurosporine (3u-O-demethylstaurosporine) (297) is produced by demethylation of staurosporine (295), by an enzyme which could be repressed in the parental strain, was excluded. Subsequent experiments have corroborated that O-methylation (382) is the final step in the biosynthetic pathway of staurosporine (295) and that the mutant M14 is lacking the O-methylase enzyme required for this step (294,383) (Scheme 3.13). In 1996, Fredenhagen et al. proposed some plausible intermediates in the biosynthesis of K-252a (SF 2370) (330), based on the isolation of several, closely related, minor metabolites, either to staurosporine or to oxime TAN-1030A (313) (300), from the staurosporine-producing strain S. longisporoflavus. The absolute stereochemistry of TAN-1030A (313) was similar as K-252a (SF 2370) (330) at the bridging atoms 2u and 5u. TAN-1030A might be formed by oximation of the H N

O

CO2H NH2 N H 408 L-Tryptophan H N

Sugar Parent strain

Parent strain

and mutants M13+M14

N N and mutant 14 H H M13 blocked 293 Staurosporinone (K-252c) Staurosporine Aglycone H N

O

O

O -Methylation Parent strain N Me HO

O

N

and mutant 13 M14 blocked

N Me MeO

H NHMe

297 O-Demethylstaurosporine (3′-O-Demethylstaurosporine)

O

N H

NHMe 295 (+ )-Staurosporine (AM-2282)

Scheme 3.13

Biogenesis of Carbazole Alkaloids

173

corresponding ketone derivative, 4u-deoxime-4u-oxo-TAN-1030A (316) (see Scheme 2.80), another minor metabolite of strain S. longisporoflavus R 19, which could be easily formed by oxidation of a sugar hydroxy function. Ring contraction of TAN-1030A (313) under Beckmann conditions leads to 437 (384). It is therefore conceivable that TAN-1030A (313) is the biosynthetic precursor which is converted by the microorganism to the proposed intermediate 437, which could not be isolated from fermentation broth; instead, the corresponding N-methyl derivative, 3u-methylamino-3u-deoxy-K-252a (332), was found. It could be presumed that the same enzyme which introduces the N-methyl group (382) into staurosporine might be responsible for this transformation and might be unable to discriminate between substrates with five- and six-membered ring systems. The free amino group of intermediate 437 could be converted to the hydroxy group of K-252a (SF-2370) (330). This metabolite was found to be co-produced in small amounts by the staurosporineproducing strain S. longisporoflavus R 19 (300) (Scheme 3.14). H N

H N

O

O

Ring contraction N N H H 293 Staurosporinone (K-252c) Staurosporine Aglycone

H N

N

O

Me MeO

H

N HO 313 TAN-1030A H N

N

O

O

N

Me MeO

H NHMe

NH2

O 332 3′-Methylamino-3′-deoxy-K-252a

437 H N

Me MeO

Me MeO

N

O

O

N

O

O

H

N

N

H N

O

N

N H

Me HO

OH

O

O

N H

OH O 331 K-252b

O 330 K-252a (SF-2370)

Scheme 3.14

174

Chemistry and Biology of Carbazole Alkaloids

Prior to these studies, the same authors isolated various minor metabolites related to staurosporine, and also staurosporine with a nitro function at C-4u. These studies suggest TAN-1030A (313) as a key intermediate for the degradation product of staurosporine and for the staurosporine congeners (301). In 1994, Steglich et al. isolated lycogalic acid A (443) and staurosporinone (293), together with traces of arcyriaflavin A (345) and arcyriarubin A (349), from the slime mold (Myxomycetes) Lycogala epidendrum (385). The co-occurrence of these alkaloids points to a close biosynthetic relationship among them (252,255,385). Prior to this report on lycogalic acid A, Hoshino et al. reported the same alkaloid as a new metabolite of tryptophan from the mutant of Chromobacterium violaceum and named as chromopyrrolic acid (443). Tracer experiments with 13C-tryptophan showed incorporation into chromopyrrolic acid, indicating the formation through the biosynthetic condensation of two molecules of tryptophan (386). In 2006, Walsh et al. reported for the first time a complete enzyme-catalyzed biosynthetic pathway from L-tryptophan (408) [or 7-chloro-L-tryptophan (438)] to the staurosporine and rebeccamycin aglycons, K-252c (293) and 1,1-dichloroarcyriaflavin A (446) (387). These studies are in agreement with the previously reported biosynthetic pathways of staurosporine and rebeccamycin which are based on the isolation of putative intermediates of gene disruption studies from Streptomyces sp. TP-A0274 (388–390) and L. aerocolonigenes ATCC 39243 (391,392), respectively. Walsh’s pathway uses a series of oxidative transformations (Scheme 3.15) involving the use of biosynthetic enzymes StaP, StaC, and RebC through an intermediate lycogalic acid (chromopyrrolic acid) (443) and dichlorolycogalic acid (dichlorodichlorochromopyrrolic acid) (444). The pathways to the two aglycons follow very similar routes, differing only by the chlorination at the 7-position of L-tryptophan en route to rebeccamycin, and the oxidation state of the pyrrole-derived fivemembered ring, taking the form of a maleimide in rebeccamycin and a pyrrolinone in the staurosporine aglycone. Subsequent N-glycosylation (389) and tailoring modifications follow divergent pathways toward rebeccamycin (337) and staurosporine (295). The formation of lycogalic acid (chromopyrrolic acid) (443), a key biosynthetic intermediate, through the joint action of RebO, an L-amino acid oxidase, and RebD (or StaD), a heme-containing oxidase, was shown to proceed via the condensation of two molecules of indole-3-pyruvic acid imine (439) (393). StaP and StaC (or RebP and RebC) are involved in aglycone ring construction. The overall reaction is catalyzed by StaP, a cytochrome P450 enzyme, and is intriguing, since it involves both aryl–aryl coupling to give the central six-membered ring of the indolocarbazole scaffold, as well as double oxidative decarboxylation to facilitate a net four- to eight-electron oxidation by converting lycogalic acid (chromopyrrolic acid) (443) into the three aglycone products, K-252c (293), arcyriaflavin A (345), and 7-hydroxy K-252c (445). It is pertinent to note that the ability of the StaP/StaC and StaP/RebC systems to transform possible biosynthetic intermediates to the final aglycon products showed that arcyriarubin A (349) is not a biosynthetic intermediate in the conversion of lycogalic acid (chromopyrrolic acid) (443) to the aglycon products, K-252c (293), arcyriaflavin A (345), and 7-hydroxy K-252c (445). Aglycons 293, 345, and 445 are not interconvertible, but appear to diverge from a common biosynthetic intermediate. Incorporation experiments with 18O-labeled dioxygen or 18O-labeled

175

Biogenesis of Carbazole Alkaloids

RebO StaO

NH2

RebH RebF

O

NH4

N H

R

408 L-Tryptophan R = H 438 7-Chloro-L-tryptophan R = Cl

H2O

NH

N H

R

CO2H

CO2H

CO2H

N H

R

439 R = H

441 R = H

440 R = Cl

442 R = Cl

StaD RabD H N

HO2C

CO2H

N N H H R R 443 Lycogalic acid (Chromopyrrolic acid) R = H 444 R = Cl StaP RabP StaC

RabC H N

R

N H

O

N H

H N

HO

R

R

293 Staurosporinone (K-252c) Staurosporine Aglycone R = H H N O

N Me MeO

O

N H

O

O

N H

R

N H

R

O

N H

R

345 Arcyriaflavin A R = H 446 R = Cl

445 R = H

H N

O

N

N H

O

O

N H

Cl

NHMe 295 (+)-Staurosporine (AM-2282)

H N

Cl

OH

HO

337 Rebeccamycin OH OMe

Scheme 3.15

water involving lycogalic acid (chromopyrrolic acid) (443) and the StaP/StaC and StaP/RebC systems demonstrated that the amide oxygen of K-252c (293) and both oxygens of arcyriaflavin A (345) are directly derived from dioxygen (387) (Scheme 3.15).

176

Chemistry and Biology of Carbazole Alkaloids

Examining the structures of the sesquiterpenoid carbazole alkaloids, tubingensins A (379), B (380), aflavazole (381), and dihydrotubingensins A (382) and B (383), it is likely that they are biogenetically related, and could have originated from a common intermediate, nominine (448) (394). This hypothesis was supported by the isolation of nominine (448) and 20,25-dihydrooxyaflavinine (452) from the sclerotia of the same Aspergillus spp. (347). Although this biogenetic hypothesis is lacking experimental support, it is postulated that nominine (448), an indole diterpenoid alkaloid which functions as a key intermediate for the sesquiterpenoid carbazole alkaloids, tubingensins A (379) and B (380), aflavazole (381), and the dihydrotubingensins A (382) and B (383) arises from geranyl–geranylindole (447), a biogenetic precursor of the indole diterpenoid alkaloids (394). Geranyl–geranylindole (447) would lead to dihydrotubingensin A (382) through nominine (448), with cyclization at the indole C-2, after the rotation around the indole C-3 bond. Dihydrotubingensin A (382), under dehydrogenation conditions, could form the aromatized analog, tubingensin A (379) (394). The co-occurrence of these two sesquiterpenoid carbazole alkaloids in Aspergillus tubingensis supports the

OH

N H 447 Geranyl-geranylindole

N H 448 Nominine HO

HO H

N H

Me Me

Me Me

N H 382 Dihydrotubingensin A

449

HO Me Me N H 379 Tubingensin A

Scheme 3.16

Biogenesis of Carbazole Alkaloids

177

HO OH

Me Me N H

N H

449

448 Nominine

Me Me

HO H

HO

Me Me

N H

N H 383 Dihydrotubingensin B

450

Me Me HO

N H 380 Tubingensin B

Scheme 3.17

oxidative transformation of the unstable dihydrocarbazole to tubingensin A (379) (349) (Scheme 3.16). The formation of tubingensin B (380) starting from nominine (448) could be rationalized through dihydrotubingensin B (383), which is formed by cyclization at the indole C-2 of 449 involving the prenyl group and an exocyclic double bond, followed by ring expansion, as shown in intermediate 450. The co-occurrence of dihydrotubingensin B (383) and tubingensin B (380) from A. tubingensis supports the oxidative transformation of the unstable dihydrocarbazole to tubingensin B (380) (349) (Scheme 3.17). The formation of aflavazole (381) from the proposed common biosynthetic intermediate, nominine (448), could proceed through aflavinine (451) and 20,26-dihydrooxyaflavinine (452) by way of the transformations depicted in

178

Chemistry and Biology of Carbazole Alkaloids

Me H

Me OH

OH Me

H

N H

N H 448 Nominine Me HO 20

Me

451 Aflavinine Me HO

Me OH

Me OH

Me

H

H

25

Me

N OH H 452 20,25-Dihydrooxyaflavinine

N H 381 Aflavazole

Scheme 3.18

Scheme 3.18. The occurrence of nominine (448), aflavinine (451), 20,25-dihydrooxyaflavinine (452), and aflavazole (381) in the sclerotia of the same Aspergillus spp. may be considered circumstantial evidence in favor of this biogenetic proposal (347). The occurrence of pityriazole (389), along with malasseziazoles A (390), B (391), and C (392), in the same source, namely, cultures of the human pathogenic yeast Malassezia furfur, indicates a common biogenesis among these structurally diverse carbazole derivatives. As proposed by Steglich et al., pityriazole (389) and malasseziazole B (391) could be derived from a common biogenetic precursor 454 through the transformations shown in Scheme 3.19. Metabolite 454 in turn could be obtained by oxidative coupling of two indol-3-yl pyruvate (441) molecules at C-2 and C-3u, followed by thiamine pyrophosphate (TPP)-catalyzed decarboxylation of the resulting dimer 453 to the formyl derivative 454. Dehydrogenation of 454, followed by 6p-electrocyclization and aromatization, could lead to malasseziazole B (391), an indolo[2,3-b]carbazole. The formation of pityriazole (389), a structurally different 9H-carbazole derivative could be rationalized by a TPP-catalyzed C–C bond formation of 454, followed by dehydration of the resulting hydroxy acid 455 (358) (Scheme 3.19). In 1999, Rickards et al. proposed a rational biosynthetic approach for calothrixins A (377) and B (378), novel pentacyclic carbazole alkaloids with a quinolino[4,3-b] carbazole-1,4-quinone framework. This hypothesis uses a common metabolite 458,

Biogenesis of Carbazole Alkaloids

HOOC

O

HOOC

O

179

O Oxidation

2

COOH

N H

N H

TPP

− CO2

N H

441 Indol-3-yl pyruvate

453 COOH

O

O

HO COOH

− H2O

O

TPP

N H

O

HOOC

OH

N H 389 Pityriazole

N H 454

N H 455

COOH

N H

N H

H N

NH2 N

N

S N H 456

OPP

N

Thiamine pyrophosphate (TPP)

CHO

− 2H

HOOC

O

H N

HOOC

O

H N

− 2H N CHO H 391 Malasseziazole B

N H

CHO 457

Scheme 3.19

which has an indolo[2,3-a]carbazole framework and is closely related to the known 5-cyano-6-methoxyindolo[2,3-a]carbazole (358) (see Scheme 2.93). Oxidation of the 4-aminophenol of the metabolite 458, followed by hydrolytic cleavage of the corresponding quinone imine (459), would afford a 2-aminophenyl-substituted quinone 460. Rotation around the biaryl bond and condensation of the amine with the formyl group or its equivalent would lead to calothrixin B (378). N-Oxidation of 378 would afford calothrixin A (377). Labeling studies with L-tryptophan (408), the established precursor of several indolo[2,3-a]carbazole metabolites (235), would also

180

Chemistry and Biology of Carbazole Alkaloids

HO

CO2H

CHO

O

CHO

N H

N H

N

NH2 N H

N H

408 L-Tryptophan

458 O

N H

O

CHO

O

N H

H2N

460

N

O

378 Calothrixin B O

O

N H

459

N

O

377 Calothrixin A

Scheme 3.20

support the formation of the common metabolite (458). The occurrence of the calothrixins A (377), B (378), and 5-cyano-6-methoxyindolo[2,3-a]carbazole (358) in cyanobacterial genera is circumstantial evidence in favor of this biogenetic pathway (345) (Scheme 3.20).

CH A PT ER

4 Biological and Pharmacological Activities of Carbazole Alkaloids

Previously in this series, Kapil (1) and Chakraborty (3) described some of the biological properties of carbazole alkaloids. Since then, a great interest in this area has developed, as attested by some special reviews (7,8,190,192,194,195,255,256,259,260,395–397). In this section, we have summarized some of the important biological and pharmacological activities of this class of alkaloids.

I. ANTI-TUMOR ACTIVE CARBAZOLES Cancer and related diseases represent one of the major causes of death for humankind. The etiology of cancer is multiple, but great progress has been made in recent times toward the understanding of these diseases with the discovery of oncogenes. Various natural products of plant and animal origin constitute the major sources for compounds affecting such oncogenes. With the passage of time, a wide range of synthetic analogs based on natural products emerged as therapeutically useful anti-tumor agents. Among these natural products, the carbazole alkaloids constitute one of the important classes of natural products. Within the carbazole alkaloids, natural and synthetic congeners of the pyrido[4,3-b]carbazole and the indolo[2,3-a]pyrrolo[3,4-c]carbazole alkaloids comprise a large group of therapeutically useful anti-tumor agents, either in current clinical use, or in the various stages of clinical development (190,192,194,195,255,256,259,260,395,396). In addition to these classes of alkaloids, 7-methoxymukonal (3-formyl-2-hydroxy7-methoxycarbazole) (68) (see Scheme 2.14) belongs to the 2-oxygenated, tricyclic carbazole alkaloid series and was more active in the brine shrimp lethality assay than 7-methoxyheptaphylline (79) (see Scheme 2.15), whereas against the human colon adenocarcinoma (HT-29), 7-methoxyheptaphylline (79) was more active than 7-methoxymukonal (3-formyl-2-hydroxy-7-methoxycarbazole) (68) (89). Koenoline (8) (see Scheme 2.4), which belongs to the 1-oxygenated tricyclic carbazole alkaloid series, has shown cytotoxic activity against cultured KB cells (32). Earlier than these reports, similar cytotoxic activity was also reported for girinimbine (115) (see Scheme 2.22) and mahanimbine (139a) (7) (see Scheme 2.27). Spurred by these results, further studies on Murraya species indicated that pyrayafoline D (isomahanine) (138) 181

182

Chemistry and Biology of Carbazole Alkaloids

(see Scheme 2.26) possessed brine shrimp lethality (398), and 9-formyl-3-methylcarbazole (6) (see Scheme 2.3) showed weak cytotoxicity against B16 mouse melanoma and adriamycin-resistant P388 mouse leukemia cell lines (17). Murrayaquinone A (107) (see Scheme 2.21) showed significant cytotoxicity against SK-MEL-5 and Colo205 cells (399). Recently, pyrayafoline D (isomahanine) (138) (see Scheme 2.26) also showed significant cytotoxic activity against the human leukemia cell line HL-60. This cytotoxicity was mediated through apoptosis by activation of the caspase-9/caspase-3 pathway, through mitochondrial dysfunction (131). Similar activity was also shown by another pyrano[2,3-a]carbazole alkaloid, mahanine (149) (Scheme 2.29), and a bis-pyrano[2,3-a]carbazole alkaloid, murrafoline-I (180b) (see Scheme 2.39). This was the first report of the cytotoxic evaluation of bis-carbazole alkaloids (131). In 1970, Rice et al. studied a diverse range of 3-substituted 1,2,3,4-tetrahydrocarbazole derivatives in a preliminary pharmacological screening for general stimulation, depression, and autonomic activity, and found that 3-carboethoxy-9-(3-dimethylaminopropyl)-1,2,3,4-tetrahydrocarbazole (461) exhibited growth inhibition at a concentration of 1 mg/mL in mammary carcinoma tissue (400). These studies were based on the carcinogenic activity observed for the bis-angular bis-benzocarbazoles reported by Buu-Hoı¨ et al. (401). Carbazole alkaloids with a benzo-annulated ring system are found very rarely in nature. However, a large structural variety of these ring systems was known as synthetic analogs due to their potential as anti-tumor agents. Among the various benzocarbazoles, a series of dihydrobenzo[a]carbazoles (462–465) with oxygen functions were shown to bind estrogen receptors and inhibit the growth of mammary tumors of rats (257,402,403). The benzo[a]carbazoles 466 and 467 exhibit pronounced cytotoxic activity against leukemia, renal tumor, colon cancer, and malignant melanoma tumor cell lines (257). Among the different 2-deazaellipticine derivatives, the benzo[b]carbazole 468 was found to have cytostatic activity against L1210 leukemia cells (194,404,405) (Scheme 4.1). In 1984, Gribble et al. reported for the first time a novel 1,10-bis-(6-methyl-5Hbenzo[b]carbazol-11-yl)decane (469) which has potential bifunctional nucleic acid intercalating properties (406). To function as anti-tumor active drugs, one of the most important cytostatic mechanisms of action of coplanar annelated polycyclic compounds is their intercalation with DNA (405). Ten years later, Kuckla¨nder et al. studied a series of 5H-benzo[b]carbazole quinone derivatives for their cytotoxic activity against colon and lung cancer cells, and found that the heteroannelated 5H-benzo[b]carbazole quinone derivative 470 was the most active among the various analogs (407) (Scheme 4.2). Ellipticine (228), a representative member of the pyrido[4,3-b]carbazole alkaloids and its analogs, was found to be highly active against various experimental tumors and leukemias. Although the parent alkaloid ellipticine is too toxic to be useful, an ellipticine analog, elliptinium (2-N-methyl-9-hydroxy ellipticine acetate-NMHE) (celiptiums, NSC 264-137) (472) was introduced in 1977 in cancer chemotherapy (197–201). Since then, pyridocarbazoles and related ring systems have made a tremendous development, both in the synthesis and in their biological evaluation. These were comprehensively reviewed by Suffness and Cordell in Volume 25 (408) and by Gribble in Volume 39 (192) of this series. In addition to these excellent reviews, there are several other important articles that provide coverage of the biological profile of the ellipticine alkaloids, together with their synthesis

183

Biological and Pharmacological Activities of Carbazole Alkaloids

CO2C2H5

R1

HO

N

N

N

R2

N

N

R3 1

461

2

OH

3

464

462 R , R = OAc; R = H 463 R1, R3 = OAc; R2 = H

HO

R2

O

N N R1

N OH

N O

466 R1 = SO2Ph; R2 = H

465

468

467 R1, R2 = Me

Scheme 4.1

N O

O

N

N

H

H

N O

469

470

Scheme 4.2

(8,185,189,190,194,195). Besides the clinically active monointercalator elliptinium, ditercaliniums (NSC 335 153) (471), a bis-intercalator of DNA is also used in clinical trial for the treatment of cancer (409). In the late 1980s, a second generation of ellipticine-derived anti-tumor agents was developed, including the new clinical candidates, datelliptium [2-(diethylamino-2ethyl)-9-hydroxyellipticinium chloride-DHE] (473) (192,410), retellipticine (BD-84) (474) (192,411), and pazellipticine (PZE, BD-40) (475) (192,412) (Scheme 4.3). Datelliptium (473), which was obtained by simple modification of the N-2 methyl group of elliptinium (472), showed better in vivo activity than elliptinium in the L1210, P388, B16, colon 38, and M5076 reticulosarcoma test systems. The increased anti-tumor potency is believed to be due to increased diffusion across cellular membranes and a more favorable biodistribution in vivo (410). Similar to datelliptium, retellipticine (BD-84) (474) showed potent activity against P388, L1210, B16, M5076, and colon 38 systems in vivo (411). An azaellipticine derivative, pazellipticine (PZE, BD-40), has excellent in vitro activity against L1210 cells (412). The complete in vivo anti-tumor mechanism of action of ellipticine and its derivatives is still not well understood. However, a tremendous amount of work has

184

Chemistry and Biology of Carbazole Alkaloids

N

N

N

N 2Cl

MeO

OMe

N H

N H

471 Ditercalinium,®(NSC 335153) HO

(CH2)2NH(C2H5)2

HO

N

N 2 Cl

OAc N H

N H

472 Elliptinium ® (Celiptium, NMHE, NSC 264-137) (C2H5)2HN(H2C)3HN

473 Datelliptium (DHE)

(C2H5)2HN(H2C)3HN H

MeO

N

H N

N

2 Cl

2 Cl N H

N H

474 Retellipticine (BD-84)

475 Pazellipticine (BD-40)

Scheme 4.3

been carried out to solve this enigma, and based on these studies it may be concluded that ellipticine and derivatives interact in vivo by more than one mechanism (189). Among these various mechanisms, one of the most widely supported mode of action of monointercalators, such as ellipticine and its derivatives, for the cytotoxic activity is DNA strand breakage associated with the enzyme topoisomerase II. In performing its role in the cleavage and rejoining of DNA strands (catenation, decatenation, relaxation, unknotting), topoisomerase II binds to the 5-phosphate on adjacent DNA strands four base pairs apart to form an enzyme–DNA complex. It is the interaction between this complex and certain drugs, such as ellipticine and derivatives, which results in the stabilization of the complex and the formation of a cleavable complex, leading eventually to the cleavage of double stranded DNA (189). Unlike ellipticine and its derivatives, detercalinium does not stimulate DNA cleavage by DNA topoisomerase II. In contrast, its antitumor activity is through a new mechanism characterized by a delayed toxicity on L1210 cell cultures (409). In addition to the aforementioned drugs, clinical trials of several other natural pyrido[4,3-b]carbazole alkaloids and a number of synthetic analogs showed them to be potent inhibitors of several cancerous disorders, but pre-clinical toxicology indicated a number of side effects, including hemolysis and cardiovascular effects (192).

185

Biological and Pharmacological Activities of Carbazole Alkaloids

Although the indolo[2,3-a]pyrrolo[3,4-c]carbazole alkaloids were found to exhibit various biological activities, the greatest interest is focused on compounds that possess anti-tumor and neuroprotective properties. These activities may be due to different mechanisms of action, including DNA intercalation, inhibition of DNA topoisomerases, and inhibition of protein kinases. These efforts generated indolocarbazole derivatives with improved properties for the treatment of cancer, neurodegenerative disorders, and diabetes-associated pathologies; as a result, several analogs have entered clinical trials (255,256,259,260,270,395,396). Based on their structural features and mechanism of anti-tumor activity, the indolo[2,3-a]pyrrolo[3,4-c]carbazole alkaloids are divided into two major groups. One group includes the inhibitors of DNA topoisomerase I, such as rebeccamycin and its congeners, without inhibitory properties toward kinases, such as CDK1/cyclinB, CDK5/p25, and PKC. Most of the members of this group contain a sugar moiety attached by a b-glycosidic linkage to one of the indole nitrogen atoms of the aglycon. Localized in the cell core, topoisomerase I controls the topology of DNA, and takes part in replication, transcription, and recombination processes. Topoisomerase I also relaxes the superstranded DNA through single-chain rupture and subsequent reunion of chains. Rebeccamycin and its derivatives were found to induce the cleavage of DNA with topomerase I due to stabilization of the DNA–enzyme complex. The stabilization of DNA with a single-chain rupture is fatal for rapidly dividing cells (by the mechanism of apoptosis). Rebeccamycin (337) (see Scheme 2.86) is undergoing phase III clinical testing as an anti-tumor agent. Other derivatives such as NSC 655649 (476) (413–415), bacatecarins (BMY 27557, XL 119, BMS 181176) (477) (416), Edotecarins (ED-749, J-107088) (478) (417,418), NB 506 (L-753000) (479) (419–421), and BMS-250749 (480) (422), a fluoro-glycosylated fluoroindolocarbazole are at various stages of development (270) (Schemes 4.4 and 4.5). The second group of compounds includes the protein kinase C (PKC) inhibitors, such as staurosporine and its derivatives. Usually, they contain a sugar moiety linked

NH

OH

N

tartrate N

O

N

N H

Cl O

N Cl

O

O

O

N H

Cz

OH

HO

N

O

O

HO

476 NSC 655649

O

O

N H

OH

OH

HO

HO OH OMe

N

Cl

OH

OH

HN N

OH OMe ® 477 Bacatecarin (BMY 27557, XL 119 BMS 181176)

Scheme 4.4

OH OMe ® 478 Edotecarin (ED-749, J-107088)

186

Chemistry and Biology of Carbazole Alkaloids

NHCHO N O

O

H N

O

O

F N

N H

HO O

F N

N H

OH

OH

OH

O

HO

HO OH OMe

OH F

479 NB 506 (L-753000)

480 BMS-250749

Scheme 4.5

to both indole nitrogen atoms of the indolocarbazole core. Protein kinases play a key role in the transfer of information from the cell periphery to its nucleus, and to the apparatus of gene transcription. The activation of PKC upon coupling of a receptor with a ligand modulates the activity of the target proteins due to transfer of the phosphate group of ATP to the OH groups of serine or threonine in these proteins. Target proteins can act as regulators of gene differentiation, proliferation, expression, including the induction of multiple resistances of tumor cells to the action of drugs. PKC can also regulate the angiogenesis, invasiveness, and programmed cell death. Therefore, inhibitors of PKC can be regarded as potential anti-tumor agents. At least 12 different isoforms of PKC may be expected to occupy various positions in the cell and tissues. A basic problem in the development of PKC inhibitors is the selectivity with respect to other kinases, and also to different isoforms of PKC. Many derivatives of staurosporine, K-252a, and their analogs have been prepared in order to obtain more specific PKC inhibitors in both the indolocarbazole and 2,3-bis(indol-3-yl)maleimide series, based on structure activity relationship studies. These studies led to more efficient and more specific compounds which entered phase I and II clinical trials. UCN-01 (325a) (see Scheme 2.83), the C-7 hydroxy derivative of staurosporine, entered phase I and II clinical trials in combination with topotecan in ovarian cancers, and in combination with cisplatin or carboplatin in patients with advanced refractory solid tumors (423–426). CGP 41251 (PKC412, N-benzoyl staurosporine) (481) entered a phase I pharmacokinetic study (427,428). CEP-701 (482), a derivative of the bacterial metabolite K-252a, is a tyrosine kinase inhibitor and has entered phase II clinical trials for the treatment of acute myelogenous leukemia (429). CEP-1347 (KT-7515) (483), a 3,9disubstituted (alkylthiomethyl)-K-252a derivative, has the ability to inhibit cell death and maintain the trophic status of neurons in culture by inhibiting the activation of the c-Jun N-terminal kinase (JNK) pathway (430). The possible importance of the JNK pathway in neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases provides a rationale for the use of CEP-1347 for the treatment of these diseases (431) (Scheme 4.6). Go¨ 6976, a non-glycosidic/non-aminoalkyl substituted indolocarbazole lactam was shown to be a potent and selective PKC inhibitor with a remarkable

187

Biological and Pharmacological Activities of Carbazole Alkaloids

H N

H N

O

H N

O

O

S

N

O

N

Me MeO Me

N

N

O

Me

H

H

HO O

OH

N

N

O

Me

H

HO

O 481 CGP 41251 (PKC412)

N

S

OMe

483 CEP-1347 (KT-7515)

482 CEP-701

Scheme 4.6

H N

O

O

H N

O

H N

O N

N NC

N Me

484 Gö 6976

N N

O

N H

N O N

485 Gö 6850 (GF109203X)

486 LY-333531

Scheme 4.7

discrimination between Ca2+-dependent subtypes a and b1 and the Ca2+-independent isoforms d, e, and z. Go¨ 6976 inhibits HIV-1 induction by bryostatin 1 (a PKC activator), tumor necrosis factor a, and interleukin 6 (256) (Scheme 4.7). Go¨ 6850 (GF-109203X) (485), a dimethylaminoethyl analog of 2,3-bis(indol-3-yl) maleimide was shown to be a selective inhibitor of PKC with anti-inflammatory activity in several in vivo and in vitro murine models of acute inflammation (432) (Scheme 4.7). Eli Lilly’s LY-333531 (486), a new macrocyclic analog of staurosporine, was discovered to be a potent and specific inhibitor of the PKC b-isozymes, indicating it to be a clinically useful agent for PKC-mediated human diseases, such as the vascular dysfunctions associated with diabetes mellitus (433,434) (Scheme 4.7). In addition to the aforementioned natural and synthetic analogs of staurosporine and rebeccamycin, a number of non-glycosidic indolocarbazoles and staurosporinerelated bisindolylmaleimides, such as the arcyriaflavin derivatives (see Scheme 2.89), are currently being evaluated in human clinical trials as anti-tumor agents (256,396,435,436). In addition to this activity, these derivatives have shown antimicrobial activity against Bacillus cereus and anti-viral activity against human cytomegalovirus (HCMV) (437,438). Comparison of the D1/CDK4 inhibitory activity of arcyriaflavin derivatives (see Scheme 2.89) and their bis-indolylmaleimide

188

Chemistry and Biology of Carbazole Alkaloids

counterparts (see Scheme 2.90) indicated that arcyriaflavin derivatives are selective G1 blockers, while the bis-indolylmaleimides arrest cells in the G2/M phase (439). Cyclin–CDK complexes regulate the progression of cells through the cell cycle. To date, strong evidence suggests a G1-phase role for D-type cyclins through the association with CDK4 and CDK6. CDK2 complexes with cyclin E and participates in the G1/S transition, whereas association with cyclin A peaks at S phase and may have a profound effect on proliferation. Moreover, CDK1 (Cdc2) plays an essential role in mitosis by interaction with B-type cyclin in the G2/M transition (439,440). The dictyodendrin class of carbazole alkaloids (see Schemes 2.70 and 2.71) completely inhibit telomerase activity (at a concentration of 50 mg/mL). It is known that 90% of human tumors show telomerase activity, which is absent in normal cells. Telemorase is a ribonucleoprotein enzyme that adds repeating known telomers to the DNA sequence (251).

II. ANTIBIOTIC CARBAZOLES Among the various carbazole derivatives, murrayanine (3-formyl-1-methoxycarbazole) (9) (see Scheme 2.4) was the first carbazole alkaloid isolated from a natural source and it shows antimicrobial properties (35). In 1978, Das et al. studied the insecticidal and antimicrobial properties of some carbazole, tetrahydrocarbazole, and 1-oxotetrahydrocarbazole derivatives (352). The antibiotic properties of carbazomycin B (261) (see Scheme 2.64) and related alkaloids attracted wider attention. Carbazomycin B was active against Glomerella cingulate No. 3 and Elsinoe¨ fawcetti at a MIC of 3 mg/ mL, whereas against Trichophyton asteroides 429 and Trichophyton mentagrophytes 833 it was active at a concentration of 12.5 mg/mL (231). 4-Deoxycarbazomycin B (487), a degradation product of carbazomycin B, showed significant inhibitory activity against various Gram-positive and Gram-negative bacteria (441) (Scheme 4.8). In 2003, Sunthitikawinsakul et al. described the anti-mycobacterial activity of various 3-methylcarbazole derivatives, including 3-formylcarbazole (3), methyl carbazole-3-carboxylate (4) (see Scheme 2.2), clausine K (clauszoline-J) (51) (see Scheme 2.11), and 7-methoxymukonal (68) (see Scheme 2.14) against Mycobacterium tuberculosis H37Ra. Except for clausine K (clauszoline-J) (51), all of these alkaloids also showed anti-fungal activity against Candida albicans (442). In 2005, Franzblau et al. reported the in vitro anti-TB activity of various carbazole derivatives such as 3-formylcarbazole (3), methyl carbazole-3-carboxylate (4) (see Scheme 2.2), lansine

O

O

OMe

OMe

Me N H

Me

487 4-Deoxycarbazomycin B

MeO

Me N H

N H

O

488

Scheme 4.8

489

OMe Me OAc

Biological and Pharmacological Activities of Carbazole Alkaloids

189

(69) (see Scheme 2.14), 3-formyl-6-methoxycarbazole (97), and micromeline (100) (see Scheme 2.19) against M. tuberculosis (H37Rv) (103). Recently, in the screening of carbazole derivatives for inhibition of M. tuberculosis growth, two synthetic analogs, the carbazole-1,4-quinone 488 and the 6-acylcarbazole 489, with MIC values of 2.2 and 4.0 mg/mL against M. tuberculosis were identified; these compounds were relatively non-toxic for the mammalian cell line (443–445) (Scheme 4.8). The alkaloid K-252a (330) (see Scheme 2.85) was examined against several microbes and found to be active against Micrococcus luteus, Micrococcus flavus FDA16, and Corynebacterium bovis 1810 with a MIC of 6.25 mg/mL (314). In 1986, researchers at Bristol-Myers and Schering Plough reported the antimicrobial properties of AT2433-A1 (339), AT2433-A2 (340), AT2433-B1 (341), and AT2433-B2 (342) (see Scheme 2.87). All these derivatives are active against Grampositive bacteria, such as M. luteus (ATCC 9341), Bacillus subtilis (ATCC 6633), Staphylococcus aureus (A 9537), Streptococcus faecalis (A 20688), and Streptococcus faecium (ATCC 9790). AT2433-B2 (342) has shown activity against the Gram-negative bacterium Escherichia coli SS 1431 (326,327). In addition to these carbazole alkaloids, isomers of glycozoline and girinimbine were tested against various microbes and found to be active against S. aureus (446). Some aminoacyl carbazoles were found to be active against B. subtilis (ICC-Strain) and B. cereus (NRRL-B-569) (447).

III. ANTI-VIRAL CARBAZOLES The tubingensins A (379) and B (380) showed activity against the widespread crop pest Heliothis zea, and display in vitro anti-viral activity against herpes simplex virus type 1 with IC50 values of 8 and 9 mg/mL, respectively (346) (see Scheme 2.100). Some bis-basic ethers of carbazoles are anti-viral. When tested against Encephalo myocarditis viral infection, several N-ethyl substituted bis-basic carbazoles of the general formula 490 were shown to be active (448) (Scheme 4.9). In 2000, Boyd et al. reported for the first time an anti-HIV active carbazole alkaloid, siamenol (89) (see Scheme 2.17). This prenylated carbazole alkaloid inhibited HIV-1 induced cytopathic inhibitor activity in an XTT-tetrazolium assay with EC50 2.6 mg/mL (85,449). Recently, Kongkathip et al. reported anti-HIV-1 activity for O-methylmukonal (glycosinine) (38) (see Scheme 2.9), 7-methoxy-O-methylmukonal (2,7-dimethoxy-3-formylcarbazole) (48) (see Scheme 2.10), and clausine K (clausazoline-J) (51). These studies showed strong anti-HIV-1 activity for R1

R2

N 490 R1 = COOR, CONMe2 R2 = Et, Bu, Hexyl

Scheme 4.9

190

Chemistry and Biology of Carbazole Alkaloids

O-methylmukonal (glycosinine) (38) with an EC50 value of 12 mM, and an IC50 of 680 mM for inhibition of tetrazolium conversion to formazan. Therefore, it had a potential therapeutic index (PTI) of 56.7, while 7-methoxy-O-methylmukonal (3-formyl-2,7-dimethoxycarbazole) (48) and clausine K (clauszoline-J) (51) exhibited anti-HIV-1 activity with EC50 values of 29.1 and 34.2 mM, respectively. These alkaloids did not exert reverse transcriptase (RT) inhibitory activity, indicating interaction at another stage(s) in the replication cycle of HIV-1 (58). Likewise, the carbazole alkaloids, glybomine B (60) (see Scheme 2.12) and glycoborinine (174) (see Scheme 2.36) indicated weak to moderate anti-HIV activity with IC50 values of 9.73 and 4.47 mg/mL, respectively (450).

IV. ANTI-INFLAMMATORY CARBAZOLES The anti-inflammatory properties of several carbazole derivatives have attracted widespread attention. Some acidic tetrahydrocarbazoles have been shown to have anti-inflammatory activity (451). Among these derivatives, 1-ethyl-8-n-propyl1,2,3,4-tetrahydrocarbazole-1-acetic acid (491) was found to be a novel antiinflammatory agent (451), and 6-chloro-1,2,3,4-tetrahydrocarbazole-2-carboxylic acid (492) was clinically active in the treatment of acute gout (452). Carprofen (493), a COX-2 (cyclooxygenase) inhibitor, has received significant attention as a substitute for non-steroidal anti-inflammatory drugs (453). Its activity is comparable to indomethacin, with less toxic side effects (production of gastric ulcers and blockade of diarrhea). In vitro cellular effects of carprofen (493) were found to be higher than those of ibuprofen, and were almost comparable to those of hydrocortisone. The anti-inflammatory activity of carprofen is probably dependent on inhibition of some neutrophil–macrophage function (454). It stimulates acid secretion without effecting basal acid secretion. The enhancement of secretagoguestimulated acid secretion was dependent on extracellular calcium. It was suggested that the compound acts at a post-receptor site between adenylate cyclase and a protein pump. The drug probably increases calcium efflux through the plasma membrane and decreases the endogenous prostaglandin E2 content. Carprofen was approved for use in dogs, cows, and horses as Imadyls or Rimadyls as an antiinflammatory drug with weak ulcerogencity activity and fecal occult bleeding (455) (Scheme 4.10).

Cl

Cl CO2H

N H 491

CO2H

N H 492

Scheme 4.10

N H

O

OH

493 Carprofen (Imadyl® , Rimadyl® )

Biological and Pharmacological Activities of Carbazole Alkaloids

191

V. ANTI-MALARIAL CARBAZOLES In 1998, Bringmann et al. reported the anti-plasmodial activity of a series of monoand bis-natural and structurally modified carbazoles and found that the synthetic compound 1,4-diacetoxy-3-methylcarbazole (168) showed higher activity (IC50 1.79 mg/mL) against Plasmodium falciparum than natural 1-hydroxy-3-methylcarbazole (23) (see Scheme 2.6) (166). In the following year, Rickards et al. reported the anti-malarial active quinolino[4,3-b]carbazole-1,4-quinone alkaloids, calothrixins A (377) and B (378) (see Scheme 2.99) from photoautrophic cultures of Calothrix cyanobacteria. These carbazole alkaloids inhibited the growth in vitro of a chloroquine-resistant strain of the malaria parasite, P. falciparum at nanomolar concentrations (345). In 2000, Yenjai et al. reported the anti-plasmodial activity of 2-oxygenated carbazole alkaloids against P. falciparum. In their studies, clausine H (clauszoline-C) (50) (see Scheme 2.11) and heptaphylline (76) (see Scheme 2.15) showed activity with IC50 values of 3.2–6.4 and 5.5–10.7 mg/mL, respectively (456). Prior to these studies, a report on the anti-plasmodial activity of 3- and 4-carbazole dialkylaminocarbinols had appeared (457).

VI. DIVERSE PHARMACOLOGICALLY ACTIVE CARBAZOLES N-Alkylamino carbazoles (e.g., 494 and 495) possess significant anti-convulsant and diuretic activity. Introduction of an aminopropyl chain at the N-atom seems to enhance the anti-convulsant activity in combination with methoxy groups at positions 2, 3, and 4, or a chlorine atom at the C-2 and C-3 positions (458). Rimcazoles (BW 234U) (496) is a novel anti-pyretic, neuroleptic agent. It was found to be a specific competitive antagonist of s-sites in the brain. It reverses psychotic conditions induced in humans by phencyclidine and/or s-opiod antagonists, probably by binding to receptors in the brain (459–461). Rimcazole has an indirect effect on dopamine neurons with relative selectivity for A10 dopamine cells (462). Some neuroleptic agents, like cycloindole (497), which has a modified tryptamine structure, and flucindole (498), a difluoro analog of cycloindole, have found use in therapy because of their anti-depressant and anti-psychotic activity (463,464) (Scheme 4.11). 3-Chlorocarbazole (385) (see Scheme 2.102), isolated from female bovine urine, has Diazepam-like activity (354). In 1997, carvedilol (Coregs, Kredexs) (499), a vasodilating b-adrenergic blocking agent, was approved for the treatment of hypertension and heart failure (465). In addition, carvedilol is also approved for the treatment of angina (465). Carvedilol is a multiple action, non-specific b- and a1-adrenergic receptor blocker (465–468) and a potent anti-oxidant agent (469) (Scheme 4.12). Carazolol (BM 51.052) (500), a further b-adrenergic blocking carbazole derivative, was prescribed as a veterinary medicine for use in pigs to relieve the stress of parturition, reduce the incidence of the mastitis, metritis, agalactia syndrome, prevent frenzy during mating, and alleviate tachycardia. However, it is most widely used to reduce stress during transportation from farm to slaughterhouse, and the subsequent incidence of pale, soft, and exudative (PSE) meat caused by stressinduced accelerated glycogen metabolism in muscle. Unlike other clinically

192

Chemistry and Biology of Carbazole Alkaloids

Cl

OMe

OMe

N

N

N Me N Me

Me N Me 494

N N

H

495 496 Rimcazole® (BW 234U) Me N Me

Me N Me

F

N H

F

497 Cycloindole

N H

498 Flucindole

Scheme 4.11 OMe O OH

N H

O

O OH

N H

N H

N H

499 Carvedilol (Coreg®, Kredex® )

500 Carazolol ®(BM 51.052)

Scheme 4.12

employed b-blockers, carazolol is largely devoid of intrinsic sympathomimetic activity (470–472) (Scheme 4.12). Murrayaquinone A (107) (see Scheme 2.21) was found to produce a triphasic inotropic response of guinea-pig papillary muscle. This triphasic inotropic response is not mediated through a receptor mechanism, but through a mechanism involving ATP production (473). Ramatroban (BAY U 3405) (501) functions as a novel, dual antagonist of the thromboxane A2 (TXA2) receptor and chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTh2), a newly identified prostaglandin D2 (PGD2) receptor (474,475). It is known that TXA2 contributes to various diseases such as bronchial asthma, ischemic heart disease, cerebrovascular disorders, and allergic rhinitis (475). In rabbits, the sudden death produced by arachidonic acid was antagonized by pretreatment with Bay U 3405 (502), showing it to be a thromboxane A2 antagonist with anti-thrombotic activity (3). Therefore, ramatroban (BAY U 3405) may be beneficial in the treatment of atherosclerosis (Scheme 4.13). Wu et al. studied a range of natural carbazole alkaloids isolated from Murraya euchrestifolia for platelet aggregation inhibitory activity, and found that murrayamine A (7-hydroxygirinimbine, mukoenine-C) (120) (see Scheme 2.22) and murrayamine-M

Biological and Pharmacological Activities of Carbazole Alkaloids

193

F H N S O O

N CO2H 501 Ramatroban®(BAY u 3405)

Scheme 4.13

(162) (see Scheme 2.32) showed potent inhibitory activity on rabbit platelet aggregation with an IC50 of 2 mg/mL induced by collagen and platelet activation factor (PAF), respectively (18). Pyrrolo[2,3-c]carbazole alkaloids (see Schemes 2.70–2.72) isolated from the dark green marine sponge, Dictyodendrilla sp., showed inhibitory activity against bovine lens aldose reductase catalyzing the reduction of aldoses to polyols which, on accumulation in cells, may result in diabetes. These alkaloids could provide prevention from such ailments (250). The inhibition of lipid peroxidation induced by free radicals generated in the presence of Fe2+ and ascorbic acid by carazostatin (247) (see Scheme 2.61) is higher than that with the brain-protective agent, flunarizine or a-tocopherol, which has freeradical-scavenging activity. Carazostatin may be helpful for the alleviation of tissue damage due to the action of superoxide radicals and subsequent peroxidative disintegration of cell membranes (476,477). Carbazomycin B (261) (see Scheme 2.64) was also found to inhibit lipoxygenase activity, which could be related to free-radicalscavenging effects (476,477). In the 1990s, a range of functionally different carbazole alkaloids, such as the neocarazostatins A (266), B (268), and C (267) (see Scheme 2.65) (239) and the carbazoquinocins A (272), B (273), C (274), D (275), E (276), and F (277) (see Scheme 2.67) (246), and carquinostatin A (278) (241) (Scheme 2.68) were isolated from different Streptomyces sp. which have shown strong inhibitory activity against lipid peroxidation. In addition to these natural carbazoles, some semi-synthetic carbazoles have shown lipid peroxidation inhibitor activity. These results suggest that these natural and semi-synthetic carbazole alkaloids may be useful as a new class of therapeutic agents for various diseases, such as myocardial and cerebral ischemia, arteriosclerosis, renal failure, inflammation, and rheumatoid arthritis, which might be caused by tissue damage due to the generation of free radicals and subsequent peroxidative disintegration of cell membranes (476,477). Recently, some N-substituted carbazolyloxyacetic acid derivatives were investigated for the inhibition and modulation of Alzheimer’s disease (AD) associated g-secretase, and it was found that selective reduction of Ab42 and an increase of the less aggregatory Ab38 fragment occurred (478). Various 9-N,N-diethylaminopropyl-1,2,3,4-tetrahydrocarbazoles have been tested against Chagas’ disease (American trypanosomiasis), a human tropical parasitic disease. It was found that 8-chloro- and/or 8-methoxy-substituted analogs may have promise as trypanocidal substances (479).

CH A PT ER

5 Chemistry of Carbazole Alkaloids

I. GENERAL METHODS FOR CARBAZOLE CONSTRUCTION From the initial discovery till today, biologically active carbazole alkaloids isolated from nature may have quite simple but in some cases also structurally complex substitution patterns. Therefore, a large number of classical and non-classical methods has been developed for the synthesis of the carbazole framework. In earlier times, the method that was most utilized for the preparation of aromatic carbazoles was the dehydrogenation of a 1,2,3,4-tetrahydrocarbazole. The next most used precursors are biphenyls with an ortho nitrogen substituent and diphenylamines. In the progress of time, a large number of synthetic methods has been developed which can be regarded as general procedures. Most of these methods offer carbazoles in good to excellent yields and use starting materials which are either commercially available or accessible by short synthetic routes. Some of these methods were covered in various reviews (4–8,480,481), as well as in the chapters by Kapil (1), Husson (2), and Chakraborty (3) in Volumes 13, 26, and 44 of this series. In the following section, we summarize the different synthetic methods. Additionally, the application of these procedures to the total synthesis of natural products will be covered in the appropriate sections.

A. Synthesis of Carbazoles by Deoxygenation of Nitrobiphenyls 1 Watermann and Vivian’s Method Deoxygenation of o-nitrobiphenyl (502) to carbazole (1) was realized first by Waterman and Vivian using stoichiometric iron oxalate at 2001C (482,483) (Scheme 5.1).

Fe(COO)2 2 H2O NO2

205−215 °C (63%)

502

N H 1

Scheme 5.1

195

196

Chemistry and Biology of Carbazole Alkaloids

P(OEt)3 R1

R2

reflux

NO2

R1

R2

N H 504

503

Scheme 5.2 R4

R4

R3 R2

N3

R3

kerosene 180 − 200 °C

R1

505

R2 N H

R1

506

Scheme 5.3

2 Cadogan’s Method Later, Cadogan developed a similar deoxygenative cyclization using refluxing triethylphosphite as solvent. Subsequently, this method remained as the most common procedure for this conversion which tolerates a variety of substituents on the o-nitrobiphenyls (503) to afford diverse, functionalized carbazole derivatives (504) (484). The widely accepted mechanism for this transformation involves exhaustive deoxygenation to a singlet nitrene that undergoes a downstream C–H insertion (485,486). In the initial studies by Cadogan, alternative deoxygenation reagents (triphenylphosphine, phosphorus trichloride) were investigated, but triethyl phosphite was the reagent of choice. While broad in scope, the generation of a large amount of phosphorus waste represents a disadvantage of this approach (484) (Scheme 5.2). Recently, transition metal catalyzed variants of this reaction with CO as the stoichiometric reductant have been developed (487).

B. Synthesis of Carbazoles from Azidobiphenyls An important route to the carbazoles is the thermal or photolytic decomposition of ortho-azidobiphenyls. Of the two procedures, thermolysis proceeds in higher yields. One advantage of photolysis is that it proceeds at room temperature and would therefore be compatible with thermally labile functional groups.

1 Thermal Decomposition In 1951, Smith and Brown reported the synthesis of carbazole 506 by thermal decomposition of ortho-azidobiphenyl (505) in kerosene at 1801C (488). The reaction is believed to proceed via loss of nitrogen gas forming a nitrene, followed by cyclization to 9a-hydro-9H-carbazole. A rapid [1,5]sigmatropic rearrangement restores the aromaticity of the intercepting aromatic ring producing carbazole (485,486). This was the first application of a nitrene intermediate in the synthesis of nitrogen-containing heterocycles (486). A variety of functional groups are tolerated under the reaction conditions (488,489) (Scheme 5.3).

Chemistry of Carbazole Alkaloids

197

2 Photolytic Decomposition The photolytic decomposition of ortho-azidobiphenyls 507 to carbazoles 508 is not as high yielding as the thermolytic procedure, and the reaction times are longer. However, the reaction proceeds under milder conditions (488,489). The reaction mechanism has been studied, and it was concluded that two intermediates were present in the reaction, both of which were capable of rearranging to carbazole (490) (Scheme 5.4).

C. Synthesis of Carbazoles by Cyclization of 2,2u-Diaminobiphenyls Among the two cyclization procedures that utilize 2,2u-diaminobiphenyls, the Ta¨uber synthesis has been most widely used and proceeds in higher yields than the diazotization reaction. The application of this method to the synthesis of carbazoles is limited by the availability of 2,2u-diaminobiphenyls.

1 Ta¨uber’s Method In 1892, Ta¨uber reported the synthesis of carbazole (1) by the cyclization of 2,2u-diaminobiphenyl (509). This reaction relies on high temperatures and acidic conditions involving cyclization with the elimination of ammonia (491,492). This method works well with chloro- and nitro-substituted 2,2u-diaminobiphenyls. However, the general application of this methodology to the synthesis of carbazoles is limited by the limited availability of 2,2u-diaminobiphenyls (493) (Scheme 5.5).

2 Diazotization of 2,2u-Diaminobiphenyls As an alternative to the Ta¨uber method, 2,2u-diaminobiphenyl (509) was transformed to carbazole (1) using diazotization conditions. This reaction proceeds intramolecularly by displacement of nitrogen. With this procedure, only moderate yields of carbazoles were obtained. The reaction is mechanistically similar to the Graebe–Ullmann synthesis (494) (Scheme 5.6). R2

R2 hν, tetralin rt

N3

R1

507

N H

R1

508

Scheme 5.4 H2N H3PO4 NH2

200−210°C (100%)

509

Scheme 5.5

N H 1

198

Chemistry and Biology of Carbazole Alkaloids

H2N NaNO2 HOAc, H2O (49%)

NH2

N H 1

509

Scheme 5.6 R2 O

R2

25% HOAc reflux

H2NHN

N NH

1

R1

R 511

510

512 R2

R2 chloranil N H 513

or Pd/C R1

N H

R1

514

Scheme 5.7

D. Synthesis of Carbazoles by Cyclization of Arylhydrazones A large number of carbazole syntheses involve the preparation and dehydrogenation of hydrocarbazoles, mainly 1,2,3,4-tetrahydrocarbazoles. They are usually prepared by either the Fischer–Borsche synthesis or the Japp–Klingemann reaction. The most commonly used dehydrogenating agents are palladium on charcoal or chloranil (495,496).

1 Fischer–Borsche Synthesis The Fischer method (497) of indole synthesis by the indolization of an arylhydrazone by treatment with an acid catalyst was applied to the synthesis of tetrahydrocarbazoles by Borsche (498). The cyclohexanone phenylhydrazone (512), obtained by reacting cyclohexanone (510) with phenylhydrazine (511), on indolization, furnished tetrahydrocarbazole 513 which, on dehydrogenation, afforded carbazole 514. The success of the reaction is dependent on the reagent used for indolization and the dehydrogenating agent. The mechanism for the formation of the tetrahydrocarbazole involves a tautomeric equilibrium and the formation of a new C–C bond via a [3,3]-sigmatropic rearrangement followed by elimination of ammonia (495,496,498) (Scheme 5.7).

2 Japp–Klingemann Reaction The preparation of the hydrazone required in the Borsche method was accomplished very conveniently using the Japp–Klingemann reaction (499,500). The reaction uses formylcyclohexanone (515) and a diazotized aromatic amine (516) for the synthesis

199

Chemistry of Carbazole Alkaloids

of hydrazone 517. Using this method, better yields of the hydrazones were achieved. Mechanistically, this reaction proceeds via the electrophilic attack of an aryldiazonium cation at the anionic carbon atom of an active methinyl compound to give an intermediate azo compound, which undergoes hydrolysis under the reaction conditions with expulsion of the carbon substituent, to give an aryl hydrazone (495,496,501) (Scheme 5.8).

E. Syntheses of Carbazoles by Diverse Annulation Methods 1 Graebe–Ullmann Synthesis Transformation of 1-arylbenzotriazole (520) to carbazole (1) under thermal conditions is known as the Graebe–Ullmann synthesis (502). This transformation is very sensitive to the nature of the substituents on the benzotriazole. However, unsubstituted 1-arylbenzotriazole (520) affords carbazole in nearly quantitative yield. The required starting material, 1-arylbenzotriazole (520), is prepared by the diazotization of N-(2-aminophenyl)aniline (519) (503,504). Limited reports on the mechanism of the Graebe–Ullmann reaction have appeared. Presumably, a diradical intermediate is involved in the thermolysis of the triazole (505) (Scheme 5.9).

2 Nenitzescu Carbazole Synthesis As an extension of the Nenitzescu indole synthesis, p-benzoquinone (521) was condensed with various electron-withdrawing anilines 522 in the presence of trifluoroacetic acid (TFA) to give 6-hydroxycarbazoles 523. Besides the low yield of

R2 Cl

CHOH

R2

aq. NaOAc MeOH

N N

O

R1

515

516

N NH R1

O 517

R2

R2 hydrazine hydrate

HOAc conc. HCl O

N H

KOH, reflux

N H

1

R

R1

513

518

Scheme 5.8

NH2

N

HNO2

N N

N H 519

520

Scheme 5.9

neat, Δ −N2

N H 1

200

Chemistry and Biology of Carbazole Alkaloids

R3 O

HO

2

R O

R2

CF3COOH reflux

H2N 1

R 522

521

R3

N H 523

R1

Scheme 5.10

1. aq. NaHSO3, Δ NHNH2 524

X

2. conc. HCl

525 X = OH 526 X = NH2

N H 527

Scheme 5.11

the 6-hydroxycarbazoles, this reaction suffers from the formation of many byproducts (506). Mechanistically, this reaction proceeds with the 1,4-addition of the aniline reacting as an enamine, followed by condensation of the aniline to the benzoquinone. This mechanism is supported by the by-product formation (506,507) (Scheme 5.10).

3 Bucherer Synthesis of Benzocarbazoles The Bucherer carbazole synthesis involves the treatment of a naphthyl alcohol (525) or a naphthylamine (526) with phenylhydrazine (524) in the presence of aqueous sodium bisulfite to afford, after work-up, benzocarbazole (527) (508). Mechanistically, this reaction resembles the Fischer indole synthesis and is based on the condensation of the naphthyl alcohol or naphthylamine in its oxo form with phenylhydrazine, and subsequent rearrangement (496,505,508–510) (Scheme 5.11).

4 Cyclization of b-Keto Sulfoxides Oikawa and Yonemitsu reported a general method for the synthesis of 2-hydroxycarbazoles (529) by the acid-catalyzed cyclization of the b-keto sulfoxide 528 (511). The required b-keto sulfoxide was derived from nucleophilic attack of dimethyl sulfoxide on methyl 3-indolepropionate. The key step in this synthesis is an intramolecular nucleophilic attack on the electron-rich indole nucleus by the carbocation derived from the b-keto sulfoxide in the presence of acid. Finally, the intermediate tetrahydrocarbazole aromatizes by elimination of methanethiol under the conditions of the reaction to produce the hydroxycarbazole (511) (Scheme 5.12).

5 Annulation of a 2,3-Disubstituted Indole Takano et al. reported an efficient synthesis of the carbazole framework using the annulation of a 2,3-disubstituted indole (512,513). This method involves the condensation of 2-benzyltryptamine (530) with ethoxymethylene acetoacetate (531) to give the enamine 532, which, on treatment with acetic anhydride/acetic acid (3:2),

Chemistry of Carbazole Alkaloids

R3

R3

R2

201

R2

acid O

OH

solvent, reflux

R1 N S O H Me

N H

528

R1

529

Scheme 5.12 O

OEt EtOH rt

NH2 N H 530

EtO

R

EtOOC

O

531

HN N H 532

COMe

R

COOEt Ac2O HOAc

Me N H 533

R

Scheme 5.13

cyclizes to the carbazole 533. This one-pot transformation is believed to proceed via a Fischer-base-type intermediate which promotes the crucial cyclization and the removal of the ethylamine side chain (512,513) (Scheme 5.13).

6 Diels–Alder Reaction of Indolo-2,3-quinodimethanes The application of indolo-2,3-quinodimethanes and their cyclic analogs in the synthesis of carbazole alkaloids has attracted wide interest since they could undergo Diels–Alder reactions with a wide variety of dienophiles to afford functionalized carbazole derivatives. This represents the shortest and most elegant method for the preparation of selectively functionalized carbazole derivatives (514). The reactive indolo-2,3-quinodimethanes are generated in situ generally from N-protected 2,3-disubstituted indoles (514,515). Generation of reactive indolo-2,3quinodimethanes was achieved by fluoride-induced, 1,4-elimination of silylated indolyl ammonium salts, and was applied in the synthesis of substituted tetrahydrocarbazoles (516). Subsequently, the iodide-induced 1,4-elimination of N-benzoyl-2,3-bis(bromomethyl)indole (534) methodology was developed for the synthesis of reactive indolo-2,3-quinodimethanes and was applied for the first time in the synthesis of substituted carbazoles (e.g., 536) (517) (Scheme 5.14). Later, independently, different anionic indolo-2,3-quinodimethanes which exhibit pronounced diene reactivity were developed from 2-cyano-1-methylindole-3acetonitrile (537) (518,519) and 1,2-dimethylindole-3-carboxaldehyde (539) (520) by reacting with strong base. These quinodimethanes were used in the synthesis of polyfunctionalized carbazole derivatives (538 and 541) (Scheme 5.15).

202

Chemistry and Biology of Carbazole Alkaloids

COOMe

COOMe Br Br

NaI, DMF 50 to 55°C

N Bz 534

COOMe

COOMe

N Bz

535

536

Scheme 5.14 NC

NC

COOMe

COOMe LDA, THF

COOMe

CN

N Me 537

H

535

538

NH2

R3

R3

O

1. LDA, THF R2

2. PyOTf, C6H6, Δ

Me

N R1

COOMe

N Me

539

2

R

N R1

540

541

Scheme 5.15 O

R3

R2 solvent

O

reflux

N H

R3

R1

542

540

R1

Me

Me

COOEt

COOEt 1. AlCl , CH Cl , rt 3 2 2

O N Me SO2Ph

R2 N H 543

545

2. 6% Na(Hg) (57%)

544

N H

Me

546

Scheme 5.16

Stable, cyclic analogs of indolo-2,3-quinodimethane derivatives were generated from pyrano[3,4-b] (542) (521–525) or furo[3,4-b] (544) (193,526–528) indole derivatives. Later, this strategy has been extended to pyrrolo[3,4-b], thieno[3,4-b] and selenolo[3,4-b]indole derivatives (193,514,528). In all these cases, the 2,3-bis(methylene)-2,3-dihydroindole structure is stabilized by the presence of a heteroatom capable of conjugation in the ring. Even so, such compounds are still reactive and afford cycloadducts useful for subsequent transformations. In accord with the Diels– Alder/bridge extrusion methodology, they react initially with dienophiles to form the bridged adducts. Finally, the bridging unit is removed from these adducts to form selectively functionalized carbazole derivatives (193,514,528) (Scheme 5.16).

203

Chemistry of Carbazole Alkaloids

OAc

AcO

R2

R3

R1/R4 1. mesitylene, reflux 2. DDQ, 1,4-dioxane

R1

R4

N Bn

R2/R3

N Bn

547

548

549

Scheme 5.17

R3

R3

R2 COOH COOH

N H 550

1. reflux COOR1

2. chloranil or Pd/C reflux

N H

551 R2

R1

COOMe

H/CN N H 553

COOMe

R2

552

cat. CF3COOH 250°C or toluene, reflux

535

R2

R1 COOMe

N H 554

COOMe

Scheme 5.18

This methodology was efficiently applied to a wide variety of natural and nonnatural carbazole alkaloids. For the first time, application of sequential Diels–Alder reactions to an in situgenerated 2,3-dimethylenepyrrole was shown with various dienophiles 548 to afford 2,3,6,7-tetrasubstituted carbazoles (549). This novel tandem Diels–Alder reaction leads to carbazole derivatives in two steps, starting from pyrrole 547 and 2 equivalents of a dienophile, and is followed by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) oxidation of the intermediate octahydrocarbazole. Mechanistically, the formation of the intermediate octahydrocarbazole appears to involve two sequential [4+2] cycloadditions between the exocyclic diene generated by the thermal elimination of acetic acid and a dienophile (529) (Scheme 5.17).

7 Diels–Alder Cycloaddition of Vinylindoles Diels–Alder reaction of vinylindoles with dienophiles has been established as a versatile and flexible methodology for the synthesis of carbazole alkaloids. Among the two different vinylindoles, 3-vinylindoles were the first to be explored for the Diels–Alder cycloaddition methodology with a range of dienophiles to give polyfunctionalized carbazole derivatives. This reaction is catalyzed by trifluoroacetic acid, and the yield in the absence of the acidic catalyst is very low. The reaction of substituted 3-vinylindoles 550 and 553 with ethylenic dienophiles 551 and acetylenic dienophiles 535 leads, via a tetrahydrocarbazole and a dihydrocarbazole, to the corresponding carbazoles (552 and 554), respectively (530,531) (Scheme 5.18).

204

Chemistry and Biology of Carbazole Alkaloids

OMe

OMe 1. solvent, reflux

N H 555

R2

2. Pd/C or DDQ

R1

R2 N H

R1

556

Scheme 5.19 OEt

OEt KOt-Bu

N PhO2S

t-BuOH, 90°C OR

557

Me N H

OR

558 OH Me N H

1

R

559

Scheme 5.20

Later, Pindur et al. developed an easy route to 2-vinylindoles with an unsubstituted 3-position, and these were efficiently employed as heterocyclic dienes for the synthesis of a diverse range of carbazole derivatives (532,533).

8 Electrocyclic Reactions to Carbazoles The electrocyclic reaction of divinylindoles to functionalized carbazole derivatives has emerged as an efficient method for the synthesis of a diverse range of carbazole derivatives. This reaction has been achieved at high temperatures in the presence of palladium on charcoal or DDQ. The palladium catalyst or DDQ act as dehydrogenating agent (534,535) (Scheme 5.19). A new benzannulation methodology was developed in order to overcome the limitations of electrocyclic ring closure of divinylindoles. The cyclization is achieved via an allene-mediated electrocyclic reaction of 2,3-difunctionalized indoles. This method is more efficient for the synthesis of highly substituted 2-methyl carbazole alkaloids (559). The 3-alkenyl-2-propargylindole 557, a precursor for the allene intermediate, was prepared from 2-formylindole over several steps using simple functional group transformations (536,537) (Scheme 5.20). A new method for the benzannulation of indole involving the thermal cyclization of 3-buta-1,3-dienylindoles (560 and 561) was described for the synthesis of 3-methoxycarbazole alkaloids 562 (538–540). Contrary to earlier benzannulation procedures, this method involves the ring closure of a 3-buta-1,3-dienylindole without the loss of the methoxy group at the 3-position of the carbazole nucleus. The 3-buta-1,3-dienylindole required for this method was obtained by Sakamoto’s procedure (538,539) starting from 1-acetyl-2-methoxy-1,2-dihydroindole-3-one by

205

Chemistry of Carbazole Alkaloids

R2

R1

R6

OR3

R6 cis-decalin

OR3 N R5

reflux

OR4

560 R3 = TMS; R4 = Me; R5 = Ac

R2 N H

R1

562

561 R3, R4, R5 = COOEt

Scheme 5.21

R3

1. Cu, K2CO3, pyridine 2. 20% KOH, EtOH

R2

NHAc Br

R3

1

R 563

564 R3 R

R2

H2N

Pd catalyst, Ligand base, solvent

N H 567

R2 1

R

1

565

R 566

R = Cl, Br, I, OTf, ONf

Scheme 5.22

a Wittig reaction, followed by silylation, as well as Beccalli’s procedure (540) by condensation of indole-2,3-dione with the 3-methyl-4-phenylbut-3-en-2-one (Scheme 5.21).

9 Cyclization of Diarylamines Intramolecular cyclization of diphenylamines to carbazoles is one of the most versatile and practical methods. This has been achieved photochemically, thermally in the presence of elemental iodine at 3501C, or with platinum at 450–5401C, via free radicals with benzoyl peroxide in chloroform, or by using activated metals such as Raney nickel or palladium on charcoal. Most of these methods suffer from low to moderate yields, and, in some cases, harsh reaction conditions (8,480). Formerly, the diphenylamines 567 required for the synthesis of carbazole alkaloids were obtained through the Ullmann–Goldberg procedure using acetanilide (563) and a bromobenzene derivative 564 as coupling partners, followed by alkaline hydrolysis (541). Alternatively, the palladium(0)-catalyzed Buchwald–Hartwig amination protocol also provides diphenylamines. This method is superior to the Ullmann–Goldberg procedure since it uses only catalytic amounts of palladium(0) and proceeds in high yield under mild reaction conditions. In addition, this procedure works for aromatic halides and for aryl triflates and their structural analogs (542,543) (Scheme 5.22).

206

Chemistry and Biology of Carbazole Alkaloids

Δ or hν or

N H 567

R1

R3

I2 Pd(OAc)2

R2

HOAc,, Δ cat.. Pd(OAc)2 Cu(OAc)2 HOAc, Δ

R3 R2 N H 568

R1

Scheme 5.23

˚ kermark et al. reported the palladium(II)-mediated intramolecular oxidative A cyclization of diphenylamines 567 to carbazoles 568 (355). Many substituents are tolerated in this oxidative cyclization, which represents the best procedure for the cyclization of the diphenylamines to carbazole derivatives. However, stoichiometric amounts of palladium(II) acetate are required for the cyclization of diphenylamines containing electron-releasing or moderately electron-attracting substituents. For the cyclization of diphenylamines containing electron-attracting substituents an overstoichiometric amount of palladium(II) acetate is required. Moreover, the cyclization is catalyzed by TFA or methanesulfonic acid (355). We demonstrated that this reaction becomes catalytic with palladium through a reoxidation of palladium(0) to palladium(II) using cupric acetate (10,544–547). Since then, several alternative palladium-catalyzed carbazole constructions have been reported (548–556) (Scheme 5.23).

10 Iron-Mediated Synthesis of Carbazoles Tricarbonyliron-coordinated cyclohexadienylium ions 569 were shown to be useful electrophiles for the electrophilic aromatic substitution of functionally diverse electron-rich arylamines 570. This reaction combined with the oxidative cyclization of the arylamine-substituted tricarbonyl(Z4-cyclohexadiene)iron complexes 571, leads to a convergent total synthesis of a broad range of carbazole alkaloids. The overall transformation involves consecutive iron-mediated C–C and C–N bond formation followed by aromatization (8,10) (Schemes 5.24 and 5.25). Over the past 15 years, we developed three procedures for the iron-mediated carbazole synthesis, which differ in the mode of oxidative cyclization: arylamine cyclization, quinone imine cyclization, and oxidative cyclization by air (8,10,557,558). The one-pot transformation of the arylamine-substituted tricarbonyl(Z4-cyclohexadiene) iron complexes 571 to the 9H-carbazoles 573 proceeds via a sequence of cyclization, aromatization, and demetalation. This iron-mediated arylamine cyclization has been widely applied to the total synthesis of a broad range of 1-oxygenated, 3-oxygenated, and 3,4-dioxygenated carbazole alkaloids (Scheme 5.24). In the quinone imine cyclization of iron complexes to carbazoles, the arylaminesubstituted tricarbonyl(Z4-cyclohexadiene)iron complexes 571 are chemoselectively oxidized to a quinone imine 574 prior to cyclodehydrogenation. This mode of cyclization is particularly applicable for the total synthesis of 3-oxygenated tricyclic carbazole alkaloids (Scheme 5.25). More recently, an environmentally benign method using air as an oxidant has been developed. Following this approach, in the presence of air the

Chemistry of Carbazole Alkaloids

R6 R5 (OC)3Fe X

3

R

R4 R3

1

R 570

R 571

cyclization by air

R4

R5

arylamine cyclization

R3

(OC)3Fe R6

R2

H2N

1

569

= PF6

MeCN

R2

H2N

= BF4

R6 (OC)3Fe R5

R4

207

R4

R5

R3

Me3NO R2 N H 572

R6

Pd/C

R2 N H 573

R1

R1

Scheme 5.24

R6 (OC)3Fe

R4 OR3

R5

MnO2

R4 O

R5

(H2O)

R2

H2N

R6 (OC)3Fe

R2

HN 1

R1 571

R 574

v. a. MnO2

Tl(OCOCF3)3

R4

R5

R5

O

(OC)3Fe

R4

OR3

1. Me3NO R2

R6 N

2. Alkylation

R1

575

R6

R2 N H 576

R1

Scheme 5.25

tricarbonyliron-complexed cyclohexadienylium ions 569 and the arylamines 570 are directly transformed to tricarbonyliron-complexed 4a,9a-dihydrocarbazoles 572. These, on demetalation and subsequent aromatization, lead to 9H-carbazoles 573. This eco-friendly method offers an excellent alternative to the previous cyclization procedures (Scheme 5.24).

11 Molybdenum-Mediated Synthesis of Carbazoles Despite many applications of the iron-mediated synthesis of carbazoles, this method offers limited access to 2-oxygenated tricyclic carbazoles due to the moderate yield

208

Chemistry and Biology of Carbazole Alkaloids

R3

R3 OC Mo

2

R

PF6

OC

MeCN

OC

R2 Mo

H

OC

1

R

R1 NH2

NH2 577

578

579

R3 MnO2 R2 N H 568

R1

Scheme 5.26

R1

cat. Rh

2

R

R3 N Ts 580

R1

R4

R4

R3 R5

R5 581

N Ts 582

R2

Scheme 5.27

for the oxidative cyclization (81,559). To overcome this limitation, and as a complementary method, we developed an alternative, molybdenum-mediated approach. Using this method, the electrophilic aromatic substitution of the electron-rich arylamine 578 by the molybdenum-complexed cation 577 affords regio- and stereoselectively the molybdenum complexes 579. Cyclization with concomitant aromatization and demetalation using activated manganese dioxide leads to the carbazole derivatives 568 (8,10,560) (Scheme 5.26).

12 Rhodium-Catalyzed Synthesis of Carbazoles Intermolecular cyclotrimerization of alkynes using Wilkinson’s catalyst has also afforded substituted carbazole derivatives. This reaction was extended to an intramolecular version by offering the possibility for a six-membered ring annulation that cannot be achieved easily in the corresponding intermolecular version. Intramolecular cyclotrimerization is completely regioselective due to an additional tether. Crossed-alkyne cyclotrimerizations between the diynes 580 and the monoalkynes 581 with a catalytic amount of RhCl(PPh3)3 afforded substituted carbazoles 582. The high efficiency of the carbazole formation could be rationalized by the conformational restrictions present in the diynes 580 (561) (Scheme 5.27).

Chemistry of Carbazole Alkaloids

HO

R2

209

R2

hexane Cr(CO)5 N R1

OMe

583

R2

50°C R2

N R1

584

585 3

R3

R

OH

toluene

Cr(CO)5 N H

OMe

R2

90 to 110°C

R1

586

R2 N H

R1

587

Scheme 5.28

13 Annulations of Chromium–Carbene Complexes The Do¨tz benzannulation reaction, based on the alkyne cycloaddition to chromium carbene complexes, is the most important application of Fischer carbene complexes. Among the various Fischer carbene complexes, alkoxy and aminocarbene complexes of chromium undergo a novel inter- and intramolecular tandem alkyne insertion/ carbene annulation sequence to give 9H-carbazoles and 11H-benzo[a]carbazoles. The annulation of indole carbene complexes 583 with acetylene derivatives 584 affords hydroxycarbazole derivatives 585. In this reaction, the indole carbene complexes 583 undergo intermolecular acetylene 584 insertion followed by carbene annulation (562). Recently, an intramolecular version of this method was reported by using 3-(2-vinyl)indolylcarbene complexes in the total synthesis of carbazole-3,4-quinone alkaloids (563). The (alkylanilino)carbene chromium complexes 586, under thermal conditions, undergo a tandem insertion–cyclization sequence to give 11H-benzo[a]carbazoles 587. This reaction is known to occur through a tandem alkyne insertion–carbonylation to give the indolylketene intermediate, which, on electrocyclic ring closure involving the p-system, results in the formation of oxygenated 11H-benzo[a]carbazoles (564,565) (Scheme 5.28).

14 Palladium-Catalyzed Annulation of Internal Alkynes An efficient synthesis of functionalized carbazoles was developed by the palladiumcatalyzed annulation of a variety of internal alkynes. This reaction involves arylpalladation of the alkyne, followed by intramolecular Heck olefination, and double bond isomerization. The iodoindole 588 reacts with the alkyne 589 in the presence of a catalytic amount of palladium(0) to give substituted carbazoles 590. In this reaction two new C–C bonds are formed in a single step. Higher reaction temperatures were necessary due to the low reactivity of the iodoindole (566) (Scheme 5.29).

15 Double N-arylation of Primary Amines The double N-arylation of primary amines or ammonia equivalents 592 with 2,2u-biphenylylene ditriflate (591) under Buchwald–Hartwig N-arylation conditions gave the unsymmetrically multi-substituted carbazoles 593. Among the various

210

Chemistry and Biology of Carbazole Alkaloids

R1

R1

I

R2

cat. Pd(0)

Ph

Ph

N Me

R2

N Me

588

589

590

Scheme 5.29 R1 OTf OTf

H2N R3

cat. Pd(0) R2

592

N

R1

R3 593

R2 591

Scheme 5.30

I

MgCl LiCl i -PrMgCl LiCl

50°C

R N N N

594

R N N N

595

N H

R

596

Scheme 5.31

ammonia equivalents, O-tert-butyl carbamate served as the best nitrogen source. The required 2,2u-biphenylylene ditriflate 591 was easily prepared by the Suzuki– Miyaura coupling of o-halophenols with o-hydroxyphenylboronic acids (567,568) (Scheme 5.30).

16 Carbazole Synthesis Using Arylmagnesium Reagents The reaction of iodo-substituted aryltriazenes 594 with i-PrMgCl
LiCl afforded functionalized carbazoles 596. In this reaction, evaporation of i-PrI resulting from the I/Mg-exchange is important before heating; otherwise, unwanted cross-coupling products with i-PrI are observed. Mechanistically, this reaction could proceed with the formation of an arylmagnesium derivative 595 followed by intramolecular addition of the triazene onto nitrogen with the elimination of hydroxylamine (569) (Scheme 5.31).

II. TOTAL SYNTHESES OF CARBAZOLE ALKALOIDS This part of the review covers only the total synthesis of biologically active natural carbazole alkaloids. In the following sections, all of the total syntheses since 1990 are

Chemistry of Carbazole Alkaloids

R

R

[Fe(0)] N H

H2N

OMe

7 Murrayafoline A R = Me

211

OMe 597

8 Koenoline R = CH2OH

598 R = Me 599 R = OMe 600 R = COOMe

9 Murrayanine R = CHO 10 Mukoeic acid R = COOH 11 Mukonine R = COOMe

Scheme 5.32

covered, although this is an update of the treatise which appeared in 1993 by Chakraborty (3) in Volume 44 of this series. Recently, a large number of total syntheses has appeared for this class of natural products.

A. Tricyclic Carbazole Alkaloids This section includes the carbazole alkaloids that have substitutions and functionalizations without any further heterocyclic fusions and annulations on the 9H-carbazole nucleus. Further, irrespective of their natural sources, based on the oxygenated substitution pattern, these tricyclic carbazole alkaloids were classified into the following sub-sections.

1 1-Oxygenated Tricyclic Carbazole Alkaloids Among the several strategies developed for carbazole syntheses, organometallic approaches to carbazoles have received special attention, since they have led, in many cases, to highly convergent total syntheses of carbazole alkaloids (8,10, 570–572). The iron-mediated retrosynthesis of 1-oxygenated carbazoles 7–11 leads to cyclohexadiene (597) and the corresponding arylamines 598–600 as synthetic precursors (Scheme 5.32). The two key steps for the construction of the carbazole framework by the ironmediated approach are, first, C–C bond formation by electrophilic aromatic substitution of the arylamine with the tricarbonyliron-complexed cyclohexadienyl cation and, second, C–N bond formation and aromatization by an oxidative cyclization. Application of this methodology provides murrayanine (9) and koenoline (8) in three steps and 15%, and in four steps and 14% overall yield, respectively, starting from the commercial nitroaryl derivative 601 (573,574) (Scheme 5.33). Catalytic hydrogenation of the nitroarene 601 afforded the corresponding arylamine 598. An electrophilic aromatic substitution of the arylamine 598 by

212

Chemistry and Biology of Carbazole Alkaloids

(OC)3Fe

Me

Me

(OC)3Fe

BF4

H2, Pd/C OMe NO2

EtOH (96%)

NH2

601

OMe MeCN, 25°C (88%)

H2N OMe

598

603 CH2OH

CHO KBH4

v. a. MnO2 toluene, 25°C (18%)

Me

602

N H 9

OMe

MeOH, 25°C (90%)

N H

OMe

8

Scheme 5.33

reaction with tricarbonyl(Z5-cyclohexadienylium)iron tetrafluoroborate (602) afforded the tricarbonyl iron complex 603. The iron complex salt 602 is readily available by 1-aza-1,3-butadiene-catalyzed complexation of 1,3-cyclohexadiene with pentacarbonyliron, followed by hydride abstraction using triphenylcarbenium tetrafluoroborate. The oxidative cyclization of the iron complex 603 with very active manganese dioxide in toluene at room temperature led directly to murrayanine (9). This one-pot conversion is rationalized by a four-step sequence. First, oxidation of the methyl group to the formyl group. Second, a cyclizing dehydrogenation to the 4b,8a-dihydro-9H-carbazole. Third, aromatization to a 20-electron complex, and fourth, spontaneous demetalation to murrayanine (9). Murrayanine (9) was transformed to the cytotoxic carbazole alkaloid koenoline (8) by borohydride reduction (573,574) (Scheme 5.33). As shown above, a direct synthesis of murrayafoline A by the iron-mediated arylamine cyclization using the arylamine 598 is not feasible due to unavoidable concomitant oxidation of the methyl group on cyclization of the complex 603 (see Scheme 5.33). In order to overcome this problem, the iron-mediated iminoquinone cyclization was applied for the total synthesis of murrayafoline A (7) (Scheme 5.34). The methyl group of murrayafoline A (7) was introduced by nucleophilic addition of methyllithium to the carbonyl group of the resulting tricarbonyl-complexed 4b,8adihydrocarbazol-3-one (606). The iron complex 604 required for the synthesis of the quinone imine complex 606 was obtained by electrophilic substitution of 2,4-dimethoxyaniline (599) with the iron complex cation 602. A direct, iron-mediated, iminoquinone cyclization of 604 failed to give the desired cyclized quinone imine complex 606. Therefore, the two-step procedure with isolation of the intermediate non-cyclized quinone imine 605 was applied. Oxidation of complex 604 using commercial manganese dioxide afforded the non-cyclized iminoquinone 605 in 77% yield. All attempts to cyclize the complex 605 with very active manganese dioxide led only to decomposition. However, oxidative cyclization of 605 with thallium(III) trifluoroacetate furnished the required cyclized iminoquinone complex 606 in 40% yield. Addition of methyllithium to the complex 606 provided the corresponding tertiary carbinol 607 as a 1:1 diastereomeric mixture. Treatment of the complex 607

Chemistry of Carbazole Alkaloids

OMe

(OC)3Fe

OMe

MeCN

(OC)3Fe BF4

NH2

602

OMe 25 to 75°C (61%)

H2N OMe

599

604

(OC)3Fe

O

MnO2, CH2Cl2 25°C

Tl(OCOCF3)3, NaHCO3

MeOH, 0°C (40%)

HN

(77%)

213

OMe 605

OH

O (OC)3Fe

(OC)3Fe

MeLi, THF N

−40°C OMe

Me N

(40%)

OMe

607

606

Me

Me p-TsOH benzene, 80°C

(OC)3Fe N OMe H 608 (10%) v. a. MnO2, CH2Cl2

N H

OMe

7 (4%)

25°C

Scheme 5.34

with p-toluenesulfonic acid (p-TsOH) in refluxing benzene afforded murrayafoline A (7) directly by elimination of water with concomitant aromatization and demetalation. However, the yield of murrayafoline A (7) was only 4%, along with the corresponding 4b,8a-dihydro-9H-carbazole 608 in 10% yield. Complex 608 was smoothly converted to murrayafoline A (7) with very active manganese dioxide (574) (Scheme 5.34). The total synthesis of mukonine (11) and mukoeic acid (10) starts from the arylamine 600. An optimized procedure for the reaction of the complex salt 602 with the arylamine 600 in refluxing acetonitrile provided the iron complex 609 in 61% yield. The iron complex 609 is subjected to smooth cyclodehydrogenation by reacting with air in TFA to afford the 4b,8a-dihydro-9H-carbazole 610. Aromatization of 610 with concomitant demetalation with ferricenium hexafluorophosphate in the presence of sodium bicarbonate provided mukonine (11) in 50% yield (route A: three steps, 15% overall yield) (80). An alternative method for the aromatization of the intermediate dihydro-9H-carbazole 610 to mukonine (11) was provided by demetalation and subsequent catalytic dehydrogenation, albeit in low yield (81). Alternatively, in a one-pot operation, 609 was transformed to mukonine (11) by the iron-mediated arylamine cyclization with very active manganese dioxide

214

Chemistry and Biology of Carbazole Alkaloids

COOMe

(OC)3Fe

COOMe

MeCN

(OC)3Fe

OMe

BF4

NH2

602

25 to 75°C (61%)

H2N OMe 609

600 TFA, toluene, air, 25°C (50%)

route A

v. a. MnO2 toluene, 25°C route B

(54%)

Cp2FePF6, Na2CO3 COOMe (OC)3Fe

COOMe

ClCH2CH2Cl, 83°C (50%)

N H 610

OMe

1. Me3NO, acetone, 25°C 2. 10% Pd/C, toluene, 110°C (2 steps, 34%)

N H

OMe

11 KOH, EtOH 78°C (86%) COOH

N H 10

OMe

Scheme 5.35

in 54% yield (route B: two steps, 33% overall yield). Finally, ester cleavage of mukonine (11) provided mukoeic acid (10) in 86% yield (574) (Scheme 5.35). An alternative access to murrayanine (9) was developed starting from the mukonine precursor 609. The reduction of the ester group of 609 using diisobutylaluminum hydride (DIBAL) afforded the benzylic alcohol 611. In a one-pot reaction, using very active manganese dioxide, 611 was transformed to murrayanine (9) (574) (Scheme 5.36). Chowdhury et al. reported the syntheses of clausenol (28) and clausenine (14) by Fischer–Borsche indolization of the hydrazone 517a (40). Under Japp–Klingemann conditions, the required hydrazone 517a was obtained by condensation of 2-hydroxymethylene-5-methylcyclohexanone (515a) with 4-methoxybenzene diazonium chloride (516a). Indolization of the hydrazone 517a with concentrated HCl and acetic acid furnished the oxotetrahydrocarbazole 518a. Palladium-catalyzed dehydrogenative aromatization of 518a led to clausenol (28). Finally, methylation of 28 with diazomethane afforded clausenine (14) (40) (Scheme 5.37). Murakami et al. reported the total synthesis of 1-hydroxy-3-methylcarbazole (23) and murrayafoline A (7) by classical Fischer indolization of the O-methanesulfonyl phenylhydrazone derivative 614 (575). The compound 614 was prepared from the corresponding aminophenol 612 via 2-hydrazino-5-methylphenol p-toluenesulfonate

215

Chemistry of Carbazole Alkaloids

(OC)3Fe

(OC)3Fe

COOMe

CH2OH

DIBAL,THF −78 to 25°C (62%)

H2N OMe

H2N OMe

609

611 CHO

v. a MnO2 toluene, 25°C (26%)

N H

OMe

9

Scheme 5.36

MeO

Me

Cl N N

Me N N H

MeOH

HOHC O 515a

516a

MeO aq. NaOAc

MeO

(49.5%)

O

517a MeO

Me

Me

10% Pd/C

HOAc conc. HCl (64.5%)

N H

decalin (19.9%)

O

OH

28

518a MeO

N H

Me

CH2N2 N H

OMe

14

Scheme 5.37

(613) by reacting with cyclohexanone (510). Under Fischer indolization conditions (TsOH/benzene), the O-mesylphenylhydrazone 614 was transformed to the tetrahydrocarbazoles 615 and 616 in 63% and 3% yield, respectively. The mesyloxy compound 615 was dehydrogenated with 10% Pd/C in nitrobenzene to afford 1-mesyloxy-3-methylcarbazole (617). Hydrolysis of the mesyl group of 617 with potassium hydroxide in diethylene glycol afforded 1-hydroxy-3-methylcarbazole (23). Finally, O-methylation of 23 gave murrayafoline A (7). This synthesis provides 1-hydroxy-3-methylcarbazole (23) and murrayafoline A (7) in 48% and 40% overall yield and five and six steps, respectively, based on the aminophenol 612 (575) (Scheme 5.38). Brenna et al. reported the synthesis of mukonine (11) from 3-formylindole (618) via a base-promoted cyclization of a mixed anhydride of mono-ester mono-acid 619 (576).

216

Chemistry and Biology of Carbazole Alkaloids

O

Me

1. iso-amylONO NH2 HCl

Me

510

2. SnCl2, TsOH

NHNH2 TsOH

(81%)

OH

MsCl, Et3N

OH 613

612 Me

Me

Me

OMs

N H

TsOH

N

benzene

614

N OMs H 615 (2 steps, 63%)

N H 616 (2 steps, 3%)

Pd/C, nitrobenzene (99%) Me

Me

N H 617

diethylene glycol (95%) OMs

Me Me2SO4

KOH N H 23

OH

KOH (83%)

N H 7

OMe

Scheme 5.38

The key step in this annulation methodology is assumed to proceed through a 1,6-electrocyclic reaction involving a ketene intermediate 620. The mono-acid 619 required for the key cyclization step was prepared through Stobbe condensation of 3-formylindole (618) and dimethyl succinate. In a one-pot procedure, compound 619 was transformed to the aromatic derivative 621 by reacting with ethyl chloroformate in the presence of triethylamine. After base-promoted cleavage of the carbonic ester, 621 was transformed to clausine E (clauszoline-I) (25). Methylation of 25 with diazomethane gave mukonine (11). Finally, saponification of 11 in ethanolic sodium hydroxide afforded mukoeic acid (10). This method provides clausine E (clauszoline-I) (25) (three steps, 34% yield), mukonine (11) (four steps, 33% yield), and mukoeic acid (10) (five steps, 30% yield) based on 3-formylindole (618), and is formally complementary to Moody’s electrophilic substitution of a 2-substituted indole. So far, this is the best method for the synthesis of clausine E (clauszoline-I) (25), mukonine (11), and mukoeic acid (10) because of the experimental simplicity and easy availability of the reagents (576) (Scheme 5.39). Bringmann et al. reported the total synthesis of mukonine (11) and its transformation into seven further oxygenated carbazole alkaloids: murrayafoline A (7), koenoline (8), murrayanine (9), mukoeic acid (10), 1-hydroxy-3-methylcarbazole (23), O-demethylmurrayanine (24), and clausine E (clauszoline-I) (25) (577). The relay compound, mukonine (11) was prepared starting from 3-formylindole (618) through a sodium acetate in acetic anhydride-promoted cyclization of the intermediate mono-acid obtained by TFA-mediated cleavage of the tert-butoxycarbonyl (Boc) and

Chemistry of Carbazole Alkaloids

217

O OMe OH

1. dimethyl succinate CHO NaOMe, MeOH, 45°C 2. 5% HCl (42%)

N H

O

N H

618

ClCO2Et Et3N, THF

619 COOMe

COOMe

1. NaOH, MeOH, rt

• N O H

N H

620

OCOOEt

2. 5% HCl (2 steps, 81%)

621 COOH

COOMe 1. NaOH, EtOH, 50°C 2. 5% HCl N H 25 R = H 11 R = Me

OR

(92%) CH2N2, CH2Cl2, rt (97%)

N H 10

OMe

Scheme 5.39

tert-butyl ester of the mixed ester 624. After protection of 3-formylindole (618) as the N-Boc derivative 622, the mixed ester 624 was prepared via Horner–Emmons reaction of 622 with the phosphonate 623. Compound 624 was transformed to mukonine (11) in 69% overall yield in a four-step sequence: removal of the Boc group with concomitant cleavage of the tert-butyl ester, cyclization with sodium acetate in acetic anhydride, methanolysis, and O-methylation. This method is an extension of Brenna’s methodology. Using the following common functional group manipulations, mukonine (11) was transformed into further oxygenated carbazole alkaloids. The reduction of mukonine with lithium aluminum hydride, led to murrayafoline A (7), which, on further O-demethylation with boron tribromide, afforded 1-hydroxy-3-methylcarbazole (23). Reduction of mukonine (11) with DIBAL gave koenoline (8). Oxidation of 8 with activated manganese dioxide led to murrayanine (9), and subsequent treatment with boron tribromide, provided O-demethylmurrayanine (24). Saponification of mukonine (11) with potassium hydroxide in ethanol afforded mukoeic acid (10). O-Demethylation of mukonine (11) with boron tribromide afforded clausine E (clauszoline-I) (25) (577) (Scheme 5.40). Lin and Zhang reported the synthesis of 1-hydroxy-3-methylcarbazole (23) starting from the nitro derivative 625 (578). This synthesis uses a Buchwald–Hartwig amination for the synthesis of the diphenylamine 628. After protection of the hydroxy group in the nitrophenol 625 as a benzyl ether, the nitro group was reduced to the corresponding amino derivative 627. Amination of 627 with iodobenzene under Buchwald–Hartwig conditions afforded the diarylamine 628. Palladium(II)mediated cyclization of 628 led to the carbazole derivative 629, albeit in low

218

Chemistry and Biology of Carbazole Alkaloids

O

O

(EtO)2P

CHO

CH2Cl2, rt

N H

623 NaH, THF, 0 to 50°C (69%)

N

(96%)

Boc 622

618

1. TFA, CH2Cl2/H2O, rt

O OEt Ot-Bu

2. NaOAc, Ac2O, 140°C 3. K2CO3, MeOH, 65°C

COOMe

4. Me2SO4, K2CO3 acetone, 56°C (4 steps, 69%)

O

N Boc 624

COOH

N H

O

CHO

Boc2O, DMAP

N H

COOMe KOH, EtOH/H2O

BBr3, CH2Cl2

78°C (99%)

0°C to rt, MeOH (97%) COOMe

OMe

N H 11

CH2OH

OMe

OMe

11

10

N H 8

OEt Ot-Bu

N H 25

OH

OMe Me

DIBAL, Et2O

LiAlH4

−78°C (90%)

Et2O/CH2Cl2, rt (80%)

N H 7

OMe

BBr3, CH2Cl2 0°C to rt, MeOH (96%)

MnO2, CCl4, rt (84%) CHO

Me

CHO BBr3, CH2Cl2

N H 9

OMe

0°C to rt, MeOH (90%)

N H 24

OH

N H

OH

23

Scheme 5.40

yield. Finally, debenzylation using catalytic hydrogenation conditions furnished 1-hydroxy-3-methylcarbazole (23) (578) (Scheme 5.41). Kikugawa et al. reported the synthesis of murrayafoline A (7) starting from the N-(N,N-diarylamino)phthalimide derivative 630 by reaction with AlCl3 in benzene

Chemistry of Carbazole Alkaloids

219

(579). Under these conditions, 1-bromo-3-methylcarbazole 631 was formed via an intramolecular C–C bond formation by trapping of the diphenylnitrenium ion. In this reaction, the phthalimido group plays an important role for the generation and stabilization of a diphenylnitrenium ion. Finally, direct methoxide displacement of bromine from 631 led to murrayafoline A (7) (579) (Scheme 5.42). Tamariz et al. reported the synthesis of mukonine (11) based on a regioselective Diels–Alder reaction of N-phenyl-4,5-dimethylidene-2-oxazolidinone (634) with methyl propiolate (635). The diene 634 was prepared in moderate yield from the condensation reaction of 2,3-butanedione (632) with phenyl isocyanate (633). In an optimized reaction procedure using drastic basic hydrolytic conditions (KOH/ MeOH), followed by methylation with dimethyl sulfate, the adduct 636, was

Me

Me

Me Fe, H2O

BnBr, NaOH DMSO

HO

BnO

(86%)

NO2

NO2

625

NH4Cl, reflux (83%)

BnO NH2

626

Pd2(dba)3, PPh3 18-crown-6, NaOt-Bu

627

Me

Ph-I, THF. 40°C

N H

(93%)

Pd(OAc)2 HOAc, reflux (32%)

OBn

628 Me

Me 10% Pd/C, H2 (73%)

N H 629

OBn

N H 23

OH

Scheme 5.41

Me Br

Me

5 eq. AlCl3 benzene, rt (22%)

N NPhth 630

N H 631

Me

N H 7

NaOMe, CuI

OMe

Scheme 5.42

Br

DMF, 120°C (92%)

220

Chemistry and Biology of Carbazole Alkaloids

O O

O Ph N C O 632

O

Et3N, Li2CO3

Ph N

dioxane, 25°C (54%)

633

COOMe

635

O

MeOH/H2O, 25°C (50%) 634

COOMe

O

2. Me2SO4, K2CO3 acetone, 65°C

N Ph

COOMe

1. KOH, MeOH/H2O, 65°C

(65%) 636

N H

OMe

637

COOMe Pd(OAc)2 HOAc,160°C (63%)

N H 11

OMe

Scheme 5.43

transformed to the diphenylamine 637. Finally, cyclization of 637 using stoichiometric Pd(OAc)2 in acetic acid furnished mukonine (11) (580) (Scheme 5.43). Two years later, this methodology was extended to the 1-oxygenated carbazole alkaloids, murrayanine (9) and murrayafoline A (7). For this total synthesis, the required key cycloadduct 639 was obtained by Lewis acid-catalyzed regioselective cycloaddition of the diene 634 to acrolein (638). Contrary to the synthesis of mukonine (11) (see Scheme 5.43), prior to basic hydrolysis, the Diels–Alder adduct 639 was aromatized with DDQ in refluxing benzene to furnish the corresponding aromatic derivative 640. Hydrolysis of 640 under mild basic conditions gave the diphenylamine 642. Then, methylation using MeI followed by palladium(II)promoted cyclization of 643 furnished murrayanine (9). Following this pathway, murrayafoline A (7) was also synthesized. For this synthesis, the required aromatic cycloadduct 641 was obtained in quantitative yield by palladium-catalyzed hydrogenation of 640 (581) (Scheme 5.44). Fagnou et al. reported the synthesis of mukonine (11) starting from methyl vanillate (644). This synthesis uses both a palladium(0)-catalyzed intermolecular direct arylation and an intramolecular cyclization reaction. Triflation of methyl vanillate (644) afforded the aryl triflate 645. Using a Buchwald–Hartwig amination protocol, the latter was subjected to direct arylation with 2-chloroaniline (646) to furnish the corresponding diarylamine 647. Finally, intramolecular cyclization of 647 afforded mukonine (11). To date, this is the best synthesis (three steps, 75% overall yield) available for mukonine based on commercially available methyl vanillate (644) (582) (Scheme 5.45). Mal et al. reported a new benzannulation strategy for the synthesis of murrayafoline A (7) via anionic [4+2] cycloaddition of the furoindolone 650 (583,584). Using a literature procedure, Fischer indolization of 3-(2-phenylhydrazono)dihydrofuran-2(3H)-one (648) afforded the furoindolone 649 (583). This was

Chemistry of Carbazole Alkaloids

O Ph N

CHO

O

BF3 Et2O, −78°C

reflux (69%)

N Ph 639

(91%)

1. NaOH, MeOH/H2O 25 to 65°C

R

O

R

2. MeI, K2CO3 acetone, reflux

N Ph 640 R = CHO 641 R = Me

DDQ, benzene

O

634

O

CHO

O

638

221

N H

H2, Pd/C, EtOAc, 25°C

OMe

642 R = CHO (77%) 643 R = Me (79%)

(97%) R

Pd(OAc)2, HOAc 140 to 160°C

N H

OMe

9 R = CHO (73%) 7 R = Me (71%)

Scheme 5.44 Cl

COOMe

OMe OH 644

THF, −78 to 0°C (92%)

COOMe

Cl N H

COOMe

1.1 eq. Tf2O 2 eq. DIPEA

OMe OTf 645

NH2

646 2.5 mol% Pd2(dba)3 10 mol% 2-(di-tert-butylphosphino)-2 ′-methylbiphenyl 1.4 eq. K3PO4 DME, 80°C (85%)

3 mol% Pd(OAc)2 6 mol% [HPCy3][BF4] 2 eq. K2CO3, DMA, 130°C

OMe

(86%)

647

COOMe

N H 11

OMe

Scheme 5.45

derivatized to the N-benzyl derivative 650. Annulation of compound 650 with methyl crotonate in the presence of lithium diisopropylamide (LDA) gave compound 651. Demethoxycarbonylation of 651 with concentrated KOH in methanol, followed by O-methylation of the intermediate 1-hydroxycarbazole 652 using dimethyl sulfate, and finally debenzylation of 652 by refluxing in TFA with a catalytic amount of trifluoromethanesulfonic acid (TfOH), furnished murrayafoline A (7) (584) (Scheme 5.46).

222

Chemistry and Biology of Carbazole Alkaloids

O

HCl (40%)

N

K2CO3, BnCl

O N H 649

NH

O 648

NaI, acetone (62%)

O

Me methyl crotonate

O N Bn 650

O

KOH, MeOH COOMe

LDA (64%)

N Bn

reflux (56%)

OH

651 Me

Me 1. Me2SO4, K2CO3, acetone, reflux

N Bn

2. cat. CF3SO3H, CF3COOH OH

(2 steps, 55%)

652

N H

OMe

7

Scheme 5.46

Mene´ndez et al. reported the synthesis of murrayafoline A (7) by palladium(II)mediated oxidative double C–H activation of a diarylamine assisted by microwave irradiation (585). The aniline derivative 598 was obtained by O-methylation of 5-methyl-2-nitrophenol (625) followed by catalytic hydrogenation. The required diarylamine 654 was obtained by N-arylation of the aniline derivative 598 with phenyllead triacetate (653) in the presence of copper(II) acetate. Under microwaveassisted conditions, in the presence of more than the stoichiometric amount of palladium(II) acetate and a trace of dimethylformamide, the diarylamine 654 was cyclodehydrogenated to murrayafoline A (7) (585) (Scheme 5.47).

2 2-Oxygenated Tricyclic Carbazole Alkaloids Although a large number of 2-oxygenated tricyclic carbazole alkaloids have been isolated from different natural sources, only a few syntheses of this class of alkaloids were reported. This is mainly due to the lack of general methods, as well as the difficulty associated with the known synthetic methods, to build up the required substitution pattern. Prior to 1990, some total syntheses of 2-oxygenated carbazoles were reported and were covered in the earlier treatises by Kapil (1), Husson (2), and Chakraborty (3) in Volumes 13, 26, and 44 of this series. Since 1990, the only total syntheses which appeared in the literature for this class of carbazole alkaloids were transition metal-mediated or -catalyzed approaches, respectively. These general approaches offered a series of 2-oxygenated carbazole alkaloids (8,10). The retrosynthetic analysis of the 2-oxygenated carbazole alkaloids, 2-methoxy-3methylcarbazole (37) and mukonidine (54), based on an iron-mediated approach, led to the iron-complexed cation 602 and the arylamines 655 and 656 as precursors (Scheme 5.48). The electrophilic aromatic substitution of 655 with the iron-complexed cation 602 afforded the iron complex 657 in almost quantitative yield. Treatment of 657 with

Chemistry of Carbazole Alkaloids

1. KOH, MeI, Bu4NHSO4 toluene, rt

Me

(AcO)3Pb

Me

653

2. H2, 10% Pd/C, rt

NO2

NH2

(2 steps, 93%)

OH

OMe

625

223

Cu(OAc)2, CH2Cl2, rt (76%)

598 Me Me

N H

2 eq. Pd(OAc)2, DMF (3 drops) MW, 600 W, 1 min. (71%)

OMe

N H 7

654

OMe

Scheme 5.47 R2

R2

OR1 1

OR N H

(OC)3Fe BF4

602

NH2 655 R1, R2 = Me

37 2-Methoxy-3-methylcarbazole R1, R2 = Me

656 R1 = H; R2 = COOMe

54 Mukonidine R1 = H; R2 = COOMe

Scheme 5.48

very active manganese dioxide led only to slow decomposition. However, reaction of complex 657 with iodine in pyridine furnished 2-methoxy-3-methylcarbazole (37) in 11% yield, along with the diene 658 in 44% yield (559) (Scheme 5.49). For the total synthesis of mukonidine (54), the required arylamine 656 was obtained quantitatively from commercial 4-aminosalicylic acid (659) using diazomethane (559). However, for large-scale preparation, this transformation was better achieved with sulfuric acid and methanol (81). The reaction of the arylamine 656 with the iron-complex salt 602 provided the iron complex 660 in 87% yield. The high yield of C–C bond formation was ascribed to the high nucleophilicity of the orthoamino position of the aromatic nucleus arising from the hydroxy group in the 3-position of the arylamine. The iron-mediated arylamine cyclization of the complex 660 using very active manganese dioxide, iodine in pyridine (559), or ferricenium hexafluorophosphate (81) failed, which was ascribed to the known problem caused by free hydroxy groups in these reactions. However, the oxidative cyclization of complex 660 in toluene, in the presence of air at room temperature, provided the iron-complexed dihydrocarbazole 661 (80,81). Various attempts to transform complex 661 to mukonidine (54) using very active manganese dioxide or ferricenium hexafluorophosphate in the presence of sodium carbonate led to complete decomposition. However, oxidation of complex 661 with p-chloranil (tetrachloro-1,4benzoquinone) in toluene by aromatization and demetalation afforded mukonidine

224

Chemistry and Biology of Carbazole Alkaloids

Me OMe

(OC)3Fe

MeCN, 25°C

(OC)3Fe

Me

(93%)

BF4

602

H2N

NH2 655

OMe 657

Me Me

I2, pyridine OMe

90˚C

OMe

H2N

N H 37 (11%)

658 (44%)

Scheme 5.49

COOH OH

CH2N2 ether (100%)

NH2 659

COOMe OH

(OC)3Fe

COOMe

+ 602, MeCN 25 to 35°C (87%)

NH2

H2N

656

OH 660

COOMe (OC)3Fe

toluene, TFA

toluene, p-chloranil OH

air, 25°C

N H 661

110°C

COOMe COOMe OH N H 54 (2 steps, 22%)

H2N

OH

662 (2 steps, 21%)

Scheme 5.50

(54) in 22% yield based on complex 602, along with the biphenyl derivative 662 (21% yield). Alternatively, the final transformation of complex 661 to mukonidine (54) was achieved by demetalation with trimethylamine N-oxide in acetone, followed by catalytic dehydrogenation with palladium on activated carbon in toluene under reflux (11% yield based on the complex 602) (80,81) (Scheme 5.50). Despite many applications of the iron-mediated carbazole synthesis, the access to 2-oxygenated tricyclic carbazole alkaloids is limited due to the moderate yields for the oxidative cyclization. To overcome this problem, a molybdenum-mediated approach was developed as a complementary method. This alternative synthesis of

Chemistry of Carbazole Alkaloids

225

carbazole derivatives involves the oxidative cyclization of an arylamine at a dicarbonyl[Z5-cyclopentadienyl]molybdenum-coordinated Z3-cyclohexenyl ligand. The retrosynthetic analysis of the 2-oxygenated carbazole alkaloids, 2-methoxy-3methylcarbazole (37), O-methylmukonal (glycosinine) (38), 2-hydroxy-3-methylcarbazole (52), and mukonal (53) based on the molybdenum-mediated approach led to the molybdenum-complexed cation (663) and 3-methoxy-4-methylaniline (655) as precursors (Scheme 5.51). The cationic molybdenum complex, dicarbonyl (Z4-cyclohexadiene)(Z5-cyclopentadienyl)molybdenum hexafluorophosphate (663), required for the electrophilic substitution, was easily prepared quantitatively through known literature procedures (586,587). Electrophilic substitution of 3-methoxy-4-methylaniline (655) by the complex 663 leads to the molybdenum complex 664. Oxidative cyclization of complex 664 with concomitant aromatization using activated commercial manganese dioxide provides 2-methoxy-3-methylcarbazole (37) in 53% yield (560). In contrast, cyclization of the corresponding tricarbonyliron complex to 37 was achieved in a maximum yield of 11% on a small scale using iodine in pyridine as the oxidizing agent (see Scheme 5.49). 2-Methoxy-3-methylcarbazole (37) serves as a relay compound for the synthesis of further 2-oxygenated tricyclic carbazole alkaloids. Oxidation of the methyl group using DDQ gave O-methylmukonal (glycosinine) (38), which, on demethylation with boron tribromide, provided mukonal (53). Ether cleavage of 37 with hydrogen bromide/acetic acid gave 2-hydroxy-3-methylcarbazole (53) (560) (Scheme 5.52). Retrosynthetic analysis of the 2,7-dioxygenated carbazole alkaloids, 7-methoxyO-methylmukonal (48), clausine H (clauszoline-C) (50), clausine K (clauszoline-J) (51), and clausine O (72), based on an iron-mediated approach, led to 2-methoxysubstituted iron complex salt 665 and 3-methoxy-4-methylaniline (655) as precursors (588) (Scheme 5.53). Electrophilic aromatic substitution of 3-methoxy-4-methylaniline (655) using the 2-methoxy-substituted iron complex salt 665, followed by oxidative cyclization with concomitant aromatization of the resulting iron complex salt 666, affords 2,7-dimethoxy-3-methylcarbazole (667). Oxidation of the carbazole 667 with DDQ

Me

R2

OC 1

OR

OMe

Mo PF6

OC

N H

NH2

37 2-Methoxy-3-methylcarbazole

663

R1, R2 = Me 38 O-Methylmukonal (Glycosinine) R1 = Me; R2 = CHO 52 2-hydroxy-3-methylcarbazole R1 = H; R2 = Me 53 Mukonal R1 = H; R2 = CHO

Scheme 5.51

655

226

Chemistry and Biology of Carbazole Alkaloids

Me

Me OC

OMe

Mo PF6

OC

OMe

OC

MeCN, 25°C

Mo

H

OC

(53%)

NH2

NH2 663

655

664 Me

MnO2, benzene

Me HBr, HOAc

OMe

80°C (53%)

OH

135°C (78%)

N H 37

N H 52

DDQ, MeOH, 25°C (92%) CHO

CHO BBr3, CH2Cl2

OMe N H

OH

−78 to 25°C

N H 53

(78%)

38

Scheme 5.52 OMe

R2

Me OMe

3

1

R O

OR

(OC)3Fe BF4

N H

665

48 7-Methoxy-O-methylmukonal

NH2 655

R1 = Me; R2 = CHO; R3 = H 50 Clausine H (Clauszoline-C) R1,R3 = Me; R2 = COOMe 51 Clausine K (Clauszoline-J) R1,R3 = Me; R2 = COOH 72 Clausine O R1,R3 = H; R2 = CHO

Scheme 5.53

leads to 7-methoxy-O-methylmukonal (48), which subsequently can be used as a relay compound to the other 2,7-dioxygenated carbazole alkaloids (Scheme 5.54). Oxidation of 48 using manganese dioxide in methanol in the presence of potassium cyanide provides clausine H (clauszoline-C) (50) quantitatively, which on ester cleavage affords clausine K (clauszoline-J) (51). Cleavage of both methyl ethers of 51 on treatment with boron tribromide led to clausine O (72) (588). Bedford et al. reported the total synthesis of glycozolidine (40) and clausine P (46) using the palladium(0)-catalyzed sequential amination and C–H activation reactions

Chemistry of Carbazole Alkaloids

OMe

Me

Me OMe MeCN, rt

(OC)3Fe

(OC)3Fe MeO

(76%)

BF4

665

227

OMe H2N

NH2 655

666 Me

I2, pyridine, 90°C

DDQ OMe

MeO

(68%)

N H 667

MeOH/H2O, rt (67%)

CHO

CHO BBr3, CH2Cl2 MeO

OMe N H 48 MnO2, KCN MeOH, rt (100%)

−78 to −25°C (68%)

HO

OH N H 72

COOMe

COOH KOH, EtOH

MeO

OMe N H 50

reflux (53%)

OMe

MeO N H 51

Scheme 5.54

of 2-chloroaniline 669 with arylbromides 670 and 671 (589). Buchwald–Hartwig amination of 2-chloroaniline 669 with 4-bromoanisole (670) led to the formation of the intermediate diarylamine 672. Subsequent ring closure under palladium(0)catalyzed thermal conditions in 1,4-dioxane yielded glycozolidine (40). Similarly, the two-step methodology was applied to the total synthesis of clausine P (46) starting from the same chloroaniline 669 and 2-bromoanisole (671). This two-step process was achieved in a microwave-assisted one-pot procedure involving two, sequential catalytic transformations (589) (Scheme 5.55).

3 3-Oxygenated Tricyclic Carbazole Alkaloids Danheiser et al. developed a new aromatic annulation methodology for the total synthesis of hyellazole (245) by irradiation of the heteroaryl a-diazo ketone 675 in the presence of 1-methoxypropyne (590). This reaction proceeds via the photochemical Wolff rearrangement of the heteroaryl a-diazo ketone 675 to generate a vinylketene, followed by a cascade of three pericyclic reactions. A diazo transfer to N-Boc-3-acetylindole (674) provided the corresponding a-diazo ketone 675. Irradiation of a 1,2-dichloroethane solution of 675 and

228

Chemistry and Biology of Carbazole Alkaloids

R

Cl

MeO

NH2 BH3 SMe2, C6H5Cl 0 to 80 to 130°C (81%)

668 R = COOH 669 R = Me OMe

MeO

Br

Br

670

671

cat. Pd(OAc)2

+ 671, cat. Pd(OAc)2 cat. [HPt-Bu3][BF4], NaOt-Bu cat. [HPt-Bu3][BF4], NaOt-Bu toluene, MW, 160°C toluene, MW, 160°C (81.5%) (80%) MeO

Cl N H

cat. Pd(OAc)2 cat. [HPt-Bu3][BF4] NaOt-Bu toluene, reflux (91%)

Me

Me

OMe

OMe

N H

MeO

672

46

cat. Pd(OAc)2 cat. [HPt-Bu3][BF4], NaOt-Bu 1,4-dioxane, reflux (61.5%) MeO

Cl N OMe H

Me OMe

673 cat. Pd(OAc)2

cat. [HPt-Bu3][BF4], NaOt-Bu 1,4-dioxane, reflux (80%) Me OMe

N H 40

Scheme 5.55

1-methoxypropyne gave the 1-hydroxycarbazole 678. Mechanistically, this annulation involves a photochemical Wolff rearrangement of the a-diazo ketone 675 to generate a vinylketene intermediate, which combines with 1-methoxypropyne in a regiospecific [2+2] cycloaddition. Further irradiation results in a 4p-electrocyclic ring opening of the cyclobutenone 676 to the dienylketene 677, and subsequent 6p electrocyclization to afford a 2,4-cyclohexadienone, which, on tautomerization, furnishes the hydroxycarbazole 678. After conversion of the hydroxycarbazole 678 to the corresponding triflate 679, the phenyl group was introduced at C-1 by a Stille cross-coupling reaction with trimethylphenylstannane in the presence of a catalytic amount of tetrakis(triphenylphosphane)palladium to afford hyellazole (245) (590) (Scheme 5.56). Moody et al. reported the synthesis of the 3-oxygenated carbazole alkaloids, hyellazole (245) (591,592) and carazostatin (247) (593,594) based on their pyrano[3,4-b]indol-3-one methodology (Scheme 5.57). This synthetic strategy involves the use of a 1-substituted pyrano[3,4-b]indol-3-one 542 as a stable

Chemistry of Carbazole Alkaloids

O

O

1. LiHMDS, THF, −78°C 2. CF3COOCH2CF3, MeSO2N3

Me

Et3N, H2O, MeCN

N Boc

229

N2

N Boc

(2 steps, 86% overall)

674

675 MeO

Me OMe

MeOC CMe ClCH2CH2Cl

O

hν, reflux (56%)

676 OMe

Me3SnPh, LiCl 10 mol% Pd(PPh3)4

Me N Boc

dioxane, 94 to 150°C

R

(63%)

678 R = OH

Tf2O, DMAP, pyridine (97%)

679 R = OSO2CF3

Me

• N O Boc 677

N Boc

OMe Me N H

Ph

245

Scheme 5.56

O O N H 542

1

R

R3

R2 −CO2

R2

R

N H

540

543

3

R1

Scheme 5.57

equivalent of indolo-2,3-quinodimethanes in the Diels–Alder reaction with the alkyne 540 to afford carbazole derivatives 543 by concomitant loss of carbon dioxide. For the synthesis of carazostatin (247) the required 1-heptylpyrano[3,4-b]indol-3one (681) was obtained from indol-3-ylacetic acid (680) by reaction with octanoic anhydride in the presence of boron trifluoride etherate. Diels–Alder reaction of the pyrone 681 with ethyl 3-trimethylsilylpropynoate (682) afforded the desired carbazole 683 with complete regioselectivity, following the loss of carbon dioxide. The ester group in carbazole 683 was directly reduced to a methyl group by reacting with an excess of lithium aluminum hydride. Transformation of the trimethylsilyl group of the carbazole 684 into a hydroxy group was achieved by a three-step sequence employing mild oxidizing conditions. Thus, the 1,2-dialkyl-3-trimethylsilylcarbazole 684 was converted into carazostatin (247) in 44% overall yield by mercuriodesilylation, followed by hydroboration and oxidation (593,594) (Scheme 5.58).

230

Chemistry and Biology of Carbazole Alkaloids

HOOC

O (C7H15CO)2O N H 681

(75%)

680

SiMe3

682

O

BF3 Et2O

N H

EtOOC

PhBr, reflux (74%)

C7H15

SiMe3

SiMe3 LiAlH4, dioxane

COOEt N H

Me

reflux (99%)

C7H15

N H

683

C7H15

684

1. Hg(OAc)2, HOAc

OH

2. BH3 THF, H2O2, aq. NaOH Me

3. aq. HCl (44% overall)

N H

C7H15

247

Scheme 5.58 OR2

OTMS

1

O

Me

Me N R1 H 245 Hyellazole

PPh3

O N R1 Ac OMe 685

2

R = Ph; R = Me 247 Carazostatin R1 = C7H15; R2 = H

N Ac 686

OMe

Me R1

687a R1 = Ph 687b R1 = C7H15

Scheme 5.59

Sakamoto et al. reported the synthesis of hyellazole (245) and carazostatin (247) based on the benzannulation of indoles. This method involves an electrocyclization of the 3-(1,3-butadienyl)indoles 685, which derive from the indolin-3-one 686 and the phosphorus ylides 687 (Scheme 5.59). Wittig reaction of the readily available 1,2-dihydroindol-3-one (686) with phosphoranes 687 afforded the enones 688, which were treated with trimethylsilyl iodide (TMSI) in the presence of 1,1,1,3,3,3-hexamethyldisilazane (HMDS) to give the corresponding trimethylsilyl enol ethers 685. The electrocyclic reaction of the enol ethers 685 in boiling cis-decalin (bp 1951C) gave the 3-silyloxycarbazoles 690. The reaction sequence probably involves the isomerization of the enol ethers 685, followed by electrocyclization and aromatization of the intermediate dihydrocarbazoles 689 by elimination of methanol. Removal of the silyl group from the 3-silyloxycarbazoles 690 with tetrabutylammonium fluoride (TBAF) afforded the 3-hydroxycarbazoles 691. The 3-hydroxycarbazole 691a was methylated to give

Chemistry of Carbazole Alkaloids

231

O O

+ 687, reflux

Me

1

N Ac 686

OMe a R = Ph (dioxane) b R1 = C7H15 (toluene)

N R1 Ac OMe 688a (85%) 688b (72%)

OTMS Me

CH2Cl2 −20°C to rt

OTMS cis-decalin Me

reflux

N R1 Ac OMe

TMSI, HMDS

N OMe R1 Ac 689a-b

685a (80%) 685b (75%)

−MeOH

OMe

1. methylation 2. 50% NaOH OR2 Me N Ac 690 R2 = TMS 691 R2 = H

cat. Bu4NHSO4 benzene (72% overall)

Me N H 245

Ph OH

R1

LiAlH4, THF, 0°C TBAF, THF 0°C

(57%)

691a (2 steps, 56%) 691b (2 steps, 13%)

Me N H 247

C7H15

Scheme 5.60

N-acetylhyellazole, which on deacetylation with sodium hydroxide under phase transfer conditions afforded hyellazole (245) (538,539). Removal of the acetyl group from N-acetylcarazostatin (691b), by reduction with lithium aluminum hydride, provided carazostatin (247) (595) (Scheme 5.60). Using a modification of Sakamoto’s indole benzannulation protocol (see Scheme 5.59), Beccalli et al. reported the synthesis of the 3-methoxycarbazole alkaloids hyellazole (245) and 6-chlorohyellazole (246) (540) (Scheme 5.61). Unlike Sakamoto’s methodology, this method requires a good leaving group at the 2-position of the indole moiety of the 3-(1,3-butadienyl)indoles 692 to facilitate the aromatization of the intermediate dihydrocarbazole by eliminating the dehydrogenation step. The key intermediates 692 required for the thermal cyclization were prepared from the readily available indole-2,3-diones 693. The condensation of 693 with 3-methyl-4-phenylbut-3-en-2-one (694) afforded the 3-hydroxy derivatives 695. The dehydration of 695, followed by selective reduction of the 3,1u-double bond of compounds 696, provided the 3-alkyl derivative 697. Finally, the compounds 697 were transformed to the 3-(1,3-butadienyl)indoles 692 by reaction with an excess of ethyl chloroformate (Scheme 5.62). The thermal cyclization of 3-(1,3-butadienyl)indoles 692 in refluxing cis-decalin afforded the carbazoles 698. Selective hydrolysis of the 3-carbonate ester, methylation of the corresponding 3-hydroxycarbazoles 699 with methyl iodide in the presence of

232

Chemistry and Biology of Carbazole Alkaloids

Me R

OMe

OCOOEt

Me N H

OCOOEt N COOEt

Ph

245 R = H 246 R = Cl R

Ph

R

692a R = H 692b R = Cl

O

Me

Ph

Me

O N H 693a R = H

O 694

693b R = Cl

Scheme 5.61 Me R

O

Me

Et2NH, EtOH

Me

O

N H

Ph

R

O

N H 695a R = H (70%) 695b R = Cl (75%)

694

Me R

3′

1′ 2′

1

CH2Cl2 reflux

N H

EtOH/THF, 60°C

O

Ph

R aq. Na2S2O4

O

2

Me

Ph 4′

3

SO2Cl2

HO O

rt O

693a R = H 693b R = Cl

Ph

O N H

O

697a R = H (93%) 697b R = Cl (65%)

696a R = H (87%) 696b R = Cl (45%) Me

Ph

R Et3N, ClCOOEt, CH2Cl2 0°C to rt

OCOOEt OCOOEt

N COOEt

692a R = H (54%) 692b R = Cl (42%)

Scheme 5.62

sodium hydride, and subsequent alkaline hydrolysis under reflux gave hyellazole (245) and 6-chlorohyellazole (246) (540) (Scheme 5.63). Shin and Ogasawara reported a new total synthesis of carazostatin (247) from N-carbethoxy-2-iodoaniline (700) and 1-decyne involving two aromatic annulation

Chemistry of Carbazole Alkaloids

Me

Ph

R

OCOOEt

R OCOOEt cis-decalin reflux OCOOEt

OH , aq. MeOH Me

reflux, 5 min.

N

N COOEt

Ph COOEt

692a R = H (54%) 692b R = Cl (42%)

698a R = H (72%) 698b R = Cl (83%)

OH

R

233

OMe

R 1. NaH, MeI, THF

Me N

Ph COOEt

Me 2. OH, aq. MeOH reflux, 3 h

699a R = H (80%) 699b R = Cl (88%)

N H

Ph

245 R = H (96%) 246 R = Cl (98%)

Scheme 5.63

reactions as key steps (596). The palladium-catalyzed cross-coupling of N-carbethoxy-2-iodoaniline (700) and 1-decyne afforded the arylacetylene 701. The first aromatic annulation of the arylacetylene 701 by a base-induced indolization provided 2-octylindole (702). Following a standard procedure, 2-octylindole (702) was transformed to 2-octyltryptamine (704) in four steps. The condensation of 2-octyltryptamine (704) with ethyl(2-ethoxymethylene)acetoacetate (705) provided the conjugated enamine 706 required for the second aromatic annulation. In a onepot operation, compound 706 was transformed to the carbazole 707 by refluxing in a 5:3 mixture of acetic anhydride and acetic acid. Finally, using the indicated four-step sequence (–COOEt-–CH2OH-–CHO-–OCHO-–OH), the carbazole 707 was converted to carazostatin (247) (596) (Scheme 5.64). The total syntheses of carazostatin (247), hyellazole (245), and 6-chlorohyellazole (246) based on our iron-mediated annulation require 1,3-cyclohexadiene (597) and the corresponding arylamines 708 and 709 as precursors (597–600) (Scheme 5.65). For the synthesis of carazostatin (247), the required arylamine 708 was synthesized starting from 1-methoxycyclohexa-1,3-diene (710) and methyl 2-decynoate (711). The key step in this route is the Diels–Alder cycloaddition of 710 and 711, followed by retro-Diels–Alder reaction with extrusion of ethylene to give 2-heptyl-6-methoxybenzoate (712). Using a three-step sequence, the methoxycarbonyl group of compound 712 was transformed to the methyl group present in the natural product. 3-Heptyl-3-methylanisole (713) was obtained in 85% overall yield. Finally, the anisole 713 was transformed to the arylamine 708 by nitration and subsequent catalytic hydrogenation. This simple sequence provides the arylamine 708 in six steps and with 26% overall yield (597,598) (Scheme 5.66). Electrophilic aromatic substitution of 708 with the iron-coordinated cation 602 afforded the iron-complex 714 quantitatively. The iron-mediated quinone imine cyclization of complex 714, by sequential application of two, differently activated, manganese dioxide reagents, provided the iron-coordinated 4b,8adihydrocarbazole-3-one 716. Demetalation of the iron complex 716 with concomitant

234

Chemistry and Biology of Carbazole Alkaloids

C8H17 I

1-decyne, cat. PdCl2(PPh3)2

Na/EtOH, reflux

cat. CuI, Et3N, reflux (89%)

NH COOEt

(98%)

NH COOEt

700

701 1. H2C NMe2 Cl CH2Cl2, rt

N H 702

NMe3I

C8H17 2. MeI, MeOH, rt

O

C8H17

N H 703

H N

OEt OEt

705 C8H17

EtOH, rt

EtOOC C8H17

N H

704 (4 steps, 36%)

COMe Ac O/HOAc 2 reflux

706 1. DIBAL, CH2Cl2, −78°C 2. Dess-Martin, CH2Cl2, rt

COOEt Me N H

MeOH, rt, then NaBH4, 0°C

O

NH2

N H

1. NaCN, DMF, 100°C 2. NaBH4, CoCl2 6H2O

OH Me

3. MCPBA, KF, CH2Cl2, 0°C 4. LiAlH4, THF, 0°C (67% overall)

C7H15

N H

707

C7H15

247

Scheme 5.64 R3

OR2

OMe

[Fe(0)] Me N H

H2N

R1

597

Me R

708 R = C7H15 709 R = Ph

247 Carazostatin R1 = C7H15; R2,R3 = H 245 Hyellazole R1 = Ph; R2 = Me; R3 = H 246 6-Chlorohyellazole R1 = Ph; R2 = Me; R3 = Cl

Scheme 5.65

tautomerization using trimethylamine N-oxide afforded carazostatin (247) (597,598) (Scheme 5.67). Alternatively, using the iron-mediated arylamine cyclization, a short access to carazostatin (247), albeit in lower yield, was achieved. The oxidation of the complex 714 with ferricenium hexafluorophosphate in the presence of sodium carbonate

Chemistry of Carbazole Alkaloids

OMe

OMe

COOMe

COOMe

200 to 210°C 14 d, − C2H4 (84%)

C7H15 710

235

C7H15

711

712 OMe

1. LiAlH4, ether 2. PBr3, ether

1. HNO3, CH2Cl2 2. H2, 10% Pd/C

Me

3. LiAlH4, ether (85% overall)

C7H15

MeOH (36% overall)

713

OMe Me C7H15 NH2 708

Scheme 5.66

OMe

(OC)3Fe

Me (OC)3Fe

(100%)

C7H15

BF4

OMe

MeCN, 82°C H2N

NH2

602

Me C7H15 714

708 (OC)3Fe

O

MnO2 CH2Cl2, 25°C (78%)

HN

Me C7H15

v.a. MnO2 CH2Cl2, 25°C (78%)

715 O

OH

(OC)3Fe

Me3NO 2H2O Me N

C7H15

acetone, 25°C (74%)

716

Me N H 247

C7H15

Scheme 5.67

followed by demetalation with concomitant tautomerization of the intermediate iron-coordinated 4b,8a-dihydrocarbazol-3-one 716 using trimethylamine N-oxide led to carazostatin (247) (598). The arylamine 709 required for the total synthesis of hyellazole (245) was synthesized by Diels–Alder reaction of 1-methoxycyclohexa-1,3-diene (710) and ethyl phenylpropynoate 711. The biphenyl derivative 719 thus obtained was transformed to the arylamine 709 by excecuting a similar reaction sequence as shown in Scheme 5.66. The arylamine 709 was obtained in six steps and 7% overall yield based on 1-methoxycyclohexa-1,3-diene (710) (599,600) (Scheme 5.68). The drawback of the aforementioned sequence is the low yield (30%) of the desired regioisomer 719 in the Diels–Alder reaction. Therefore, the overall yield of the intermediate biphenyl derivative 720 by the route shown in Scheme 5.68 was

236

Chemistry and Biology of Carbazole Alkaloids

OMe

130°C, 4 d −C2H4 Ph 717

710

Ph

COOEt

COOEt

Ph

718 (61%)

1. LiAlH4, ether 2. PBr3, CH2Cl2 719

OMe

OMe

COOEt

719 (30%) OMe

OMe

3. LiAlH4, toluene (66% overall)

Me

1. HNO3 /H2SO4, CH2Cl2

Ph

2. H2, 10% Pd/C, MeOH (38% overall)

720

Me Ph NH2 709

Scheme 5.68

OMe

OMe OMe OMOM

OMe Me

1. K, THF, rt 2. MeI, 0°C (75%)

OMOM

721

MeOH, rt

722

OMe Me

(2 steps, 70 to 80%)

OH 723

OMe Tf2O, pyridine

Me

0.6 M HCl

OTf

Me

5 mol% Pd(PPh3)4 PhB(OH)2, DME, 85°C (80%)

724

Ph 720

Scheme 5.69

limited to 20%. However, Azzena et al. reported a new synthesis of the biphenyl derivative 720 starting from 1,2-dimethoxy-3-methoxymethoxybenzene (721) (601). The key step in this approach is a Suzuki-Miyaura cross-coupling of the triflate 724 with phenylboronic acid using 5 mol% Pd(PPh3)4. This alternative method provides the biphenyl derivative 720 in four steps and 48% overall yield based on compound 721 (600) (Scheme 5.69). Electrophilic substitution at the arylamine 709 using the complex salt 602, provided the iron complex 725 quantitatively. Sequential, highly chemoselective oxidation of the iron complex 725 with two, differently activated, manganese dioxide reagents provided the tricarbonyliron-complexed 4b,8a-dihydrocarbazol-3-one (727) via the non-cyclized quinone imine 726. Demetalation of the tricarbonylironcomplexed 4b,8a-dihydrocarbazol-3-one (727), followed by selective O-methylation, provided hyellazole (245) (599,600) (Scheme 5.70). An alternative method for the oxidative cyclization of the arylamine-substituted tricarbonyl(Z4-cyclohexa-1,3-diene)iron complex (725) is the iron-mediated arylamine cyclization. Using ferricenium hexafluorophosphate in the presence of sodium carbonate provided hyellazole (245) directly, along with the complex 727, which was also converted to the natural product (599,600) (Scheme 5.71). For the synthesis of 6-chlorohyellazole (246), the required arylamine 709 was prepared in very good overall yield starting from commercially available

Chemistry of Carbazole Alkaloids

OMe Me

+ 602

(OC)3Fe

OMe

MeCN, 82°C (98%)

Ph

H2N

NH2 709

Me

237

MnO2 toluene, 25°C (85%)

Ph 725 O

(OC)3Fe

O HN

v.a. MnO2

Me Ph 726

(OC)3Fe Me

CH2Cl2, 25°C (78%)

N

Ph

727 OH

OMe K2CO3, MeI

Me3NO 2H2O Me

acetone, 25°C (95%)

N H 728

Ph

Me

acetone, 56°C (93%)

N H 245

Ph

Scheme 5.70 (OC)3Fe

OMe Me

H2N

Cp2FePF6, Na2CO3 CH2Cl2, 25°C (50%)

Ph 725 O

OMe

(OC)3Fe Me N

Ph

727

Me N H 245

Ph

1. Me3NO 2H2O, acetone, 25°C 2. K2CO3, MeI, acetone, 56°C (88% overall)

Scheme 5.71

2,6-dimethoxytoluene (729). Nitration of 729 using claycop afforded selectively the desired nitro derivative 730. After demethylation, the corresponding hydroxy derivative 731a was transformed to the triflate 731b, which, on Suzuki–Miyaura cross-coupling with phenylboronic acid, led to the biphenyl derivative 732. Finally, catalytic hydrogenation of 732 afforded the corresponding arylamine 709. This improved route affords the arylamine 709 in five steps and 76% overall yield (previous route: six steps, 18%) (602) (Scheme 5.72). Electrophilic substitution of the arylamine 709 with the complex salt 602 gave the iron complex 725 quantitatively. The iron-mediated arylamine cyclization, by

238

Chemistry and Biology of Carbazole Alkaloids

OMe

OMe Me OMe

claycop, ether Ac2O, rt (94%)

729

OMe Me OMe

Me

AlCl3 CH2Cl2, rt

R

(96%)

NO2 730

NO2 Tf2O, Et3N CH2Cl2, −20°C (97%)

731a R = OH 731b R = OTf OMe

OMe cat. Pd(PPh3)4, PhB(OH)2 K3PO4, dioxane, 80°C (87%)

NO2

Me

H2, Pd/C

Ph

MeOH, rt (100%)

732

Me Ph NH2 709

Scheme 5.72

oxidation with ferricenium hexafluorophosphate in the presence of sodium carbonate, transformed the complex 725 into hyellazole (245) in two steps and 84% yield. Alternatively, in a one-pot operation, the iron complex 725 was directly transformed into hyellazole (245) in 69% yield by reacting with 3 equivalents of N-bromosuccinimide (NBS) in the presence of an excess of sodium carbonate. Taking the improved synthesis of the arylamine 709 into account, hyellazole (245) was obtained in eight steps and 63% overall yield (602). An attempt to directly convert hyellazole (245) to 6-chlorohyellazole (246) by reaction with N-chlorosuccinimide in the presence of a catalytic amount of hydrochloric acid led exclusively to 4-chlorohyellazole. On the other hand, bromination of 245 using NBS and a catalytic amount of hydrobromic acid gave only the expected 6-bromohyellazole (733). Alternatively, a direct one-pot transformation of the iron complex 725 to 6-bromohyellazole (733) was achieved by reaction with an excess of NBS and switching from oxidative cyclization conditions (basic reaction medium) to electrophilic substitution conditions (acidic reaction medium). Finally, a halogen exchange reaction with 4 equivalents of cuprous chloride in N,N-dimethylformamide (DMF) at reflux, transformed 6-bromohyellazole (733) into 6-chlorohyellazole (246) (602) (Scheme 5.73). Hibino et al. reported the total synthesis of carazostatin (247) and hyellazole (245) using a benzannulation method based on the electrocyclization of a 2,3-difunctionalized indole via an allene intermediate (536,537). The 3-alkenyl-2-propargylindole 736, used as common precursor for the total synthesis of carazostatin (247) and hyellazole (245), was prepared in five steps and 51% overall yield starting from 2-formylindole (734). The thermal electrocyclization of 736 via the intermediate allene 737 was achieved by heating at 901C in tert-butyl alcohol in the presence of potassium tert-butoxide to afford the desired carbazole 738 (43% yield), along with the N-deprotected carbazole 739 (41% yield). However, using alkaline hydrolytic conditions, 738 was transformed to the carbazole 739 as the sole product. Subsequent cleavage of the MOM ether of 739 using trimethylsilyl chloride (TMSCl) and sodium iodide, followed by treatment with trifluoromethane sulfonic anhydride (Tf2O) and pyridine, afforded the triflate 740. The introduction of either the heptyl side chain or

Chemistry of Carbazole Alkaloids

OMe Me

+ 602

(OC)3Fe

OMe

MeCN, 82°C (98%)

Ph

239

Me

H2N

NH2

Ph 725

709 1. Cp2FePF6, Na2CO3 2. Me3NO 3. MeI (84% overall)

1. 3 eq. NBS, 1 eq. Na2CO3, MeCN, rt 2. 1.2 eq. NBS, 0.45 eq. HBr, MeCN (69% overall)

OMe

Br

OMe

NBS, cat. HBr Me N H 245

Ph

Me

MeCN, rt (92%)

N H 733

Ph

4 eq. CuCl, DMF, 153°C (96%) Cl

OMe Me N H

Ph

246

Scheme 5.73

the phenyl group at C-1 by Suzuki cross-coupling reaction transformed the triflate 740 to the carbazoles 741 and 742, respectively. Finally, cleavage of the ethyl ether of 741 using boron tribromide afforded carazostatin (247). Similarly, cleavage of the ethyl ether of 742 led to the hydroxycarbazole 728, which, on O-methylation, provided hyellazole (245) (536,537) (Scheme 5.74). Witulski and Alayrac reported the synthesis of hyellazole (245) using a rhodiumcatalyzed alkyne cyclotrimerization (561). The key diyne 746 precursor required for cyclotrimerization with 1-methoxy propyne (747) was obtained in three steps starting from readily available 2-iodoaniline (743). Using Sonogashira reaction conditions, 2-iodoaniline (743) was reacted with trimethylsilylacetylene followed by N-tosylation and protodesilylation to afford the alkyne 744. The alkyne 744 underwent N-ethynylation with alkynyliodinium triflate 745 to furnish the diyne 746. Using Wilkinson’s catalyst, [RhCl(PPh3)3], crossed alkyne cyclotrimerization between diyne 746 and 1-methoxy propyne (747) led to N-tosylhyellazole (748) in 89% yield and an isomeric ratio of 30:1. Isomerically pure hyellazole was obtained by deprotection of the tosyl group with TBAF in refluxing tetrahydrofuran (THF), followed by crystallization (561) (Scheme 5.75). Our total syntheses of the carbazomadurins A (253) (603) and B (254) (604) use the palladium-catalyzed fusion of three building blocks 749, 750, and 751, and a

240

Chemistry and Biology of Carbazole Alkaloids

OEt

N H

1. Bu3Sn Pd(PPh3)2, DMF, 80°C

I

1. I2, KOH, DMF, rt CHO 2. NaH, PhSO2Cl DMF, 0°C (67% overall)

CHO 2. HC CMgBr, THF, rt N 3. MOMCl, i-Pr2EtN SO2Ph CH2Cl2, 0°C 735 (76% overall)

734 OEt

OEt KOt-Bu

N OMOM SO2Ph

•

t-BuOH, 90°C

N OMOM SO2Ph 737

736 2 N NaOH, MeOH/THF (75%) OEt

OEt 1. TMSCl, NaI, MeCN, −20°C

Me N OMOM SO2Ph 738

Me N H

OMOM

2. Tf2O, pyridine, CH2Cl2, rt (47% overall)

739 OR

BC7H15

OEt

PdCl2(dppf), NaOH THF, 80°C (85%)

740

C7H15

741 R = Et

Me N H

Me N H

247 R = H

BBr3 (90%)

OTf OR PhB(OH)2, Pd(PPh3)4 (96%)

Me N H 742 R = Et

K2CO3, MeI (95%)

728 R = H

Ph BBr3 (90%)

245 R = Me

Scheme 5.74

zirconium-catalyzed generation of the E-configured double bond (Scheme 5.76). One of the three building blocks, the aryl triflate 749, was easily prepared in 91% overall yield in two steps starting from isovanillic acid (752). After esterification of 752, the corresponding methyl ester 753 was reacted with triflic anhydride using 2,6-lutidine as base to give the corresponding triflate 749 (Scheme 5.77). Another building block, the arylamine 750, was prepared from 2-bromo-6nitrotoluene (754) in 44% overall yield in five simple steps. Transfer hydrogenation of

241

Chemistry of Carbazole Alkaloids

1. trimethylsilylacetylene cat. PdCl2(PPh3)2 cat. CuI, Et3N, DMF, rt

I NH2

H KHMDS, toluene, 0°C

2. TsCl, pyridine, THF 3. TBAF, THF, 0°C

NH Ts 744

(80% overall)

743 H

Me

Ph I OTf

Ph

745 (56%) OMe

OMe

747

Ph

Me

10 mol% RhCl(PPh3)3 toluene, rt

N Ts

N Ph Ts 748 (30:1)

(89%)

746

OMe TBAF, THF, reflux Me

(98%)

N H

Ph

245

Scheme 5.75 HO OMe

COOMe

OH

Me

[Pd]

HO

Me Me Me

N H

R

Bu3Sn Br

OTf R

253 Carbazomadurin A R=H

OMe

NH2

749

750

751a R = H 751b R = Me

254 Carbazomadurin B R = Me

Scheme 5.76 COOH

COOMe H2SO4

OH OMe 752

MeOH, 65°C (91%)

COOMe 2,6-lutidine, Tf2O

OH OMe

CH2Cl2, −10°C to rt (100%)

753

OTf OMe 749

Scheme 5.77

754 using hydrazine hydrate afforded 3-bromo-2-methylaniline (755), which was converted to the corresponding phenol 756 via diazotization. After methylation of 756, the corresponding anisole 757 was subjected to nitration using claycop, followed by reduction, which led to the arylamine 750 (603) (Scheme 5.78).

242

Chemistry and Biology of Carbazole Alkaloids

NO2 Me

N2H4 H2O, FeCl3 activated carbon

Br

MeOH, 65°C (96%)

OH

NH2 Me 1. NaNO , H SO , 0°C 2 2 4

Me

2. H2SO4, H2O, Δ (83%)

Br

Br

754

755 OMe Me

MeI, KOH, DMSO, rt (91%)

Br 757

756

1. claycop, Ac2O, CCl4, rt 2. N2H4 H2O, FeCl3 activated carbon MeOH, 65°C (61% overall)

OMe Me Br NH2 750

Scheme 5.78

1. Me3Al, Cp2ZrCl2 CH2Cl2, rt

758

I

2. I2, THF, 0°C (70%)

759

1. t-BuLi, ether, −78°C 2. Bu3SnCl, −78°C to rt (74%)

Bu3Sn 751a

Scheme 5.79

The stereospecific construction of the trisubstituted double bond of the side chain at C-1 of carbazomadurins A (253) and B (254) was achieved using Negishi’s zirconium-catalyzed carboalumination of alkynes 758 and 763, respectively. Reaction of 5-methyl-1-hexyne (758) with trimethylalane in the presence of zirconocene dichloride, followed by the addition of iodine, afforded the vinyl iodide 759 with the desired E-configuration of the double bond. Halogen–metal exchange with tertbutyllithium, and reaction of the intermediate vinyllithium compound with tributyltin chloride, provided the vinylstannane 751a (603) (Scheme 5.79). Assuming an S configuration for carbazomadurin B (254), the synthesis of the chiral alkenylstannane 751b was achieved in six steps and 11% overall yield from commercial (S)-( )-2-methyl-1-butanol (760). After confirming an enantiomeric purity of W99% ee for 760, it was transformed to the corresponding bromo derivative 761. Conversion of 761 to the Grignard reagent and Wurtz coupling with allyl bromide led to the alkene derivative 762. Subsequent bromination, followed by double dehydrobromination with potassium tert-butoxide in the presence of catalytic amounts of [18]-crown-6, provided (S)-(+)-5-methyl-1-heptyne (763). Executing the similar reaction sequence of the transformation of 5-methyl-1-hexyne (758) to the E-configured vinylstannane 751a (see Scheme 5.79), the 1-heptyne 763 was transformed to the E-alkenylstannane 751b (604) (Scheme 5.80).

Chemistry of Carbazole Alkaloids

PBr3, pyridine

HO 760

0°C to rt (63%)

243

1. Mg, ether

Br

2. allyl bromide, rt (58%)

761

762

1. Me3Al, Cp2ZrCl2 CH2Cl2, rt

1. Br2, CHCl3, 0°C 2. KOt-Bu, cat. [18]-crown-6 hexane, Δ (64% overall)

2. I2, THF, 0°C (60%)

763

1. t-BuLi, ether, −78°C

I 764

2. Bu3SnCl, −78°C to rt (78%)

Bu3Sn 751b

Scheme 5.80

Using Buchwald–Hartwig amination conditions, the aryl triflate 749 and the arylamine 750 were coupled to afford the N,N-diarylamine 765. Subsequent palladium(II)-mediated oxidative cyclization of 765 led to the carbazole 766. Cleavage of both methyl ethers, followed by double silylation, afforded the bis(tert-butyldiphenylsilyl) (TPS) ether 767 with a switch of the protecting group. Palladium(0)-catalyzed Stille coupling of the 1-bromocarbazole 767 and the alkenylstannanes 751a and 751b furnished the 1-alkenylcarbazoles 768a and 768b, respectively. Reduction of the methyl ester using DIBAL-H led to the corresponding benzylic alcohols 769a and 769b which served as common precursors for the carbazomadurins and epocarbazolines. Finally, removal of both silyl protecting groups from the disilyl-protected precursors 769 with TBAF provided the carbazomadurins A (253) (603) and B (254) (604) (Scheme 5.81). All attempts to achieve a direct transformation of the carbazomadurins A (253) and B (254), as well as the disilyl-protected carbazomadurins A (769a) and B (769b), into the epocarbazolins A (258) and B (259) were unsuccessful and resulted in complete decomposition. Therefore, prior to the epoxidation, the disilyl-protected carbazomadurins A (769a) and B (769b) were transformed to the corresponding trisilyl-protected carbazomadurins A (770) and B (771) by treatment with TPS chloride in the presence of stoichiometric amounts of 4-(dimethylamino)pyridine (DMAP). Epoxidation of the fully protected carbazomadurins A (770) and B (771) with dimethyldioxirane at 201C, followed by desilylation, provided racemic epocarbazolin A (258) and epocarbazolin B (259) (605) (Scheme 5.82). Duval and Cuny reported the total syntheses of hyellazole (245) and 6-chlorohyellazole (246) starting from diketoindoles 777a and 777b (606). In this methodology, the key step is the base-catalyzed intramolecular aldol condensation of the ketoindoles to fully functionalized 3-hydroxycarbazoles. The diketoindoles 777 were prepared in three steps starting from indol-3-ylacetic acid (680) and 5-chloro indol-3-ylacetic acid (774) in 75% and 66% overall yield, respectively. The indole acids 680 and 774 were converted into Weinreb amides 775, followed by reaction with ethyl Grignard reagent to afford the corresponding indol3-yl ketones 776. In order to introduce the second carbonyl moiety, the 3-substituted

244

Chemistry and Biology of Carbazole Alkaloids

COOMe

COOMe OMe H2N

OTf

CsCO3, toluene, 100°C (62%)

Me Br

OMe 749

OMe

cat. Pd(OAc)2, cat. BINAP N OMe H

750

Me Br

765 COOMe

OMe 1. BBr3, CH2Cl2, −78°C to rt

Pd(OAc)2 dioxane/HOAc, 100°C (43%)

Me MeO

N H

2. TPSCl, imidazole, DMF, 70°C

Br

(70% overall)

766 COOMe

COOMe

OTPS

OTPS

+ 751, cat. Pd(PPh3)4 Me TPSO

N H

toluene, 110°C

Br

TPSO

TPS = t-BuPh2Si

Me Me Me

N H

R

767 768a R = H (95%) 768b R = Me (90%) HO

HO OTPS

OH

DIBAL-H

TBAF

toluene, 0°C TPSO

N H

Me Me Me

THF, rt R

769a R = H (70%) 769b R = Me (80%)

HO

N H

Me Me Me

R

253 R = H (2 steps, 70%) 254 R = Me (2 steps, 80%)

Scheme 5.81

indoles 776 were subjected to Friedel–Crafts benzoylation with benzoyl chloride in the presence of an excess of zinc chloride to give the diketoindoles 777. The basecatalyzed intramolecular cyclization of diketoindoles 777 with sodium hydroxide led to the 3-hydroxycarbazoles 728 and 778 in 85% and 74% yield, respectively. Finally, O-methylation with methyl iodide in the presence of potassium carbonate in refluxing acetone afforded hyellazole (245) and 6-chlorohyellazole (246) (606) (Scheme 5.83).

4 3,4-Dioxygenated Tricyclic Carbazole Alkaloids Our approach for the total syntheses of carbazomycins A (260), B (261), C (262), D (263), and E (264), based on the iron-mediated construction of the carbazole framework by consecutive C–C and C–N bond formation, leads to the iron complex salts 602 and 779 and the fully functionalized arylamines 780a–c (607–610) (Scheme 5.84). The arylamine 780a required for the total synthesis of carbazomycin A (260) was prepared from commercially available 2,3-dimethylphenol (781). The regioselective

245

Chemistry of Carbazole Alkaloids

HO

TPSO OTPS

OTPS TPSCl, DMF

Me Me Me

N H

TPSO

DMAP, rt

N H

TPSO

R

769a R = H 769b R = Me

Me Me Me

R

770 R = H (100%) 771 R = Me (100%) TPSO OTPS

dimethyldioxirane

TBAF, THF

acetone/CH2Cl2, −20°C TPSO

N H

Me Me Me O

rt (in the dark) R

772 R = H (53%) 773 R = Me (53%) HO OH

HO

N H

Me Me Me O

R

(+ −)-258 R = H (24%) 259 R = Me (18%)

Scheme 5.82

introduction of the second oxy substituent in the ortho-position to the hydroxy group was achieved by acetylation of 781 and subsequent ortho-selective Fries rearrangement of the intermediate acetoxy derivative to the desired acetophenone 782. Methylation of 782 followed by a regioselective Baeyer–Villiger oxidation afforded the acetoxy compound 783. Regioselective nitration of 783 using the preformed complex of fuming nitric acid and SnCl4 at 781C afforded the desired nitro derivative which, on deacetylation, led to the corresponding nitro phenol 784. Finally, methylation of 784, followed by palladium-catalyzed hydrogenation, furnished the arylamine 780a (609) (Scheme 5.85). Electrophilic aromatic substitution of the arylamine 780a using the iron-complex salt 602 afforded the iron-complex 785. Oxidative cyclization of complex 785 in toluene at room temperature with very active manganese dioxide afforded carbazomycin A (260) in 25% yield, along with the tricarbonyliron-complexed 4b,8a-dihydro-3Hcarbazol-3-one (786) (17% yield). The quinone imine 786 was also converted to carbazomycin A (260) by a sequence of demetalation and O-methylation (Scheme 5.86). The synthesis via the iron-mediated arylamine cyclization provides carbazomycin A (260) in two steps and 21% overall yield based on 602 (607–609) (Scheme 5.86). Selective oxidation of the iron complex 785 with commercial manganese dioxide in dichloromethane at room temperature afforded the iron-complexed

246

Chemistry and Biology of Carbazole Alkaloids

O

R

O

R 1. ClCOOi-Pr, NMM, THF, −20°C

OH

N OMe

2. MeNHOMe HCl, Et3N, DMF, 0°C

N H 680 R = H

Me

N H 775a R = H

774 R = Cl

775b R = Cl O

R

O

R

EtMgBr, THF

PhCOCl, ZnCl2

0°C to rt

ether

N H 776a R = H

777b R = Cl (66% overall)

776b R = Cl R

O N Ph H 777a R = H (75% overall)

OMe

R

OH MeI, K2CO3

NaOH, EtOH Me N Ph H 728 R = H (85%)

Δ

acetone, reflux

778 R = Cl (74%)

Me N Ph H 245 R = H 246 R = Cl

Scheme 5.83

R2O

R3

OMe Me

N H 2

H2N

Me R1

260 Carbazomycin A 1

OMe

(OC)3Fe X

R1

OR2

R3

3

R ,R = Me; R = H 261 Carbazomycin B

602 R3 = H; X = BF4 3

779 R = OMe; X = PF6

780a R1,R2 = Me 780b R1 = Me; R2 = H 780c R1 = CHO; R2 = H

R1 = Me; R2,R3 = H 262 Carbazomycin C R1= Me; R2 = H; R3 = OMe 263 Carbazomycin D R1,R2 = Me; R3 = OMe 264 Carbazomycin E R1 = CHO; R2,R3 = H

Scheme 5.84

4b,8a-dihydro-3H-carbazol-3-one (786) in 63% yield. Finally, demetalation of the quinone imine 786, followed by O-methylation of the intermediate 3-hydroxycarbazole using NaH/Me2SO4, gave carbazomycin A (260). The iron-mediated quinone imine cyclization provides carbazomycin A (260) in four steps and 35% overall yield based on 602 (608,609) (Scheme 5.86).

247

Chemistry of Carbazole Alkaloids

OH

1. Ac2O, pyridine DMAP, reflux

Me

2. AlCl3, 135°C (82% overall)

Me

Ac

OAc OH

OMe

1. LiH, THF, Me2SO4 2. MCPBA, CH2Cl2, 25°C (69% overall)

Me Me

Me Me

782

781

OH

1. HNO3, SnCl4, CH2Cl2 −78 to 25°C 2. KOH, EtOH, 25°C (63% overall)

783

O2N

OMe

1. CH2N2, ether OMe 2. H , 10% Pd/C 2

OMe

EtOH, 25°C (87% overall)

Me Me

H2N

Me Me

784

780a

Scheme 5.85 OMe OMe H2N

Me Me

OMe

(OC)3Fe

+ 602 MeCN, 25°C (84%)

OMe H2N

MnO2 CH2Cl2, 25°C (63%)

Me

786

Me

780a

785 v.a. MnO2 toluene, 25°C MeO

MeO

O

OMe

(OC)3Fe Me N

Me N Me H 260 (25%)

Me

786 (17%)

1. Me3NO 2H2O, acetone, 25°C 2. NaH, Me2SO4, ether, 25°C (66% overall)

Scheme 5.86

The arylamine 780b required for the total synthesis of carbazomycin B (261) was obtained by catalytic hydrogenation, using 10% palladium on activated carbon, of the nitroaryl derivative 784 which was obtained in six steps and 33% overall yield starting from 2,3-dimethylphenol 781 (see Scheme 5.85). Electrophilic substitution of the arylamine 780b with the iron-complex salt 602 provided the iron complex 787 in quantitative yield. The direct, one-pot transformation of the iron complex 787 to carbazomycin B 261 by an iron-mediated arylamine cyclization was unsuccessful, probably because the unprotected hydroxyarylamine moiety is too sensitive towards the oxidizing reaction conditions. However, the corresponding O-acetyl derivative

248

Chemistry and Biology of Carbazole Alkaloids

788 was transformed to carbazomycin B by oxidative cyclization with very active MnO2, followed by cleavage of the ester. The total synthesis of carbazomycin B (261) via the iron-mediated arylamine cyclization was completed in four steps and 33% overall yield based on the iron-complexed cation 602 (608,609) (Scheme 5.87). Six years later, we described a considerably improved total synthesis of the carbazomycins A (260) and B (261) using highly efficient synthetic routes to the arylamines 780a and 794 (610). Moreover, this methodology uses air as an oxidant for the construction of the carbazole framework by oxidative coupling of the ironcomplexed cation 602 with the arylamines 780a and 794. The optimized procedure for the synthesis of the arylamine 780a started from commercially available 3-methylveratrole (789). The electrophilic bromination of 789 led to the corresponding 4-bromo derivative 790. Halogen–metal exchange of 790 with butyllithium, and subsequent methylation by iodomethane, afforded 3,4-dimethylveratrole. Regioselective nitration of 3,4-dimethylveratrole using fuming nitric acid in a 3:1 mixture of acetic anhydride and glacial acetic acid provided the 5-nitro derivative 791. Finally, catalytic hydrogenation of 791 using 10% palladium on activated carbon provided the arylamine 780a. This novel route provides the arylamine 780a in four steps and 55% overall yield based on 3-methylveratrole (789) (610) (Scheme 5.88). Using a one-pot process of oxidative cyclization in air, the arylamine 780a was transformed to the tricarbonyl(Z4-4b,8a-dihydro-9H-carbazole)iron complex 792. Finally, demetalation of 792 and subsequent aromatization gave carbazomycin A (260). This synthesis provided carbazomycin A (260) in three steps and 65% overall yield based on 602 (previous route: four steps and 35% yield based on 602) (610) (Scheme 5.88). The arylamine 794 required for the improved total synthesis of carbazomycin B (261) was prepared in quantitative yield by hydrogenation of the nitroaryl derivative 793 (see Scheme 5.85). Oxidative coupling of the iron complex salt 602 and the arylamine 794 in air afforded the tricarbonyl(Z4-4b,8a-dihydro-9H-carbazole)iron complex (795). Demetalation of 795, followed by aromatization, led to O-acetylcarbazomycin B (796). OH

OH OMe

O2N

Me Me

OMe

H2, 10% Pd/C EtOH, 25°C (99%)

H2N

Me Me

784

+ 602 MeCN, rt (96%)

780b HO

OR

(OC)3Fe

OMe H2N

Me

2. 10% aq. NaOH, reflux (41% overall)

Me 787 R = H 788 R = Ac

OMe

1. v.a. MnO2, toluene, rt

Ac2O, pyridine DMAP, CH2Cl2, rt (84%)

Scheme 5.87

Me N H 261

Me

249

Chemistry of Carbazole Alkaloids

OMe

OMe OMe

OMe

NBS, MeCN 25°C (88%)

Me

2. 100% HNO3 Ac2O/HOAc (3:1), 0°C (65% overall)

Me Br 790

789

1. BuLi, THF, −78°C MeI, −78 to 25°C

OMe

OMe OMe

O2N

OMe

H2, 10% Pd/C MeOH (96%)

Me Me

H2N

+ 602, MeCN air, 5 d (78%)

Me Me 780a

791 MeO

OMe

(OC)3Fe

MeO

1. 8 eq. Me3NO 2H2O acetone, 56°C

Me

Me 2. 10% Pd/C, o -xylene 145°C Me (83% overall)

N H

OMe

N H

Me

260

792

Scheme 5.88 OAc

OAc OMe (see Scheme 5.85)

OMe

(64%)

Me

O2N

Me 783

H2, 10% Pd/C EtOH, rt (99%)

Me Me 793

OAc

H2N

AcO

OMe

1. + 602, MeCN 25°C, 5 d, Ar

Me

2. air, MeCN, 25°C, 15 d (80%)

Me 794 1. 8 eq. Me3NO 2H2O acetone, 56°C 2. 10% Pd/C, o-xylene 145°C (70% overall)

OMe

(OC)3Fe Me N H

Me

795 AcO

HO

OMe

OMe

LiAlH4, THF Me N H 796

Me

25°C (84%)

Me N H 261

Me

Scheme 5.89

Finally, cleavage of the ester group afforded carbazomycin B (261). This synthesis offers carbazomycin B (261) in four steps and 55% overall yield based on 602 (previous synthesis: four steps and 30% overall yield based on 602) (610) (Scheme 5.89).

250

Chemistry and Biology of Carbazole Alkaloids

Retrosynthetic analysis of the carbazomycins C (263) and D (264) based on the iron-mediated construction of the carbazole framework leads to tricarbonyl [3-methoxy-(1–5-Z)-cyclohexadienyl]iron hexafluorophosphate (779) and the arylamines 780a and 780b (see Scheme 5.84) as synthetic precursors (611). The arylamines 780a and 780b have been used previously as precursors for the total syntheses of carbazomycin A (260) and B (261) (see Schemes 5.86, 5.87 and 5.88). The total synthesis of carbazomycin C (262) was achieved by executing similar reaction sequences as in the iron-mediated arylamine cyclization route described for the synthesis of carbazomycin B (261) (see Scheme 5.87). The electrophilic substitution of the arylamine 780b using the complex salt 779 afforded the iron complex 797, which was transformed to the corresponding acetate 798. Using very active manganese dioxide, compound 798 was cyclized to O-acetylcarbazomycin C (799). Finally, saponification of the ester afforded carbazomycin C (262) (four steps and 25% overall yield based on 779) (611) (Scheme 5.90). The total synthesis of carbazomycin D (263) was completed using the quinone imine cyclization route as described for the total synthesis of carbazomycin A (261) (see Scheme 5.86). Electrophilic substitution of the arylamine 780a by reaction with the complex salt 779 provided the iron complex 800. Using different grades of manganese dioxide, the oxidative cyclization of complex 800 was achieved in a twostep sequence to afford the tricarbonyliron complexes 801 (38%) and 802 (4%). By a subsequent proton-catalyzed isomerization, the 8-methoxy isomer 802 could be quantitatively transformed to the 6-methoxy isomer 801 due to the regio-directing effect of the 2-methoxy substituent of the intermediate cyclohexadienyl cation. Demetalation of complex 801 with trimethylamine N-oxide, followed by O-methylation of the intermediate 3-hydroxycarbazole derivative, provided carbazomycin D (263) (five steps and 23% overall yield based on 779) (611) (Scheme 5.91). The arylamine 780c required for the total synthesis of carbazomycin E (264) was prepared in seven steps starting from vanillyl alcohol (803). Vanillyl alcohol (803) was transformed to the tetrasubstituted aryl derivative 804 via generation of the benzyl methyl ether followed by ortho-directed lithiation and subsequent

OH OMe

MeO (OC)3Fe

H2N

PF6

Me

779

MeCN, 25°C

780b

H2N

AcO

797 R = H

CH2Cl2, 25°C (33%)

MeO

OMe

v.a. MnO2

Me Me

798 R = Ac

MeO

OMe

MeO

dil. aq. NaOH (96%)

Me

OR

(OC)3Fe

Ac2O, pyridine DMAP, CH2Cl2, rt (84%) HO

OMe

NaOH, H2O Me N H 799

Me

reflux (90%)

Me N H 262

Scheme 5.90

Me

Chemistry of Carbazole Alkaloids

OMe

H2N

OMe

+ 779 MeCN, 25°C

Me

dil. aq. NaOH (79%)

Me

OMe

(OC)3Fe MeO H2N

OMe

1. MnO2, CH2Cl2 25°C

Me

2. v.a. MnO2 CH2Cl2, 25°C

Me

780a

251

800 cat. CF3COOH, CH2Cl2, 25°C (quant.) MeO

MeO (OC)3Fe

MeO

O

O

(OC)3Fe Me N

Me

Me

N

MeO

801 (2 steps, 38%)

Me

802 (2 steps, 4%) MeO

MeO

OMe

1. Me3NO 2H2O, acetone, 25 to 40°C Me

2. K2CO3, MeI, acetone, 56°C (71% overall)

N H 263

Me

Scheme 5.91 OH

OH OMe

CH2OH

OR

1. MeOH, p-TsOH

OMe DDQ, CH Cl 2 2

2. 3 eq. BuLi, THF, MeI (72% overall)

Me

H2O (73%)

CH2OMe 804

803

Ac2O, pyridine DMAP, CH2Cl2 (95%)

OR

CH2Cl2, −78 to 0°C (31%)

O2N

Me CHO

807 R = Ac 808 R = H

Me CHO 805 R = H 806 R = Ac OH

OMe

SnCl4, HNO3

OMe

OMe

H2, 10% Pd/C EtOH, 25°C (91%)

KOH, EtOH, H2O, 25°C (94%)

H2N

Me CHO 780c

Scheme 5.92

methylation. After DDQ oxidation of the benzyl methyl ether 804, the corresponding aldehyde 805 was converted to the O-acetyl derivative 806. Nitration of 806 to the nitrobenzaldehyde 807 was achieved using the complex of tin tetrachloride and fuming nitric acid. Ester cleavage to the nitrophenol 808 with potassium hydroxide and subsequent catalytic hydrogenation afforded the desired arylamine 780c (612) (Scheme 5.92).

252

Chemistry and Biology of Carbazole Alkaloids

Electrophilic aromatic substitution of the arylamine 780c using the iron-complex salt 602 provided the iron complex 809 in 26% yield. The low yield of complex 809 was ascribed to the strong electron-withdrawing effect of the formyl group. After acetylation of complex 809, the resulting O-acetyl derivative 810 was subjected to iron-mediated arylamine cyclization with very active manganese dioxide to give O-acetylcarbazomycin E (811). Finally, base-mediated saponification of 811 afforded carbazomycin E (264). The overall yield for the iron-mediated total synthesis of carbazomycin E (264) is low (four steps and 4% overall yield based on 602) (612) (Scheme 5.93). However, to date it represents the only total synthesis reported for this natural product. By analogy with carquinostatin A (275) (see Scheme 2.68) we assumed an R-configuration of the stereogenic center for neocarazostatin B (268). Based on this assumption, the retrosynthetic analysis of neocarazostatin B (268) leads to the protected 6-bromocarbazole 813 as the key intermediate. For the regioselective introduction of the prenyl group, a reaction of the 6-bromocarbazole 813 with the dimeric p-prenylnickel bromide complex 812 was envisaged (613) (Scheme 5.94). The fully functionalized chiral arylamine 814 with the required R-configuration of the stereogenic center for the total synthesis of neocarazostatin B (268) was obtained from commercial guaiacol (815) over eight steps in 65% overall yield (613). The same racemic arylamine (7)-814 was previously used for the racemic synthesis of neocarazostatin B and was available in 10 steps and 14% overall yield based on o-cresol, a different commercial starting material (614). Protection of 815 as a TPS ether, subsequent ortho-directed lithiation, followed by methylation of the intermediate lithio derivative, afforded the 2,3-dioxygenated toluene 816. For an R-configuration of neocarazostatin B (268), the required chiral side chain was planned to be derived from (R)-propene oxide. Hydrolytic kinetic resolution (HKR) of racemic propene oxide using Jacobsen’s (R,R)-(salen)cobalt(II) complex provided (R)-propene oxide in 99% ee (615–617). Regioselective bromination of 816, followed by halogen–metal exchange and ring opening of the (R)-propene oxide by the intermediate aryllithium, provided the (R)-2-hydroxypropylarene 817. OH OMe H2N

OR

(OC)3Fe

+ 602

OMe

MeCN, rt (26%)

Me CHO

H2N

Ac2O, pyridine DMAP, CH2Cl2, 25°C (78%)

809 R = H 810 R = Ac

AcO

touene, 25°C (25%)

Me CHO

780c

HO

OMe

OMe

NaOH, H2O, reflux Me N H

(73%)

CHO

811

Me N H 264

Scheme 5.93

v.a. MnO2

CHO

253

Chemistry of Carbazole Alkaloids

HO

Br

OMe

AcO

OMe

Br N H

Ni

Me OH

Ni Br

812

268 Neocarazostatin B

Me OAc

N H 813 [Fe(0)] OAc

OMe H2N

Me OAc

597 814

Scheme 5.94

OH

1. TPSCl, Et3N, reflux OMe 2. BuLi, TMEDA ether, 25°C MeI, −78 to 25°C (94% overall)

815

OTPS 1. NBS, MeCN, 25°C OMe 2. t-BuLi, THF Me 816

(R )-(+)-propene oxide, −78°C (91% overall)

TPS = t-BuPh2Si OTPS 1. TBAF, THF/H2O OMe 25°C Me OH 817

OAc

2. Ac2O, Et3N, DMAP CH2Cl2, 25°C (98% overall)

OMe

1. fuming HNO3 HOAc , 25°C

Me OAc

2. H2, Pd/C MeOH, 25°C

818

OAc OMe H2N

Me OAc 814

Scheme 5.95

Removal of the silyl protecting group using TBAF, and subsequent acetylation, led to the diacetate 818. Regioselective nitration and catalytic hydrogenation provided the (R)-arylamine 814 (613) (Scheme 5.95). The construction of the carbazole framework was achieved by slightly modifying the reaction conditions previously reported for the racemic synthesis (614). Reaction of the iron complex salt 602 with the fully functionalized arylamine 814 in air provided the tricarbonyliron-coordinated 4b,8a-dihydrocarbazole complex 819 via sequential C–C and C–N bond formation. This one-pot annulation is the result of an electrophilic aromatic substitution and a subsequent iron-mediated oxidative cyclization by air as the oxidizing agent. The aromatization with concomitant demetalation of complex 819 using NBS under basic reaction conditions, led to the carbazole. Using the same reagent under acidic reaction conditions the carbazole was

254

Chemistry and Biology of Carbazole Alkaloids

transformed to the 6-bromocarbazole 820 as a result of electrophilic bromination. Prenyl coupling of the 6-bromocarbazole 820 with 2 equivalents of the in situ-prepared dimeric p-prenylnickel bromide complex 812 from prenyl bromide and tetra carbonylnickel(0) afforded di(O-acetyl)neocarazostatin B (821) in 66% yield, along with some hydrodebrominated product. Finally, reductive cleavage of both ester groups by treatment with lithium aluminum hydride provided (R)-( )-neocarazostatin B (268). This synthesis provides enantiopure neocarazostatin B in five steps and 36% overall yield based on the iron complex salt 602 (613) (Scheme 5.96). Smooth conversion of (R)-( )-neocarazostatin B (268) to carquinostatin A (278) was achieved by oxidation using cerium(IV) ammonium nitrate (CAN). The identity of the absolute configuration of both alkaloids, and also the enantiopurity of neocarazostatin B (>99% ee), has been additionally confirmed by the transformation of carquinostatin A (278) to the (R,R)-Mosher ester 822 by reaction with (S)-(+)-amethoxy-a-(trifluoromethyl)phenylacetyl (MTPA) chloride (613) (Scheme 5.97). Clive et al. reported the total synthesis of carbazomycin B (261) by radical cyclization of the sulfonamide 827, followed by deprotection and dehydrogenation. The bromo sulfonamide 824 required for the preparation of the key intermediate 827 was obtained from the arylamine 794 (609) (see Schemes 5.85 and 5.89). Alkylation of 824 with 3-bromo-1-cyclohexene (825) gave two conformational isomers of 826 (ratio 3:2). Hydrolysis, followed by benzylation of 826, led to the corresponding O-benzyl derivative 827. The inseparable isomers of 827 were subjected to radical cyclization with triphenyltin hydride in refluxing benzene to afford the hexahydrocarbazole 828 in only 39% yield along with the major by-product 829. Treatment of the hexahydrocarbazole 828 with sodium-naphthalene gave the corresponding hydroxy derivative as a result of deprotection of the N-tolylsulfonyl and O-benzyl groups, and finally, dehydrogenation with 10% Pd/C in triglyme, provided carbazomycin B 261 (618) (Scheme 5.98). Beccalli et al. reported a synthesis of carbazomycin B (261) by a Diels–Alder cycloaddition using the 3-vinylindole 831 as diene, analogous to Pindur’s synthesis of 4-deoxycarbazomycin B (619). The required 3-vinylindole, (Z)-ethyl 3-[(1-ethoxycarbonyloxy-2-methoxy)ethenyl]-2-(ethoxy-carbonyloxy)indole-1-carboxylate (831), was synthesized starting from indol-2(3H)one (830) (620). The Diels–Alder reaction of the diene 831 with dimethyl acetylene dicarboxylate (DMAD) (535) gave the tetrasubstituted carbazole 832. Compound 832 was transformed to the acid 833 by alkaline hydrolysis. Finally, reduction of 833 with Red-Als afforded carbazomycin B (261) (621) (Scheme 5.99). Crich and Rumthao reported a new synthesis of carbazomycin B using a benzeneselenol-catalyzed, stannane-mediated addition of an aryl radical to the functionalized iodocarbamate 835, followed by cyclization and dehydrogenative aromatization (622). The iodocarbamate 835 required for the key radical reaction was obtained from the nitrophenol 784 (609) (see Scheme 5.85). Iodination of 784, followed by acetylation, afforded 3,4-dimethyl-6-iodo-2-methoxy-5-nitrophenyl acetate 834. Reduction of 834 with iron and ferric chloride in acetic acid, followed by reaction with methyl chloroformate, led to the iodocarbamate 835. Reaction of 835 and diphenyl diselenide in refluxing benzene with tributyltin hydride and azobisisobutyronitrile (AIBN) gave the adduct 836 in 40% yield, along with 8% of the recovered substrate and 12% of the deiodinated carbamate 837. Treatment of 836 with phenylselenenyl bromide in dichloromethane afforded the phenylselenenyltetrahydrocarbazole 838. Oxidative

255

Chemistry of Carbazole Alkaloids

AcO

OAc OMe (OC)3Fe

H2N

BF4

Me OAc

602

OMe

(OC)3Fe

MeCN, air 25°C, 7 d (68%)

Me OAc

N H 819

814 1. 2 eq. NBS, 5 eq. Na2CO3 MeCN, 25°C

Br

2. 1.02 eq. NBS, cat. HBr

OMe 2 eq. + 812 Me OAc

N H 820

MeCN, 25°C (88% overall)

AcO

AcO

DMF, 65°C (66%)

HO

OMe

OMe

LiAlH4, ether N H 821

Me OAc

25°C (92%)

Me OH

N H 268

Scheme 5.96

HO

O

OMe

O

3 eq. CAN N H

Me OH

MeCN/H2O, 0°C (92%)

N H

268

278 O

(S)-(+)-MTPA chloride pyridine, CHCl3, 25°C

Me OH

N H

O MeO C6H5 Me CF3 O O

822

Scheme 5.97

deselenation and rearomatization of 838 with tert-butylhydroperoxide (TBHP) afforded the fully aromatized carbazole, which, on base-mediated saponification, led to carbazomycin B (261) (622) (Scheme 5.100).

5 Tricyclic Carbazolequinone and Carbazole-1,4-quinol Alkaloids The tricyclic carbazolequinones represent an important class of carbazole alkaloids with a quinone moiety in the A-ring of the carbazole nucleus. This family of

256

Chemistry and Biology of Carbazole Alkaloids

OAc OH

OMe

(see Schemes 5.85 and 5.89) (6 steps, 36% overall) (ref. 609)

Me Me

H2N

Br2/dioxane CHCl3 (86%)

Me Me

781

794 OAc

Br

OAc OMe

H2N

Me Me

TsCl, pyridine CH2Cl2, 4 d (86%)

Br

OMe

Br TsHN

825 K2CO3, acetone, 56°C

Me Me

823

824 OBn

OAc Br N Ts

OMe

1. KOH, EtOH 2. BnBr, aq. NaOH

Me

N Ts

Bu4N Br , CH2Cl2, rt

Me

OMe

Br

Me Me

827

826 BnO H

OBn

OMe

OMe

Ph3SnH, AIBN Me

benzene, reflux H

N

Ts 828 (39%)

TsHN Me

Me Me 829 (major) HO

OMe

1. Na-naphthalene, THF, rt 2. 10% Pd/C, triglyme, 210°C (46% overall)

Me N H 261

Me

Scheme 5.98

carbazole alkaloids is divided into two groups, depending on the position of the quinone moiety in the A-ring of the carbazole nucleus: the carbazole-1,4-quinones and the carbazole-3,4-quinones. In addition to these two subfamilies, this section also includes the carbazole-1,4-quinol alkaloids. To date, several syntheses have been reported for the natural 1,4-quinone alkaloids and their analogs. In 1994, Furukawa published a review on the isolation and synthesis of natural carbazole-1,4-quinones (105). Six years later, Fillion et al. published a comprehensive review with the coverage of various synthetic approaches towards natural and non-natural carbazole-1,4-quinones (106). In this section, we cover only the total syntheses of the natural carbazole-1,4-quinone alkaloids which have appeared since 1990. In contrast to other sections, this section also includes the formal total syntheses.

257

Chemistry of Carbazole Alkaloids

OMe

(ref. 620)

O

N H

MeOOC

OCOOEt

(2 steps)

122°C, 2 d (90%)

OCOOEt N COOEt

830

COOMe

535

831

EtOOCO

HO

OMe

OMe

NaOH, MeOH/H2O COOMe

COOMe

reflux (74%)

N

COOMe COOEt

N H

832

COOH

833 HO

OMe

Red-Al, dioxane Me

reflux (75%)

N H 261

Me

Scheme 5.99 OH OH

OMe

(see Scheme 5.85) Me Me

(6 steps, 36% overall) (ref. 609)

O2N

2. Ac2O, pyridine (79% overall)

Me Me

781

1. NaI, I2, BuNH2

784 OAc

OAc OMe

I O2N

Me Me

1. Fe, FeCl3, HOAc 2. MeOCOCl, pyridine (70% overall)

HN MeOOC

834

Me

Bu3SnH, AIBN benzene, Δ

OAc OMe

OMe HN MeOOC

Me Me

Me Me

837 (12%)

836 (40%) AcO H PhSeBr (74%)

Me

cat. (PhSe)2

835 OAc

HN MeOOC

OMe

I

HO

OMe

OMe

1. TBHP, benzene, Δ

Me 2. NaOH, Δ (40% overall) PhSe H Me COOMe 838 N

Scheme 5.100

Me N H 261

Me

258

Chemistry and Biology of Carbazole Alkaloids

Furukawa et al. reported the total synthesis of murrayaquinone A (107) by a palladium(II)-mediated oxidative cyclization of the corresponding 2-arylamino-5methyl-1,4-benzoquinones. 2-Anilino-5-methyl-1,4-benzoquinone (842) was prepared starting from 2-methyl-1,4-benzoquinone 841 and aniline 839, along with the regioisomeric 2-anilino-6-methyl-1,4-benzoquinone (844). The oxidative cyclization of 2-anilino-5-methyl-1,4-benzoquinone (842) with stoichiometric amounts of palladium(II) acetate provided murrayaquinone A (107) in 64% yield. This method was also applied to the synthesis of 7-methoxy-3-methylcarbazole-1,4-quinone (113) starting from 3-methoxyaniline (840) (623). Seven years later, Chowdhury et al. reported the isolation of 7-methoxy-3-methylcarbazole-1,4-quinone (113) from the stem bark of Murraya koenigii and named it koeniginequinone A (113) (49) (Scheme 5.101). An alternative regioselective synthesis of 2-anilino-5-methyl-1,4-benzoquinone (842) was developed using 2-bromo-6-methyl-1,4-benzoquinone (846) (route A) and 4,4-dimethoxy-2-methylcyclohexa-2,5-dienone (849) (route B) as synthetic equivalents for methyl-1,4-benzoquinone (841) (623) (Scheme 5.102). Miki and Hachiken reported a total synthesis of murrayaquinone A (107) using 4-benzyl-1-tert-butyldimethylsiloxy-4H-furo[3,4-b]indole (854) as an indolo-2,3quinodimethane equivalent for the Diels–Alder reaction with methyl acrylate (624). 4-Benzyl-3,4-dihydro-1H-furo[3,4-b]indol-1-one (853), the precursor for the 4H-furo[3,4-b]indole (854), was prepared in five steps and 30% overall yield starting from dimethyl indole-2,3-dicarboxylate (851). Alkaline hydrolysis of 851 followed by N-benzylation of the dicarboxylic acid with benzyl bromide and sodium hydride in DMF, and treatment of the corresponding 1-benzylindole-2,3-dicarboxylic acid with trifluoroacetic anhydride (TFAA) gave the anhydride 852. Reduction of 852 with sodium borohydride, followed by lactonization of the intermediate 2-hydroxymethylindole-3-carboxylic acid with 1-methyl-2-chloropyridinium iodide, led to the lactone 853. The lactone 853 was transformed to 4-benzyl-1-tert-butyldimethylsiloxy4H-furo[3,4-b]indole 854 by a base-induced silylation. Without isolation, the O

O Me

R

HOAc H2O, rt

NH2

O Me

R

O

N H

R O

842 R = H (60%) 843 R = OMe (50%)

839 R = H 841 840 R = OMe

Pd(OAc)2, HOAc reflux O

Me

R N O H 107 R = H (64%) 113 R = OMe (65%)

Scheme 5.101

N Me H O 844 R = H (31%) 845 R = OMe (26%)

259

Chemistry of Carbazole Alkaloids

O Br

+ 839 Me HOAc/H O, rt 2 (90%) route A

O 846

Me

OMe

849

Me

N H

Me

H2 N H

O

847

O

MeO

OH

O Br

O

+ 839, THF BuLi, 78°C to rt (37%) route B

OH

848

Me N H MeO OMe

H

air (64%)

(82%) O Me

850 N H 842

O

Scheme 5.102

furoindole 854 was reacted with methyl acrylate to afford the carbazole 855 with the desired regioselectivity. After reduction of the carbazole 855 with lithium aluminum hydride, the corresponding 3-methylcarbazole was acetylated to give 4-acetoxy-9benzyl-3-methylcarbazole (856). Treatment of 856 with aluminum trichloride in anisole furnished a mixture of the debenzylated carbazoles 857 and 858 in 43% and 37% yield, respectively. However, by deacetylation with 10% hydrochloric acid, compound 857 was transformed to 4-hydroxy-3-methylcarbazole 858. Finally, the oxidation of 858 with Fremy’s salt (potassium nitrosodisulfonate) afforded murrayaquinone A (107) (624) (Scheme 5.103). Starting from the known 1,2,3,4-tetrahydrocarbazol-4(9H)-one (859) (625–628), Matsuo and Ishida reported a total synthesis of murrayaquinone A (107) (629,630). After protection of the NH group of tetrahydrocarbazolone 859 with 4-methoxybenzyl chloride (PMBCl), methylation at C 3 was achieved by deprotonation with lithium cyclohexylisopropylamide (LCIA). In order to introduce the 2,3-double bond, the enone 860 was successively treated with LCIA and phenylselenenyl chloride in the presence of HMPA to give a mixture of the phenylselenenylated compound 861 and the aromatized product 862 in 38% and 30% yield, respectively. Further, 861 was converted to the fully aromatic compound 862 by treatment with peracetic acid. Oxidation of 862 with Fremy’s salt led to the corresponding quinone in good yield. However, all attempts to remove the N-protecting group of this quinone intermediate failed. Therefore, prior to deprotection of the nitrogen atom, the 4-hydroxy group was protected by acetylation to afford the 4-acetoxycarbazole 863. After deprotection of the N-atom in 863, the ester group was hydrolyzed to give the corresponding 4-hydroxycarbazole 858. Finally, oxidation with Fremy’s salt transformed the compound 858 to murrayaquinone A (107) (629,630) (Scheme 5.104). Hanaoka et al. reported a total synthesis of murrayaquinone A (107) based on an anionic [4+2] cycloaddition of the indole ester 864 with phenyl b-trimethylsilylvinyl sulfone (865) (631). The reaction of the MOM-protected indole 864 with phenyl

260

Chemistry and Biology of Carbazole Alkaloids

COOMe

O

1. H2O, OH 2. BnBr, NaH, DMF

O

COOMe 3. (F3CCO)2O (44% overall)

N H 851

N Bn 852

O

O

OTBDMS TBDMSCl

O N Bn

2. BF3 Et2O (87% overall)

N Bn

853

2. lactonization (67% overall)

1. methyl acrylate THF, −78°C

O

base

1. NaBH4, THF

854

HO

AcO

COOMe

Me AlCl3

1. LiAlH4, dioxane 2. Ac2O, pyridine (84% overall)

N Bn

anisole

N Bn 856

855 10% HCl, hot THF (85%) AcO

Me

HO

O

Me

Me

(KSO3)2NO (83%) N H 857 (43%)

N H 858 (37%)

N H 107

O

Scheme 5.103

b-trimethylsilylvinyl sulfone (865) in the presence of LDA afforded the cycloadduct 866 with the required regioselectivity. Methylation of 866 with methyl iodide in the presence of potassium tert-butoxide gave the two diastereoisomers 867 and 868 in 31% and 25% yield, respectively. This mixture was treated with TBAF in THF to afford the 4-hydroxycarbazole 869. Oxidation of 869 with [bis(trifluoroacetoxy) iodo]benzene gave N-MOM-murrayaquinone A (870). Finally, removal of the methoxymethyl group with hydrochloric acid in methanol provided murrayaquinone A (107) (631) (Scheme 5.105). Wu et al. reported the total synthesis of clausenaquinone A (112) using a palladium(II)-mediated oxidative cyclization of the 2-arylamino-5-methoxy-1,4benzoquinone 874 (107). This total synthesis was undertaken to establish the structure of natural clausenaquinone A (112). The key intermediate, 2-(3-hydroxy-4methylanilino)-5-methoxy-1,4-benzoquinone (874), required for this synthesis, was obtained by the reaction of 5-amino-o-cresol (873) with 2-methoxy-1,4-benzoquinone (872) which was readily obtained by oxidation of methoxyhydroquinone (871). The palladium(II)-mediated oxidative cyclization is non-regioselective. Thus, the cyclization of the 2-arylamino-5-methoxy-1,4-benzoquinone 874 with palladium(II)

261

Chemistry of Carbazole Alkaloids

O

O

Me

1. NaH, MPMCl, DMF, rt

LCIA, HMPA

2. LCIA, MeI, THF (70% overall)

N H

PhSeCl, THF −23 to −14°C to rt

N PMB

859

860 PMB = p-methoxybenzyl LCIA = lithium cyclohexylisopropylamide

30% H2O2, HOAc, −2 to 0°C (49%) O

HO

Me SePh

AcO

Me

Me

AcCl, Et3N

N PMB

CH2Cl2 (89%)

N PMB

861 (38%)

N PMB

862 (30%) HO

N H 858

(66% overall)

O

(KSO3)2NO KH2PO4

Me

1. AlCl3, anisol, 0 to 3°C 2. aq. HCl/MeOH, reflux

863

acetone/H2O, rt (84%)

Me

N H 107

O

Scheme 5.104

O COOEt Me N MOM

SO2Ph

TMS

(63%)

TMS

N MOM

865

864

866 O

O

Me

KOt-Bu MeI

SO2Ph

TMS

TMS N MOM

O

Me (59%)

TBAF, THF (85%)

868 (25%)

PhI(OCOCF3)2 N MOM 869

Me

SO2Ph N MOM 867(31%) HO

SO2Ph

LDA, THF, −70°C

O

Me

Me

HCl/MeOH N O MOM 870

Scheme 5.105

(93%)

N H 107

O

262

Chemistry and Biology of Carbazole Alkaloids

acetate in acetic acid under reflux provided clausenaquinone A (112) and the regioisomeric product 875 in a 1:1 ratio (107) (Scheme 5.106). ˚ kermark et al. applied (548) a catalytic version of Furukawa’s palladium-mediated A (stoichiometric) cyclization of 2-anilino-5-methyl-1,4-benzoquinone (842) to a total synthesis of murrayaquinone A (107) (see Scheme 5.101) (623). In this cyclization, only 5 mol% of palladium(II) acetate and an excess of TBHP as reoxidant were used (548). Subsequently, a catalytic cyclization of 842 to murrayaquinone A (107), using oxygen for the reoxidation of palladium, was reported (549) (Scheme 5.107). Murakami et al. reported (575) a total synthesis of murrayaquinone A (107) by oxidation of 1-hydroxy-3-methylcarbazole (23) with Fremy’s salt, as previously described by Martin and Moody (632). The hydroxycarbazole 23 required for this synthesis was obtained via the Fischer indolization of the O-methanesulfonyl phenylhydrazone 614 (575) (see Scheme 5.38). The oxidation of 1-hydroxy-3methylcarbazole (23) with Fremy’s salt afforded murrayaquinone A (107) as the major product, along with a 5% yield of isomeric carbazole-1,2-quinone 876 (575) (Scheme 5.108). Me

OH

O OMe

OMe

Na2Cr2O7

HO

NH2

873 MeOH

H2SO4 OH 871

O Me

OMe

HO

N H 874

O 872 O

Me

OMe

OH O

Me

O

OMe

Pd(OAc)2 HOAc

HO N H 112

N H 875

O

O

Scheme 5.106 O

O Me NH2 839

O 841

Me

EtOH, rt N H 842

O

0.05 eq. Pd(OAc)2 2.5 eq. TBHP HOAc (67%)

0.05 eq. Pd(OAc)2, O2 HOAc, 95°C (86%)

O

N H 107

Scheme 5.107

Me

O

Chemistry of Carbazole Alkaloids

263

Me

Me

(see Scheme 5.38) (5 steps, 48%)

NH2 HCl

N H 23

OH 612 O

OH

Me

Me

(KSO3)2NO O

acetone/H2O

N O H 107 (80%)

N O H 876 (5%)

Scheme 5.108 O

O

O

O

Me

Me CuCl , NaHCO 2 3 NH

MeCN, 40°C (30%)

Br O

Bn 877

TsNHNH2 N Bn 879

878

HOAc, rt (84%)

O

TsHN N

O

N Bn

Me

O

1. aq. Na2S2O4, CH2Cl2 2. 6 eq. BuLi, THF, rt 3. air oxidation (41% overall)

N Bn 881

880 O

Me

O

O

Me

Me

TFA, cat. TfOH

DDQ, dioxane reflux (89%)

O

N Bn 882

O

reflux (60%)

N H 107

O

Scheme 5.109

Murphy and Bertrand reported a total synthesis of murrayaquinone A (107) based on his bromo-enamino ketone/enamino ester annulation route (633). This annulation methodology starts from the N-benzylenaminone (877) and 5-bromo-2-methyl-1,4benzoquinone (878). Reaction of 877 and 878 led to the desired regioselective annulation product 879 involving Michael addition, followed by in situ reoxidation and dehalocyclization. The hexahydrocarbazoletrione 879 was transformed to Nbenzylmurrayaquinone A (882) using Shapiro’s deoxygenation–olefination and subsequent dehydrogenation with DDQ. Finally, debenzylation of 882 in TFA with a catalytic amount of TfOH afforded murrayaquinone A (107) (633) (Scheme 5.109). Saha and Chowdhury reported the total synthesis of koeniginequinones A (113) and B (114) to confirm the assigned structures for these natural 3-methylcarbazole-

264

Chemistry and Biology of Carbazole Alkaloids

1,4-quinone alkaloids (49). This synthesis uses a Fischer indolization as a key step involving the corresponding phenylhydrazones 517b and 884. The required phenylhydrazones 517b and 884 were obtained by a Japp–Klingemann reaction of 2-hydroxymethylene-5-methylcyclohexanone 515a and the aryldiazonium chlorides 516b and 883, respectively. Aromatization of the 1-oxotetrahydrocarbazoles 518b and 885 with 5% palladium on charcoal at 170–1801C in a sealed tube afforded the 1-hydroxycarbazoles 886 and 887. Finally, oxidation of 886 and 887 with Fremy’s salt provided koeniginequinone A (113) and B (114) in 65.5% and 72% yield, respectively (49) (Scheme 5.110). Chowdhury et al. reported a synthesis of murrayaquinone A (107) starting from 3-methylcarbazole (2) (634). In a one-pot operation, direct, photochemical oxidation of 3-methylcarbazole (2) in a solution of methanol using UV light at 254 nm led to murrayaquinone A (107) in 24% yield. This reaction is assumed to proceed via photoperoxidation involving the intermediates 888a and 888b (634) (Scheme 5.111). This transformation supports the biogenetic relationship between the carbazoloquinones and the corresponding carbazoles. Recently, we reported two-step total syntheses of murrayaquinone A (107), koeniginequinone A (113), and koeniginequinone B (114) starting from the commercially available arylamines 839, 840, and 889, respectively (635). In these syntheses, catalytic amounts of palladium(II) acetate were used for the key transformations of the 2-arylamino-5-methyl-1,4-benzoquinones 842, 843, and 890 to the corresponding 3-methylcarbazole-1,4-quinones 107, 113, and 114. The required 2-arylamino-5-methyl-1,4-benzoquinones 842, 843, and 890 were obtained in improved yield by the addition of the arylamines 839, 840, and 889 to 2-methyl1,4-benzoquinone (841) using Musso’s conditions. Finally, palladium(II)-catalyzed R

Me Cl

MeO

N N

R

aq. NaOAc MeOH

HOHC

MeO

O 515a

516b R = H

N N H

O 517b R = H (75%) 884 R = OMe (70%)

883 R = OMe R

Me 5% Pd/C, EtOH/H2O

HOAc, conc. HCl MeO

110°C

Me

N H

O

170 to 180°C sealed tube

518b R = H (65.5%) 885 R = OMe (75%) R

O

R

Me

Me

(KSO3)2NO, KH2PO4 MeO N H

acetone,dioxane, rt OH

MeO N H

O

113 R = H (65.5%) 114 R = OMe (72%)

886 R = H (66%) 887 R = OMe (62%)

Scheme 5.110

265

Chemistry of Carbazole Alkaloids

O Me

Me MeOH, O2

O

UV light, 254 nm (24%)

N H

O

N H 107

O

N H 888a

2

Me

H

N H H 888b

O

Me

O

Scheme 5.111 O

O R2

Me

R1

−2 to −4°C, 4 to 5 d

NH2 1

HOAc/MeOH/H2O

O 841

2

839 R ,R = H

R1

N H

O

2

842 R ,R = H (70%) 843 R1 = OMe; R2 = H (65%) 890 R1,R2 = OMe (64%) O

R2 2.5 eq. Cu(OAc)2 HOAc, Δ, air

Me

1

840 R1 = OMe; R2 = H 889 R1,R2 = OMe

cat. Pd(OAc)2

R2

Me

R1 N H

O

107 R1,R2 = H (73%) 113 R1 = OMe; R2 = H (44%) 114 R1,R2 = OMe (69%)

Scheme 5.112

oxidative cyclization of 842, 843, and 890 afforded the 3-methylcarbazole-1,4-quinone alkaloids murrayaquinone A (107), koeniginequinone A (113), and koeniginequinone B (114), respectively (635) (Scheme 5.112). In addition to the aforementioned syntheses of various carbazole-1,4-quinone alkaloids, many formal syntheses for this class of carbazole alkaloids were also reported. These syntheses involve the oxidation of the appropriate 1- or 4-oxygenated-3-methylcarbazoles using Fremy’s salt (potassium nitrosodisulfonate), or PCC (pyridinium chlorochromate), or PhI(OCOCF3)2 [bis(trifluoroacetoxy)iodo]benzene. Our iron-mediated formal synthesis of murrayaquinone A (107) was achieved starting from murrayafoline A (7) (see Scheme 5.34). Cleavage of the methyl ether in murrayafoline A (7) and subsequent oxidation of the resulting intermediate hydroxycarbazole with Fremy’s salt provided murrayaquinone A (107) (574,632) (Scheme 5.113).

266

Chemistry and Biology of Carbazole Alkaloids

OMe (6 steps, 1% overall) (OC)3Fe

OMe

(see Scheme 5.34) (ref. 574)

BF4

NH2 599

602

Me N H 648

(6 steps, 5% overall)

N O O

(see Scheme 5.46) (ref. 584)

O

N H 7

OMe

Me 1. BBr3, CH2Cl2, −78°C

N H 107

2. (KO3S)2NO, H2O/acetone (ref. 574,632)

O

Scheme 5.113 HO CHO N H 891

Me

(7 steps, 26% overall)

Cl

(ref. 636,637)

N H 858

O

Me

Fremy's salt (see Scheme 5.104) (ref. 629,630)

N H 107

O

Scheme 5.114

Mal et al. also reported a formal synthesis of murrayaquinone A (107) starting from murrayafoline A (7). However, the required murrayafoline A (7) was obtained by the benzannulation of furoindolone, which was prepared by Fischer indolization of 3-(2-phenylhydrazono)dihydrofuran-2(3H)-one (648) (see Scheme 5.46) (584) (Scheme 5.113). Hibino et al. reported a formal synthesis of murrayaquinone A (107) starting from 2-chloro-3-formylindole (891) by an allene-mediated electrocyclic reaction involving the indole 2,3-bond. The 4-hydroxy-3-methylcarbazole (858), a known precursor for murrayaquinone A (107), and required for this formal synthesis was obtained in seven steps, and 26% overall yield, starting from the 2-chloro-3-formylindole (891) (636,637) (Scheme 5.114). Scott and So¨derberg also reported a formal synthesis of murrayaquinone A (107) starting from 4-hydroxy-3-methylcarbazole (858) which was obtained from the

Chemistry of Carbazole Alkaloids

267

1,2-dihydro-4-(3H)-carbazolone 896 (638). This synthesis starts from 6-methyl-2cyclohexenone (892) and uses two, sequential, palladium-catalyzed, intermolecular Stille cross-coupling and reductive N-heteroannulation steps. Iodination of 892 followed by Stille cross-coupling of the corresponding iodo derivative 893 with the arylstannane 894 gave the annulation precursor 895. Reductive cyclization of 895 afforded the carbazolone 896. Dehydrogenation of the carbazolone 896 using Pd/C in a mixture of diphenyl ether and 1,2,4-trimethylbenzene at 2301C led to 4-hydroxy3-methylcarbazole (858). Finally, the literature-known oxidation of 858 using Fremy’s salt (629,630) leads to murrayaquinone (107) (638) (Scheme 5.115). On the basis of their earlier aromatic annulation strategy (see Scheme 5.64) (596), Shin and Ogasawara reported the first enantioselective total synthesis of carbazoquinocins A (272) and D (275) (639). The required methyl-substituted secondary chiral stereogenic center of the alkyl side chain at C-1 of carbazoquinocins A and D was introduced starting from the O-benzyl (R)-glycidol (R)-897. Thus, the (R)-glycidol (R)-897 was transformed to ethyl (S)-6-benzyloxy-3methyl-4(E)-hexenoate (S)-899 via addition of acetylide followed by spontaneous isomerization, stereoselective reduction, and Claisen–Johnson rearrangement. The chiral ester (S)-899 was converted to (R)-4-methyl-6-phenylthiohexanol (R)-902. The primary alcohol (R)-902 was then transformed to the terminal acetylene (R)-904, a common intermediate for the synthesis of carbazoquinocins A (272) and D (275). Chain elongation of (R)-904 by two carbon atoms led to (R)-905, the chiral precursor for carbazoquinocin D (275) (639) (Scheme 5.116). Using Sonogashira conditions, the (R)-acetylenes (R)-904 and (R)-905 were coupled with N-carbethoxy-2-iodoaniline 700 to afford the aryl acetylenes (R)-906 and (R)-907. Executing similar functional group transformations as reported SnBu3

O

NO2

O Me

I

I2, CCl4

CuI, NMP, 80°C (87%)

pyridine (71%) 892

O

894 Me PdCl (PhCN) , Ph As 2 2 3

Me NO2 895

893 O

Pd(dba)2, dppp 1,10-phenanthroline CO (6 atm), DMF, 80°C (97%)

HO

Me Pd/C, Ph2O, 230°C 1,2,4-trimethylbenzene (63%)

N H 896

O

Me

Me

Fremy's salt N H 858

(ref. 629,630)

N H 107

Scheme 5.115

O

268

Chemistry and Biology of Carbazole Alkaloids

1. LiC CH/(CH2NH2)2 H BnO

H

DMSO, 0°C to rt

O 2. KOt-Bu (79% overall)

BnO

(R)-898

(R )-897 BnO

OH

COOEt

LiAlH4

1. LiAlH4, THF, 0°C to reflux 2. MeC(OEt)3, cat. pivalic acid 140°C 3. H2, Pt2O, EtOH, rt (79% overall)

X

THF, 0°C (98%) (S )-899

PhSSPh, Bu3P THF, rt CBr4, PPh3 CH2Cl2, rt

LiC CH/(CH2NH2)2 Y

DMSO, 0°C to rt (80% overall)

(R )-900 X = OBn, Y = OH (R )-901 X = OBn, Y = SPh (R )-902 X = OH, Y = SPh

BBr3, CH2Cl2, 0°C

(R )-903 X = Br, Y = SPh

1. LDA, EtI HMPA/THF (1:8) SPh (R )-904

2. KAPA, (CH2NH2)2 −78 to −23°C (70% overall)

SPh (R)-905

KAPA = potassium 3-aminopropylamide

Scheme 5.116

previously for the total synthesis of carazostatin (247) (see Scheme 5.64) (596), the aryl acetylenes (R)-906 and (R)-907 were transformed to the 3-ethoxycarbonyl-2methylcarbazoles (S)-908 and (S)-909, and subsequently to the 3-hydroxy-2methylcarbazoles (S)-910 and (S)-911. Finally, oxidation of the 3-hydroxycarbazoles (S)-910 and (S)-911 with benzeneseleninic anhydride [(PhSeO)2O] yielded quantitatively (S)-( )-carbazoquinocin A (272) and (S)-( )-carbazoquinocin D (275), respectively (639) (Scheme 5.117). Hibino et al. reported the total synthesis of the carbazoquinocins B (273), C (274), D (275), E (276), and F (277) by his previously reported benzannulation method involving an allene-mediated, electrocyclic reaction of 2,3-functionalized indoles (536,537). The carbazole triflate 740, a key-intermediate in the total synthesis of carazostatin (247) and hyellazole (245) (see Scheme 5.74) (536,537), also served as a common precursor for the total synthesis of the carbazoquinocins B–F (273–277). A Suzuki cross-coupling reaction of the carbazole triflate 740 with 9-alkyl-9-borabicyclo[3.3.1]nonane (9-alkyl-9BBN) 912a–e afforded the 1-alkylcarbazoles 913, 741, and 914–916 (56–85% yield). Cleavage of the ether by treatment of 913, 741, and 914–916 with boron tribromide gave the corresponding 3-hydroxycarbazoles 917, 247, and 918–920 (64–97% yield). Finally, the 3-hydroxycarbazoles 917, 247, and 918–920 were transformed to carbazoquinocin B (273), C (274), D (275), E (276), and F (277) in 70–95% yield, respectively, by oxidation with benzeneseleninic anhydride (537) (Scheme 5.118). Our total synthesis of carbazoquinocin C (274) based on the iron-mediated construction of the carbazole framework as a key step uses the fully functionalized arylamine 921 and cyclohexadiene (597) as precursors (640) (Scheme 5.119). The required arylamine 921 was prepared in a straightforward manner starting from commercial 3-methylveratrole (789). Regioselective bromination of the veratrole 789 afforded the 4-bromo derivative 790 in 88% yield. Halogen–metal

Chemistry of Carbazole Alkaloids

269

SPh

I NH COOEt

n+1

+(R )-904/ or (R)-905 PdCl2(PPh3)2, CuI Et3N, reflux (89%)

(see Scheme 5.64) NH COOEt (R )-906 n = 2 (R )-907 n = 4

700 COOEt

OH (see Scheme 5.64)

Me N H

Me N H

n

(S)-908 n = 1 (8 steps, 20%) (S)-909 n = 3 (8 steps, 19%) O

n

(S)-910 n = 1 (4 steps, 20%) (S)-911 n = 3 (4 steps, 19%) O

(PhSeO)2O CH2Cl2, rt

Me N H

n

272 n = 1 (~100%) 275 n = 3 (~100%)

Scheme 5.117

exchange of 790 using butyllithium, followed by alkylation with 1-bromoheptane and subsequent regioselective nitration of the intermediate 4-heptyl derivative with fuming nitric acid in a mixture of acetic anhydride and glacial acetic acid (3:1), gave the 5-nitro derivative 922 in 50% overall yield. Finally, catalytic hydrogenation of the nitro derivative 922 led to the arylamine 921 in 83% yield (640). Reaction of the iron complex salt 602 with the arylamine 921 in the presence of air led directly to the tricarbonyl(Z4-4b,8a-dihydro-9H-carbazole)iron complex (923) by a one-pot C–C and C–N bond formation. Demetalation of complex 923 and subsequent aromatization by catalytic dehydrogenation afforded 3,4-dimethoxy-1heptyl-2-methylcarbazole (924), a protected carbazoquinocin C. Finally, ether cleavage of 924 with boron tribromide followed by oxidation in air provided carbazoquinocin C (274) (640) (Scheme 5.120). A common precursor, the 6-bromocarbazole derivative 927, required for the total synthesis of the carbazole-3,4-quinone alkaloids (7)-carquinostatin A [(7)-278] (641) and (7)-lavanduquinocin [(7)-280] (642), was prepared by iron-mediated one-pot C–C and C–N bond formation. Recently, the same methodology was adopted for the first enantioselective total synthesis of carquinostatin A (278) (643) and lavanduquinocin (280) (644). The key intermediate, 6-bromocarbazole 927, required for the first enantioselective total synthesis of carquinostatin A (278) and lavanduquinocin (280) arises from the (R)-arylamine 928 and the iron complex salt 602 (Scheme 5.121).

270

Chemistry and Biology of Carbazole Alkaloids

B R

OEt (see Scheme 5.74)

912a-e Me

CHO (9 steps, 17.5%)

N H

N H

OTf

a R = (CH2)4CHMe2 b R = (CH2)6Me c R = (CH2)4CHMeCH2Me d R = (CH2)5CHMe2 e R = (CH2)6CHMe2

740

734

OEt

OH BBr3, CH2Cl2

Me N H

R

(PhSeO)2O Me

−78°C to rt (64 to 97%)

913 R = (CH2)4CHMe2 741 R = (CH2)6Me 914 R = (CH2)4CHMeCH2Me 915 R = (CH2)5CHMe2 916 R = (CH2)6CHMe2 O

PdCl2(dppf), NaOH, THF (56 to 85%)

N H

R

THF, 50°C (70 to 95%)

917 R = (CH2)4CHMe2 247 R = (CH2)6Me 918 R = (CH2)4CHMeCH2Me 919 R = (CH2)5CHMe2 920 R = (CH2)6CHMe2

O Me

N H

R

273-277

Scheme 5.118 O

OMe

O

OMe

[Fe(0)] Me N H

C7H15

H2N 597

274 Carbazoquinocin C

Me C7H15 921

Scheme 5.119

The chiral side chain of the (R)-arylamine (928) derived from (R)-propene oxide and was obtained in 99% ee by Jacobsen’s HKR of racemic propene oxide using (R,R)-(salen)cobalt(II) complex (615–617). The regioselective bromination of 3-methylveratrole (789) afforded the corresponding 4-bromo derivative 790 in almost quantitative yield. Halogen–metal exchange using butyllithium, followed by reaction with the (R)-propene oxide, afforded the (R)-carbinol 929. Protection of 929 as the (R)-acetate 930 and subsequent regioselective nitration, followed by catalytic hydrogenation of the intermediate 5-nitro derivative, led to the (R)-arylamine 928 (643) (Scheme 5.122).

Chemistry of Carbazole Alkaloids

OMe

OMe OMe

25°C, 3 h (88%)

Me

1. BuLi, THF, −78°C C7H15Br, −78 to 25°C

OMe

NBS, MeCN

2. 100% HNO3 Ac2O/HOAc (3:1), 0°C (50% overall)

Me Br

789

790 OMe OMe

O2N

(OC)3Fe

OMe

MeOH, 25°C (83%)

Me C7H15

BF4

OMe

H2, Pd/C H2N

Me C7H15

922

602 MeCN, air, 25°C, 6 d (76%)

921 MeO

MeO

OMe 1. 8 eq. Me3NO 2H2O acetone, 56°C

(OC)3Fe

Me

Me 2. Pd/C, o-xylene, 145°C N H

N H

(85% overall)

C7H15

OMe

C7H15

924

923 O

1. BBr3, CH2Cl2 −78 to 25°C

O Me

2. air, MeCN, 25°C (65% overall)

N H

C7H15

274

Scheme 5.120

O

R

N H

Br

O Me OH

278 Carquinostatin A R = prenyl 280 Lavanduquinocin R = β-cyclolavandulyl

MeO

OMe

RBr

Me OAc

N H 925 R = prenyl 926 R = β-cyclolavandulyl

927

OMe Br

OMe (OC)3Fe

H2N

BF4

Me OAc

602

926

928

Scheme 5.121

271

272

Chemistry and Biology of Carbazole Alkaloids

OMe

OMe OMe Me

NBS, MeCN 25°C, 20 h (96%)

789

OMe OMe Me

Br 790

1. BuLi, THF, −78°C

OMe

2. (R)-(+)-propene oxide −78 to 25°C (80%)

Me OH 929

OMe Ac2O, Et3N, DMAP CH2Cl2, 25°C (100%)

OMe

1. 100% HNO3 Ac2O/HOAc (3:1), 0°C

Me OAc

2. H2, 10% Pd/C MeOH, 25°C (77% overall)

930

OMe OMe H2N

Me OAc 928

Scheme 5.122

Construction of the carbazole framework was achieved by slightly modifying the reaction conditions previously reported for the racemic synthesis (641,642). The reaction of the (R)-arylamine 928 with the iron complex salt 602 in air provided by concomitant oxidative cyclization the tricarbonyliron-complexed 4b,8a-dihydro-9Hcarbazole (931). Demetalation of the complex 931, followed by aromatization and regioselective electrophilic bromination, afforded the 6-bromocarbazole 927, which represents a crucial precursor for the synthesis of the 6-substituted carbazole 3,4-quinone alkaloids. A nickel-mediated cross-coupling of the 6-bromocarbazole 927 with prenyl bromide (925) and b-cyclolavandulyl bromide (926), followed by ester cleavage and oxidation with either cobalt(III) fluoride or CAN, afforded carquinostatin A (278) (643) and lavanduquinocin (280) (644), respectively (Scheme 5.123). Our second approach for the total synthesis of carbazoquinocin C (274) uses the palladium(II)-catalyzed oxidative coupling of aniline (839) and 2-methoxy-3-methyl1,4-benzoquinone (939), followed by regioselective introduction of the heptyl side chain onto the carbazole-1,4-quinone 941 (645). The required 1,4-benzoquinone 939 was prepared starting from commercial 2,6-dimethoxytoluene (935). The titanium tetrachloride-promoted Friedel–Crafts acylation of 935 led to the acetophenone 936, which was further transformed into the aryl acetate 937 by a proton-catalyzed Baeyer–Villiger oxidation. Ester cleavage of 937 to the phenol 938 and oxidation with CAN, [(NH4)2Ce(NO3)6], afforded 2-methoxy-3-methyl-1,4-benzoquinone (939). Addition of aniline (839) to 2 equivalents of 1,4-benzoquinone 939 provided the corresponding 5-anilino-2-methoxy-3-methylbenzoquinone (940) in 84% yield with the expected regioselectivity (545,645) (Scheme 5.124). The intramolecular oxidative cyclization of the anilinobenzoquinone 940 with a catalytic amount of palladium(II) acetate in the presence of copper(II) acetate in air afforded the carbazole-1,4-quinone 941 in almost quantitative yield. The regioselective introduction of the heptyl side chain at C-1 of the carbazole-1,4-quinone 941 was achieved by a 1,2-addition of the corresponding Grignard reagent to give the carbazole-1,4-quinol 942 in 55% yield. However, 1,4-addition at C-3 and 1,2-addition at C-4 led to the regioisomeric products 943 and 944 as well. Finally, under acidic reaction conditions, the carbazole-1,4-quinol 942 was smoothly transformed to

Chemistry of Carbazole Alkaloids

MeO

OMe OMe (OC)3Fe

602

R

MeO

2. 10% Pd/C, o-xylene 15 vol.-%, 1-hexene, reflux (87% overall)

OMe Me OAc

N H 932 R = H

NBS, cat. HBr MeCN, 25°C (100%)

927 R = Br

MeO

2 eq. 812

10 eq. 926, 10 eq. (cod)2Ni

DMF, 65°C (94%)

DMF, 25°C, 7 d (36%)

MeO

OMe Me OAc

N H 933

Me OAc

N H 931

928

1. 8 eq. Me3NO 2H2O acetone, 56°C

OMe

(OC)3Fe

Me 25°C, 9 d (94%) OAc

H2N

BF4

MeCN, air

273

OMe Me OAc

N H 934

1. LiAlH4, ether, 25°C 2. CoF3, dioxane/H2O, 25°C (69% overall) O

N H 278

1. LiAlH4, ether, 25°C 2. CAN, MeCN/H2O, 25°C (64% overall) O

O Me OH

N H 280

O Me OH

Scheme 5.123

carbazoquinocin C (274) by cleavage of the methyl ether, followed by elimination of water (545,645) (Scheme 5.125). Retrosynthetic analysis of carbazoquinocin C (274) and (7)-carquinostatin A (7)-278 based on our highly convergent palladium(II)-mediated intramolecular oxidative coupling of arylamino-1,2-benzoquinones provides aniline (839) and 4-heptyl-3-methyl-1,2-benzoquinone (946) as precursors for 274, and 4-prenylaniline (945) and 4-(2-hydroxypropyl)-3-methyl-1,2-benzoquinone (947) as precursors for (7)-278 (646) (Scheme 5.126).

274

Chemistry and Biology of Carbazole Alkaloids

Ac OMe

AcCl, TiCl4 benzene, 0°C (95%)

Me OMe 935

OR OMe

OMe

MCPBA, cat. TsOH CH2Cl2, 0 to 25°C (91%)

Me OMe

Me OMe

KOH, EtOH/H2O, 25°C (90%)

936

937 R = Ac 938 R = H O

O (NH4)2Ce(NO3)6

OMe

MeCN/H2O, 0°C (90%)

Me

OMe

+839 MeOH, 25°C (84%)

O 939

N H

Me O

940

Scheme 5.124 O

N H

O

cat. Pd(OAc)2 2.5 eq. Cu(OAc)2

OMe

15 eq. C7H15MgCl Me

HOAc, 117°C 3 d, air (91%)

Me O

N H 941

940 O

O

OMe

OMe

C7H15

THF, −78°C

O

HO

C7H15 OMe

Me

Me N C7H15 HO H

N H

942 (55%)

Me N H

O

943 (8%)

O

944 (trace) O

O

MeOH/con. HBr (2.5:1) Me

25°C (92%)

N H

C7H15

274

Scheme 5.125 O

R2

O

O [Pd(II)]

R2

O

Me N H

R1

274 Carbazoquinocin C 1

Me

NH2

R1

2

R = C7H15; R = H

839 R2 = H 945 R2 = prenyl

(+ − )-278 ( + −)-Carquinostatin A R1 = CH2CH(OH)Me; R2 = prenyl

Scheme 5.126

946 R1 = C7H15 947 R1 = CH2CH(OH)Me

Chemistry of Carbazole Alkaloids

275

The veratrole 948, required for the preparation of the 5-anilino-4-heptyl-3-methyl1,2-benzoquinone (950), was already used as a precursor for the iron-mediated synthesis of carbazoquinocin C (274) (see Scheme 5.120). Ether cleavage of the veratrole 948 using boron tribromide afforded the corresponding catechol 949. Oxidation of 949 with o-chloranil gave the required 1,2-benzoquinone 946 (see Scheme 5.126). The 1,2-benzoquinone 946 proved to be very labile. Therefore, it was transformed in situ to the anilino-1,2-benzoquinone 950 by addition of 0.5 equivalents of aniline (839) in methanol at low temperature. The oxidative cyclization using palladium(II) acetate in glacial acetic acid at 551C transformed compound 950 directly to carbazoquinocin C (274). Using this approach, carbazoquinocin C (274) is available in three steps and 29% overall yield based on the veratrole 948 (646) (Scheme 5.127). Among the three known methods of our total syntheses of carbazoquinocin C (274) this palladium(II)-mediated o-quinone approach combines the advantages of both previous approaches (see Schemes 5.120 and 5.125) by using a fully functionalized 1,2-benzoquinone as a building block. 4-Prenylaniline (945) required for the synthesis of (7)-carquinostatin A [(7)-278] (see retrosynthesis in Scheme 5.126) was obtained by a nickel-mediated cross-coupling reaction of the N-protected 4-bromoaniline 952 with bis[m-bromo(Z3-prenyl)nickel] (825) (646) (Scheme 5.128). Following a synthetic pathway similar to the one reported for carbazoquinocin C (274) (see Scheme 5.127), the veratrole (7)-818 was transformed to the arylamino-1,2benzoquinone (7)-954. By palladium(II)-mediated oxidative cyclization, compound

OH

OMe OMe

OH

BBr3, CH2Cl2 −78°C to rt (92%)

Me C7H15

Me C7H15

948

1. o-chloranil, ether, −6°C 2. 0.5 eq. 839, MeOH, −6°C (73%)

949 O

O O N H

O

Pd(OAc)2, HOAc

Me C7H15

Me

55°C (43%)

N H 274

950

C7H15

Scheme 5.127

Br

1. phthalic anhydride benzene, 80°C

Br 1. 2 eq. 825, DMF, 65°C 2. N2H4 H2O, MeOH, rt

2. acetyl chloride, 52°C NH2 951

(91% overall)

NPhth 952

Scheme 5.128

(91% overall)

NH2 945

276

Chemistry and Biology of Carbazole Alkaloids

(7)-954 was transformed to O-acetylcarquinostatin A (7)-955. Finally, removal of the acetyl protecting group by reduction with lithium aluminum hydride provided (7)-carquinostatin A [(7)-278] in 62% yield (Scheme 5.129). Using this methodology, (7)-carquinostatin A [(7)-278] is available in four steps, and 33% overall yield, based on the veratrole (7)-818 (646) (Scheme 5.129). Aygu¨n and Pindur reported the total synthesis of carbazoquinocin C (274) starting from N-(phenylsulfonyl)indole (956) (647). The key step in this methodology involves a polar cyclization of the 2-vinylindole 958 with oxalyl chloride. Regioselective 2-lithiation of N-(phenylsulfonyl)indole (956), followed by addition of 3-decanone, led to the carbinol 957. Elimination of water with TFA/triethylamine in chloroform, followed by removal of the protecting group with sodium hydroxide in ethanol, afforded the 2-vinylindole 958, along with an undesired double bond regioisomer (ratio 2:1, no yield given). The reaction of compound 958 with oxalyl chloride led to the corresponding indole-3-glyoxyl chloride, which on treatment with aluminum(III) chloride provided carbazoquinocin C (274) in 59% yield (647) (Scheme 5.130). This three-step synthesis was applied to a wide range of carbazole3,4-quinones (648,649). Rawat and Wulff reported the total synthesis of carbazoquinocin C (274) starting from indole 2-carboxylic acid (959) (563). This methodology uses the application of o-benzannulation of the Fischer carbene complexes 964 and 965. The fully functionalized carbene complexes 964 and 965 required for the synthesis of carbazoquinocin C (274) were prepared from commercially available indole 2-carboxylic acid (959). The heptyl-2-indolyl ketone (960) was obtained from the acid 959 through Grignard addition to Weinreb’s amide. After protection of the indole nitrogen, the corresponding N-benzyl derivative 962 was brominated to the corresponding 3-bromo derivative 963, the precursor required for the carbene complexes 964 and 965. Using the standard Fischer procedure, the 3-bromo

OH

OMe OMe Me OAc

OH

BBr3, CH2Cl2 −78 to −30°C (99%)

1. o -chloranil, ether, −10°C

2. 0.5 eq. 945, MeOH, −10°C Me (86%) OAc

(+ − )-818

(+ − )-953

O

O O N H

Me OAc

O

Pd(OAc)2, HOAc 55°C (62%)

(+ − )-954

N H LiAlH4, THF, rt (62%)

Scheme 5.129

Me OR

(+ − )-955 R = Ac + )-278 R = H (−

Chemistry of Carbazole Alkaloids

1. LDA, THF, −20°C N SO2Ph

2. 3-decanone

277

1. TFA, Et3N

HO

Me

N

2. NaOH/EtOH

C7H15 SO2Ph

956

957 O

O

(COCl)2, ether, 0°C; Me N H

Me

then AlCl3 (59%)

C7H15

N H

C7H15

274

958

Scheme 5.130 1. DCC, Et3N HN(OMe)Me OH N H 959

O

2. C7H15MgBr (68% overall)

N H 960 Br

NBS, KOH C7H15 N R 961 R = H 962 R = Bn

DMF (90%)

Me

KHMDS C7H15 Ph EtPBr 3 (93%) O

C7H15 N Bn

Me

963

NaH, BnBr (70%) 1. t-BuLi, ether 2. Cr(CO)6

1. t-BuLi, ether 2. Cr(CO)6

3. Me3OBF4 (45% overall)

3. MOMCl (48% overall) MOMO

MeO

Cr(CO)5

Cr(CO)5

C7H15

C7H15 N Bn

N Bn

Me

964

Me

965

Scheme 5.131

derivative 963 was transformed to the carbene complexes 964 and 965 in moderate yields along with hydrodebrominated by-products. Without purification, the carbene complex 964 was subjected to o-benzannulation by photolysis under an atmosphere of carbon monoxide to the N-benzylcarbazole 967. After O-methylation, the benzyl group was cleaved with potassium tert-butoxide in DMSO in the presence of oxygen. Finally, following a two-step sequence of demethylation with boron tribromide and oxidation with sodium meta-periodate, the 3,4-dimethoxycarbazole 968 was transformed to carbazoquinocin C (274) (563) (Schemes 5.131 and 5.132).

278

Chemistry and Biology of Carbazole Alkaloids

MeO

MeO Cr(CO)5 C7H15

N Bn

(65%)

N Bn

Me

966

OH 1. NaH, Me2SO4 Me 2. KOt-Bu, DMSO, O 2 (94% overall) C7H15

hν, CO, THF

967

MeO

O

OMe

O

1. BBr3, CH2Cl2, −78°C Me N H

C7H15

Me

2. NaIO4, CH2Cl2, rt (77% overall)

N H

968

C7H15

274

Scheme 5.132 MOMO

MOMO Cr(CO)5 C7H15

N Bn

Me

reflux (72%)

N Bn

Me

KOt-Bu DMSO, O2 (76%)

C7H15

969

965 MOMO

NHt-Bu

t-BuNC, THF

O

NHt-Bu

O

1. HCl, MeOH/H2O Me N H

C7H15

2. NaIO4, CH2Cl2 /H2O (82% overall)

970

Me N H

C7H15

274

Scheme 5.133

An alternative short synthesis of carbazoquinocin C (274) was achieved by thermal o-benzannulation of a different carbene complex 965 with isonitrile. Thus, the reaction of carbene complex 965 with tert-butylisonitrile in refluxing THF gave the N-benzyl carbazole 969 in 72% yield. After debenzylation, the corresponding 3-aminocarbazole 970 was subjected to cleavage of the MOM group to afford the intermediate 4-hydroxycarbazole, which, on oxidation with sodium meta-periodate, led to carbazoquinocin C (563) (274) (Scheme 5.133). The total synthesis of the carbazomycins G (269) and H (270) based on our ironmediated approach uses the O-acetylcarbazoles 971 and 972 as precursors, which are derived from the the iron-complex salts 602 and 779 and the arylamine 973 (650,651) (Scheme 5.134). The required arylamine 973 was prepared starting from the aryl acetate 937. The compound 937 was also used for the palladium(II)-catalyzed total synthesis of carbazoquinocin C (274) (545) (see Scheme 5.124) and carbazomycin G (269) (652). The acetate 937 was transformed to the corresponding 5-nitro derivative 974 by reacting with fuming nitric acid in a mixture of acetic anhydride and glacial acetic

Chemistry of Carbazole Alkaloids

O

R

OMe

AcO

R

Me Me N HO H

279

OMe Me

N H

269 Carbazomycin G R=H 270 Carbazomycin H R = OMe

OMe

971 R = H 972 R = OMe

OH R

OMe

(OC)3Fe

H2N

X

Me OMe 973

602 R = H; X = BF4 779 R = OMe; X = PF6

Scheme 5.134 OAc OMe

(see Scheme 5.124)

Me

Me

OMe

OMe

935

937

0°C (92%)

EtOH/H2O, 25°C (93%)

Me OMe

O2N

Me OMe

OH OMe

O2N

OMe

974

OH KOH

OAc

100% HNO3 OMe Ac O/HOAc (3:1) 2

OMe

H2, Pd/C MeOH, 25°C (95%)

975

H2N

Me OMe 973

Scheme 5.135

acid (3:1). Finally, ester cleavage to the phenol 975 and catalytic hydrogenation afforded the arylamine 973 (Scheme 5.135). This route provides the arylamine 973 in three steps, and 81% overall yield, on a multigram scale starting from the aryl acetate 937 (650,651) (Scheme 5.135). The reaction of the iron-complex salts 602 and 779 with the arylamine 973 afforded the iron complexes 976 and 977, both in 96% yield. Subsequent O-acetylation provided the corresponding acetates 978 and 979 in almost quantitative yield. The iron-mediated arylamine cyclization of the O-acetyl derivative 978 using very active manganese dioxide provided the carbazole 971 in 72% yield. Under similar reaction conditions, the O-acetyl derivative 979 gave a mixture of the carbazoles 972 and 980 in 35% and 17% yield, respectively (650,651) (Scheme 5.136).

280

Chemistry and Biology of Carbazole Alkaloids

OH R

OMe

(OC)3Fe

H2N

X

OH

(OC)3Fe MeCN 25°C

Me

OMe

R H2N

602 R = H; X = BF4

976 R = H (96%)

973

779 R = OMe; X = PF6

977 R = OMe (96%) OAc

(OC)3Fe Ac2O, DMAP, Et3N

OMe

R

CH2Cl2, 25°C

Me OMe

OMe

H2N

Me

v.a. MnO2 CH2Cl2, 25°C

OMe 978 R = H (98%) 979 R = OMe (96%) R

AcO

AcO

OMe

OMe

Me N H

OMe

971 R = H (72%) 972 R = OMe (35%)

Me MeO

N H

OMe

− 980 R = OMe (17%)

Scheme 5.136

The oxidation of the O-acetylcarbazole derivatives 971 and 972 with CAN, [(NH4)2Ce(NO3)6], led to the carbazole-1,4-diones 941 and 981, the immediate precursors for carbazomycin G (269) and H (270). The carbazole-1,4-quinone 941 also served as precursor for the palladium(II)-catalyzed total synthesis of carbazoquinocin C (274) (545,645). Finally, addition of an excess of methyllithium to 941 and 981 afforded carbazomycins G 269 and H 270 (the products of 1,2-addition at C-1) in 71% and 42% yield, along with the corresponding 2,3-dimethylcarbazole-1,4-quinones 982 and 983 in 12% and 14% yield (the products of 1,4-addition at C-3 followed by elimination) (650,651) (Scheme 5.137). Our palladium(II)-catalyzed approach for the carbazomycins G (269) and H (270) requires the carbazole-1,4-quinones 941 and 981 as precursors (compare the ironmediated synthesis, see Scheme 5.137). These intermediates should result from oxidative cyclization of the arylamino-1,4-benzoquinones, which in turn are prepared from the arylamines 839 and 984 and 2-methoxy-3-methyl-1,4-benzoquinone (939) (652) (Scheme 5.138). One of the carbazole-1,4-quinones, 3-methoxy-2-methylcarbazole-1,4-quinone (941), required for the total synthesis of carbazomycin G (269), was already used as a key intermediate for the total synthesis of carbazoquinocin C, and was obtained by the addition of aniline (839) to 2-methoxy-3-methyl-1,4-benzoquinone (939), followed by oxidative cyclization with catalytic amounts of palladium(II) acetate (545,645) (see Schemes 5.124 and 5.125). Similarly, in a two-pot operation, 4-methoxyaniline (984) was transformed to 3,6-dimethoxy-2-methylcarbazole-1,4-quinone

Chemistry of Carbazole Alkaloids

AcO

R

O

R

OMe

281

OMe

(NH4)2Ce(NO3)6 Me N OMe H 971 R = H

Me

MeCN/H2O, 0°C

N H

O

941 R = H (95%) 981 R = OMe (54%)

972 R = OMe O

R

OMe

O

R

Me

MeLi, THF −78 to 25°C

Me N Me HO H 269 R = H (71%)

N O H 982 R = H (12%)

Me

270 R = OMe (42%)

983 R = OMe (14%)

Scheme 5.137 R

O

OMe

O

R

Me Me N HO H

OMe Me

N H

269 Carbazomycin G R=H 270 Carbazomycin H R = OMe

O

941 R = H 981 R = OMe

O R

OMe NH2 839 R = H 984 R = OMe

Me O 939

Scheme 5.138

(981) in 61% overall yield (Schemes 5.139 and 5.140). Finally, regioselective addition of methyllithium to the carbazole-1,4-quinones 941 and 981 afforded carbazomycins G (269) and H (270), respectively (652) (Scheme 5.140). Hibino et al. reported the total synthesis of carbazomycin G (269) by the regioselective addition of methyllithium onto 3-methoxy-2-methylcarbazole-1,4quinone (941) (653). The required immediate precursor of carbazomycin G, carbazole-1,4-quinone 941, was obtained from 3-(2-methoxyethenyl)-N-(phenylsulfonyl)indole (986). The benzannulation involves an allene-mediated electrocyclic reaction of a 6p-electron system generated from the 2-propargylindole 989, which was derived from the 3-vinylindole 986 in three steps. Thus, reaction of a mixture of the E- and Z-isomers 986 with LDA, followed by addition of DMF, afforded the 3-[(E)-2-methoxyethenyl]indole-2-carbaldehyde (987)

282

Chemistry and Biology of Carbazole Alkaloids

MeO

O

NH2

OMe (see Scheme 5.124)

OMe

Me

Me

OMe 935

O 939

984 MeOH, 25°C (83%)

O

(see Scheme 5.124)

OMe

MeO O N H

OMe N H

Me O

985

Me O

940

Scheme 5.139

O MeO

OMe N H

Me O

OMe

cat. Pd(OAc)2 2.5 eq. Cu(OAc)2 HOAc, 117°C

940 R = H 985 R = OMe R

O

R

Me N H

O

941 R = H (88%) 981 R = OMe (73%) O

OMe

MeLi, THF −78 to 25°C

Me N Me HO H 269 R = H (71%) 270 R = OMe (41%)

Scheme 5.140

in 41% yield, along with the unreactive Z-isomer 986 (14% yield). The lower reactivity of the lithiated Z-isomer towards DMF was explained by the formation of a more stable six-membered ring chelate. Addition of ethynylmagnesium bromide to 987 afforded the propargyl alcohol 988. After protection as the MOM ether, the compound 989 was subjected to electrocyclic reaction by treatment with potassium tert-butoxide in tert-butanol and THF at 901C to afford the 1,3-dioxygenated carbazole 990 via an allene intermediate. Cleavage of the MOM ether with chlorotrimethylsilane and sodium iodide gave the corresponding 1-hydroxycarbazole 991. Oxidation of 991 with [bis(trifluoroacetoxy)iodo]benzene in aqueous acetonitrile provided the carbazole-1,4-quinone 941. Using our previously developed regioselective methyllithium addition protocol (650–652), the compound 941 was transformed to carbazomycin G (269) (653) (Scheme 5.141).

Chemistry of Carbazole Alkaloids

OMe

OMe HC CMgBr

LDA, DMF/THF −78 to 0°C (41%)

N SO2Ph

N OR SO2Ph 988 R = H 989 R = MOM O

OMe

KOt-Bu t-BuOH, THF rt to 90°C (85%)

MOMCl, i-Pr2EtN CH2Cl2, rt to 50°C (98%)

THF, 0°C (87%)

CHO N SO2Ph 987

986 OMe

283

PhI(OCOCF3)2 Me N H

OR

990 R = MOM 991 R = H O

OMe

MeCN/H2O, 0°C (98%)

MeCN, −20°C TMSCl, NaI (69%) OMe

MeLi, THF Me N H 941

O

−78 to 0°C (87%)

Me N Me HO H 269

Scheme 5.141

6 Other Tricyclic Alkaloids This section covers the total synthesis of simple tricyclic carbazoles which are not covered in Sections II.A.1–II.A.5, and includes the tricyclic carbazoles substituted either at the C-ring or at the 9(N)- of the carbazole nucleus. Kawasaki and Somei reported the first total synthesis of 3-formyl-9methoxycarbazole (105) starting from the hexahydrocarbazole 992 (654). Prior to regioselective iodination, 992 was transformed to the 9-methoxycarbonyl derivative 993 by reaction with methyl chloroformate. After regioselective iodination of 993 with iodine and sodium periodate (NaIO4), the corresponding 3-iodocarbazole 994 was subjected to alkaline hydrolysis to afford 4b,8a-cis-hexahydro-3-iodocarbazole 995 in 85% yield. Using a literature procedure (655), the hexahydrocarbazole 995 was transformed to 3-iodo-9-methoxy-tetrahydrocarbazole (996) in two steps and 37% overall yield. Halogen–metal exchange of 996 using butyllithium, followed by reaction with DMF led to 3-formyl-9-methoxy-tetrahydrocarbazole (997). Finally, dehydrogenation of the tetrahydrocarbazole 997 with DDQ furnished 3-formyl-9methoxycarbazole (105) (654) (Scheme 5.142). Bhattacharyya et al. reported the first total synthesis of clausenalene (90) to establish its structure (99). This total synthesis uses Japp–Klingemann and Fischer– Borsche reactions as key steps. The phenyl hydrazone 1000 required for the transformation to 1-oxo-tetrahydrocarbazole 1001 under Fischer–Borsche conditions was obtained by condensation of 2-hydroxymethylene-5-methylcyclohexanone (999) with diazotized 3,4-methylenedioxyaniline (998) using Japp–Klingemann conditions. Wolff–Kishner reduction of 1001 furnished 3-methyl-6,7-methylenedioxy-1,2,3,4tetrahydrocarbazole (1002), which, on aromatization with 10% Pd/C in decalin, afforded clausenalene (90) (99) (Scheme 5.143).

284

Chemistry and Biology of Carbazole Alkaloids

H

H

(61%) ClCOOMe CH2Cl2, Et3N (89%)

992 R = H 993 R = COOMe I

H

(85%)

N COOMe 994

1. MeOH, H2O, H2O2 sodium tungstate

I BuLi, DMF

2. CH2N2, ether (37% overall)

N H

H

alkaline hydrolysis

H2SO4, HOAc, H2O

N R

H

I

H

I2, NaIO4

(50%)

N OMe

995

996 CHO

CHO DDQ, benzene (29%)

N OMe

N OMe 105

997

Scheme 5.142

Me aq. NaOAc

O Cl N N

O

(65%)

O

N N H

O 999

998 HOAc conc. HCl

MeOH

HOHC

Me

O

Me

O

ethylene glycol hydrazine hydrate

O N H 1001

O

1000

KOH, reflux O

Me

O O N H 1002

Me

O 10% Pd/C decalin, reflux

O N H 90

Scheme 5.143

During the course of photoformylation studies on methoxycarbazoles with chloroform, Chowdhury and Saha reported the synthesis of 3-formyl-6-methoxycarbazole (97) starting from 3-methoxycarbazole (1003) (656). In this transformation, the desired 3-formyl-6-methoxycarbazole (97) was obtained in only 10% yield, along with the other major regioisomeric formyl carbazoles, 1004 (14%)

Chemistry of Carbazole Alkaloids

285

MeO CHCl3, hν Ba(OH)2

N H 1003 MeO

CHO

MeO

MeO

N H

N H

97 (10%)

CHO

N H

OHC

1004 (14%)

1005 (33%)

Scheme 5.144

Me NHNH2

Me benzene

O

524

N H 1007

1006

Me

Me Pd/C 1,2-dichlorobenzene

NaH/THF ClCOOC2H5 0 to 5°C

N H

N COOC2H5 5

2 HCOOH Me

N CHO 6

Scheme 5.145

and 1005 (33%). The high yield of 1-formyl-3-methoxycarbazole (1005) suggests that the methoxy group activates the nucleus during photoformylation (656) (Scheme 5.144). Chakrabarty et al. reported the syntheses of 9-carbethoxy-3-methylcarbazole (5) and 9-formyl-3-methylcarbazole (6) to confirm the assigned structures (17). The syntheses use 3-methylcarbazole (2) as a common intermediate, which was obtained under Fischer–Borsche conditions starting from phenylhydrazine (524) and 4-methylcyclohexanone (1006). Reaction of 3-methylcarbazole (2) with sodium hydride (NaH), followed by addition of ethyl chloroformate, afforded 9-carbethoxy3-methylcarbazole (5). 9-Formyl-3-methylcarbazole (6) was obtained by reaction of 3-methylcarbazole (2) with formic acid (17) (Scheme 5.145).

286

Chemistry and Biology of Carbazole Alkaloids

Chakravarty et al. reported the synthesis of glycoborine (87) to confirm the assigned structure (98). This synthesis also led to the reassignment of the structure of glycozolicine (88) as 8-methoxy-3-methylcarbazole, which was supported by synthesis. Both these syntheses involve the Fischer–Borsche reaction as the key step. The hydrazones 1010 and 1011, required for these syntheses, were obtained by condensation of hydrazines 1008 and 1009 with 4-methylcyclohexanone (1006), respectively. Under Fischer–Borsche conditions, the hydrazone 1010 was transformed to the desired 5-methoxytetrahydrocarbazole 1012 in only 6% yield, along with 54% of the regioisomeric 7-methoxytetrahydrocarbazole 1013. The high yield of the wrong regioisomeric product is explained by the electronic and steric effects of the methoxy group. Finally, dehydrogenation of 1012 in the presence of chloranil in xylene led to glycoborine (87). Using a similar reaction sequence, the hydrazone 1011 was transformed to glycozolicine (88) in 15% overall yield (98) (Scheme 5.146). Witulski and Alayrac reported the synthesis of clausine C (clauszoline-L) (101) by a rhodium-catalyzed alkyne cyclotrimerization of diyne 1014 and propiolic ester 635 (561). Analogous to the hyellazole (245) synthesis (see Scheme 5.75), the diyne precursor 1014 required for this key cyclotrimerization reaction was obtained starting from readily available 2-iodo-5-methoxyaniline. Using Wilkinson’s catalyst, [RhCl(PPh3)3], crossed-alkyne cyclotrimerization of 1014 and 635 led to Ntosylclausine C (1015) in 78% yield in an isomeric ratio of 3.8:1. Finally, deprotection of the tosyl group with TBAF in refluxing THF afforded clausine C (clauszoline-L) (101) (561) (Scheme 5.147). Selvakumar et al. reported the total synthesis of 3-formyl-9-methoxycarbazole (105) starting from 3-fluoro-4-nitrotoluene (1016) (657). This methodology uses a novel benzannulation strategy involving ring closing metathesis (RCM) as key step. Nucleophilic aromatic substitution of methyl cyanoacetate and 3-fluoro-4-nitrotoluene (1016) led to the cyanoester 1017 in almost quantitative yield. The alkylation of 1017 with allyl bromide, followed by rearrangement (658) of 1018 in a solution of NaCl and DMSO at 1551C, led to the required 1-methoxyindole 1019. Reaction of the nitrile R1

R1 Me NHNH2

Me

benzene HOAc

O

2

R2

R

1008 R1 = OMe, R2 = H 1

1006

1010 R1 = OMe, R2 = H

2

1011 R1 = H, R2 = OMe

1009 R = H, R = OMe R1

N N H

R1

Me

Me

chloranil, xylene R2

N H

100°C R2

N H

1012 R1 = OMe, R2 = H (6%)

87 R1 = OMe, R2 = H (85%)

1013 R1 = H, R2 = OMe

88 R1 = H, R2 = OMe (15% overall)

Scheme 5.146

Chemistry of Carbazole Alkaloids

H

COOMe

COOMe

635

H MeO

287

MeO

10 mol% RhCl(PPh3)3 toluene, rt

N Ts

N Ts 1015 (3.8:1)

(78%)

1014

COOMe TBAF, THF, reflux MeO

(98%)

N H 101

Scheme 5.147

Me

CN

NCCH2COOMe NaH, THF

F NO2

Me

0 to 60°C (94%) 1017

COOMe

NC

Me

CN

NaCl, DMSO NO2

155°C (85%)

CHO N OMe

DIBAL, toluene −78°C (85%)

N OMe 1019

1018 Me

allyl bromide NaH, DMF 0°C to rt (77%)

NO2

1016 Me

COOMe

HO

Me allyltributyltin

Grubb's catalyst

BuLi, THF, −78°C (83%)

CH2Cl2, rt to reflux (72%)

N OMe

1020

1021 Me

CHO DDQ, HOAc, rt

N OMe 1022

(45%)

N OMe 105

Scheme 5.148

1019 with DIBAL, followed by transmetalation of the resulting aldehyde 1020 with allyltributyltin, cleanly afforded the alcohol 1021. Treatment of the alcohol 1021 with Grubbs’ catalyst resulted in the 9-methoxycarbazole 1022 by cyclization with concomitant dehydration. Finally, reaction of 1022 with DDQ in acetic acid afforded 3-formyl-9-methoxycarbazole (106) (657) (Scheme 5.148). Using our palladium(II)-catalyzed approach, we reported the total syntheses of a wide range of 7-oxygenated carbazole alkaloids, including siamenol (89),

288

Chemistry and Biology of Carbazole Alkaloids

clauszoline-K (98), 3-formyl-7-hydroxycarbazole (99), clausine C (clauszoline-L) (101), clausine M (102), and clausine N (103) (546). The relay compound 1025 required for the synthesis of all of these 7-oxygenated carbazole alkaloids was obtained starting from commercially available 4-bromotoluene (1023) and m-anisidine (840) in two steps and 72% overall yield. Buchwald– Hartwig amination of 4-bromotoluene (1023) with m-anisidine (840) furnished quantitatively the corresponding diarylamine 1024. Oxidative cyclization of 1024 using catalytic amounts of palladium(II) acetate afforded 3-methyl-7-methoxycarbazole (1025). Oxidation of 1025 with DDQ led to clauszoline-K (98), which, on cleavage of the methyl ether using boron tribromide, afforded 3-formyl-7-hydroxycarbazole (99) (546) (Scheme 5.149). Clauszoline-K (98) was transformed quantitatively to clausine C (clauszoline-L) (101) by treatment with manganese dioxide and potassium cyanide in methanol. Ether cleavage of clausine C (101) gave clausine M (102), while saponification of the ester led to clausine N (103) (Scheme 5.150). Regioselective electrophilic bromination of the carbazole 1025 afforded the 6-bromocarbazole 1026. Cleavage of the methyl ether to 1027 and subsequent nickel-mediated coupling using a dimeric p-prenylnickel bromide complex prepared in situ from prenyl bromide 925 and bis(1,5-cyclooctadiene)nickel(0) led directly to siamenol (89) (546) (Scheme 5.151). One year later, we extended the aforementioned palladium(II)-catalyzed approach to a series of 6-oxygenated carbazole alkaloids, glycozoline (86), glycozolinine (glycozolinol) (91), glycomaurrol (92), micromeline (100), and methyl 6-methoxycarbazole-3-carboxylate (104) (547). The palladium(0)-catalyzed coupling of 4-bromoanisole (670) and p-toluidine (1028), followed by palladium(II)-catalyzed oxidative cyclization, afforded directly glycozoline (86).

Me MeO

Cs2CO3, toluene, reflux (100%)

NH2 Br 840

6 mol% Pd(OAc)2 5 mol% rac-BINAP

Me MeO

1023

10 mol% Pd(OAc)2 2.5 eq. Cu(OAc)2 HOAc, reflux (72%)

Me

DDQ MeOH/H2O, rt

MeO

(79%)

N H 1025 CHO

CHO BBr3, CH2Cl2

MeO N H 98

N H 1024

−78 to −20°C (34%)

HO

Scheme 5.149

N H 99

Chemistry of Carbazole Alkaloids

289

COOMe

CHO 26 eq. MnO2, 4.8 eq. KCN MeO

MeO

MeOH, rt (100%)

N H 98

KOH, EtOH/H2O, reflux (99%)

N H 101 BBr3, CH2Cl2 −78 to −20°C (52%)

COOH

COOMe

MeO

HO N H 103

N H 102

Scheme 5.150 Me

Me

Br NBS, CH2Cl2

MeO

−78°C to rt (100%)

N H 1025

Me

Br HO N H 1027

BBr3, CH2Cl2 MeO N H 1026

9.5 eq. 925 12 eq. (cod)2Ni DMF, rt, 6 d (47%)

−78°C to rt (100%)

Me HO N H 89

Scheme 5.151

For the syntheses of further 6-oxygenated carbazole alkaloids, glycozoline (86) was used as relay compound (Schemes 5.152–5.154). Cleavage of the ether with boron tribromide transformed glycozoline (86) into glycozolinine (glycozolinol) (91). Further, oxidation of 86 with DDQ gave 3-formyl-6-methoxycarbazole (97) (Scheme 5.152). Regioselective bromination of glycozolinine (91) at C-5 and subsequent nickel-mediated prenylation provided glycomaurrol (92) (547) (Scheme 5.153). Oxidation of 3-formyl-6-methoxycarbazole (97) with manganese dioxide and potassium cyanide in methanol afforded methyl 6-methoxycarbazole-3-carboxylate (104). Regioselective bromination of 97 afforded the 5-bromocarbazole 1031. Cleavage of the methyl ether to 1032, followed by nickel-mediated prenylation, provided micromeline (100) (547) (Scheme 5.154). So¨derberg et al. reported a formal synthesis of clausenalene (90) starting from 3-methyl-6,7-methylenedioxy-1-oxo-1,2,3,4-tetrahydrocarbazole (1001) (659). The required tetrahydrocarbazole 1001 was obtained starting from 5-methyl-1,3cyclohexadione (1033) using two sequential palladium-catalyzed intermolecular

290

Chemistry and Biology of Carbazole Alkaloids

MeO

Me Br

7 mol% Pd(OAc)2 8 mol% rac-BINAP

MeO

Me

Cs2CO3, toluene, 110°C (97%)

H2N

670

1028

10 mol% Pd(OAc)2 2.5 eq. Cu(OAc)2

MeO

Me

HOAc, 117°C (60%)

N H 1029

DDQ MeOH/H2O, rt (76%)

N H 86

MeO

BBr3, CH2Cl2

CHO

−78°C to rt (97%) HO

N H 97

Me

N H 91

Scheme 5.152

HO

HO

Me

Br

Me

NBS, CH2Cl2, rt (45%)

N H 91

9 eq. 925 14 eq. (cod)2Ni DMF, rt, 6 d (25%)

N H 1030

Me

HO

N H 92

Scheme 5.153

Stille cross-coupling and reductive N-heteroannulation steps. Iodination of 1033, followed by Stille cross-coupling of the corresponding iodo derivative 1034 with the arylstannane 1035, gave the annulation precursor 1036. Reductive N-heteroannulation of 1036 afforded the carbazolone 1001, which was previously (99) (see Scheme 5.143) used to prepare clausenalene (90) via a Wolff–Kishner reduction followed by aromatization (659) (Scheme 5.155).

291

Chemistry of Carbazole Alkaloids

CHO

MeO

COOMe

MeO 26 eq. MnO2 5 eq. KCN, MeOH, rt (97%)

N H 97

Br

MeO

N H 104 CHO BBr3, CH2Cl2

NBS, cat. HBr MeCN, rt (82%)

HO

Br

−78 to −20°C (50%)

N H 1031

CHO

CHO

HO

9 eq. 925 14 eq. (cod)2Ni DMF, rt, 6 d (52%)

N H 1032

N H 100

Scheme 5.154

I2, PPh3 Me MeCN, Et N 3

O

I

Me

Pd(dba)2, dppp 1,10-phenanthroline CO (6 atm) DMF, 80 to 90°C (100%)

SnBu3

O

NO2

1035 PdCl2(PhCN)2

O 1034

Me

O

Me

O O

Ph3As, CuI NMP, 80°C (91%)

(90%) O 1033

O

NO2

O

1036

Me

O (see Scheme 5.143)

O N H

(ref. 99) O

1001

O N H 90

Scheme 5.155

B. Pyranocarbazole Alkaloids Furukawa et al. reported a palladium(II)-mediated intramolecular cyclization of arylamino-1,4-benzoquinones to carbazole-1,4-quinones (623). Previously, this facile synthetic approach was applied to various 3-methylcarbazole-1,4-quinone alkaloids (623) (see Schemes 5.101 and 5.102). As an extension, this methodology was further

292

Chemistry and Biology of Carbazole Alkaloids

applied to the total synthesis of the pyrayaquinones A (175) and B (176). The required starting materials, 7-amino- (1039) and 5-amino-2,2-dimethyl-2H-chromene (1041) were prepared from acetamidophenol (1037) and 3-chloro-3,3-dimethyl-1butyne via etherification and a Claisen rearrangement, followed by hydrolysis (Scheme 5.156). Condensation of the aminochromenes 1039 and 1041 with 2-methyl-1,4benzoquinone (841) afforded 2-(2,2-dimethyl-2H-chromen-7-ylamino)- (1042) and 2-(2,2-dimethyl-2H-chromen-5-ylamino)-5-methyl-1,4-benzoquinone (1043), along with the corresponding 6-methyl isomers. Finally, reaction of the benzoquinones 1042 and 1043 with stoichiometric amounts of palladium(II) acetate in acetic acid under reflux furnished pyrayaquinone A (175) and B (176) in 78% and 50% yield, respectively (623) (Schemes 5.157 and 5.158). Retrosynthetic analysis of girinimbine (115) and murrayacine (124), based on our molybdenum-mediated approach, provides the molybdenum complex salt 577 and the 5-aminochromene 1044 as potential precursors (660) (Scheme 5.159). Starting from commercially available 2-methyl-5-nitroaniline (1045), the required 5-amino-2,2,8-trimethylchromene (1044) was obtained in four steps and 52% overall (8%) Me Me

NHCOMe

NHR

1038 R = COMe 1. ClC(Me)2C CH

OH

O

1039 R = H

2. Et2NPh, Δ

6 N HCl (49%)

1037 (10%)

O

NHR

Me Me 1040 R = COMe 1041 R = H

6 N HCl (99%)

Scheme 5.156 O

O

Me

Me HOAc/H O, rt 2 Me Me

O

(14%)

NH2

Me

O 1039

HOAc, reflux (78%)

O

N H 1042

841 O

Pd(OAc)2

Me

Me

Me Me O N H 175

O

Scheme 5.157

O

293

Chemistry of Carbazole Alkaloids

O O

Me Me HOAc/H O, rt 2

NH2

O Me

Me

O

Me

N H

O

(14%)

841

1041

1043 O

Me

Pd(OAc)2 HOAc, reflux (50%)

O

Me

O Me

N H

Me

O

176

Scheme 5.158 Me

R

OC O

N H

Me

O

Mo PF6

Me Me

OC NH2

Me 577

115 Girinimbine R = Me

1044

124 Murrayacine R = CHO

Scheme 5.159

yield. The reaction of 1045 with nitrous acid afforded the phenol 1046, which was alkylated by 3-chloro-3-methylbut-1-yne (1047) to the aryl propargyl ether 1048. The key step of this synthesis is the transformation of the aryl propargyl ether 1048 to the 5-nitrochromene 1049 by a [3,3]-sigmatropic rearrangement and subsequent cyclization. Heating of 1048 in o-xylene at reflux for 14 h provided the 5-nitrochromene 1049 in 93% yield. Finally, reduction of the 5-nitrochromene 1049 with tin in methanolic hydrochloric acid afforded the 5-aminochromene 1044 (Scheme 5.160). Reaction of the 5-aminochromene 1044 with the complex salt 577 provided via an electrophilic aromatic substitution regio- and diastereoselectively the molybdenum complex 1050. The oxidative cyclization of complex 1050 with concomitant aromatization and demetalation using activated manganese dioxide led directly to girinimbine (115) in 50% yield. Oxidation of girinimbine (115) with DDQ in methanol afforded murrayacine (124) in 64% yield (660) (Scheme 5.161). For the transformation of girinimbine (115) to dihydroxygirinimbine (133), girinimbine was oxidized by m-chloroperbenzoic acid (MCPBA) to give a mixture of the two regioisomeric 3-chlorobenzoic acid esters 1051 and 1052 in 82% yield (ratio 1.5:1). The hydrolysis of the 3-chlorobenzoates 1051 and 1052 with methanolic sodium hydroxide provided dihydroxygirinimbine 133 in 43% yield, along with 53% of the corresponding cis-diol 1053 (660) (Scheme 5.162).

294

Chemistry and Biology of Carbazole Alkaloids

Cl

Me

Me Me

Me NH2

OH

NaNO2 H2SO4/H2O, Δ (87%)

NO2 1045

Me

Me

KI, K2CO3 MeCN, 82°C (81%)

NO2

NO2

1046 Me O

o-xylene, 140°C

1048 Me

Me Me

(93%)

Me

O

1047

Me

O

Sn, HCl/MeOH, 80°C

Me

(79%)

NO2

NH2

1049

1044

Scheme 5.160 Me

Me OC

O

Mo PF6

Me THF, K2CO3

Me

OC

577

Mo

Me

H

OC

65°C (21%)

NH2

NH2

1044

1050 Me

CHO

MnO2, CH2Cl2

DDQ O

40°C (50%)

N H

O

Me MeOH, 25°C (64%) Me

N H

115

124

Me

Me MCPBA

O

Me Me

O

CH2Cl2, 25°C (82%)

N H R1O

Me

Me OR2

1051 R1 = 3-Cl-C6H4CO; R2 = H

115

1052 R1 = H; R2 = 3-Cl-C6H4CO Me NaOH MeOH, Δ

O N H HO

Me Me

Me OH

133

O N H HO 1053

Scheme 5.162

Me Me

Scheme 5.161

N H

Me

O

OC

Me

Me OH

295

Chemistry of Carbazole Alkaloids

C. Bis-Carbazole Alkaloids The bis-carbazole alkaloids typically contain previously known monomeric carbazoles as structural subunits. To date, bis-carbazole alkaloids have been isolated from plants of two genera of the family Rutaceae, Murraya and Clausena, and are linked either by a methylene unit, a bisbenzylic ether bridge, a bond joining one aromatic portion directly to an annelated dihydropyran unit, or by a biaryl bond. Many reviews have appeared on the monomeric carbazole alkaloids. However, in these articles only a few bis-carbazole alkaloids were listed (3,5–7). For the first time, in 1992, Furukawa et al. compiled all of the bis-carbazole alkaloids that were known to the end of 1992 (158). Tasler and Bringmann summarized to the end of 2001, the occurrence, stereochemistry, synthesis, and biological activity of the bis-carbazoles linked through a biaryl bond (159). We compiled to the mid of 2002, the occurrence, stereochemistry, synthesis, and the biological activity of all classes of bis-carbazoles (8). In this section, we cover the total syntheses of the natural biscarbazole alkaloids reported since 1990. Furukawa et al. reported the syntheses of the murrafolines-D (181), -G (182), and -H (183) starting from murrayafoline A (7) and girinimbine (115) (146). This synthetic effort was undertaken to confirm the assigned structures of murrafolines -D (181), -G (182), and -H (183) isolated from Murraya euchrestifolia (146). Reaction of murrayafoline A (7) and girinimbine (115) in the presence of an ion-exchange resin (Nafion 117) in refluxing aqueous methanol for 27 h afforded the murrafolines -D (181), -G (182), and -H (183). For this synthesis no yields were given, moreover, this reaction was non-regioselective. When the reaction was extended to longer reaction times, several oligomers of girinimbine (115) were formed (146) (Scheme 5.163). Bringmann et al. reported the first total synthesis and stereoanalysis of bismurrayaquinone-A (215) by oxidation of bis(O-demethylmurrayafoline A) (204) (661). The required monomer, 1-hydroxy-3-methylcarbazole (O-demethylmurrayafoline Me

Me

MeOH O N H 7

N H

OMe

Nafion 117 reflux, 27 h

Me Me

115 Me

Me

N H

Me

O Me Me

Me

O Me

N H Me

Me Me

MeO

N H 181

MeO

N H

Me

N H 182

Scheme 5.163

Me

O N H 183

O Me Me

296

Chemistry and Biology of Carbazole Alkaloids

A) (23), was obtained in an improved yield using the modified literature procedure (28) starting from benzene diazonium chloride (1054) and hydroxymethylene-5methylcyclohexanone (1055). A biomimetic coupling of 1-hydroxy-3-methylcarbazole (O-demethylmurrayafoline A) (23) by reaction with di-tert-butyl peroxide [(tBuO)2] afforded the dimer of O-demethylmurrayafoline A (204). Finally, oxidation of 204 with PCC afforded (7)-bismurrayaquinone-A (215). The resolution of atropoenantiomers was achieved by chiral HPLC using Chiracel OF. The assignment of the absolute configuration of the two enantiomers (S)-215 and (R)-215 was achieved by comparison of their theoretical and experimental circular dichroism (CD) spectra (166,167,661) (Scheme 5.164). In the following year, Bringmann et al. showed a further application of a biomimetic oxidative coupling of murrayafoline A (7) to the first total synthesis of murrastifoline F (191) (162). This work also includes the resolution of (7)-murrastifoline F (191), the stereochemical assignment of its atropisomers, and the determination of the enantiomeric ratio present in an authentic root extract of M. koenigii. Murrayafoline A (7) required for this total synthesis was obtained starting from 3-formylindole (618) (577) (see Scheme 5.40). Lead tetraacetate-mediated oxidative non-phenolic biaryl coupling of 7 led to murrastifoline F (191) in 60% yield. The Me

Me (2 steps, 58%) N N Cl

(ref. 31)

HOHC

1054

O

N H

1055

1056 Me

10% Pd/C, Ph2O 1,2,4-trimethylbenzene 220 to 230°C (72%)

Me

N H

OH

N H 23

(t-BuO)2 chlorobenzene, reflux (81%)

OH

O H N

HO

N H

O Me 215

204 O

O

Me Me

Me Me O

O N H

O

O

N

H N

Me O

PCC, CH2Cl2 ether, rt (73%)

Me

O

N H

O

O

N H

H (S )-215

(R )-215

Scheme 5.164

O

297

Chemistry of Carbazole Alkaloids

resolution of racemic 191 was performed by O-demethylation, derivatization with Mosher’s reagent, and chromatographic resolution of the resulting diastereomers. The assignment of the absolute configuration of the atropisomers (S)-191 and (R)-191 was based on CD spectroscopy in combination with quantum chemical CD, as well as ROESY experiments of the diastereomeric Mosher derivatives (162) (Scheme 5.165). In the same year, Bringmann et al. reported the first total synthesis of the methylene-bridged dimeric carbazole alkaloids, chrestifoline A (192) and bismurrayafoline-A (197) starting from their monomeric halfs, murrayafoline A (7) and koenoline (8) and the carbazole ester 1057, respectively (662). Acid treatment of a 3:1 mixture of murrayafoline A (7) and koenoline (8) led to chrestifoline A (192) in 70% yield. Addition of murrayafoline A (7) to a mixture of 1057 and lithium aluminum hydride in ether and dichloromethane afforded bismurrayafoline-A (197) in 19% yield (662) (Scheme 5.166). In addition to the aforementioned methods, the same group also reported a stereoselective synthesis of axially chiral bis-carbazole alkaloids by application of their ‘‘lactone concept’’ (663) and a reductive biaryl coupling leading to 2,2u-bis-carbazoles (664). We reported the first total synthesis of 1,1u-bis(2-hydroxy-3-methylcarbazole) (213) using our molybdenum-mediated construction of the carbazole framework (560). The required monomer, 2-hydroxy-3-methylcarbazole (52), was obtained in three steps, and 22% overall yield, starting from dicarbonyl(Z4-cyclohexa-1,3diene)(Z5-cyclopentadienyl)molybdenum hexafluorophosphate (663) and 3-methoxy-4-methylaniline (655) (560) (see Scheme 5.52). Finally, oxidative coupling of the monomer 52 using p-chloranil afforded 1,1u-bis(2-hydroxy-3-methylcarbazole) (213) in 38% yield (560) (Scheme 5.167). Murphy and Bertrand reported a second total synthesis (7)-bismurrayaquinoneA (215) via the bromoquinone-enaminone annulation (633). Reaction of the 4-methoxybenzyl-protected enamino ketone 1058 and 5-bromo-2-methyl-1,4-benzo˚ quinone (878) with copper(II) chloride in the presence of sodium bicarbonate and 3 A molecular sieves (MS) afforded, in low yield, the dimer 1059. Mechanistically, the

Me

CHO

Pb(OAc)4, BF3 Et2O

(see Scheme 5.40) (ref. 577)

N H 618

N H 7

OMe

Me

N

N H

OMe

OMe Me

MeCN, rt (60%)

Me

Me

1. O-demethylation 2. resolution via the

N

Mosher esters 3. O-methylation N H

OMe (S )-191

191

Scheme 5.165

N

OMe Me N H

OMe (R)-191

OMe Me

298

Chemistry and Biology of Carbazole Alkaloids

Me

N H 7

OMe

LiAlH4

CH2OH

COOEt ether/CH2Cl2, rt N H

N H

OMe

8

1057 (19%)

ether, CH2Cl2 conc. HCl, rt (70%) MeO

Me

N

N H

OMe

H N

Me

OMe

N H

OMe

OMe 192

197

Scheme 5.166

Me OC

OMe

Mo PF6

Me (see Scheme 5.52)

OC

(ref. 560) NH2 663

655

OH N H 52

Me

p-chloranil MeOH, 65°C (38%)

OH H N

N H HO Me 213

Scheme 5.167

dimer 1059 might have formed by dimerization of free radicals of the first-formed annulation product. Compound 1059 was transformed to the bis(tosylhydrazone) 1060, followed by Shapiro deoxygenation–olefination and aromatization with DDQ in dioxane, to afford the bis-N-protected murrayaquinone-A 1061. Finally,

Chemistry of Carbazole Alkaloids

299

deprotection in TFA with catalytic amounts of TfOH provided (7)-bismurrayaquinone-A (215) in 60% yield (633) (Scheme 5.168). Lin and Zhang reported the first total synthesis and resolution of (7)clausenamine-A (203) involving Suzuki cross-coupling and oxidative coupling as key steps (165,665). This synthesis starts from the commercially available 2-amino-5methylphenol (1062) as shown in Scheme 5.169. After protection of the free hydroxy group in 1062 as a tosylate, 1063 was subjected to regioselective electrophilic bromination ortho to the amino group using bromo-dimethylsulfonium bromide generated in situ to afford the bromoaniline 1064. The required biphenyl 1066 was prepared quantitatively by Suzuki cross-coupling of 3,5-dimethoxyphenylboronic acid (1065) and 1064 using 5% Pd(PPh3)4 and aqueous sodium carbonate in benzene. Bromination of 1066 using 48% HBr in DMSO afforded the corresponding bromo derivative 1067. A palladium(0)-mediated oxidative cyclization of 1067 led to the carbazole 1068 in almost quantitative yield. After detosylation, the corresponding hydroxycarbazole 1069 was subjected to oxidative coupling using di-tert-butyl peroxide [(t-BuO)2] in chlorobenzene to afford (7)-clausenamine-A (203) in 90% yield (165,665) (Scheme 5.169). The resolution of racemic clausenamine-A (203) was accomplished by silica gel column chromatography of the corresponding (+)-camphorsulfonates 203a and 203b using dichloromethane/chloroform/diethyl ether (50:1:2) as the eluent. Alkaline hydrolysis of 203a and 203b provided optically pure clausenamine-A (R)-(+)-203 and (S)-( )-203 (165,665) (Scheme 5.170). The assignment of the absolute configuration was based on an X-ray analysis and the CD spectra. The same method was applied to

O

O

O Me NH Br PMB

1058

N O Me PMB

PMB = p-methoxybenzyl

878

PMB N

Me O

CuCl2, NaHCO3 3 Å MS, MeCN, rt (7%)

O

O

O

O

1059

TsHN O

N

PMB N

Me O

TsNHNH2 HOAc, rt (76%)

N O Me PMB

3. DDQ, dioxane, reflux (32% overall) O

N NHTs

1060 O

PMB N

Me O

N O Me PMB

1. aq. Na2S2O4, CH2Cl2 2. 24 eq. BuLi, THF, rt

O

H N

Me O

TFA, cat. TfOH reflux (60%)

O

1061

N H

O Me 215

Scheme 5.168

O

300

Chemistry and Biology of Carbazole Alkaloids

MeO

Me

Me TsCl, Et3N

HO NH2

CH2Cl2, rt (84%)

Me

1062

NH2

DMSO, rt (94%)

1065 TsO

Br NH2

1063

MeO

OMe

48% HBr TsO

1064

Me

5 mol% Pd(PPh3)4 2 N Na2CO3, benzene EtOH, reflux (99%)

MeO

Br

Me

MeO

H2N

OTs

1.2 eq. Pd(PPh3)4 Na2CO3

48% HBr

MeO

H2N

OTs

DMSO, rt (79.5%)

1066

MeO

N H

1068 R = Ts 1069 R = H

toluene, reflux (97%)

1067 Me

MeO

B(OH)2

OH

(t-BuO)2 chlorobenzene reflux (90%)

Me

MeO

MeO

KOH/H2O/EtOH, reflux (88%)

N H

OH

HO

Me

H N

OMe

OMe

203

Scheme 5.169

the synthesis and resolution of the demethoxylated analogs of clausenamine-A (203), including bis(O-demethylmurrayafoline A) (204) (665) (Scheme 5.170). Hao et al. reported the synthesis of 8,8v-biskoenigine (205) through oxidative coupling of its monomeric half koenigine (119). This synthesis was undertaken to confirm the assigned structure of 8,8v-biskoenigine (205) isolated from M. koenigii. Reaction of koenigine (119) with iron(III) chloride (FeCl3) in solid state at room temperature for 30 days afforded 8,8v-biskoenigine (205) in 30% yield (119) (Scheme 5.171). Chida et al. reported the first total synthesis of murrastifoline-A (186) starting from 2-amino-5-methylphenol (1062) (666,667). This synthesis involves a palladium(0)catalyzed double N-arylation of the arylamine (1082) with 2,2u-dibromobiphenyl 1075 as a key step. The synthesis of dibromobiphenyl 1075 starts from the known O-tosylate 1063 (165,665), which was prepared from commercially available 2-amino-5-methylphenol (1062). Regioselective electrophilic iodination of 1063 using N-iodosuccinimide (NIS) afforded the iodoaniline 1070. The biphenyl 1072 was prepared quantitatively by Suzuki–Miyaura cross-coupling of 2-bromophenylboronic acid (1071) and 1070 using Pd(PPh3)4 and 2 M aqueous sodium carbonate in ethanol and benzene. Sandmeyer reaction of 1072 gave dibromobiphenyl (1073). After de-O-tosylation using alkaline hydrolytic conditions, the corresponding hydroxy derivative 1074 was O-methylated to afford the required dibromobiphenyl 1075 (Scheme 5.172).

301

Chemistry of Carbazole Alkaloids

R1

Me

R1

N H

OH

H N

HO

R1

Me

R1

203 1. Et3N, CH2Cl2 (S)-camphorsulfonyl chloride, reflux 2. column chromatography on silica gel CH2Cl2 /CHCl3/ether (50:1:2) R1

Me 2 R O

R1

N H

H N

OR2 Me

R1

R1

Me 2 RO N H

R1

R1

KOH/EtOH, rt (87%)

R1 = OMe; R2 =

Me

R

R1

N H

OH

HO

Me

R1

203b

SO2 1

R1

OR2 Me

203a KOH/EtOH, rt (84%)

H N

H N

R1

O

R1

Me

R1

R1

(+)-203

N H

OH

HO

H N

R1

Me

R1

(−)-203

Scheme 5.170 Me

MeO Me

MeO

FeCl3 6H2O HO N H

O Me rt, 30 days (30%) Me

HO H N

Me

N H OH

Me O Me

119

O Me Me

OMe 205

Scheme 5.171

The second coupling component, 6-aminocarbazole 1082, was prepared starting from the same known O-tosylate 1063 (165,665). Thus, Buchwald–Hartwig palladiumcatalyzed amination of 4-bromonitrobenzene (1076) with 1063 afforded the diarylamine 1077. Treatment of 1077 with an excess of Pd(OAc)2 in acetic acid led to the carbazole 1078 in 53% yield. After protection of the carbazole nitrogen with a 2trimethylsilylethoxymethyl (SEM) group, the product 1079 was subjected to alkaline

302

Chemistry and Biology of Carbazole Alkaloids

B(OH)2

Me

HO NH2

Me

Br

TsCl, Et3N

1071

CH2Cl2, 0°C (89%)

Pd(PPh3)4, 2 M Na2CO3 benzene, EtOH, reflux (99%)

R

TsO NH2

1062

1063 R = H

NIS, DMF, 0°C (69%)

1070 R = I Br

Br

Me NaNO2, CuBr conc. H2SO4

Me

MeI, NaH

HOAc, 48% HBr rt to 80°C (64%)

H2N

Br

Me

1072

DMF, rt OR (77%)

Br

OTs

1073 R = Ts

Br

1 M KOH/EtOH, reflux (76%)

1074 R = H

OMe

1075

Scheme 5.172

O2N

Me

Br

O2N

1076 TsO NH2

Me

Pd2(dba)3, rac-BINAP NaOt-Bu, toluene, 120°C (81%)

N H

1063

OTs

Me

O2N SEMCl, NaH

N H 1078 O2N

HOAc, reflux (53%)

1077 Me

O2N

Pd(OAc)2

OTs

1 M NaOH, MeOH

DMF, 0°C (86%)

Me O2N

reflux

N OTs SEM 1079 Me

H2N

Me

NaBH2S3 N OMe SEM 1081 (8%)

N OH SEM 1080 (76%)

THF, reflux (84%)

N OMe SEM 1082

MeI, NaH, DMF, rt (100%)

Scheme 5.173

hydrolytic conditions to provide the de-O-tosyl derivative 1080, along with its methyl ether 1081, in 76% and 8% yield, respectively. O-Methylation of 1080 transformed it to 1081 quantitatively. Finally, reduction of the 6-nitrocarbazole 1081 with NaBH2S3 furnished the required 6-aminocarbazole 1082 in 84% yield (666,667) (Scheme 5.173).

303

Chemistry of Carbazole Alkaloids

Me

OMe Me

H2N Br Br

N OMe SEM 1075

20 mol% Pd2(dba)3 60 mol% 2-(dicyclohexyl-phosphino)-biphenyl NaOt -Bu, toluene, 120°C sealed tube

1082

Me

(58%) Me

OMe Me

N

4 M HCl, EtOH/THF

OMe Me

N

reflux (94%) N H

N OMe SEM 1083

OMe

186

Scheme 5.174

The double N-arylation of the 6-aminocarbazole 1082 with the dibromobiphenyl derivative 1075 under Buchwald–Hartwig N-arylation conditions afforded N-SEMmurrastifoline-A (1083) in 58% yield. Finally, the N-SEM group was removed under acidic conditions to furnish murrastifoline-A (186) in 94% yield (666,667) (Scheme 5.174). In addition to the aforementioned total syntheses, Shannon et al. observed the formation of an N–C3-linked dimer during the transformation of a 3-bromocarbazole to a 3-cyanocarbazole by reaction with copper(I) cyanide in DMF under reflux (668). Harrity et al. reported the synthesis of non-natural (7)-N,Nu-dimethylbismurrayafoline A via a chromium-mediated benzannulation, followed by a palladium-catalyzed oxidative coupling reaction (669).

D. Benzocarbazole Alkaloids Prior to the isolation of the natural benzocarbazole alkaloids, purpurone (281) and ningaline D (282), a wide range of different isomeric benzocarbazoles was synthesized. This widespread synthetic activity on the non-natural benzocarbazoles was justified because of their useful pharmacological properties (194,257,400–407). The methods that were often employed for the synthesis of the various benzocarbazole derivatives range from polar (ionic) over radical to pericyclic type reactions. Complementary to these more classical synthetic strategies, various transition metal-mediated reactions have been applied. We previously compiled all of these methods that were known to the middle of 2002 (8). In this section, we cover only the total synthesis of natural benzocarbazole alkaloids, although some new methods were used for the synthesis of the functionally diverse non-natural benzocarbazoles (670–685). Peschko and Steglich reported the first biomimetic total synthesis of purpurone (281) starting from 3-(3,4-dimethoxyphenyl)pyruvic acid (1084), 2-(4-methoxyphenyl) ethylamine (1085) and 2u,2u,2u-trichloroethyl-2-bromo-2-(3,4-dimethoxyphenyl)acetate

304

Chemistry and Biology of Carbazole Alkaloids

(1088) (686). Oxidative dimerization of two molecules of 3-(3,4-dimethoxyphenyl)pyruvic acid (1084), followed by subsequent condensation with 2-(4-methoxyphenyl)ethylamine (1085), led to the formation of the pyrrolo dicarboxylic acid 1086. Decarboxylation of 1086 by treatment with TFA afforded the pyrrole 1087 in almost quantitative yield. The two-fold Friedel–Crafts alkylation of 1087 with the bromoester 1088 led to the key intermediate 1089. Cleavage of the ester groups in 1089 under mild conditions by reacting with Zn and aqueous NH4OAc in THF, followed by regioselective cyclization of the diacid 1090 on heating with Ac2O/KOAc led to the diacetate 1091. Saponification of 1091 with aqueous sodium hydroxide, followed by demethylation of the intermediate purpurone nonamethyl ether with an excess of boron tribromide in dichloromethane under addition of cyclohexene as a bromine scavenger led to purpurone (281) (686) (Scheme 5.175). Boger et al. reported the first total synthesis of ningaline D (282) starting from the diphenylacetylene 1092 and dimethyl 1,2,3,4-tetrazine-3,6-dicarboxylate (1093) (687). In this synthesis, the key step is the formation of the fully substituted pyrrole core using an inverse electron demand heterocyclic azadiene Diels–Alder reaction followed by a reductive ring contraction of the resultant 1,2-diazine. The key [4+2] cycloaddition reaction of 1092 with dimethyl 1,2,3,4-tetrazine-3,6dicarboxylate (1093) in refluxing toluene led to the symmetrical 1,2-diazine 1094. Reductive ring contraction of 1094 by treatment with Zn/TFA, followed by N-alkylation of the resulting pyrrole with the phenylethyl iodide 1095 afforded the corresponding N-alkyl pyrrole 1096. A double Dieckmann condensation of 1096 by treatment with NaH cleanly afforded the bisphenol 1097. Conversion of the bisphenol 1097 to the corresponding bistriflate 1098, followed by double Suzuki coupling with 3,4-dimethoxyphenylboronic acid (1099), provided the diester 1100. Hydrolysis of the diester 1100 to the dicarboxylic acid 1101 was affected by treatment with potassium tert-butoxide. Using modified Curtius rearrangement conditions [diphenyl phosphorazidate (DPPA) and triethylamine], the dicarboxylic acid 1101 was transformed to the corresponding diisocyanate, which, on in situ hydrolysis, afforded permethylningaline D (1102) in 70% yield. Demethylation of 1102 with an excess of boron tribromide led to ningaline D (282) in almost quantitative yield (687) (Scheme 5.176).

E. Furocarbazole Alkaloids Carbazole alkaloids condensed to a furan ring represent a relatively new class of natural products. Until now, only four, natural furocarbazole alkaloids were isolated. Recently, we summarized the occurrence, biological activities, and total synthesis of these heteroarylcarbazoles (175,176). Six years after the original isolation, we reported the first total synthesis of furostifoline (224) (688). This synthesis is based on an iron-mediated construction of the carbazole nucleus using 1,3-cyclohexadiene (597) and the 4-amino-7methylbenzofuran (1103) as precursors (Scheme 5.177). The required 4-amino-7-methylbenzofuran (1103) was prepared starting from the commercial 2-methyl-3-nitrophenol (1104) over five steps in 52% overall yield. In this sequence, the key step is the annulation of the furan ring using bromoacetaldehyde

305

Chemistry of Carbazole Alkaloids

OMe MeO

MeO

O

OMe

COOH 1. BuLi, THF, −78°C 2. I2, −78 to 25°C OMe

R

NH2

3. MeO

R

N

OMe 1085 4 Å MS (57%)

1084

OMe 1086 R = COOH

TFA, CHCl3, reflux (95%)

1087 R = H MeO

O

OMe MeO

MeO

OMe

OCH2CCl3 MeO Br 1088

Ac2O, KOAc

COOR

ROOC N

acidic Al2O3, CHCl3, reflux

reflux (63%)

(57%) OMe

MeO

OMe

MeO OMe 1089 R = CH2CCl3 1090 R = H MeO

OMe MeO

1. 5% aq. NaOH, air MeOH, 55°C

OMe

(60% overall)

OH

O N OH

HO OH

HO

OMe

MeO

HO

OH

O

2. BBr3, cyclohexene CH2Cl2, −78°C

N MeO

HO

OMe

OCOMe

MeOCO

Zn dust, aq. NH4OAc THF, 25°C (89%)

OH 281

OMe 1091

Scheme 5.175

diethyl acetal as a C2-building block. The alkylation of 1104 with bromoacetaldehyde diethyl acetal afforded the ether 1105, which was hydrogenated to the corresponding arylamine 1106. After protection of the amino group to the phthalimide 1107, an Amberlyst 15-catalyzed cyclization provided 7-methyl-4-phthalimidobenzofuran (1108). Finally, deprotection of the phthalimido group afforded the required 4-amino-7-methylbenzofuran (1103) in 79% yield (Scheme 5.178).

306

Chemistry and Biology of Carbazole Alkaloids

OMe MeO

Me MeO

R

R N toluene N (87%)

N N R MeO

MeO

R

R

I

1095

Cs2CO3

R R

R

(59% overall)

N N 1094 R = COOMe

1093 R = COOMe

OMe

1. Zn, TFA Me O O OMe 2. MeO

1092 R = COOMe OMe MeO

MeO

OMe

OMe MeO

MeO

OMe MeO MeO

NaH DMF (81%)

R

R R

R

N

1099 1

1

R

R

2

N

OMe

Pd(PPh3)4, K2CO3 LiCl, DME (88%)

2

OR

RO

OMe

OMe

OMe 1097 R1 = COOMe; R2 = H

1096 R = COOMe

Tf2O, pyridine (92%)

1098 R1 = COOMe; R2 = Tf MeO

B(OH)2

OMe MeO

OMe

RO

OR

RO

OR

1. DPPA, i-Pr2NEt CH2Cl2, 25°C R

R

OMe

MeO

N OR

RO

OMe

MeO

O

O

2. H2O/THF, air, reflux (70% overall)

N

OR

RO OR

OMe OMe 1100 R = COOMe 1101 R = COOH

OR 1102 R = Me

t-BuOK, H2O, DMSO (84%)

BBr3, CH2Cl2 (96%)

282 R = H

Scheme 5.176 Me

Me [Fe(0)]

N H 224

H2N

O

597

Scheme 5.177

O

1103

307

Chemistry of Carbazole Alkaloids

NO2

NO2 BrCH2CH(OEt)2

H2, Pd/C

K2CO3, DMF, 153°C (81%)

OH Me

O Me

1104

OEt MeOH, 25°C (99%) OEt

1105

NH2

NPhth

Amberlyst 15 chlorobenzene

phthalic anhydride OEt

O Me

CHCl3, 61°C (88%)

OEt

O Me

1106

OEt OEt

120°C (93%)

1107 NH2

NPhth N2H4 H2O O Me 1108

MeOH, 25°C (79%)

O Me 1103

Scheme 5.178

(OC)3Fe

Me

Me

MeCN, 25°C

(OC)3Fe

(100%)

H2N

BF4

O

602

H2N O 1109

1103 Me 3.5 eq. I2, air pyridine, 90°C (36%)

N H 224

O

Scheme 5.179

Electrophilic aromatic substitution of the 4-aminobenzofuran 1103 with the complex salt 602 afforded the iron complex 1109 in quantitative yield. Cyclization of the complex 1109 with concomitant aromatization was achieved by oxidation with an excess of iodine in pyridine at 901C in air to afford directly furostifoline (224) (688,689) (Scheme 5.179). Four years later, we reported an improved iron-mediated total synthesis of furostifoline (224) (689). This approach features a reverse order of the two cyclization reactions by first forming the carbazole nucleus, then annulation of the furan ring. As a consequence, in this synthesis the intermediate protection of the amino function is not necessary (cf. Schemes 5.178 and 5.179). The electrophilic aromatic substitution at the arylamine 1106 by reaction with the iron complex salt 602 afforded the iron

308

Chemistry and Biology of Carbazole Alkaloids

complex 1110. The iron-mediated arylamine cyclization of complex 1110 with iodine in pyridine led to the carbazole 1111. Annulation of the furan ring by reaction of the carbazole 1111 with catalytic amounts of Amberlyst 15 in chlorobenzene at 1201C afforded directly furostifoline (224) This synthesis provides furostifoline in only five steps and 21% overall yield based on the nitrophenol 1104 (689) (Scheme 5.180). The first synthesis required seven steps to achieve a 19% overall yield based on the same starting material (688,689) (see Schemes 5.178 and 5.179). Recently, we reported the first total synthesis of furoclausine A (225) following the improved protocol developed for the synthesis of furostifoline (224) (see Scheme 5.180). This strategy to furoclausine A (225) suggested tricarbonyl(Z5-2-methoxycyclohexadienylium)iron tetrafluoroborate (1112) and the arylamine 1106 as precursors (Scheme 5.181). The arylamine 1106 previously served as the starting material for our improved total synthesis of furostifoline (224) and was obtained in two steps and 80% overall yield from 2-methyl-3-nitrophenol (1104) (see Scheme 5.178). Electrophilic substitution of the arylamine 1106 by reaction with the iron complex salt 1112 led regioselectively to the iron complex 1113. Oxidative cyclization of complex 1113 with iodine in pyridine provided the carbazole 1114. Annulation of the furan ring by reaction of the carbazole 1114 with catalytic amounts of Amberlyst 15 in chlorobenzene at 1201C afforded 8-methoxyfurostifoline (1115). Oxidation of 1115 with DDQ, followed by cleavage of the methyl ether using boron tribromide (BBr3), afforded furoclausine A (225) (690) (Scheme 5.182). Beccalli et al. reported a total synthesis of furostifoline (224) starting from indole3-acetic acid (680) (691). The key step of this strategy is the oxidative

(OC)3Fe BF4

Me H2N

O

(OC)3Fe

Me

602 OEt OEt

MeCN, 25°C (97%)

H2N

OEt

1106

1110 Me

3.5 eq. I2, air pyridine, 90°C (40%)

OEt

O

O N H 1111

Me

Amberlyst 15 OEt chlorobenzene 120°C (66%)

OEt

O

N H 224

Scheme 5.180

OMe

CHO

Me

[Fe(0)] HO N H 225

O

(OC)3Fe

H2N

BF4

O

OEt OEt

1112

Scheme 5.181

1106

Chemistry of Carbazole Alkaloids

309

OMe (OC)3Fe

Me H2N

MeO (OC)3Fe

BF4

Me

1112 OEt

O

MeCN, 25°C (87%)

OEt

H2N

O

OEt OEt

1106

1113 Me OEt

I2, pyridine air, 90°C (71%)

O

MeO N H 1114

OEt

Amberlyst 15 chlorobenzene, 120°C (82%)

Me 1. DDQ, MeOH/H2O, 25°C 2. 2 eq. BBr3, CH2Cl2 MeO N H 1115

O

−78 to −20°C, 3 d (18% overall)

CHO HO N H 225

O

Scheme 5.182

photocyclization of the 3-substituted indole 1121. Reaction of indole-3-acetic acid (680) with diethyl dicarbonate in the presence of DMAP led to the 1-ethoxycarbonyl derivative 1116. Deprotonation of 1116 with sodium bis(trimethylsilyl)amide (NaHMDS), followed by quenching of the resulting anion with acetic anhydride, afforded a 3.5:1 ratio of the enol acetate 1117 and enol 1118 in 89% total yield. Additionally, the enol acetate 1117 was converted to the desired enol 1118 in 93% yield by treatment with dimethylamine in dichloromethane (two steps, 84% overall yield of 1118). Alternatively, deprotonation of 1116 with LDA, and reaction of the corresponding lithioanion with acetic anhydride, led to the enol 1118 as the sole product in 68% yield. The enol 1118 was transformed to an inseparable, diastereoisomeric 1:1 mixture of the vinyl triflate 1119. The palladium(0)-catalyzed cross-coupling of the triflate 1119 with 2-(tributylstannyl)furan (1120) afforded the vinylfuran 1121 as a 1:1 mixture of diastereoisomers. Photocyclization of the vinylfuran 1121 in the presence of iodine as the oxidizing agent provided the furo[3,2-a]carbazole 1122 in 69% yield. Alkaline hydrolysis of 1122 gave the acid 1123 via the N-deprotected furo[3,2-a]carbazole. Finally, decarboxylation of 1123 afforded furostifoline (224) (691) (Scheme 5.183). In the same year, Hibino et al. reported a total synthesis of furostifoline (224) employing a new type of electrocyclic reaction (636). This cyclization proceeds through a 2-alkenyl-3-allenylindole intermediate, which is derived from 2-(fur-3-yl)3-propargylindole 1128. Compound 1128 was prepared starting from 2-chloroindole3-carbaldehyde (891), furan-3-boronic acid (1124), and ethynylmagnesium bromide. Vilsmeier reaction of 2-oxindole (830) afforded 2-chloroindole-3-carbaldehyde (891). Suzuki cross-coupling of 891 with furan-3-boronic acid (1124), followed by protection of the indole nitrogen with benzyloxymethyl (BOM) chloride, led to

310

Chemistry and Biology of Carbazole Alkaloids

HOOC

EtOOC 1. THF, −70°C

O(COOEt)2 MeCN, DMAP (95%)

N H 680 EtOOC

EtOOC

Me OAc

EtOOC

Me Tf2O, i-Pr2NEt

OH N COOEt 1118 (20%)

N COOEt 1117 (69%)

NaHMDS, Ac2O 2. HOAc

N COOEt 1116

CH2Cl2 (69%)

Me OTf

N COOEt 1119

CH2Cl2, Me2NH (93%) O

SnBu3

1120 CuI, LiCl Pd(PPh3)4, THF, Δ (95%)

EtOOC

EtOOC

Me

N COOEt

O

(69%)

1121 HOOC

N COOEt

O

1122 Me

Me

1. MeOH/H2O, KOH, Δ 2. EtOH/H2O, KOH, Δ (84% overall)

Me

benzene, I2, hν

quinoline N H 1123

O

Cu, Δ (86%)

N H 224

O

Scheme 5.183

N-BOM-protected 2-(fur-3-yl)indole-3-carbaldehyde (1126). Grignard reaction of 1126 with ethynylmagnesium bromide afforded the propargyl alcohol 1127, which, on BOM protection, afforded 2-(3-furyl)-3-propargyl indole 1128. Thermal electrocyclic reaction of 1128 in the presence of potassium tert-butoxide gave the 4-oxygenated furo[3,2-a]carbazole 1129. Removal of the N,O-BOM groups of the furo[3,2-a]carbazole 1129 under Birch conditions led to a separable mixture of the N(hydroxymethyl)furo[3,2-a]carbazole 1130 (41%) and the furo[3,2-a]carbazole 1131 (51%). Compound 1130 was converted to 1131 in 93% yield by treatment with Triton B. For the final transformation of the furocarbazole 1131 to furostifoline (224), the hydroxy group was removed via reductive elimination of the intermediate triflate 1132 (636,637) (Scheme 5.184). Tima´ri et al. described a total synthesis of furostifoline (224) starting from commercial o-cresol (1133). The key steps in this approach are the Suzuki coupling to the o-nitrobiaryl 1139 and subsequent Cadogan’s reductive cyclization via a nitrene intermediate (692). Bromination of o-cresol (1133) led to 5-bromocresol (1134), which, on alkylation with bromoacetaldehyde diethyl acetal, followed by P2O5-promoted cyclization in

311

Chemistry of Carbazole Alkaloids

(HO)2B

POCl3, DMF O

N H 830

O

CHO 1124

(73%)

N H 891

Cl

Pd(OAc)2, PPh3 Et3N, DMF, 100°C (84%)

RO CHO N R 1125 R = H 1126 R = BOM BOMO

HC CMgBr O

KOt-Bu, t-BuOH

THF, rt (99%)

O

N BOM

BOMCl, K2CO3, DMF, rt (98%)

1127 R = H 1128 R = BOM HO

Me

THF, 90°C (61% overall) BOMCl, NaH THF, 0°C HO

Me

Me

Na, liq. NH3 N BOM 1129

O

−78°C

N CH2OH 1130 (41%)

O

N H 1131 (51%)

O

Triton B, THF/H2O, 100°C (93%) TfO Tf2O, pyridine CH2Cl2, rt (92%)

Me

Me Pd(OAc)2, HCOOH

N H 1132

O PPh3, Et3N, DMF, 60°C (99%)

N H 224

O

Scheme 5.184

85% H3PO4 at 1401C, afforded 5-bromo-7-methylbenzofuran (1136). A halogen–metal exchange reaction of 1136 with butyllithium, and subsequent treatment with tributyl borate, gave the boronic acid 1137. The palladium(0)-catalyzed cross-coupling of the boronic acid 1137 with 2-bromonitrobenzene (1138) provided the o-nitrobiaryl 1139 in 72% yield. Using Cadogan’s method, by reductive cyclization with triethyl phosphite, the o-nitrobiaryl 1139 was directly transformed to furostifoline (224) in 42% yield (692) (Scheme 5.185). Yasuhara et al. reported a total synthesis of furostifoline (224) by the oxidative photocyclization of 3-(indol-2-yl)-2-(isopropenyl)furan (1146), which was obtained by Sonogashira coupling of ethyl 2-ethynylphenylcarbamate (1143) with 3-bromo-2propenylfuran (1142) (693). 2-Acetyl-3-bromofuran (1141) was prepared by Friedel–Crafts acylation of 3-bromofuran (1140). Wittig reaction of 1141 with methyltriphenylphosphonium bromide and butyllithium led to 3-bromo-2-propenylfuran (1142), which, on Sonogashira coupling with ethyl 2-ethynylphenylcarbamate (1143), provided N-protected (2-isopropenylfur-3-yl)ethynylaniline 1144. The TBAF-promoted

312

Chemistry and Biology of Carbazole Alkaloids

Me

Me OH

OH

Me2SBr Br CH2Cl2, rt (81%)

100°C (75%)

Br

1133

Me

BrCH2CH(OEt)2 K2CO3, DMF

1134

O Br

EtO 1135 Me

Me O

H3PO4, P2O5 chlorobenzene, 140°C (51%)

OEt

THF, −70°C, H2O (85%)

Br

O

BuLi, B(OBu)3 (HO)2B

1136

1137

NO2 Br

Me 1138 Pd(0), Na2CO3 DME/H2O, reflux (72%)

Me O

NO2

P(OEt)3, reflux (42%)

1139

N H

O

224

Scheme 5.185

cyclization of 1144 provided 3-(indol-2-yl)-2-(isopropenyl)furan (1146) in 47% yield, along with the deprotected aniline 1145 in 33% yield. Compound 1145 was recycled to the N-ethoxycarbonyl derivative 1144 in 76% yield by protection of the amino group. Finally, oxidative photocyclization of the 2-substituted indole 1146 in the presence of catalytic amounts of iodine afforded furostifoline (224) (693) (Scheme 5.186). In 2007, we reported the first total synthesis of the furo[2,3-c]carbazole eustifoline-D (227) starting from glycozolinine (91), which was obtained in three steps and 56% overall yield starting from 4-bromoanisole (670) and p-toluidine (1028) (see Scheme 5.152). Williamson ether synthesis by alkylation of glycozolinine (91) with 2-bromo-1,1-diethoxyethane, and subsequent annulation of the furan ring with catalytic amounts of Amberlyst 15 in chlorobenzene at reflux, provided eustifoline-D (227), along with isoeustifoline-D (1148), in a ratio of 4.3:1. This method provides eustifoline-D (227) in five steps and 20% overall yield based on 4-bromoanisole (670) (547) (Scheme 5.187).

F. Pyrrolo[2,3-c]carbazole Alkaloids Recently, Fu¨rstner et al. reported the first total synthesis of the pyrrolo[2,3-c]carbazole alkaloids dictyodendrin B (284a) (694,695), C (286a) (695), and E (288a) (695) in the form of their ammonium salts starting from the common intermediate 1157. This relay compound 1157 was prepared on a multigram scale starting from commercial 3-hydroxy-2-nitroacetophenone (1149) over seven steps. This sequence comprises a toluenesulfonylmethyl isocyanide (TosMIC) cycloaddition, a low valent titaniuminduced reductive oxamide coupling, and a photochemical tandem 6p-electrocyclization/aromatization as key steps for the generation of pyrrole, indole, and pyrrolocarbazole frameworks, respectively.

Chemistry of Carbazole Alkaloids

Br

Br

Br MeCOCl, AlCl3

O

CH2Cl2, 0 to 5°C

O

Ph3PMeBr

Me

(51%) 1140

O

BuLi, THF, rt (82%)

O

Me

1141

1142

Me NHCOOEt

1143

TBAF, THF

O

reflux

PdCl2(PPh3)2, CuI i-Pr2NH, DMF, reflux

NHCOOEt 1144

(79%)

ClCOOEt, pyridine, 0°C (76%) Me Me

Me toluene, I2

O O

N H

NH2

hν, rt (24%)

N H

1146 (47%)

1145 (33%)

O

224

Scheme 5.186

Me (see Scheme 5.152)

MeO

(ref. 547)

H2N

Br 670

Me

HO

N H 91

1028 OEt EtO

Me

O

BrCH2CH(OEt)2

Amberlyst 15

K2CO3, DMF, 152°C (75%)

chlorobenzene 120°C

O

Me

N H 227 (48%)

N H 1147 Me

O

N H 1148 (11%)

Scheme 5.187

313

314

Chemistry and Biology of Carbazole Alkaloids

Prior to base-induced condensation with 4-methoxybenzaldehyde, the free hydroxy group in 3-hydroxy-2-nitroacetophenone (1149) was protected as an isopropyl ether 1150. The resulting chalcone 1151 was treated with TosMIC in the presence of NaH at low temperature to afford a pyrrole, which, on in situ N-alkylation with 4-MeOC6H4(CH2)2Br, led to the corresponding N-alkyl derivative 1152. Reduction of the nitro group in 1152 with Fe/HCl furnished the aniline 1153 in almost quantitative yield. Compound 1153 was acylated by the acid chloride 1154 to give the amide 1155. Reaction of the ketoamide 1155 with titanium on graphite, prepared from TiCl3 and 2 equivalents KC8 in refluxing DME, led to the desired indole 1156 in up to 93% yield. In a single operation, irradiation of 1156 with UV light (Hanovia Hg lamp, 250 W) in MeCN, followed by addition of Pd/C in nitrobenzene, led to the desired pyrrolocarbazole 1157 in 81% yield as result of a 6p-electrocyclization with concomitant aromatization (Schemes 5.188 and 5.189). Regioselective bromination of the pyrrolocarbazole 1157 with NBS led to the bromocarbazole 1158, which, on halogen–metal exchange with butyllithium and O

NO2

O OR

Me

Oi-Pr

p-MeOC6H4CHO

NaOH, MeOH, 70°C (74%) 2-bromopropane, K2CO3 DMF, 100°C (99%)

1149 R = H 1150 R = i-Pr

NO2

MeO 1151

MeO O

O

1. TosMIC, NaH THF, −30°C

Cl

R

OMe

Oi-Pr

2. p-MeOC6H4(CH2)2Br reflux (83% overall)

N

CH2Cl2, Et3N, cat. DMAP (89%)

OMe 1152 R = NO2 1153 R = NH2

OMe

1154

Fe, aq. HCl, EtOH (96%)

OMe

MeO

MeO MeO O

HN

N

TiCl3/ KC8, DME O Oi-Pr pyridine, reflux (71 to 93%)

N

i-PrO

N H

OMe OMe

OMe 1156 1155

Scheme 5.188

OMe

Chemistry of Carbazole Alkaloids

MeO

1156

R

hν, MeCN Pd/C cat.

i-PrO

OMe

N H

OMe

1157 R = H 1158 R = Br

NBS, THF, 0°C (69%)

TPAP, NMO

N

i-PrO

3. p-MeOC6H4CHO −78°C to rt (97 % overall)

OMe

HO

MeO

1. MeLi, THF, −78°C OMe 2. BuLi, −78°C

N

nitrobenzene (81%)

315

OMe

4 Å MS, CH2Cl2 (66%)

OMe

N H

OMe 1159 OMe

O

MeO

N

RO

N H

1160 R = i-Pr 1161 R = H

OMe OMe

OMe BCl3, CH2Cl2, −20°C (85%)

Scheme 5.189

subsequent quenching of the intermediate lithio species with 4-methoxybenzaldehyde, led to 1159. Oxidation of the benzylic alcohol 1159 to the corresponding ketone 1160 was achieved in dilute CH2Cl2 solution with tetra-n-propylammonium perruthenate (TPAP) and N-methylmorpholine N-oxide (NMO). Selective cleavage of the isopropyl ether in 1160 with BCl3, followed by reaction of the resulting phenol 1161 with trichloroethyl chlorosulfuric acid ester, gave the aryl sulfate 1162 in 92% yield. Exhaustive demethylation of 1162 with BCl3 under phase transfer conditions, followed by reductive cleavage of the remaining trichloroethyl moiety with Zn/HCOONH4, led to dictyodendrin B (284a) (694,695) (Schemes 5.189 and 5.190). Selective cleavage of the isopropyl ether in 1157 with BCl3, followed by reaction of the resulting phenol 1163 with trichloroethyl chlorosulfuric acid ester gave the aryl sulfate 1164. After complete demethylation of 1164 with BCl3, the resulting phenol was reacted with H2O2 in MeCN to give the quinone 1165. Finally, reductive cleavage of the trichloroethyl ester moiety in 1165 with excess zinc dust and ammonium formate in MeOH, followed by stirring of the crude reaction mixture under an

316

Chemistry and Biology of Carbazole Alkaloids

OMe

O

MeO

N

OMe

N OMe H 1161

HO

DABCO, CH2Cl2 (92%)

OMe

OMe

O

MeO

N

O

O

S O O Cl3C

N H

Cl3CCH2OSO2Cl

OMe

1. BCl3, Bu4NI CH2Cl2, 0°C to rt 2. Zn, HCOONH4, MeOH (58% overall)

OMe OMe

284a

1162 OH

O

HO

N

MO3SO

N H

OH OH

OH

284 M = Na 284a M = NH4

Scheme 5.190

oxygen atmosphere, led to dictyodendrin C (286a) in 76% yield over two steps (695) (Scheme 5.191). For the total synthesis of dictyodendrin E (288a), the required benzylidene substituent at C-2 (see Scheme 2.71) was introduced almost quantitatively by palladium-catalyzed benzylation of the bromide 1156 with the borate complex 1166. Thus, reaction of 1156 with borate complex 1166, which was generated in situ from 9-methoxy-9-borabicyclo[3.3.1]nonane (9-MeO-9-BBN) and 4-methoxybenzylmagnesium chloride with Pd(OAc)2 and Buchwald’s sterically encumbered S-PHOS ligand, led to the coupling product 1167 in 90% yield. Selective removal of the isopropyl ether in 1167 with BCl3, followed by reaction of the resulting phenol with trichloroethyl chlorosulfuric acid ester, gave the aryl sulfate 1168. After cleavage of the methyl ethers with BCl3, the sensitive hydroxy derivative 1169 was subjected to immediate reductive cleavage of the trichloroethyl group followed by DDQ oxidation to afford dictyodendrin E (288a) in its ammonium salt form (695) (Scheme 5.192).

Chemistry of Carbazole Alkaloids

317

MeO N

OMe BCl3, CH2Cl2, 0°C (75%)

OMe

N H

i-PrO

OMe

1157 MeO N

OMe

1163 R = H 1164 R = SO3CH2CCl3 HO

Cl3CCH2OSO2Cl DABCO, THF (71%)

O N

O

O

S O O Cl3C

1. BCl3, Bu4NI, CH2Cl2, 0°C 2. aq. H2O2 (30% w/w), MeCN (57% overall)

OMe

N H

RO

OMe

N H 1165

OH

1. Zn, HCOONH4, MeOH 2. O2 (1 atm), MeOH (76% overall)

OH

286a

O

HO

O N

MO3SO

N H

OH OH

O

286 M = Na 286a M = NH4

Scheme 5.191

G. Pyrido[4,3-b]carbazole Alkaloids The strong interest in the synthesis of pyrido[4,3-b]carbazole alkaloids started in the late 1960s with the disclosure of the antitumor activity of ellipticine (228) and 9-methoxyellipticine (229) (see Scheme 2.56) in several animal and human tumor systems. This discovery made these alkaloids to important synthetic targets and induced extensive studies of structure modification. These synthetic efforts have

318

Chemistry and Biology of Carbazole Alkaloids

MeO

Br

MeO

N

OMe B

OMe

MgCl

1166 OMe

N H

i-PrO

10 mol% Pd(OAc)2 20 mol% S-PHOS DMF/THF (90%)

OMe

1156 OMe

MeO N

1. BCl3, CH2Cl2, −20°C to rt 2. Cl3CCH2OSO2Cl, DABCO, CH2Cl2 (83% overall)

OMe

N H

i-PrO

OMe

OMe

1167 OR

RO

1. Zn, HCOONH4, MeOH

N

O

O

S O O Cl3C

N H

OR

2. DDQ, THF (75% overall)

288a

OR OR

1168 R = Me 1169 R = H

OH

HO BCl3, Bu4NI CH2Cl2, 0°C (85%)

N

MO3SO

N H

OH OH

O

288 M = Na 288a M = NH4

Scheme 5.192

been reviewed in this series by Gilbert (696), Cordell (697), Suffness and Cordell (408), and Gribble (192) in the Volumes 8, 17, 25, and 39, respectively. In addition to these comprehensive reviews, various reviews have appeared elsewhere, covering different aspects of the pyrido[4,3-b]carbazole alkaloids and their analogs (8,185–191,195,196,698,699). Further, in 1991 Gribble (193) and in 1994 Moody (525) wrote personal accounts on the synthesis of the antitumor pyridocarbazole alkaloids. Pindur et al. have published a series of articles on the intercalating properties of pyrido[4,3-b]carbazole alkaloids (190,194,405).

Chemistry of Carbazole Alkaloids

319

Herein, as an update of Volume 39 of this series (192), we summarize the total syntheses of natural pyrido[4,3-b]carbazole alkaloids developed since 1990. Gribble et al. reported the total syntheses of ellipticine (228), olivacine (238a), 9-methoxyellipticine (229), and 9-hydroxyellipticine (230) starting from the keto lactam 1181 and its methoxy derivative 1182 (700,701) The ketolactam 1181 was available in four steps, and 71% overall yield, starting from indole 1170. Thus, indole 1170 was converted to N-phenylsulfonylindole (956) by treatment with n-butyllithium followed by the addition of benzenesulfonyl chloride. Regiospecific 2-lithiation of 956 with LDA and quenching of the intermediate 2-lithioindole 1173 with pyridine 3,4-dicarboxylic anhydride (1175) led to the desired keto acid 1176 in 92% yield, along with 8% of the regioisomeric product 1178. After cleavage of the N-phenylsulfonyl protecting group, the keto acid 1179 was smoothly cyclized to the keto lactam 1181 in quantitative yield. Low temperature addition of methyllithium to keto lactam 1181 led to the diol 1189 as two unstable diastereomers, which, without purification, were treated with sodium borohydride (NaBH4) to afford ellipticine (228) in 82% yield (700,701) (Schemes 5.193 and 5.194). An analogous sequence to that described for ellipticine was used to convert 5-methoxyindole (1171) to 9-methoxyellipticine (229). Noteworthy is the fact that none of the other regioisomeric keto acid could be detected by analysis of the crude product 1177. Using this sequence, 9-methoxyellipticine (229) was obtained in 47% overall yield based on 1171. O-Demethylation of 9-methoxyellipticine (229) R

R

R

1. BuLi, THF, −78°C N H

LDA, THF

2. PhSO2Cl, −78°C

N SO2Ph

−75 to 0°C

Li N SO2Ph

956 R = H (91%)

1170 R = H

1173 R = H

1172 R = OMe (84%)

1171 R = OMe

1174 R = OMe

O N

O

R

O

−100°C

R

N

1175

N

+ N PhO2S

O

COOH

1176 R = H (92%) 1177 R = OMe (~100%)

N PhO2S

O

COOH

1178 R = H (8%) R

N

K2CO3, aq. MeOH, Δ N H

O

COOH

1179 R = H (~100%) 1180 R = OMe (~100%)

Scheme 5.193

320

Chemistry and Biology of Carbazole Alkaloids

R

R Ac2O

O N H

N 1181 R = H (~100%) 1182 R = OMe (~100%)

1179 R = H 1180 R = OMe R

Me

R

Me

N

R

Me N LiO Li

HO

Me

LiO

N

O

OLi

N 1183 R = H 1184 R = OMe

R

−100°C

O N

N Me LiO

2 eq. MeLi

O N

COOH 80 to 85°C

N

1185 R = H 1186 R = OMe

Me

1187 R = H 1188 R = OMe

Me

Me N

N

NaBH4, EtOH, Δ

H2O N HO H

LiO

(82% overall)

Me

N H

1189 R = H

Me

228

1190 R = OMe NaBH4 EtOH, Δ (75% overall)

MeO

Me

HO

N

Me N

pyridine HCl N H

Me

200°C (93%)

229

N H

Me

230

Scheme 5.194

with pyridine hydrochloride led to 9-hydroxyellipticine (230) (701) (Schemes 5.193 and 5.194). As an extension of this methodology, Gribble et al. reported a formal total synthesis of olivacine (238a). This synthesis starts from the same keto lactam 1181, used for the synthesis of ellipticine (228), and exploits the lower reactivity of the lactam carbonyl as compared to the carbonyl of the keto lactam. Reaction of the keto lactam 1181 sequentially with methyllithium and superhydride (LiBHEt3) led to 11-demethylellipticine (1191) in 57% yield, along with 30% of ellipticine (228). Finally, using Kutney’s procedure (220), 11-demethylellipticine (1191) could be transformed to olivacine (238a) (701) (Scheme 5.195). Gribble et al. also reported a new annulation strategy for the total synthesis of ellipticine (228) (527). This methodology utilizes a Diels–Alder reaction between

321

Chemistry of Carbazole Alkaloids

1181

Me

1. 1 eq. MeLi, THF, −100°C 2. 1 eq. LiBHEt3, −100°C

N

N

3. NaBH4, EtOH, reflux (57% overall)

N H

Me

1191 (57% overall)

N H

Me

228 (30% overall) Me N

(54%) (ref. 220)

N Me H 238a

Scheme 5.195 CHO

(4 steps) (21% overall)

N H 618

Me O

Me

(6 steps) (46% overall)

N Me SO2Ph 544

N H 1192

Scheme 5.196

1,3-dimethyl-4-(phenylsulfonyl)-4H-furo[3,4-b]indole (544) and 3,4-pyridyne (1193), followed by extrusion of the oxygen bridge. Furo[3,4-b]indole 544 was prepared from commercially available 3-formylindole (618) in 21% overall yield, using four simple functional group transformations. Alternatively, a longer, albeit higher yielding synthesis of 544 was also developed starting from 3-ethylindole (1192) (527) (Scheme 5.196). Diels–Alder reaction of the furoindole 544 with 3,4-pyridyne (1193), generated in situ via two different ways, led to a mixture of the two possible cycloadducts 1194 and 1195 in approximately equal amounts. Without purification, the crude adducts 1194 and 1195 were treated with basic sodium borohydride (NaBH4) to afford a separable mixture of ellipticine (228) and isoellipticine (1196) in 23% and 29% yield, respectively (527) (Scheme 5.197). Six years later, the same authors reported an improved version of their earlier synthesis of ellipticine (228) (527) (Scheme 5.197) by using the 1-(p-methoxybenzyl)5,6-dihydropyridone (1197) as 3,4-pyridyne surrogate (702,703). Thus, the dimethylfuroindole 544 was treated with the unsaturated lactam 1197 (prepared from dvalerolactam in three steps) in the presence of trimethylsilyl triflate (TMSOTf) to afford the carbazole 1199 as a single product in 40% yield. The low yield is presumably a consequence of decomposition of the intermediate adduct 1198 during

322

Chemistry and Biology of Carbazole Alkaloids

Me

Me N

N NaBH4

O

NaOH/MeOH

N H N

544

N H

Me

Me

228 (23% overall)

1194 Me

Me

1193 O N Me H 1195

NaBH4

N

N

NaOH/MeOH

N Me H 1196 (29% overall)

Scheme 5.197 O N

PMB

TMSO Me

Me 1197

O

O

TMSOTf, CH2Cl2

N Me SO2Ph 544

PMB N

N PhO2S

PMB = p-methoxybenzyl Me

O

OTf

Me 1198 Me

PMB N

H2O

N 1. LiAlH4, THF, reflux

NaHCO3 N H

Me

2. 10% Pd/C, decalin reflux

N H

Me

228 (20% overall)

1199

Scheme 5.198

the reaction. Reduction of the carbonyl group with lithium aluminum hydride, followed by aromatization with concomitant debenzylation, transformed the carbazole 1199 to ellipticine (228) (702,703) (Scheme 5.198). Murakami et al. reported a total synthesis of ellipticine (288) starting from 9-benzyl-4-methyl-1,2,3,4-tetrahydro-9H-carbazole (1200) (704,705). Using an optimized Vilsmeier–Haack protocol, the tetrahydrocarbazole (1200) was transformed to the desired 3-formylcarbazole 1202 in 38% yield, along with the other minor carbazole derivatives 1201 and 1203 in 1% and 26% yield, respectively. The 3-formylcarbazole 1202 was converted to the imine 1204 and then to the tosyl amide 1205. Finally, using modified Pomeranz–Fritsch cyclization conditions, the amide 1205 was transformed to ellipticine (228), involving a spontaneous sequence of detosylation, aromatization, and debenzylation. However, the Birch reduction, used for the removal of the benzyl group, also reduced the pyridine ring to dihydroellipticine, which subsequently had to be rearomatized with 10% Pd/C to

Chemistry of Carbazole Alkaloids

323

ellipticine (228). Therefore, an alternative route was developed involving removal of the benzyl group prior to formation of the pyridine ring. The Birch reduction of the imine 1204 removed the benzyl group with concomitant reduction of the C–N double bond. Tosylation of the resulting amine gave the acetal 1206. Cyclization of the tosylate 1206 using Jackson and Shannon’s conditions (706) with hydrochloric acid in dioxane provided ellipticine (228) along with 13% of 2-tosyl-1,2-dihydroellipticine (1207) (704,705) (Scheme 5.199). Following a similar synthetic sequence, starting from 9-benzyl-1,2,3,4-tetrahydro-9H-carbazole, the same authors also reported the synthesis of olivacine (238a) (704,705). Ba¨ckvall and Plobeck reported a formal synthesis of ellipticine (228) starting from indole (707). The [4+2] cycloaddition of 1-indolylmagnesium iodide (1208) with 3-(phenylsulfonyl)-2,4-hexadiene (1209) afforded the tetrahydrocarbazole

Me

Me

Me

Me

CHO

CHO

POCl3 DMF 120°C

N Bn 1200

N Bn

N Bn

Bn = C6H5CH2 1201 (1%)

N Bn

Me

1202 (38%)

CH2NMe2

1203 (26%)

H2NCH2CH(OEt)2, 100°C (81%) Ts

Me

Me

N

N 1. NaBH4, MeOH, rt

N Bn

Me

OEt OEt

2. TsCl, Na2CO3 THF, rt (84% overall)

1204

N Bn

Me

1205

1. liq. NH3/Li, THF 2. TsCl, Na2CO3 THF, H2O, rt (81% overall)

1. 6 M HCl, dioxane, reflux 2. liq. NH3/Li 3. 10% Pd/C, tetralin, 210°C (32% overall)

Ts

Me

Me

N

N 6 M HCl

N H 1206

OEt OEt

Me

OEt OEt

dioxane, reflux (ref. 706)

Ts

Me

N H

N

Me 1207

Scheme 5.199

N H 228

Me

324

Chemistry and Biology of Carbazole Alkaloids

1210 as the major diastereoisomer. Michael addition of lithio acetonitrile to the tetrahydrocarbazole 1210 gave the hexahydrocarbazole 1211. Reductive desulfonation of 1211 with sodium amalgam in buffered methanol to 1212, followed by aromatization with chloranil, provided the carbazole 1213. Reduction of compound 1213 using CoCl2/NaBH4 to the amine, and subsequent formylation with ethyl formate, led to the formamide 1214. The known formamide 1214 was previously reported (708) to provide ellipticine (228) in 77% overall yield, by Bischler– Napieralski cyclization to dihydroellipticine and subsequent aromatization (Scheme 5.200). Based on the cycloaddition of (E)-2-(phenylsulfonyl)-1,3-pentadiene with 1-indolylmagnesium iodide (1208) (84% yield), a similar reaction sequence was used for a formal synthesis of olivacine (238a) (707). Hibino and Sugino reported a total synthesis of ellipticine (228) and olivacine (238a) starting from N-(phenylsulfonyl)indole (956) (709). This route involves a thermal electrocyclic reaction of a conjugated hexatriene system, which is generated by a [1,5]-sigmatropic reaction of the 2-alkenylindoles 1217 and 1218. The 2-alkenylindoles 1217 and 1218 were obtained by condensation of 2-lithio-1phenylsulfonylindole 1173 with the substituted 4-acetylpyridines 1215 and 1216. Finally, thermal electrocyclic reaction of 1217 and 1218 at 460–5001C afforded ellipticine (228) and olivacine (238a) in 30% and 57% yield, respectively (709) (Scheme 5.201). This method was extended to the synthesis of the 11-demethylellipticine derivatives (709). Archer et al. reported a total synthesis of 12-hydroxyellipticine (232) starting from Gribble’s ketolactam intermediate 1181, which was obtained in five simple steps

Me H

Me SO2Ph N MgI 1208 Me H

(73%)

1209

Me CN

N H 1214

Na-Hg, MeOH 0°C to rt (94%)

H O NH

Me

1. NaBH4, CoCl2 MeOH, 0°C

chloranil xylene, reflux (64%)

N H Me H

Me

THF, −78°C

1210

R

1212 R = H

LiCH2CN

N H Me H

Me

1211 R = SO2Ph

SO2Ph

toluene, rt

N H

CN

Me

1213

Me N (ref. 708) N H 228

Scheme 5.200

Me

2. ethyl formate, THF sealed tube, 120°C (68% overall)

Chemistry of Carbazole Alkaloids

R2

325

R1 N

O Me

THF, −78°C to rt

LDA, THF −78°C to rt

Li N SO2Ph

N SO2Ph 956 R2

1215 R1 = H; R2 = Me 1216 R1 = Me; R2 = H

1173 R1

R2 N

N

460 to 500°C N H

N H 1217 R1 = H; R2 = Me 1218 R1 = Me; R2 = H

R1

Me

228 R1 = H; R2 = Me 238a R1 = Me; R2 = H

Scheme 5.201

starting from indole (1170) (710,711) (see Schemes 5.193 and 5.194). Treatment of the ketolactam 1181 with 1 equivalent of methyllithium, followed by quenching with solid ammonium chloride, gave the lactam carbinol 1220 as the major product. However, when the same reaction was quenched with water, the lactone 1219 was formed in 65% yield due to hydrolysis of the lactam carbinol 1220 by in situgenerated LiOH. The lactone 1219 was used as an intermediate for the introduction of different substituents at C-11. Addition of methyllithium to the lactone 1219, followed by reduction with sodium borohydride in refluxing ethanol, afforded, almost quantitatively, ellipticine (228). Reaction of the compound 1219 with the lithio derivative of formaldehyde diethylmercaptal, and reduction with sodium borohydride in refluxing ethanol, led to the mercaptal 1221. Cleavage of the mercaptal 1221 with bis(trifluoroacetoxy) iodobenzene [PhI(OCOCF3)2] in aqueous acetonitrile gave the 11-formyl derivative, which was reduced with sodium cyanoborohydride (NaBH3CN) to 12-hydroxyellipticine (232) (710,711) (Scheme 5.202). The same group also reported the synthesis of further pyrido[4,3-b]carbazole derivatives by condensation of 2-substituted indoles with 3-acetylpyridine (712). Sha and Yang reported the total synthesis of ellipticine (228) using the 2,4-dihydropyrrolo[3,4-b]indole (1225) as a synthetic equivalent of indolo-2,3quinodimethane in a Diels–Alder reaction with 3,4-pyridyne (1193) (713). The acetylation of 2-ethylindole (1222) with N,N-dimethylacetamide and phosphorus oxychloride, followed by protection of the indole as the corresponding phenylsulfonyl derivative, led to the N-protected indole 1223. The compound 1223 was transformed to the bromide, and then to the azido compound 1224. Staudinger reaction of the azido compound 1224 with triphenylphosphine gave the 2,4-dihydropyrrolo[3,4-b]indole, which, on protection of the pyrrolo nitrogen, led to the corresponding N-Boc derivative 1225. The Diels–Alder cycloaddition of 1225 with 3,4-pyridyne (1193), generated by reaction of 1-aminotriazolo[4,5-c]pyridine

326

Chemistry and Biology of Carbazole Alkaloids

O N

(5 steps) N H 1170

O

(see Schemes 5.193 and 5.194)

N 1181 MeLi, THF

MeLi, THF

−78 to −10°C

−100 to 10°C (65%) O

Me

LiOH, aq. THF, rt

O N

N H Me

OH

N

(75% overall) O

N 1219 1. LiCH(SEt)2, THF −30°C to rt 2. NaBH4, EtOH, reflux (45% overall)

1220

1. MeLi, THF, 0°C 2. NaBH4, EtOH, reflux (quantitative overall yield) Me

(EtS)2HC

N N

N H

N Me H 228

Me

1221 1. PhI(OCOCF3)2 aq. MeCN, rt

HOH2C

2. NaBH3CN, TFA EtOH, rt (76% overall)

N

N Me H 232

Scheme 5.202

with lead tetraacetate, provided the regioisomeric cycloadducts 1226 and 1227 in a ratio of 55:45 (62% yield). Hydrolysis of the cycloadducts 1226 and 1227 afforded the tetracyclic carbazoles 1228 and 1229 in 35% and 39% yield, respectively. Separate catalytic hydrogenation to the carbazole derivatives 1230 and 1231 (80% and 83% yield, respectively), followed by treatment with TFA provided ellipticine (228) (85% yield) and isoellipticine (1196) (78% yield) (713) (Scheme 5.203). This method was also applied to the synthesis of amino analogs of ellipticine (713). Miki et al. reported the total synthesis of ellipticine (228) starting from N-benzylindole-2,3-dicarboxylic anhydride (852) (714,715). Reaction of (3-bromo-4pyridyl)triisopropoxyltitanium (1232) with 852 gave 2-acylindole-3-carboxylic acid 1233 in 86% yield. Decarboxylation and debenzylation of 1233 led to the ketone 1234. Wittig olefination of the ketone 1234, followed by catalytic hydrogenation,

327

Chemistry of Carbazole Alkaloids

O Me

1. POCl3, MeCONMe2 2. KH, DME, PhSO2Cl

N H

Me

1222

1. NBS, CCl4, (PhCOO)2 2. NaN3, THF, H2O

N PhO2S

Me

1223 N

O

Me Me N3

N PhO2S 1224

Me

1. PPh3, THF

1193

NBoc

2. Boc2O, DMAP CH2Cl2

CH2Cl2

N Me SO2Ph 1225

NBoc Me

Y Z

Me N SO2Ph

Y Z

KOH MeOH/H2O

MeOH

N NHBoc Me H

1226 Y = N; Z = CH

1228 Y = N; Z = CH

1227 Y = CH; Z = N

1229 Y = CH; Z = N

Me

H2, 5% Pd/C

Me

H Y Z

N NHBoc Me H 1230 Y = N; Z = CH 1231 Y = CH; Z = N

Me N

TFA, CH2Cl2

N N H 228

Me

N H

Me

1196

Scheme 5.203

provided 1-(3-bromo-4-pyridyl)-1-(2-indolyl)ethane (1235). Palladium(0)-catalyzed cross-coupling of 1235 with (1-ethoxyvinyl)tributyltin (1236) led to the corresponding ethoxyvinyl derivative 1237. Finally, cyclization of 1237 with 10% hydrochloric acid led to ellipticine (228) in 87% yield (714,715) (Scheme 5.204). Two years later, the same group reported a formal synthesis of ellipticine (228) using 6-benzyl-6H-pyrido[4,3-b]carbazole-5,11-quinone (6-benzylellipticine quinone) (1241) as intermediate (716). The optimized conditions, reaction of 1.2 equivalents of 3-bromo-4-lithiopyridine (1238) with N-benzylindole-2,3-dicarboxylic anhydride (852) at 961C, led regioselectively to the 2-acylindole-3-carboxylic acid 1233 in 42% yield. Compound 1233 was converted to the corresponding amide 1239 by treatment with oxalyl chloride, followed by diethylamine. The ketone 1239 was reduced to the corresponding alcohol 1240 by reaction with sodium borohydride. Reaction of the alcohol 1240 with t-butyllithium led to the desired 6-benzylellipticine quinone (1241), along with a debrominated alcohol 1242, in 40% and 19% yield, respectively. 6-Benzylellipticine quinone (1241) was transformed to 6-benzylellipticine (1243) in 38% yield by treatment with methyllithium, then hydroiodic acid, followed

328

Chemistry and Biology of Carbazole Alkaloids

Ti(Oi-Pr)3 Br

O O N Bn 852

HOOC

N

O

THF, −96°C (86%)

N

Br

1232

1. 20% HClO4 2. AlCl3

N Bn

O

1233 OEt

N

Br N H

Br

1. Ph3P CH2 2. Pt2O, H2 O

1234 (39% overall)

N

N Me H 1235 (46% overall)

OEt

SnBu3

1236 Pd(PPh3)4 (97%)

Me N

N 10% HCl, rt

N H 1237

(87%) Me

N H 228

Me

Scheme 5.204

by tin(II) chloride. 6-Benzylellipticine (1243) was previously transformed to ellipticine (228) (716) (Scheme 5.205). Recently, the same authors reported a different route for the total synthesis of olivacine (238a) and ellipticine (228) starting from 2,4,6-trimethoxypyridine (1244) with N-benzylindole-2,3-dicarboxylic anhydride (852) (717,718). Interestingly, this method also uses the same common precursor, N-benzylindole-2,3-dicarboxylic anhydride (852) as shown in Schemes 5.204 and 5.205. Contrary to the earlier route, this sequence involves a Friedel–Crafts acylation of 2,4,6-trimethoxypyridine (1244) with N-benzylindole-2,3-dicarboxylic anhydride (852) (717,718). For the synthesis of olivacine (238a), the required 6-methyl derivative 1247 was obtained in four steps and 64.5% overall yield starting from N-benzylindole-2,3dicarboxylic anhydride (852). Thus, regioselective Friedel–Crafts reaction of 852 with 2,4,6-trimethoxypyridine (1244) in the presence of titanium(IV) chloride provided the corresponding 3-acylindole-2-carboxylic acid 1245. Prior to O-demethylation, 1245 was subjected to decarboxylation by reacting with copper chromite in quinoline to afford the ketone 1246. The compound 1246 was subjected to regioselective mono O-demethylation by treatment with 47% hydrobromic acid. Subsequent reaction with triflic anhydride (Tf2O), followed by reaction of the corresponding triflate with MeMgBr in the presence of NiCl2(dppe)2, led to the methyl derivative 1247 in 70% overall yield. Chemoselective demethylation of 1247 by treatment with boron tribromide led to a 4-hydroxy compound, which, after reduction with diborane, was reacted with triflic anhydride (Tf2O) to afford the benzyl derivative 1248. Palladium(0)-catalyzed

329

Chemistry of Carbazole Alkaloids

Li Br

O O N Bn 852 Et2NOC

HOOC

N

1238

O

THF, −96°C (42%)

Et2NOC

1239 (90% overall)

N

N O Bn 1241 (40%) 1. MeLi 2. HI 3. SnCl2 (38% overall)

N t-BuLi, THF −78°C

N Bn

O

O

2. Et2NH O

Br

NaBH4 (87%)

N Bn

1. (COCl)2

N Bn 1233

N

Br

N

Br

OH

1240 Et2NOC

N

N OH Bn 1242 (19%) Me

Me

N

N (ref. 705) N Me Bn 1243

N H

Me

228

Scheme 5.205

cross-coupling of 1248 with (1-ethoxyvinyl)tributyltin (1236), followed by cyclization of the intermediate ethoxyvinyl derivative with 10% hydrochloric acid, afforded 6-benzyl-3-methoxyolivacine (1249) in 84% yield. Debenzylation of 1249 with 47% hydrobromic acid afforded 3-methoxyolivacine (1250). After O-demethylation of 1250, the corresponding hydroxy derivative was transformed to the triflate, which on subsequent hydrogenation with ammonium formate in the presence of Pd(PPh3)4 in hot methanol afforded olivacine (238a) (717) (Scheme 5.206). For the synthesis of ellipticine (228) (718), the required 2,4-dimethoxy derivative 1251 was prepared in three steps, and 76% overall yield, starting from the previously known ketone 1246 (717). Thus, regioselective demethylation of 1246 with 47% hydrobromic acid in hot acetic acid, followed by treatment with triflic anhydride (Tf2O), gave the corresponding triflate, which, on reduction with ammonium formate in the presence of Pd(PPh3)4, was transformed to the 2,4-dimethoxy derivative 1251. Selective O-demethylation of the 4-methoxy group of 1251 was performed by treatment with boron tribromide to provide the 4-hydroxy compound 1252. After Wittig olefination of the keto derivative 1252, the corresponding olefin was subjected to catalytic hydrogenation in the presence of Adam’s catalyst (PtO2) to afford the corresponding ethane derivative 1253. The 4-hydroxy derivative was

330

Chemistry and Biology of Carbazole Alkaloids

OMe

MeO

N

O

O

MeO

O N Bn 852

N

OMe

OMe 2 CuO Cr2O3

1244 TiCl4 (98%)

O

(94%)

MeO N COOH Bn 1245

Me

MeO O

N Bn 1246

N

O

1. 47% HBr/HOAc, 50°C OMe 2. Tf2O, Et3N, CH2Cl2

OMe

3. MeMgBr, NiCl2(dppe)2 (70% overall)

MeO

1. N

SnBu3

OMe

3. Tf2O, Et3N (58% overall)

N MeO Bn 1247 OEt

Me 1. BBr3, CH2Cl2 2. B 2H6, THF

N

TfO N Bn 1248

1236 Pd(PPh3)4, LiCl (i-Pr)2NEt 2. 10% HCl (84% overall) Me

Me N OMe N R 1249 R = Bn 1250 R = H

Me

1. 47% HBr/HOAc, reflux 2. Tf2O, Et3N 3. HCOONH4 , Pd(PPh3)4 (31% overall)

47% HBr/HOAc, 80°C (93%)

N

N H

Me

238a

Scheme 5.206

transformed to the corresponding triflate, by reaction with triflic anhydride (Tf2O) in the presence of triethylamine, which, on palladium(0)-catalyzed cross-coupling with (1-ethoxyvinyl)tributyltin (1236), followed by cyclization of the intermediate ethoxyvinyl derivative with 10% hydrochloric acid, afforded 6-benzyl-3-methoxyellipticine (1254) in 71% overall yield. Finally, 6-benzyl-3-methoxyellipticine (1254) was transformed to ellipticine (228) in 22.5% overall yield by executing the similar reaction sequence as shown for the conversion of 6-benzyl-3-methoxyolivacine (1249) to olivacine (238a) (717) (see Scheme 5.206) (718) (Scheme 5.207). Ishikura et al. reported the total synthesis of ellipticine (228) starting from N-Boc indole (1256) and the vinyl bromide 1258 (719–721). This methodology involves a palladium-catalyzed, tandem cyclization-cross-coupling reaction of the indolyl borate 1257 with the vinyl bromide 1258 as the key step. Using a literature procedure, the vinyl bromide 1258 was prepared as an E/Z mixture starting from cis- and trans-crotyl alcohol. The indolyl borate 1257 was generated in situ from

Chemistry of Carbazole Alkaloids

331

MeO O

N Bn

N

1. 47% HBr/HOAc, 50°C OMe 2. Tf2O, Et3N 3. HCOONH4, Pd(PPh3)4 (76% overall)

MeO

1246

O

N OMe

N MeO Bn 1251

O

Me

N

N OMe

OMe 1. Ph3P CH2

BBr3 (88%)

N Bn

2. PtO2, H2 (49% overall)

HO

N Bn

HO

1253

1252 Me

1. Tf2O, Et3N 2. + 1236, Pd(PPh3)4;

N OMe

then 10% HCl (71% overall)

N Bn

Me

47% HBr HOAc, 80°C (98%)

1254 Me N OMe N H

Me

1. 47% HBr/HOAc, reflux 2. Tf2O, Et3N, CH2Cl2 3. HCOONH4, Pd(PPh3)4 MeOH, reflux (23% overall)

Me N

N H

Me

228

1255

Scheme 5.207

N-Boc indole (1256) and tert-butyllithium, followed by treatment with triethylborane. A palladium-catalyzed, tandem cyclization-cross-coupling reaction by heating compound 1257 with the vinyl bromide 1258 in the presence of catalytic amounts of bis(triphenylphosphine)palladium(II) chloride provided the hexatriene 1259 in 64% yield. Photolytic electrocyclization of the hexatriene 1259 led to the tetrahydropyridocarbazole 1260. Deprotection of 1260 by sequential removal of the Boc and benzyloxycarbonyl (Cbz) groups, and subsequent dehydrogenation, led to ellipticine (228) in low yield. The low yield of this step was ascribed to the presence of the free indole NH. Thus, reversal of the deprotection sequence starting from the same tetrahydropyridocarbazole 1260 led to ellipticine in an improved yield over three steps (719–721) (Scheme 5.208). This methodology was also applied to the synthesis of 6-methylellipticine derivatives starting from 1-methylindole (721). Guitia´n et al. reported a total synthesis of ellipticine (228) using a modified Gribble methodology (722,723). This approach applied 2-chloro-3,4-pyridyne (1267) as a synthetic equivalent for 3,4-pyridyne and used the polar effect of the chlorine atom for improved yields and regiocontrol of the cycloaddition with the furoindole 544. Silylation of 2-chloro-3-hydroxypyridine (1263), followed by treatment of 1264 with LDA, afforded the 4-trimethylsilylpyridine 1265. This reaction probably involves

332

Chemistry and Biology of Carbazole Alkaloids

BEt3 N Boc

N 2. Et B 3 Boc 1256

H Br

N Cbz

1257 Me

THF, 60°C (64%)

N Boc Me 1259

(41%)

2. MnO2, EtOAc, reflux

N R

Me

1260 R = Boc

TFA, CH2Cl2 (84%)

N Me Boc 1260

N

Me

1260 R = Cbz 1262 R = H

Me

N H 228

N

Me

R

Me

N Boc

N

hν, benzene

1. H2, 20% Pd(OH)2 /C THF, rt

N

Cbz

Me

Cbz

Me

Me

1258

Cbz N

H

PdCl2(PPh3)2

1261 R = H

Me

Li

1. t-BuLi, THF, −78°C

1. MnO2, EtOAc, reflux 2. TFA, CH2Cl2 (55% overall)

H2, 20% Pd(OH)2 /C, THF (90%)

Scheme 5.208

proton abstraction at C-4 and subsequent migration of the TMS group. After transformation to the triflate 1266, the 2-chloro-3,4-pyridyne (1267) is easily formed using Kobayashi’s method by treatment with fluoride. The reaction of in situ-generated 2-chloro-3,4-pyridyne (1267) with the furoindole 544 provided the two regioisomers 1268 and 1269 in a ratio of 2.4:1 (89% yield). Reductive cleavage of the ether bridge of the major product 1268 with sodium borohydride and sodium hydroxide, followed by hydrogenolysis to remove the chlorine substituent, provided ellipticine (228) in 87% overall yield. The minor adduct 1269 was transformed to isoellipticine (1196) in 65% overall yield by the same sequence of steps (722,723) (Scheme 5.209). Three years later, the same authors also reported a modified Moody approach for the total synthesis of ellipticine (228). In this route, an indolopyrone is used as a stable equivalent of indolo-2,3-quinodimethane in a Diels–Alder reaction with 2-chloro-3,4-pyridyne (1267) (723). Mal et al. reported a formal total synthesis of ellipticine (228) starting from the furoindolone 649 (583,724). In this strategy, the key step is the anionic [4+2] cycloaddition of furoindolone 649 with 3,4-pyridyne (1193). Reaction of compound 1270 with 3,4-pyridyne (1193) in the presence of LDA gave ellipticine quinone (1272)

333

Chemistry of Carbazole Alkaloids

Cl RO

Cl HO

LDA

N

(60%) 1263 R = H 1264 R =TMS

N Tf2O, i-Pr2NEt (96%)

TMS

HMDS (100%)

N

1266 Cl O

O

N F

TMS

1265

Me

+ 1267

1267

Me N 1. NaBH4 NaOH 2. H2, Pd/C

N PhO2S

Me

Cl

Cl TfO

Me

N

N H

Me

228 (87% overall)

1268

(89%) N Me SO2Ph

Me

Me O

1. NaBH4 N NaOH

544 N PhO2S

Me

Cl

1269

2. H2, Pd/C

N N Me H 1196 (65% overall)

Scheme 5.209

and isoellipticine quinone (1273) in a ratio of 2:1 (45% combined yield). Previously (725–727), the quinones 1272 and 1273 were transformed to ellipticine (228) and isoellipticine (1196) (583,724) (Scheme 5.210). Bennasar et al. reported a formal total synthesis of ellipticine (228) starting from the 3-formylindole 1274 (728). In this route, the key reaction is the regioselective, intramolecular cyclization of the 2-indolylacyl radical (in situ generated from N-benzyl selenoester 1278) onto the 4-position of the pyridine ring. Reaction of 1274 with 3-pyridylmagnesium bromide (1275), followed by triethyl silane reduction of the resulting carbinol 1276, led to the ester 1277 in 55% yield. Hydrolysis of 1277, followed by phenylselenation of the corresponding carboxylic acid, gave the selenoester 1278. The 2-indolylacyl radical generated from the corresponding N-benzyl selenoester 1278 under hexabutylditin–hn conditions underwent regioselective intramolecular reaction with pyridine to afford directly N-benzylellipticine quinone (1241). As previously described (705,716,729), the N-benzylellipticine quinone (1241) was transformed into ellipticine (228) (728) (Scheme 5.211). One year later, the same authors extended the aforementioned methodology to the total synthesis of (7)-guatambuine (233) starting from the 3-formylindole 1279 (213). Executing a similar reaction sequence as shown for the formal total synthesis of ellipticine (228) (see Scheme 5.211), the 3-formylindole 1279 was transformed to the pyridylmethylindole 1281 in two steps in 50% overall yield. After quaternization of the pyridine nitrogen with methyl iodide, the N-methylpyridinium salt 1282 was reacted with methylmagnesium chloride, followed by reduction of the intermediate 2,3-disubstituted dihydropyridine, to afford the tetrahydropyridine 1283. Hydrolysis of 1283 led to the corresponding carboxylic acid, which, on phenylselenation, afforded the selenoester 1284. Radical cyclization of 1284 in dilute benzene solution led to the stereoisomeric mixture of pyridocarbazoles 1285. Probably, this reaction

334

Chemistry and Biology of Carbazole Alkaloids

Li ClCOOEt, Et3N

O N H 649

O

LDA

O

CH2Cl2, 0°C to rt (92%)

O N O COOEt

N O COOEt 1270

1271 O

O N + 1271

N

N

LDA, −78°C, THF (45%)

1193

N H 1272

N H

O

O (2:1)

1273

Me

Me N

(ref. 725,726,727)

N N H 228

N H 1196

Me

Me

Scheme 5.210

MgBr

R

N

CHO N Bn

N

1275

COOMe −40°C to rt

1274

N Bn

COOMe

1276 R = OH 1277 R = H N

COSePh N Bn 1278

2. Et3N, PhSeCl, PBu3 THF, rt (76% overall)

Et3SiH, TFA, rt (55%) O

hν n -Bu6Sn2, 300 W benzene, reflux (42%)

N

N Bn 1241

Me N (ref. 705,716,729) N H

1. LiOH, THF/H2O (3:1) 65°C

Me 228

Scheme 5.211

O

Chemistry of Carbazole Alkaloids

335

proceeds through the formation of a 2-indolylacyl radical which could initiate the desired 6-endo cyclization without interference of the indole NH. Finally, the pyridocarbazole 1285 was transformed into (7)-guatambuine (233) by reaction with methyllithium, followed by TFA-Pd/C-promoted dehydration of the carbinol with concomitant dehydrogenation (213). Previously (211,376), (7)-guatambuine (233) was transformed to olivacine (238a) by dealkylative aromatization (213) (Scheme 5.212). Bowman et al. reported the total synthesis of ellipticine (228) involving an imidoyl radical cascade reaction (730). For this key step, the required imidoyl radical was generated from the imidoyl selanide 1290, which was obtained from ethyl 2-(4pyridyl)acetate (1286). Reaction of 1286 with LDA, followed by addition of methyl iodide, led to the corresponding methyl derivative 1287. Treatment of 1287 with 2iodoaniline (743) in the presence of trimethylaluminum (AlMe3) afforded the amide 1288. Using Sonogashira conditions, propyne is coupled with the amide 1288 to afford the aryl acetylene 1289. The aryl acetylene 1289 was transformed to the MgBr

R

N

CHO N H 1279

N MeI

1275

COOMe −40°C to rt

(90%) COOMe N H 1280 R = OH Et3SiH, TFA, rt (50%) 1281 R = H Me

Me

Me

N

N I

N H

1. MeMgCl

1. LiOH

2. NaBH4 (90%)

COOMe

1282

COOMe

N H 1283

Me

Me H

Me N

Me N

Bu3SnH N H 1284

COSePh

Me

1. MeLi

AIBN

N H 1285

2. TFA, Pd/C (45% overall)

H O

Me

Me N

N (ref. 211,376)

N H 233

2. PhSeCl, PBu3 (65% overall)

N H 238a

Me

Scheme 5.212

Me

336

Chemistry and Biology of Carbazole Alkaloids

N

O

LDA, THF −78 to 0°C, MeI (93%)

EtO

EtO Me 1287

1286

I N H

O

Me 1288

+ 743, 40°C (81%)

Me

PdCl2(PPh3)2 N CuI, Et3N, propyne

O

DMF, 20°C (88%)

SePh N Me

N

N H Me 1289

Me

1. COCl2, CH2Cl2 DMF, 20°C 2. KBH(s-Bu)3 THF, (PhSe)2, rt (48% overall)

N AlMe3, CH2Cl2

O

Me

N

N Bu3SnH, Et3B O2, toluene, 20°C (61%)

1290

N H

Me 228

Scheme 5.213

imidoyl selanide 1290 by reaction with oxalyl chloride followed by K-Selectride treatment in the presence of diphenyl diselenide. Finally, in a one-pot operation, the imidoyl selanide 1290 was transformed to ellipticine (228) by reaction with tributyltin hydride in the presence of the radical initiator triethylborane (730) (Scheme 5.213). Ho and Hsieh reported a total synthesis of ellipticine (228) starting from 4,7dimethyl-1H-indene (731). In this route, the key step is the deoxygenative cyclization of the o-nitrobiaryl 1297 using Cadogan’s method. 4,7-Dimethyl-indan-2-one (1292), which was obtained by oxidation of the corresponding indene, was reduced to the alcohol 1293 in the presence of sodium borohydride in almost quantitative yield. After iodination of 1293, the corresponding iodo derivative 1294 was transformed to the acetate 1295. Suzuki coupling of 1295 with 2-nitrobenzeneboronic acid (1296) afforded the nitrobiaryl 1297 in 79% yield. Reductive cyclization of 1297 by heating in the presence of triethylphosphite [P(OEt)3] led to the carbazole 1298. Oxidation of 1298 with DDQ, followed by in situ reduction of the keto acetate, led to the diols 1299. Oxidation of 1299 with sodium periodate (NaIO4), followed by reaction of the intermediate dicarbonyl derivative with ammonium acetate (NH4OAc), resulted in ellipticine (228) (731) (Scheme 5.214). In addition to the aforementioned total syntheses of naturally occurring pyrido[4,3-b]carbazole alkaloids, various groups have also developed synthetic strategies towards a range of pyrido[4,3-b]carbazole analogs (732–755).

H. Indolo[2,3-a]carbazole Alkaloids Since the first isolation and the discovery of the potent inhibitory activity of the microbial alkaloid staurosporine (295) against protein kinase C (PKC), the indolo[2,3-a]carbazole alkaloids have emerged as a rapidly growing family. This was attested to by the isolation of about 70 natural products. In addition to this large

Chemistry of Carbazole Alkaloids

337

Me

Me R

NaBH4

O

OH

CH2Cl2, MeOH (99%)

Me 1292

Me 1293 R = H 1294 R = I

Ac2O, pyridine DMAP, rt (99%)

I2, CH2Cl2, silfen (82%)

B(OH)2

Me

Me

NO2

I

1296 OAc Me 1295

OAc

(EtO)3P, 150°C (73%)

Me

N H 1298

Me

1. DDQ, THF, H2O 2. aq. K2CO3 3. LiAlH4, THF (67.5% overall)

OH

Me OH

N H

Me 1297

(79%) Me

Me

OAc

NO2

PdCl2(PPh3)2, NaHCO3 DME, H2O, 80°C

N

1. NaIO4, t-BuOH, H2O 2. aq. NH4OAc (87% overall)

1299

N H

Me 228

Scheme 5.214

number of natural products, a wide range of structural analogs was also reported due to their diverse and, in some cases, extraordinary biological activity. Because of this, a wide range of approaches has been developed for the synthesis of natural products as well as synthetic analogs of indolo[2,3-a]carbazole alkaloids. The explosive growth of this class of carbazole alkaloids was attested by the publication of various review articles covering different aspects (252–260,756–758). The present section describes a detailed discussion of the synthetic activity with regard to these natural products published since 1990. Raphael et al. reported the total synthesis of arcyriaflavin B (346) (759) and staurosporinone (293) (760) starting from 2-nitrocinnamaldehyde (1300). This synthetic route involves a double nitrene insertion as the key step. Wittig olefination of 2-nitro-Z-cinnamaldehyde (1300) with the phosphonium bromide 1301 led to the diene 1302. The Diels–Alder cycloaddition of 1302 with maleimide (1303), followed by dehydrogenation with DDQ, afforded the phthalimide 1304. Double deoxygenation of 1304 with triphenylphosphine (PPh3) in collidine gave O-methylarcyriaflavin B (1305). Finally, heating of 1305 with molten pyridine hydrochloride led to arcyriaflavin B (346) (759) (Scheme 5.215).

338

Chemistry and Biology of Carbazole Alkaloids

H O2N

Br

PPh3 K2CO3 NO2 cat. 18-crown-6

O

OMe 1301

1300

OMe

CH2Cl2, rt (80%)

NO2

O2N 1302

O

O

H N

O

1. 120°C

1302

N H O

2. DDQ, 170°C (75% overall)

OMe NO2

1303

reflux (65%)

O2N 1304

H N

O

PPh3, collidine

O

H N

O

O

pyridine HCl, 190°C N H

N H

OMe

(87%)

1305

N H

N H

OH

346

Scheme 5.215

Due to the difficulties associated with the removal of N-maleimide protecting groups and reduction of the imide to the lactam, Raphael et al. modified their method in 1990 for the synthesis of staurosporinone (293) (760). In this approach, the key steps are a Diels–Alder cycloaddition of dimethyl acetylenedicarboxylate (535) with 1,4-bis(o-nitrophenyl)butadiene (1307), conversion to the imide 1309 through the anhydride by reacting with ammonia, reduction to the lactam 1310, and the final transformation to staurosporinone (293). Direct deoxygenation of the lactam 1310 to staurosporinone (293) proceeded well. However, the staurosporinone (293) produced formed a complex with the generated triphenylphosphine oxide. Due to this separation problem, prior to deoxygenation, the lactam 1310 nitrogen was protected as a tetrahydropyran-2-yl (THP) group. Thus, smooth deoxygenation of 1311 with triphenylphosphine (PPh3) led to the THP-protected staurosporinone 1312, which was readily transformed to staurosporinone (293) by aqueous sulfuric acid treatment (760) (Scheme 5.216). Bergman et al. reported a synthesis of arcyriaflavin A (345) starting from indol-3ylacetic acid (680) or the corresponding methyl ester (1313) (339). The key step of their methodology is an oxidative coupling of the indol-3-ylacetic acid trianion (1314) or the methyl indol-3-ylacetate dianion (1315). Sequential addition of 2 equivalents of butyllithium and 1 equivalent of tert-butyllithium to indol-3-ylacetic acid generated the trianion 1314. Iodine-mediated oxidative coupling of 1314, followed by acidic work-up, afforded the diacid 1316. Treatment of 1316 with diazomethane led to bisindolylsuccinic acid methyl ester 1317 in 38% overall yield as a diastereomeric

Chemistry of Carbazole Alkaloids

H O2N

Br

PPh3 K2CO3 NO2 cat. 18-crown-6

O

CH2Cl2, rt (79%) 1300

1307

reflux (65% overall)

COOMe

O2N 1307

COOMe 1. 120°C 2. Pd, mesitylene

MeOOC

COOMe

1. NaOH H2O/MeOH reflux

O2N

2. aq. NH3 toluene, reflux (81% overall)

NO2 1308

535

O

NO2

1306

H N

339

O

O

R N

1. NaBH4, THF/EtOH

NO2

2. CF3COOH, TES, rt (95% overall)

O2N

NO2

TES = triethylsilane DHP = dihydropyran

1309

O

1310 R = H 1311 R = THP

THP N THF

reflux (54%)

2 M H2SO4, 50°C (80%) THP = tetrahydropyran-2-yl

DHP, PTSA CH2Cl2, rt (72%) H N

O

PPh3, collidine N N H H 1312

O2N

N H

N H 293

Scheme 5.216

mixture. However, the diester 1317 could be prepared directly in much better yield (85%) by the iodine-promoted, oxidative coupling of the dianion 1315, obtained by the addition of 2 equivalents of LDA to methyl indol-3-ylacetate (1313). Heating of the diastereomeric mixture of diester 1317 with ammonium formate in refluxing triglyme led exclusively to the trans-imide 1318 indicating the cyclization of one of the two diastereoisomers to the imide. After dehydrogenation of 1318 with DDQ, the resulting arcyriarubin A (349) was hydrogenated to afford the required cis-succinimide 1319. Finally, reaction of 1319 with refluxing TFA led to arcyriaflavin A (345) in 75% yield (339) (Schemes 5.217 and 5.218). Moody and Rahimtoola reported a short synthesis of staurosporinone (293) without the use of protecting groups at the indole or the lactam nitrogen (761,762). This route involves an intramolecular Diels–Alder reaction of the pyrano[4,3-b]indol-3-one 1325 and a subsequent cyclization by nitrene insertion. The pyrano[4,3-b]indol-3-one 1325 was obtained in four steps from ethyl indol-2-yl

340

Chemistry and Biology of Carbazole Alkaloids

O

OR

HOOC

O

O 1. 2 eq. BuLi

COOH

1. 0.5 eq. I2

2. 1 eq. t-BuLi

2. NaHSO3

N

N ( R = H) H 680 R = H 1313 R = Me

N H

1314

N H

1316 CH2N2, ether

2 eq. LDA (R = Me)

(38% overall)

OMe

MeOOC

O

COOMe

1. 0.5 eq. I2 2. NaHSO3 (85%)

N

N H

1315

N H

1317

Scheme 5.217

MeOOC

H N

O

COOMe

O

H

H

HCOONH4 N H

triglyme, reflux (55%)

N H

N H

1317

N H

1318 H N

O

O

H N

O H

dehydrogenation

H

H2, Pd/C N H

N H 349

H N

O

O

TFA, reflux (75%)

O

N H

N H 345

Scheme 5.218

DMA

N N H H 1319

Chemistry of Carbazole Alkaloids

341

acetate (1322). Reaction of 1322 with oxalyl chloride, followed by quenching with 2-nitrocinnamylamine (1321) [available in three steps from commercial 2-nitrocinnamaldehyde (1320)], afforded the 2,3-disubstituted indole 1323. Hydrolysis of the ester 1323, followed by cyclodehydration of the keto acid 1324 with acetic anhydride, led to the pyrano[4,3-b]indol-3-one 1325. The intramolecular Diels–Alder reaction of the pyrano[4,3-b]indol-3-one 1325 with concomitant loss of carbon dioxide by heating in bromobenzene under reflux, and a subsequent aromatization by oxidation in air, gave the carbazole 1326. Cyclization of 1326, by Cadogan’s method through heating in triethyl phosphite, provided staurosporinone (K-252c) (293) (761,762) (Scheme 5.219). Bonjouklian and Moore et al. reported the total synthesis of the tjipanazoles D (359) and E (370) to support the assigned structures for these natural products. Condensation of 2 equivalents of 4-chlorophenylhydrazine hydrochloride (1327) with 1,2-cyclohexanedione (1328) in the presence of air and step-wise Fischer indolization provided tjipanazole D (359) in 54% yield. Coupling of 359 with

CHO

1. NaBH4, CeCl3 2. phthalimide

NH2

Ph3P, DEAD 3. N2H4 H2O

NO2 1320

NO2 1321

(58% overall)

N H

COOEt

O

0°C to rt (76%)

N H

1322

KOH, THF/MeOH, rt (97%)

1324 R = H H N NO2

O

Ac2O, THF, rt

bromobenzene

O

(83%)

reflux (42%)

N H 1325 H N

O

H N

O

P(OEt)3 N H

O2N

THF, reflux (54%)

N H

N H 293

1326

Scheme 5.219

NO2

COOR

1323 R = Et

O

H N

O

1. (COCl)2, ether 2. + 1321

342

Chemistry and Biology of Carbazole Alkaloids

Cl

Cl Cl HCl, HOAc

H2SO4

+ O NHNH2 HCl 1327

O

EtOH, 65°C (72%)

N H

1328

1329

100°C (75%)

N N H

1. NaH, MeCN Br

2.

OAc

O AcO

Cl

Cl

OAc OAc

Cl

Cl

1330 N H

N H

3. NH3, MeOH

N

OH

N H

O

359

OH

HO OH 370

Scheme 5.220

1-bromo-a-D-glucopyranosyl-2,3,4,6-tetraacetate (1330), followed by removal of the acetyl protecting groups, led to tjipanazole E (370) (329) (Scheme 5.220). Gribble and Berthel reported the synthesis of arcyriaflavin A (345) starting from the commercially available cyclohexene imide 1331 involving double Fischer indolization as key step (336). Although this approach is much shorter, the overall yield is lower. The cyclohexene derivative 1331 was converted to the labile dialdehyde 1332, which, on further treatment with 2 equivalents of phenylhydrazine (524), led to the corresponding bis(phenylhydrazones) 1333. Double Fischer indolization of 1333 with polyphosphoric acid trimethylsilyl ester (PPSE) in nitromethane under reflux provided arcyriaflavin A (345) (336) (Scheme 5.221). This methodology was also applied to the synthesis of 6-methylarcyriaflavin (AT2433-B aglycon) (336). Danishefsky et al. described the total synthesis of rebeccamycin (337) using a stereoselective opening of the a-1,2-anhydrosugar 1339 with the sodium salt of the secoaglycon 1338 (763). Following Clardy’s and Kaneko’s procedure (325), starting from 7-chloroindole (1334), the secoaglycon 1338, a precursor of rebeccamycin (337), was obtained in 59% overall yield in three steps. This method involves sequential indole Grignard additions to N-(benzyloxymethyl)dibromomaleimide (1335). Thus, deprotonation of 7-chloroindole (1334) with methylmagnesium iodide and addition of N-(benzyloxymethyl)dibromomaleimide 1335 afforded the monoindolyl derivative 1336. After protection of the indole nitrogen with a SEM group to 1337, 7-chloroindolemagnesium iodide was added to afford the secoaglycon 1338. The stereoselective glycosidation of the secoaglycon 1338 was achieved by reaction of the sodium salt of 1338 with the a-1,2-anhydrosugar 1339 to give the b-glucopyranoside 1340 in 48% yield. After the removal of the SEM protecting group with TBAF, the photocyclization of compound 1341 afforded the indolocarbazole

Chemistry of Carbazole Alkaloids

O

H

N H H

O

1. O3, −78°C

O

CH2Cl2, MeOH 2. Me2S

O

H

O

343

NHNH2

524 N H H

MeOH

O

1332

1331

O H

H N

H N

O O H

O

PPSE nitromethane, reflux (10% overall)

N N N N H H 1333

N H

N H 345

PPSE = polyphosphoric acid trimethylsilyl ester

Scheme 5.221

glucopyranoside 1342. Hydrogenation of 1342 over Pearlman’s catalyst [Pd(OH)2], followed by ammonolysis to complete the BOM deprotection, provided rebeccamycin (337) in 72% yield (763) (Scheme 5.222). Danishefsky et al. also reported the first total synthesis of (+)-staurosporine (295) (764,765). This synthesis involves the preparation of the staurosporine secoaglycon 1343, and sequential coupling of oxazolidinone glycol 1344 with the indolic nitrogens of the aglycon acceptor 1343. Using sequential indole-Grignard additions to N-(benzyloxymethyl)dibromomaleimide, the unsymmetrical secoaglycon 1343 was obtained in three steps and 57% overall yield (see the synthesis of the secoaglycon 1338 in Scheme 5.222). The glycosylation was achieved by reaction of the sodium salt of 1343 with the 1,2-anhydrosugar 1344. The C2u-hydroxy function was removed from the indole glycoside 1345 by Barton deoxygenation to afford compound 1346. Deprotection by removal of the C6u-PMB and the indole-SEM groups, followed by photocyclization of 1347, provided the indolocarbazole glycoside 1348. The alcohol was transformed into the iodo derivative 1349, which, on subsequent elimination of hydrogen iodide with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), afforded the exo-glycal 1350 (Scheme 5.223). The intramolecular glycosylation of 1350 with potassium tert-butoxide in the presence of iodine provided the glycoside 1351. Deiodination of 1351 with tri-nbutyltin hydride, and removal of the BOM groups led to the compound 1352. Selective installation of a Boc group on the oxazolidinone nitrogen of 1352, and reprotection of the maleimide nitrogen with a BOM protecting group, furnished the indolo oxazolidinone 1353. The Boc group at the oxazolidinone ring plays a crucial role in the smooth disconnection of the oxazolidinone. Thus, the oxazolidinone in 1353 was opened with cesium carbonate in methanol to provide the hydroxy amine 1354. O-Methylation and mono-N-methylation, cleavage of the BOM group by hydrogenation over Pearlman’s catalyst, and removal of the Boc group, led to 7-oxostaurosporine (1355) in 70% overall yield. Reduction of the imide with sodium borohydride to the hydroxy lactam, and further reduction with phenylselenol in the

344

Chemistry and Biology of Carbazole Alkaloids

BOM N O

O

O N H

Cl

BOM N O

Br

1334

Br

Br

MeMgI benzene, 25°C (91%)

1335

O

benzene, 25°C (69%)

N R

Cl

1336 R = H

BOM = benzyloxymethyl SEM = [(2-trimethylsilyl)ehoxy]methyl

1337 R = SEM

1. NaH, THF 2. 3 eq. BnO

BOM N O

MeO

+ 1334, MeMgI

BOM N O

O

O

THF, NaH, 0°C SEMCl, 25°C (94%)

BnO O

1339

Cl

N N SEM H

reflux (48%)

Cl

N N SEM Cl OAc O

Cl

1338

BnO OBn OMe TBAF, 4 Å MS 1340 R = SEM THF, reflux 1341 R = H (63%) BOM N O

O

O

O

1. Pd(OH)2, H2 EtOH/EtOAc

hν, cat. I2, air benzene, 25°C (74%)

H N

Cl

N N SEM Cl OH O

2. sat. NH3 THF, 25°C (72% overall)

BnO

Cl

N H

N Cl O

OH

HO OBn OMe 1342

OH OMe 337

Scheme 5.222

presence of a catalytic amount of p-toluenesulfonic acid, provided a 1:1 mixture of (+)-staurosporine (295) and isostaurosporine (1356) (764,765) (Scheme 5.224). Hill et al. reported an efficient short synthesis of staurosporinone (293) using a palladium-mediated oxidative cyclization of the bisindolylmaleimide arcyriarubin A (349) as the key step (766). The key intermediate, arcyriarubin A (349), was prepared

Chemistry of Carbazole Alkaloids

BOM N O

O

BOM N O

O OPMB O

NaH, THF O

N N SEM H

O N

1343

reflux (47%)

BOM

O

345

N N SEM O 2′ OH 6′

OPMB

1344 N

O

BOM

O 1345 1. thiophosgene DMAP, pyridine CH2Cl2, reflux

BOM N O

O

BOM N O

O 1. DDQ, CH2Cl2 H2O, 0°C to rt

C6F5OH, reflux 2. Bu3SnH, AIBN benzene, reflux (58.5% overall)

N N SEM O

N H

2. TBAF THF, reflux (91% overall)

N O

OPMB O

N

hν, cat. I2, air

N

O

BOM

O 1346 BOM N O

O

benzene, rt (73%)

OH

BOM

O 1347 BOM N O

O THF, DBU, rt

N H

(89%)

N

N H

O

N O

R O

N

BOM

O 1348 R = OH 1349 R = I

N

O I2, PPh3, imidazole CH2Cl2, 0°c to rt (84%)

BOM

O 1350

Scheme 5.223

in one step without protection of the imide nitrogen by reaction of dibromomaleimide (1357) with 4 equivalents of indolylmagnesium bromide (1358) in benzene under reflux. Oxidative cyclization of arcyriarubin A (349) with 1 equivalent of palladium(II) acetate in acetic acid led to arcyriaflavin A (345) in 75% yield.

346

Chemistry and Biology of Carbazole Alkaloids

BOM N O

O

1350

1. Bu3SnH, AIBN benzene, reflux 2. a) H2, Pd(OH)2

KOt-Bu, I2 THF, MeOH, rt (65%)

N

EtOAc/MeOH, rt b) NaOMe, MeOH (91% overall)

N

O

IH2C

H

O N BOM

O

1351 H N

O

BOM N O

O

O 1. Boc2O, THF cat. DMAP, rt

N

O

Me

N H

2. NaH, DMF, rt BOMCl (66% overall)

Cs2CO3 N Me

H 1352

Me HO

O

BOM N O

N

H N

N

O

MeOH, rt (93%)

O

O O

N

O

O

N H

1. NaH, DMS THF, DMF, rt 2. a) H2, Pd(OH)2/C EtOAc/MeOH, rt

Boc 1353

N

b) NaOMe, MeOH 3. TFA, CH2Cl2, rt (70% overall)

NHBoc 1354 H N

O

H N

O

O

O

N

Me MeO

H NHMe 1355 H N O

1. NaBH4, EtOH, rt 2. PhSeH, cat. TsOH CH2Cl2, rt

N Me MeO

O

N H

NHMe 295 (39% overall)

N Me MeO

O

N H

NHMe 1356 (39% overall)

Scheme 5.224

Hydride reduction of 345, followed by hydrogenolytic deoxygenation of the resulting hydroxylactam afforded staurosporinone (293) (766) (Scheme 5.225). The same sequence was applied to the synthesis of the 12-methyl analog of staurosporinone (766).

Chemistry of Carbazole Alkaloids

H N

O O

H N

Br

O N MgBr 1358

Br 1357 H N

O

O

benzene reflux (29%)

347

Pd(OAc)2 N H

HOAc, 110°C (75%)

N H 349 H N

O

O

1. LiAlH4, ether, 25°C 2. 10% Pd/C, H2 N H

N H

EtOH, 25°C (63% overall)

345

N H

N H 293

Scheme 5.225

Xie and Lown reported a facile synthesis of staurosporinone (293) starting from the bisindolyl derivative 1361 (767). The key step of this synthesis is a photochemically induced oxidative cyclization of 1361. A new coupling protocol was developed for an improved synthesis of N-benzyldibromomaleimide (1359). Thus, reaction of dibromomaleic acid with benzylamine in the presence of 1,3dicyclohexylcarbodiimide (DCC) and a trace of DMAP afforded 1359 in 92% yield. Using the Grignard route, compound 1359 was transformed to the N-(benzyl)bisindolylmaleimide (1360). Under alkaline conditions, compound 1360 was transformed to the bisindolyl maleic anhydride 1361. The photolytically induced electrocyclization of 1361 in the presence of iodine as the oxidizing agent provided the indolocarbazole anhydride 1362 in 90% yield. Transformation of the anhydride 1362 to the corresponding imide by heating with ammonium acetate afforded arcyriaflavin A (345) in 92% yield. Finally, reduction of the symmetric imide 345 with zinc amalgam in a solvent mixture of hydrochloric acid, ethanol, and toluene at reflux led to staurosporinone (293) in a much improved yield (767) (Scheme 5.226). Lobo and Prabhakar et al. described the synthesis of arcyriaflavin A (345) starting from 2,2u-bisindolyl-3,3u-dithiete (1363) (768,769). In a one-pot operation, heating of 2,2u-bisindolyl-3,3u-dithiete (1363) with maleimide (1303) in 1,2-dichlorobenzene at 1881C afforded arcyriaflavin A (345) in 36% yield. This reaction is believed to proceed via a Diels–Alder [4+2] adduct 1364, followed by a retro-Diels–Alder reaction with extrusion of singlet-S2 to 4c,7a-dihydroarcyriaflavin A (1365) and dehydrogenation by dissolved oxygen or extruded sulfur to arcyriaflavin A (345) (768,769) (Scheme 5.227). Five years later, starting from 2,2u-bisindolyl-3,3u-dithiete (1363), the same group developed an improved synthesis of arcyriaflavin A (345) by an intramolecular twofold sulfur extrusion reaction (770). Faul et al. reported an improved synthesis of arcyriarubin A (349) by reaction of indolylmagnesium bromide (1358) with dichloromaleimide (1366). Following Hill’s route, 349 was transformed to staurosporinone (293) in three steps and 47% overall yield (see Scheme 5.225). This approach provides, so far, the shortest access to staurosporinone (293) with the best overall yield (771) (Scheme 5.228).

348

Chemistry and Biology of Carbazole Alkaloids

Bn N

O O

Bn N

Br

O

O

THF, toluene reflux (64%)

N MgBr

Br 1359

N H 1360

1358 O

O

N H

O

O

O

O

hν, I2, MeCN

5 N KOH, EtOH reflux (89%)

N H

H N

O

(90%)

N H 1361

N N H H 1362 H N

O

NH4OAc

O

Zn-Hg, HCl, EtOH

150°C (92%)

N H

toluene, reflux (58%)

N H

N H

345

N H 293

Scheme 5.226

S S

O

O o-dichlorobenzene

N H N H

N H

H

N H

1303

O H

SS

188°C

O

1363

H N

N H 1364

H N

O retro Diels-Alder

H

O

O

O H

−S2

−H2 (36%)

N H

H N

N H 1365

Scheme 5.227

N H

N H 345

Chemistry of Carbazole Alkaloids

H N

O H N

O Cl

O

O

toluene/ether/THF (5:1:1), rt (72%)

N MgBr

Cl 1366

349

1358

N H

N H 349

H N

O

(see Scheme 5.225) (3 steps, 47% overall)

N H

N H 293

Scheme 5.228

Three years later, the same authors developed a new route to arcyriarubin A (349) starting from methyl indole-3-glyoxylate (1368) and indole-3-acetamide (1369) (772). Methyl indole-3-glyoxylate (1368) was prepared either by treatment of indole (1170) with oxalyl chloride followed by addition of sodium methoxide at low temperature, or by refluxing 3-indole glyoxylic acid (1367) in methanol with a Dowex 50X8–100 ion-exchange resin. An intramolecular Perkin-type condensation of methyl indole-3glyoxylate (1368) and indole-3-acetamide (1369) in the presence of a 1 M solution of potassium tert-butoxide (KOt-Bu) in THF provided arcyriarubin A (349) quantitatively. Although this synthesis requires two steps, arcyriarubin A (349) was obtained in a high overall yield. Using Hill’s three-step protocol (palladium-mediated oxidative cyclization, reduction, and deoxygenation), bisindolylmaleimide 349 was transformed to staurosporinone (293) (772) (see Scheme 5.225) (Scheme 5.229). Faul et al. applied their condensation methodology, as shown in Scheme 5.229, for the total synthesis of rebeccamycin (337) and 11-dechlororebeccamycin (338) (323). For this methodology, the required symmetrical and unsymmetrical bisindolylmaleimides 1376 and 1377 were prepared by condensation of the glycosylated 7-chloroindole-3-acetamide (1372) with the methyl indole-3-glyoxylates 1373 and 1368. Using Danishefsky’s method, a selective formation of the b-N-glycoside of 7-chloroindole-3-acetamide 1372 was accomplished. The a-1,2-anhydro-sugar 1371 was prepared from commercially available tri-O-acetyl-D-glucal in four steps and 15:1 a/b-selectivity (80% overall yield). Deprotonation of 7-chloroindole-3-acetamide (1370) (obtained from 7-chloroindole in three steps and 65% overall yield) with sodium hydride in acetonitrile, followed by treatment with the a-1,2-anhydrosugar 1371, afforded the b-N-glycoside 1372 in 40% yield. The b/a-selectivity of the reaction was 16:1, and the minor a-isomer was removed by chromatography to afford the b-isomer in W98% diastereomeric purity. The methyl indole-3-glyoxylates 1373 and 1368 were readily prepared from the indoles 1334 and 1170 by reaction with oxalyl chloride at room temperature followed by addition of sodium methoxide (323) (Scheme 5.230).

350

Chemistry and Biology of Carbazole Alkaloids

OH

OMe 1. (COCl)2, ether 0 to −5°C N H

O

O O

2. NaOMe, −60°C (93% overall)

MeOH, reflux (82%)

N H 1368

1170

H N

O

NH2

O

N H 1367

O

KOt-Bu, THF 1368

(100%)

N H 1369

N H

N H

349 H N

O

(see Scheme 5.225) (3 steps, 47% overall)

N H

N H 293

Scheme 5.229

NH2

O

O

NH2

NaH, MeCN N H 1370

Cl

BnO O

N

Cl

MeO BnO

1371

O

O

OH

BnO BnO OMe 1372 (α:β = 1:16) OMe O O

1. (COCl)2, ether, rt R

N H

O

Dowex 50X8-100

2. NaOMe, MeOH

N H 1373 R = Cl (89%) 1368 R = H (93%) R

1334 R = Cl 1170 R = H

Scheme 5.230

Chemistry of Carbazole Alkaloids

351

The intramolecular Perkin-type condensation of the glycosylated 7-chloroindole3-acetamide 1372 and the methyl indole-3-glyoxylate 1373, initiated by a 1 M solution of potassium tert-butoxide in THF at room temperature, afforded the bisindolylmaleimide 1376 through an intermediate hydroxyimide 1374. The oxidative cyclization of the bisindolylmaleimide 1376 using palladium(II) triflate in DMF at 901C, followed by debenzylation with Pearlman’s catalyst [Pd(OH)2/C], provided rebeccamycin (337) in 55% yield. An analogous route, starting from methyl indole-3glyoxylate (1368) and the methyl 7-chloroindole-3-glyoxylate 1372, afforded 11-dechlororebeccamycin (338) in three steps and 52% overall yield (323) (Scheme 5.231). Wood et al. envisaged an elegant synthetic strategy for the total syntheses of the series of indolocarbazole alkaloids, (+)-staurosporine (295), ( )-TAN-1030A (313), (+)-RK-286C (318), and (+)-MLR-52 (320) using a common intermediate, a-methoxy ketone 1378, which was generated by Demjanov–Tiffeneau-like ring expansion of a furanosylated indolocarbazole 1380 (773–777). This common intermediate has all the required stereogenic centers of 295, 313, 318, and 320 already in place, and additional stereocontrolled functionalizations at C-4u and C-5u are feasible. Starting from the

NH2

O

H N

O H

O OH

+ 1373, 1368 KOt-Bu, THF

N

Cl

N

N H

Cl

O

OH

O

BnO

R

OH

BnO BnO OMe

OBn OMe

1372 (α:β = 1:16)

H N

O

1374 R = Cl 1375 R = H

O

H N

O

O

1. Pd(OTf)2, DMF, 90°C N

N H

Cl O

2. Pd(OH)2 /C, H2, THF, rt R

N

N H

Cl

OH

O

BnO

R

OH

HO OBn OMe

OH OMe

1376 R = Cl (86%) 1377 R = H (84%)

337 R = Cl (55%) 338 R = H (52%)

Scheme 5.231

352

Chemistry and Biology of Carbazole Alkaloids

DMB N O

N

DMB N O

N

O

Me MeO

N

H

O

N

Me R

N H

OH

O

O 1379 R = OMe 1380 R = H

1378 R N

H N

O

Me MeO

O

N H

OH O 330 (+)-K-252a

O

O

R N

N2

1382 R = DMB 1383 R = H

O

DMB = 3,4-dimethoxybenzyl N H

N H

1384

N H

N H

1381 R = DMB 293 R = H

Scheme 5.232

ketone 1378, a reductive amination would produce staurosporine (295), formation of the oxime would lead to ( )-TAN-1030A (313), reduction at C-4u from the convex face would provide (+)-RK-286C (318), and b-elimination of either a C-4u-amine (via Cope elimination) or a C-4u-hydroxy (via Martin’s sulfurane dehydration or Burgess dehydration), followed by dihydroxylation, would provide (+)-MLR-52 (320) (Schemes 5.232 and 5.233). The required furanosylated indolocarbazole 1380 should be readily available by reduction of 1379, a precursor of (+)-K-252a (330). For the synthesis of (+)-K-252a (330) a single-step cycloglycosidation of the selectively protected aglycon 1381 with an appropriate furanose was planned. The protected aglycon 1381 should be readily available by a rhodium-catalyzed coupling of 2,2u-bisindole 1384 with the a-diazo-bketo-g-lactam 1382 (Scheme 5.232). The 2,2u-bisindole (1384), required for the synthesis of staurosporinone (293) and the protected aglycon 1381, was prepared by a double Madelung cyclization as reported by Bergman. For the synthesis of the diazolactams 1382 and 1383, the glycine esters 1385 and 1386 were transformed to the lactams 1389 and 1390 by DCC/DMAP-promoted coupling with monoethyl malonate, followed by Dieckmann cyclization. The lactams 1389 and 1390 were heated in wet acetonitrile, and then treated with mesyl azide (MsN3) and triethylamine, to afford the diazolactams 1382 and 1383. This one-pot process involves decarboethoxylation and a diazo transfer reaction (Scheme 5.234).

Chemistry of Carbazole Alkaloids

H N

N

H N

O

N

O

Me MeO

N DMB N O

H

N

O

H OH

318 RK-286C N

H N

O

Me MeO

N HO 313 TAN-1030A

353

O

Me MeO

O

4′

N

H N

H

5′

O

O N

O

Me MeO

1378

N

N

H OH

Me MeO

OH

O

N H

NHMe 295 (+)-Staurosporine (AM-2282)

320 MLR-52

Scheme 5.233

O EtO

H N

R N

1. HOOCCH2COOEt DCC, DMAP R

EtO

COOEt

1385 R = DMB 1386 R = H R N

O

O O

2. NaOEt, EtOH

1387 R = DMB 1388 R = H R N

1. MeCN, H2O

O

2. MsN3, Et3N HO

COOEt

1389 R = DMB (83%) 1390 R = H

O

N2

1382 R = DMB (90%) 1383 R = H

Scheme 5.234

Coupling of the diazolactams 1382 and 1383 with 2,2u-bisindole (1384) in the presence of catalytic amounts of Rh2(OAc)4 and degassed pinacolone provided staurosporinone (293) directly in 25% yield, and the protected aglycon 1381 in 62% yield. This annulation is believed to proceed via the intermediates 1391, 1392 and 1393, 1394. The degassed pinacolone is both a good solvent for the 2,2u-bisindole substrate and compatible with the carbenoid chemistry (773,774) (Scheme 5.235).

354

Chemistry and Biology of Carbazole Alkaloids

R N O

O

R N

N2

1382 R = DMB 1383 R = H

Rh2(OAc)4, pinacolone sealed tube, 120°C

N H

N H

1381 R = DMB (62%) 293 R = H (25%)

N N H H 1384 −N2

−H2O

R N

R N

O HO [1,6-π] N H

O

N H

O

HO H N H

N H

1391 R = DMB

1393 R = DMB

1392 R = H

1394 R = H

Scheme 5.235

For the asymmetric synthesis of the furanose ( )-1398a,b, a novel tandem [3,3]/ [1,2] rearrangement protocol was developed to combine (R)-( )-1-nonen-3-ol [(R)-( )-1395] with methyl 2-diazo-3-oxobutyrate 1396. The reaction of (R)-( )1395 and 1396 in the presence of catalytic Rh2(OAc)4, followed by addition of boron trifluoride etherate, afforded (R)-(+)-1397 in 77% yield. Ozonolysis of (R)-(+)-1397, and subsequent acid-mediated cyclization, provided a mixture of ( )-1398a,b and (+)-1399 in 80% yield. A McCombie cycloglycosidation of the 3,4-dimethoxybenzyl (DMB)-protected aglycon 1381 with ( )-1398a,b/(+)-1399 in 1,2-dichloroethane, using camphorsulfonic acid (CSA) as catalyst, afforded in 80% yield a 1:2 regioisomeric mixture of the furanosylated indolocarbazoles (+)-1400 and (+)-1379. This reaction led selectively to a stereochemistry with the C-3u hydroxy group oriented syn to the indolocarbazole moiety. Moreover, the major regioisomer corresponded to the N-protected K-252a (330). Removal of the DMB group, using TFA and thioanisole as cation scavenger, provided (+)-K-252a (330) in 83% yield (773,774) (Scheme 5.236). The same route was applied to the syntheses of racemic K-252a and non-natural ( )-K-252a from the DMB-protected aglycon 1381 and the carbohydrates (7)-1398a,b/(7)-1399 and (+)-1398a,b/( )-1399 as precursors (773,774). In order to achieve access to the entire family of glycosylated indolocarbazoles, (+)-staurosporine (295), ( )-TAN-1030A (313), (+)-RK-286C (318), and (+)-MLR-52 (320) from a common synthetic precursor, the N-protected K-252a 1379 was subjected

355

Chemistry of Carbazole Alkaloids

O

OH Me

O

Me

5

O

1. Rh2(OAc)4, benzene OMe 2. BF Et O, reflux 3 2 (77%)

N2

O

Me

OMe HO Me

R-(−)-1395

R-(+)-1397

1396 MeO

1. O3, Me2S 2. MeOH, p-TsOH (80%)

Me MeOOC

O

OMe

O

Me MeO

OMe (+)-1399

Me MeO

O 3′

N

N H

Me MeO

(+)-1400

(80%) (1400:1379 = 1:2)

H N

O 3'

N

N

O

N H

OH O

O (+)-1379

O

Me MeO

H

OH

OH O

+ 1381 CSA, C2H4Cl2

DMB N O

DMB N

N

OMe HO

OH

(−)-1398a,b

O

O

4

TFA, CH2Cl2 anisol (83%)

330

Scheme 5.236

to regio- and stereoselective ring expansion. Compound (+)-1379 underwent lithium borohydride reduction to afford the alcohol (+)-1401, which, under Moffatt–Pfitzner oxidation conditions, led to the aldehyde (+)-1380. On treatment with boron trifluoride etherate, the aldehyde (+)-1380 underwent a rearrangement with ring expansion to the a-hydroxyketone (+)-1402 (775,776) (Scheme 5.237). Reduction of the a-hydroxyketone (+)-1402 with sodium borohydride, afforded the diol (+)-1403. The selective alkylation at the C-3u hydroxy group with sodium hydride and iodomethane provided the alcohol (+)-1404 in 80% yield. This selectivity was ascribed to the steric environment of the equatorial (C-3u) and the axial (C-4u) hydroxy groups. Removal of the DMB protecting group, by treatment of (+)-1404 with TFA in anisole, afforded (+)-RK-286C (318) in 75% yield. Dehydration of the alcohol (+)-1404 with Martin’s sulfurane led to the olefin (+)-1405, which was stereoselectively dihydroxylated using osmium tetroxide in the presence of NMO to give the dihydroxy derivative (+)-1406. Finally, removal of the DMB group in (+)1406 led to (+)-MLR-52 (320) in 77% yield (775,776) (Scheme 5.238). Reaction of the a-hydroxyketone (+)-1402 with hydroxylamine hydrochloride gave the oxime ( )-1407 in 95% yield. A bis-methylation of ( )-1407 under phase transfer conditions afforded the corresponding dimethyl derivative ( )-1408. Stereoselective hydrogenation of ( )-1408 using H2/PtO2 led to the amine

356

Chemistry and Biology of Carbazole Alkaloids

DMB N O

DMB N O

1. LiBH4, THF, rt N

O

N

Me MeO

2. 1 N HCl (89%) H

OH O (+)-1379

N

N

O

Me HO

H OH (+)-1401 benzene/DMSO pyridine TFA, DCC (71%)

CuCl, MeOH, Δ (95%)

DMB N O

DMB N O BF3 Et2O, ether N

O

N

Me HO

25 to 30°C (85%)

H

N

O

N

Me H

H OH

O

O

(+)-1402

(+)-1380

Scheme 5.237

(+)-1409. Monomethylation of the amine (+)-1409 yielded compound (+)-1410, which, on deprotection, provided (+)-staurosporine (295) (775,776) (Scheme 5.239). The reaction of the a-hydroxyketone (+)-1402 with O-benzylhydroxylamine hydrochloride afforded the benzyl-protected oxime ( )-1411. O-Methylation under phase transfer conditions led to the corresponding methyl derivative ( )-1412. Removal of the DMB protecting group from ( )-1412 followed by debenzylation of the lactam ( )-1413 by treatment with iodotrimethylsilane afforded ( )-TAN-1030A (313) (776) (Scheme 5.240). In the following years, Wood et al. further explored the rhodium carbenoid approach for the synthesis C7 methyl derivatives of K-252a (777), C2u alkyl derivatives of (7)-K-252a (778), and ( )-(7S)- and (+)-(7R)-K-252a dimers (779). Lowinger et al. (780) applied Raphael’s method (760) for the synthesis of (7)-K252a [(7)-330]. This method uses the anhydride 1362 as a key-intermediate starting from 2-nitrocinnamaldehyde (1300). The condensation of 2-nitrocinnamaldehyde (1300) with the Wittig reagent prepared from the phosphonium bromide 1306 afforded 1,4-bis(o-nitrophenyl)butadiene 1307. Diels–Alder cycloaddition of the butadiene 1307 with neat N-methylmaleimide 1414, followed by dehydrogenation with DDQ, led to the terphenyl 1415. Double nitrene insertion of 1415 by refluxing with triphenylphosphine in collidine provided, after basic hydrolysis, the anhydride 1362. Aminolysis with p-methoxybenzylamine (PMBNH2), followed by reduction,

Chemistry of Carbazole Alkaloids

DMB N O

357

DMB N O 1. NaBH4 MeOH/CH2Cl2/CHCl3

N

O

N

Me HO

2. 1 N HCl (95%)

H

N Me HO

O

O 3'

N H

4'

OH (+)-1403

(+)-1402 DMB N O

H N

O

TFA, ether

NaH, MeI, THF N

(80%)

N

O

Me MeO

anisol (75%)

N

O

Me HO

H

N H

OH (+)-1404

OH 318

Martin's sulfurane, CDCl3 (88%) R N

DMB N O

O

OsO4, NMO N

O

acetone/H2O (84%)

N

Me MeO

H

N Me MeO

(+)-1406 R = DMB

(+)-1405

320 R = H

O

N H OH

OH TFA, anisol (77%)

Scheme 5.238

afforded the PMB-protected aglycon 1416. The CSA-catalyzed, double glycosidation of the aglycon 1416 with the furanose (7)-1398 in refluxing dichloromethane gave a 2:1 mixture of the regioisomeric bis-glycosides (7)-1417 and (7)-1418 in 63% yield. Removal of the PMB group from compound (7)-1417 using TFA in the presence of anisole provided (7)-K-252a [(7)-330] in 80% yield (780) (Scheme 5.241). Ohkubo et al. reported the synthesis of the arcyriaflavins B (346), C (347), and D (348) involving a base-induced indolylation of dibromo-N-methylmaleimide 1420 and a palladium-mediated oxidative cyclization of the bisindolylmaleimides 1428, 1429, and 1430 as key steps (337). The reaction of 6-benzyloxyindole (1419) and

358

Chemistry and Biology of Carbazole Alkaloids

DMB N O

DMB N O

HONH2 HCl N Me HO

N

NaOAc (95%)

N

O

H2, PtO2

Me RO

H O

N

(−)-1407 R = H

MeI, KOH, Bu4NBr (90%)

(−)-1408 R = Me H N

DMB N O

(96%)

H

RO

(+)-1402

N

O

O

TFA, anisole N

O

(70%)

N

Me MeO

N

O

Me MeO

H NHR

O

H NHMe

O O

N

(+)-1409 R = H

H

(+)-1410 R = Me

BH3 SMe2 (91%)

Me

295

Scheme 5.239

dibromo-N-methylmaleimide 1420 with lithium hexamethyldisilazide (LiHMDS) as the base afforded the monoindolyl derivative 1421 in 93% yield. After protection of the indole nitrogen, the corresponding N-Boc derivative 1422 was coupled with the indoles 1423, 1424, and 1170 in the presence of base (LiHMDS) to afford the corresponding bisindolyl derivatives 1425, 1426, and 1427. Removal of the Boc group with methylamine afforded, in good yields, the deprotected compounds 1428–1430. Cyclization of 1428 and 1430 using DDQ, followed by debenzylation using catalytic amounts of palladium on charcoal, provided the corresponding products 1431 and 1433. The cyclization of 1429 with DDQ gave only traces of the desired product. However, the oxidative cyclization of 1429 using palladium(II) chloride in DMF, followed by debenzylation, led to the desired compound 1432 in 86.5% yield over both steps. Treatment of 1431–1433 with aqueous potassium hydroxide afforded the corresponding anhydrides 1434–1436. Finally, ammonolysis of the anhydrides 1434– 1436 provided the arcyriaflavins C (347), D (348), and B (346) (337) (Scheme 5.242). In the following year, the same authors applied this method to the synthesis of the anticancer agent NB-506 (781), ED-110 (781), and some unsymmetrical indolocarbazole glycosides (782). Gilbert and Van Vranken described the synthesis of tjipanazole F2 (372) by introduction of the halide and the glycosidic substituent at the heterocyclic skeleton without the use of protecting groups and with complete control of regioselectivity

Chemistry of Carbazole Alkaloids

DMB N O

DMB N O

BnONH2 HCl N

O

Me HO

TFA N

NaOAc (85%)

N

O (−)-1411 R = H

N

anisole (25%)

H

BnO

N

MeI, KOH, Bu4NBr (68%)

(−)-1412 R = Me H N

O

Me RO

H

(+)-1402

359

H N

O

O

TMSI, CDCl3 N

O

Me MeO

N H

(24%)

N

O

Me MeO

N BnO (−)-1413

HO

N H

N 313

Scheme 5.240

(783). The indolo[2,3-a]carbazole framework required for this synthesis was obtained by a TFA-promoted, Mannich cyclization of the readily available 1,2-bis(indol-3yl)ethane (1437). Subsequent bromination with NBS gave the racemic bromoindoline (7)-1438. Compound (7)-1438 was regioselectively glycosylated at the indoline nitrogen with 3 equivalents of D-xylopyranose in methanol under reflux to afford a 1:1 diastereoisomeric mixture of 1439. A convergent aromatization of the diastereoisomers 1439 with DDQ, followed by a halogen exchange using copper(I) chloride, provided tjipanazole F2 (372) in 61% yield over two steps (783) (Scheme 5.243). In the following year, this method was also applied to the total synthesis of tjipanazole F1 (371) (784). For this synthesis, the required bisindole 1444 was obtained starting from 5-chloroindole (1440) in three steps and 47% overall yield. Acylation of 1440 with oxalyl chloride led to the glyoxylic acid chloride 1441. Transmetalation of indolylmagnesium bromide with zinc chloride, followed by addition of the acid chloride, provided the a-diketone 1443. Exhaustive reduction of 1443 with lithium aluminum hydride (LiAlH4) afforded the corresponding bisindolylethane 1444. Executing a similar reaction sequence as shown for the synthesis of tjipanazole F2 (372) (see Scheme 5.243), the chloroindoline (7)-1445 was transformed to tjipanazole F1 (371) in two steps and 50% overall yield (784) (Scheme 5.244). Three years later, Chisholm and Van Vranken reported the first total synthesis of AT2433-A1 (339) using their acid-promoted Mannich cyclization methodology (785).

360

Chemistry and Biology of Carbazole Alkaloids

Br

H O2N

PPh3 1. LiOH, MeOH NO2 2. cat. I , toluene 2

O

reflux (89% overall) 1300

N Me O 1414 O

O

O2N 1307

O

1. 120°C 2. DDQ

O 1307

NO2

1306

t-butylbenzene 165°C (85% overall)

Me N

NO2

O

1. PPh3, collidine 160°C 2. KOH, EtOH/H2O reflux (48% overall)

O2N 1415

O

PMB N

O 1. PMBNH2, 120°C 2. Zn-Hg, 6 M HCl

N H

N H

1362 MeO

O

EtOH/toluene, reflux (57% overall))

N H

N H 1416

PMBNH2 = p-methoxybenzylamine

OMe Me OH COOMe

PMB N O

R N

O

(+ −)-1398 CSA, C2H4Cl2, reflux (63%)

N

O

Me OH COOMe

H

(+−)-1417 R = PMB (+ −)-330 R = H

N

N H

TFA, CH2Cl2, anisole

O

N

Me OH COOMe (+ −)-1418

(80%)

Scheme 5.241

For this methodology, the required chlorinated bisindolylsuccinimide (7)-1450 was prepared following Clardy’s and Kaneko’s procedure. Reaction of the 7-chloroindole Grignard compound 1447 with 1 equivalent of (N-methyl)dibromomaleimide (1420) led to the monoaddition product 1448, addition of indolylmagnesium bromide (1358) then afforded the unsymmetrical bisindolylmaleimide 1449 in 74% yield. Catalytic hydrogenation of 1449 to the bisindolylsuccinimide (7)-1450, followed by Mannich cyclization with methanesulfonic acid in chloroform, provided the hexacyclic compound (7)-1451 with high regio- and stereoselectivity. Glycosylation of the racemic chlorinated indoline (7)-1451 with the aminodisaccharide 1452 in the presence of CSA in DMF, and subsequent aromatization with DBU and iodine in dichloromethane, afforded the trimethylsilylethyl carbamate 1453. Removal of the

361

Chemistry of Carbazole Alkaloids

Me N

O

O

BnO

Me N

Br

1420

R

1421 R = H

LiHMDS

1422 R = Boc Me N O

R

+ 1422

1423 R = 6-OBn 1424 R = 5-OBn 1170 R = H Me N O

(Boc)2O, DMAP (88%)

40% MeNH2 N Boc

N H

OBn

MeOH

1425 R = 6-OBn (85% overall) 1426 R = 5-OBn (84% overall) 1427 R = H (70% overall) Me N O

O

R

1. PdCl2 or DDQ

1428 R = 6-OBn (81%) 1429 R = 5-OBn (92%) 1430 R = H (96%) O

O

R

OBn 2. 10% Pd/C THF, H2, rt

N H

O

N R

Br

O

N H

BnO

(93%)

N H 1419

N H

Br

LiHMDS, THF

O

O

N H

N H

OH

1431 R = 10-OH (100% overall) 1432 R = 9-OH (86.5% overall) 1433 R = H (76.5% overall) H N O O

O

2 M KOH R N N H H 1434 R = 10-OH (94%) 1435 R = 9-OH (91%) (90%) 1436 R = H

NH4OAc R OH 140°C

N N H H 347 R = 10-OH (72%) 348 R = 9-OH (52%) (62%) 346 R = H

OH

Scheme 5.242

2-trimethylsilylethoxycarbonyl (Teoc) group with TBAF provided AT2433-A1 (339) in 78% yield (785) (Scheme 5.245). An extension of this methodology led to another indolo[2,3-a]carbazole, AT2433B1 (341). For this synthesis, the required bisindolylsuccinimide (1455) was obtained through a catalytic hydrogenation of the readily available N-methylarcyriarubin A (1454). TFA-promoted Mannich cyclization of 1455 afforded the hexacyclic

362

Chemistry and Biology of Carbazole Alkaloids

H

Br 3 eq. D-xylose

1. TFA, rt N N H H 1437 H

MeOH, reflux (82%)

N H N H H (+ −)-1438

2. NBS, DMF (71% overall)

Br

Cl 1. DDQ, dioxane, 23°C

N H N H O

2. CuCl, DMF, reflux (61% overall)

OH

N H

N OH

O

OH

OH

HO 1439

HO 372

Scheme 5.243

Cl

O

Cl (COCl)2

ether, 0°C (88%)

N H 1441

1440 O

1442

Cl

ether, 0°C (77%)

N H

N ZnCl

O

O

Cl

Cl TFA, rt

LiAlH4 N H

N H

N H

THF, rt (70%)

1443

(74%)

1444 H

Cl

N H

Cl

H

3 eq. D-xylose N H N H H

MeOH, reflux (71%)

(+ −)-1445

N H N H O

OH OH

HO 1446

Cl DDQ dioxane, rt (70%)

N H

N OH

O

OH HO 371

Scheme 5.244

Chemistry of Carbazole Alkaloids

Me N

O

O Cl

O

Br

1447

Br

3 eq. 1358 THF/ether/toluene, Δ

N H

Cl

Br 1420

Me N

O

toluene, rt (72%)

N MgBr

O

Me N

(74%)

1448

O

Me N

O

O

H

H

H2, 10% Pd/C N H

Cl

MeSO3H

DMF (61%)

N H

Cl

Me N

H

H

CHCl3 (94%)

N H

OH

O

HO

Me N

O

O

OMe

H +

Cl

N H

(+ −)-1450

1449

O

363

HO

N H N H H (+ −)-1451

O O

1. cat. CSA, DMF O 2. I2, DBU, CH2Cl2

TeocN H

N O

OH 1452

N H

Cl

(52% overall)

OH

O

O

OH OMe

Teoc = 2-trimethylsilylethoxycarbonyl OH N Me R

1453 R = Teoc 339 R = H

TBAF, THF (78%)

Scheme 5.245

compound (7)-1456. Glycosylation of (7)-1456 with the aminodisaccharide 1452, followed by oxidative aromatization with DDQ, led to the Teoc-protected AT2433-B1 (1457). Finally, deprotection of the Teoc carbamate with TBAF provided AT2433-B1 (341) in 78% yield (785) (Scheme 5.246). Somei et al. reported the total synthesis of the cytotoxic and antiviral 5-cyano-6methoxy-11-methylindolo[2,3-a]carbazole (357) starting from indigo (1458) (786,787). A reduction of indigo (1458) with tin in acetic acid/acetic anhydride afforded 3-acetoxy-2,2u-bisindolyl (1459) in 88% yield. Heating of 1459 with dichloroacetyl chloride in ethyl acetate under reflux provided 3-acetoxy-3u-dichloroacetyl-2,2ubisindolyl (1460), which was treated with aqueous ammonia in methanol/DMF at room temperature to give the indolo[2,3-a]carbazole derivative 1461. N-Methylation

364

Chemistry and Biology of Carbazole Alkaloids

Me N

O

O

Me N

O H

O H

H2, Pd/C N H

N H 1454 Me N

O H

H

HO

H

(+ −)-1456

N H

N H 1455

OH

O

N H N H H

TFA

DMF (89%)

+

HO

TeocN H

OMe 1. cat. (NH4)2SO4 MeOH, Δ

O O

Me N

O

O 2. DDQ, dioxane (74% overall)

N O

OH 1452

O

N H OH

O

O

OH OMe

Teoc = 2-trimethylsilylethoxycarbonyl OH N Me R

1457 R = Teoc 341 R = H

TBAF, THF (78%)

Scheme 5.246

to 1462 followed by reductive cyanation afforded 5-cyano-6-hydroxy-11-methylindolo[2,3-a]carbazole 1463. Finally, O-methylation of 1463 with diazomethane afforded 5-cyano-6-methoxy-11-methylindolo[2,3-a]carbazole (357) in 86% yield (786,787) (Scheme 5.247). The two previous total syntheses of 5-cyano-6-methoxy-11-methylindolo[2,3-a] carbazole (357) by Somei et al. started also from indigo, however, gave low overall yields (788). In the following year, the same group reported the syntheses of various indolo[2,3-a] carbazoles from indigo (789). Beccalli et al. reported a new synthesis of staurosporinone (293) from 3-cyano-3(1H-indol-3-yl)-2-oxo propionic acid ethyl ester (1464) (790). The reaction of 1464 with ethyl chlorocarbonate and triethylamine afforded the compound 1465, which, on treatment with dimethylamine, led to the corresponding hydroxy derivative 1466. The triflate 1467 was prepared from 1466 by reaction with trifluoromethanesulfonic anhydride (Tf2O) in the presence of ethyldiisopropylamine. The palladium(0)catalyzed cross-coupling of the triflate 1467 with the 3-(tributylstannyl)indole 1468 afforded the vinylindole 1469 in 89% yield. Deprotection of both nitrogen atoms with sodium ethoxide in ethanol to 1470, followed by photocyclization in the presence of iodine as the oxidizing agent provided the indolocarbazole 1471. Finally, reductive cyclization of 1471 with sodium borohydride-cobaltous chloride led to staurosporinone (293) in 40% yield (790) (Scheme 5.248).

Chemistry of Carbazole Alkaloids

O H N N H

OAc HN

Sn, HOAc, Ac2O 64 to 66°C (88%)

O

365

N H

1458

1459 OAc HN

Cl2CHCOCl EtOAc, reflux (85%)

N H O

aq. 1.3% NH3 MeOH/DMF, rt (91%) CHCl2

1460 NC

Cl HO

O

N

N R

OR

NaCN

1461 R = H 1462 R = Me

DMF/H2O, 70°C (quant.)

Me2SO4, K2CO3, rt (quant.)

N H 1463 R = H 357 R = Me

N Me CH2N2, rt (86%)

Scheme 5.247

Mahboobi et al. described a novel synthesis of staurosporinone (293) (791). The intermolecular Michael addition of 1-(indol-3-yl)-2-nitroethene (1472) to methyl indol-3-ylacetate (1313) provided with high diastereoselectivity methyl 2,3bis(indol-3-yl)-4-nitrobutanoate (1473). Catalytic hydrogenation and lactamization afforded 2,3-bis(indol-3-yl)-g-butyrolactam (1474) in 87% yield. Oxidative cyclization of the cis-lactam 1474 with DDQ in the presence of catalytic amounts of p-TsOH led to staurosporinone (293) (791) (Scheme 5.249). Fukuyama et al. reported the total synthesis of (+)-K-252a (330) starting from indol3-ylacetic acid (680) (792). Formation of the allyl ester, followed by regioselective bromination, led to the 2-bromoindole 1475. The N-glycosidation of compound 1475 was carried out by deprotonation with sodium hydride and subsequent addition of the readily available 1-chloro-2-deoxy-3,5-di-O-p-toluoyl-a-D-erythro-pentofuranose (1476) and afforded the b-N-glycoside 1477 as the sole product. Compound 1477 was transformed to the diacetyl bisindole 1478 in four steps and 52% overall yield by cleavage of the allyl ester, reaction of the resulting acid with tryptamine to the amide, regioselective oxidation at the benzylic position to the ketone, and diacetylation of the indole and amide nitrogens. The base-catalyzed cyclization of the diacetyl bisindole ˚ MS afforded the lactam 1479. A non1478 with catalytic amounts of DBU and 4 A oxidative photocyclization of the lactam 1479 by sunlight, in the presence of N,N-diisopropylethylamine to promote the dehydrobromination, provided almost quantitatively the desired indolocarbazole 1480. Hydrolysis of all acyl groups followed by treatment with iodine, triphenylphosphine, and imidazole led to selective conversion of the primary alcohol to the corresponding iodide 1481 (Scheme 5.250). The conversion of the iodide 1481 to the olefin 1482 was achieved by a conventional four-step sequence. Treatment of 1482 with iodine, potassium iodide,

366

Chemistry and Biology of Carbazole Alkaloids

NC

NC

COOEt OH

OCOOEt

Et3N, CH2Cl2 (90%)

N H 1464

NC

(80%)

SnBu3

NC

N SO2Ph

COOEt

Tf2O, i-Pr2NEt

1468

OTf

(85%)

N COOEt

Me2NH, CH2Cl2

N COOEt 1465

COOEt OH

Pd(Ph3P)4, CuI LiCl, THF, Δ (89%)

N COOEt

1466 NC

COOEt

ClCOOEt

1467 NC

COOEt

COOEt

NaOEt, EtOH, Δ N EtOOC

hν, I2, MeCN

(90%)

N SO2Ph

N H

1469

(82%)

N H

1470 H N

NC

O

COOEt NaBH4, CoCl2 6H2O

N H

MeOH/THF (40%)

N H 1471

N H

N H 293

Scheme 5.248

MeOOC

NO2

N H 1472

autoclave (87%)

NO2

LDA, THF, −78°C

+

(10%)

N H 1313 H N

H2, Ra-Ni ether/EtOH

MeOOC

H

N H

N H 1473 H N

O H DDQ, p-TsOH

N H

N H 1474

benzene, rt (60%)

Scheme 5.249

N H

N H 293

O

Chemistry of Carbazole Alkaloids

O

367

Cl

TolO

O

OH 1. allyl bromide, K CO 2 3 DMF, 23°C O 2. NBS, CCl4, 23°C (79% overall)

N H

TolO

1476

O

NaH, MeCN, 23°C (97%)

Br

N H 1475

680

Ac N

1. Pd(PPh3)4, PPh3

O

pyrrolidine, CH2Cl2, 23°C 2. tryptamine, CH2Cl2, 23°C

O Br N

3. DDQ, THF/H2O, 0°C 4. 2,6-lutidine, DMAP Ac2O, 60°C

O TolO

(52% overall)

TolO

O

O

N Br N Ac O TolO TolO 1478

1477 Ac N

Ac N

O

O

i-Pr2NEt, hν

DBU, 4 Å MS N Br N Ac O

THF, 60°C (92%)

CH2Cl2, 23°C

N Ac

(96%)

TolO

N O

TolO

TolO

TolO

1479

1480 H N

O

1. KOH/H2O MeOH/THF, 23°C 2. I2, PPh3, imidazole THF, 23°C (79.5% overall)

N H

N O

I HO 1481

Scheme 5.250

and DBU provided the cycloglycoside 1483 in 93% yield. Radical deiodination of 1483, followed by cleavage of the acetate, led to the hydroxy derivative 1484. The compound 1484 was transformed to the acetylcyanohydrin 1485 over three steps in 98% overall yield by Moffatt–Pfitzner oxidation, followed by cyanation of the formed ketone with hydrogen cyanide, and acetylation. An attempted

368

Chemistry and Biology of Carbazole Alkaloids

acid-promoted methanolysis of 1485 afforded mainly the intermediate ketone (not shown in the scheme) along with only a trace of (+)-K-252a (330). Therefore, compound 1485 was transformed to the amide 1486, followed by alkaline hydrolysis to the acid and treatment with diazomethane to provide (+)-K-252a (330) (792) (Scheme 5.251).

1481

H N

1. PhSeSePh, NaBH4 EtOH/THF, 23°C 2. Ac2O, pyridine DMAP, 23°C 3. MCPBA, THF, 23°C 4. Et3N, DHP, 80°C

O

KI, I2, DBU N H

N

THF, 23°C (93%)

O

(83% overall) AcO

1482 H N

H N

O

O

1. Bu3SnH, AIBN MeCN, reflux N

O

I

2. K2CO3, MeOH, 23°C (88% overall)

N H

N

N

O

Me

H

HO

AcO 1483

1484 H N

O

1. DCC, Cl2CHCOOH DMSO, 23°C

HCl, HCOOH, 23°C

2. HCN, pyridine, MeCN, 0°C 3. Ac2O, DMAP, 25°C (98% overall)

H N

N Me NC

O

N

(88%)

H OAc 1485 H N

O

O

1. KOH/H2O MeOH/THF, 100°C N Me H2NOC

O

N

2. CH2N2, THF (65% overall)

H OAc 1486

N Me MeOOC

O

H OH 330

Scheme 5.251

N

369

Chemistry of Carbazole Alkaloids

Tome´ et al. described a synthesis of arcyriaflavin A (345) from commercially available 2-nitrobenzaldehyde (1487) (793). The construction of the indolo[2,3-a] pyrrolo[3,4-c]carbazole framework was achieved by successive Diels–Alder cycloaddition, Fischer indolization, and nitrene insertion. A Wittig reaction of 2-nitrobenzaldehyde (1487) to the ketone 1488, followed by reaction with tertbutyldimethylsilyl triflate (TBSOTf) in the presence of triethylamine, led to the diene 1489 in high yield. The Diels–Alder reaction of 1489 with maleimide (1303) afforded the endo-cycloadduct (7)-1490. Acidic hydrolysis of compound (7)-1490 gave the perhydroisoindole-1,3,5-trione (7)-1491, which, on Fischer indolization with phenylhydrazine (524) provided the regioisomers (7)-1492 and (7)-1493 in a 2:1 ratio. Dehydrogenation of (7)-1492 with DDQ to the carbazole 1494, and nitrene insertion using Cadogan’s procedure by heating in triethyl phosphite, afforded arcyriaflavin A (345) (793) (Scheme 5.252). This method was also applied to the synthesis of 3-methoxy-6-phenylarcyriaflavin A (793). O

CHO NO2

Me

TBSO TBSOTf, Et3N

Ph3P CHCOMe NO2

benzene, reflux (86%)

1487

TBS = t-butyldimethylsilyl-

1488 H N

O

O

1489

O

H3O, CH2Cl2 (70%) TBSO

O2N

O

O2N

(+ − )-1491

(+ − )-1490 H N

O

NO2 O

O

N H

HOAc/H2SO4

(+ − )-1491

EtOH, reflux

N H

NHNH2 524 H N

N H (+ − )-1493 (19%)

O

O

H N

P(OEt)3

DDQ benzene, rt (80%)

O2N

(+ − )-1492 (42%)

O

(+ − )-1492

H N

O

+ 1303, benzene reflux, rt (100%)

NO2

CH2Cl2, rt (100%)

N O2N H 1494

reflux (52%)

Scheme 5.252

N N H H 345

O

O

370

Chemistry and Biology of Carbazole Alkaloids

Five years later, the same authors reported an improved total synthesis of arcyriaflavin A (345) starting from the TBS enol ether 1490 (for the synthesis see Scheme 5.252). This route involves two indolizations based on silyl enol ether nucleophilic attack and Fischer processes. Using Cadogan’s procedure by heating in triethyl phosphite, the TBS enol ether 1490 was transformed into the ketone (7)1495, involving silyl enol ether-mediated indolization. Finally, Fischer indolization of (7)-1495 by reacting with phenylhydrazine (524) led directly to arcyriaflavin A (345) in 57% yield (794) (Scheme 5.253). Uang et al. reported a synthesis of staurosporinone (293) starting from arcyriarubin A (349). Oxidative photocyclization of bisindolylmaleimide 349 in the presence of a catalytic amount of iodine in THF/acetonitrile led to arcyriaflavin A (345) in 85% yield. Finally, using modified Clemmensen reduction conditions, arcyriaflavin A (345) was transformed to staurosporinone (293) in 68% yield (795) (Scheme 5.254). Kuethe et al. reported the synthesis of the tjipanazoles D (359), I (360), B (369), and E (370) starting from the nitro derivative 1496 (796). This route involves the synthesis of 2,2u-bisindoles, followed by a two-carbon insertion through condensation with (dimethylamino)acetaldehyde diethyl acetal to afford the indolocarbazole ring. H N

O

1490

O

H N

O

O

+ 524 HOAc/EtOH/H2O

P(OEt)3 160°C (75%)

N H (+ )-1495 −

O

reflux

N H

(57%)

N H 345

Scheme 5.253

H N

O

O

H N

O

O

hν, I2, THF/MeCN (1:1) (85%)

N N H H 349

N H 345

H N

O

Zn/Hg, THF 6 M HCl (68%)

N H

N H

N H 293

Scheme 5.254

371

Chemistry of Carbazole Alkaloids

Reaction of the TMS-nitro compound 1496 and the indole carboxaldehyde 1497 with a catalytic amount of TBAF led to the desired alcohol 1498, which, on further treatment with TFAA, followed by elimination of the corresponding trifluoroacetate with DBU, afforded the trans-stilbene 1499. Reductive cyclization of 1499 under Cadogan–Sundberg conditions afforded the bisindole 1500. Finally, condensation of 1500 with (dimethylamino)acetaldehyde diethyl acetal led to tjipanazole D (359) in 71% yield (796) (Scheme 5.255). Analogous to the aforementioned method, starting from the same nitro derivative 1496 and the indole carboxaldehyde 1501, tjipanazole I (360) was obtained in five steps and 28% overall yield (796) (Scheme 5.256).

TMS

Cl

Cl

Cl

O2N

cat. TBAF CHO N Boc

NO2 1496

N Boc

1498

1497 Cl

O2N

1. TFAA 2. DBU (33% overall)

OH Cl

P(OEt)3 or Pd(OAc)2, PPh3 (68%)

N H

Cl 1499

Cl

Cl

Cl

Cl

(OEt)2CHCH2NMe2 N H

N H

HOAc (71%)

N H 1500

N H

359

Scheme 5.255

TMS

1. cat. TBAF 2. TFAA

Cl NO2 1496

CHO 3. DBU 4. P(OEt)3 or Boc Pd(OAc)2, PPh3 1501 (35% overall)

N

Cl

Cl (OEt)2CHCH2NMe2

N H

N H

HOAc (79%)

1502

N H

N H 360

Scheme 5.256

372

Chemistry and Biology of Carbazole Alkaloids

The same authors also reported the total synthesis of tjipanazole B (369) in 66% overall yield, in two steps, by reacting tjipanazole D (359) with a-D-xylopyranosyl chloride (1503) in a biphasic mixture of MTBE and 45% aqueous KOH and Aliquat 336, followed by hydrogenation with Pd(OH)2 (796). Similarly, reaction of tjipanazole D (359) with a-D-glycopyranosyl chloride (1504) led to tjipanazole E (370) in two steps and 77% overall yield (796) (Scheme 5.257). Cai and Snieckus reported a total synthesis of 5-cyano-6-methoxy-11-methylindolo[2,3-a]carbazole (357) starting from the 2-bromoindolecarboxamide 1505 (797). This methodology uses a directed ortho- and remote metalation-cross-coupling strategy. Stille cross-coupling reaction of 2-bromoindolecarboxamide 1505 with the 2stannylated N-carboxyindole 1506 afforded the bisindolyl derivative 1507 in 77% yield. On treatment with Eschenmoser’s salt, 1507 gave the gramine derivative 1508, which, upon sequential reaction with methyl iodide, followed by reaction with KCN/18-crown-6, afforded the acetonitrile 1509. LDA-mediated cyclization of 1509, followed by immediate methylation of the unstable phenol with diazomethane, led to 5-cyano-6-methoxy-11-methylindolo[2,3-a]carbazole (357) (797) (Scheme 5.258). The powerful and varied biological activities of the indolocarbazole systems offer many potential therapeutic applications, particularly as anticancer agents, and several have reached the stage of clinical trials. Unsurprisingly, these fascinating structures have attracted substantial synthetic interest, both from the standpoint of total synthesis of the natural products themselves as discussed above, and the design of simpler analogs for probing structure activity relationships (435,437,439,440,798–852).

Cl

Cl N H

1. 45% KOH, Aliquat 336

N H

Cl

2.

359

OBn

O

1. 45% KOH, Aliquat 336 2.

OBn OBn OBn

Cl

1504 3. Pd(OH)2, H2 (77% overall)

OBn

O

OBn OBn

1503 Cl

3. Pd(OH)2, H2 (66% overall)

Cl N

Cl

Cl

N H

OH

O N

OH

N H

O OH OH 369

Scheme 5.257

HO

OH OH 370

Chemistry of Carbazole Alkaloids

O

O NEt2

NEt2

PdCl2(PPh3)2

Br

N Me

373

SnBu3 N COOH

1505

EtOH, reflux N Me

(77%)

1507

1506 Et2N O

NMe2 1. MeI, MeCN, rt 2. KCN, DMF

CH2NMe2Cl (98%)

N H

N Me

N H

18-crown-6, rt (92% overall)

1508 Et2N O

CN

MeO

CN

1. LDA, THF, 0°C to rt N Me

N H

2. CH2N2, ether, rt (83% overall)

N Me

1509

N H

357

Scheme 5.258

I. Imidazo[4,5-a]pyrrolo[3,4-c]carbazole Alkaloids Until now, this relatively new class of imidazo[4,5-a]pyrrolo[3,4-c]carbazole alkaloids includes only three natural products. These natural products showed G2 check point inhibitor activity, and thus represent a promising target for the development of new chemotherapeutic anticancer agents. Due to this fact, a wide range of analogs of imidazo[4,5-a]pyrrolo[3,4-c]carbazole alkaloids were reported for structure activity studies. Berlinck, Piers, Anderson, and co-workers described the total synthesis of granulatimide (374) and isogranulatimide (375), along with its isolation (342). This short and efficient biomimetic synthesis was undertaken to establish the assigned structures, and uses a photolytic electrocyclization of didemnimide A (373) as the key step. Reaction of the substituted imidazole 1510 with butyllithium, followed by reaction of the intermediate 5-lithioimidazole with dimethyl oxalate, afforded the a-keto ester 1511 in 66% yield. Condensation of compound 1511 with indole-3˚ MS acetamide (1369) in the presence of potassium tert-butoxide (KOt-Bu) and 4 A in DMF led to the maleimide 1512. After desulfurization of 1512 with Raney nickel (Ra-Ni) to compound 1513, the methoxymethyl group was cleaved with boron tribromide to give didemnimide A (373). Finally, the photolysis of a solution of didemnimide A (373) in acetonitrile containing a small amount of palladium on charcoal provided granulatimide (374) in 91% yield and isogranulatimide (375) in 8% yield (342) (Scheme 5.259). Two years later, Piers et al. reported an improved synthesis of isogranulatimide (375) starting from didemnimide A (373). Heating of a solution of 373 in nitrobenzene containing palladium black as the hydrogen transfer reagent at

374

Chemistry and Biology of Carbazole Alkaloids

OMe N

O

1. BuLi, THF, −78°C 2. dimethyl oxalate

SPh

KOt-Bu, DMF, rt +1369, 4 Å MS

N SPh

O

THF, −78°C (66%)

N

OMe

MeO

1510

DMF, 45°C (90%)

N 1511

O

H N

O OMe

N

1512 R = SPh

N

reflux (77%)

N H

R Ra-Ni (W-2), EtOH, reflux (85%)

1513 R = H

O

BBr3, CH2Cl2

N N H

H N

O

O

H N

N H

373

O N

MeCN, 10% Pd/C

N

O

hν, quartz vessel

H

H N

O

H

N

374 (91%)

N H

N N

375 (8%)

Scheme 5.259

O

H N

O O N

N H

N

H

H N

O

Pd black nitrobenzene, 200°C (75%)

373

N H

N N

375

Scheme 5.260

2001C led to only isogranulatimide (375) in 75% yield (853) (Scheme 5.260). The same authors also reported a series of analogs of granulatimide and isogranulatimide (853). Murase et al. reported a new synthesis of granulatimide (374) starting from 1-methoxyindole (1514) (854). This synthetic approach involves Stille coupling of stannylindole 1515 with the iodoimidazole 1516 to afford the indole–imidazole coupling product 1517 and photocyclization of the condensation product 1520 as key steps. Regioselective lithiation of 1-methoxyindole (1514) with butyllithium, followed by quenching of the intermediate 2-lithio derivative with chloro tributylstannane led to the stannylindole 1515. The Stille coupling reaction of 1515 with 4-iodo-1-(methoxymethyl)imidazole (1516) in the presence of PdCl2(PPh3)2

Chemistry of Carbazole Alkaloids

375

afforded the corresponding indole–imidazole coupling product 1517. After removal of the methoxy group in 1517, the deprotected compound 1518 was reacted with ethylmagnesium bromide to afford the corresponding Grignard reagent 1519, which, on treatment with dibromomaleimide (1357), led to the corresponding coupling product 1520. Following Pier’s procedure, with some modifications, compound 1520 was transformed to MOM-protected granulatimide (1521). Finally, removal of the MOM group in 1521 led to granulatimide (374) in 72% yield (854) (Scheme 5.261). Further application of this synthetic approach led to the granulatimide structural analogs, 10-methylgranulatimide, 17-methylgranulatimide, and 10,17-dimethylgranulatimide (854). One year later, the same authors reported a further extension of the aforementioned methodology for the synthesis of various granulatimide positional analogs (855). Prodhomme et al. reported the synthesis of a series of structurally related granulatimide and isogranulatimide isomers and analogs bearing modified heterocycles (856–860). These syntheses were undertaken to obtain an insight into the possible interactions of these analogs with the ATP binding site of the target kinase. MOM N N

I

1. BuLi, −78°C N OMe 1514

1516 SnBu3 cat. PdCl2(PPh3)2 N toluene, reflux OMe (48%) 1515

2. Bu3SnCl, THF, rt

N

Mg, THF/MeOH

MOM

N N OMe 1517

N N H 1518 H N

O EtMgBr THF, rt

N

MOM

+ 1357 THF, rt (42%)

N N MgBr

N H

H N

O O N

N H

N 1520

hυ, MeCN (80%)

O Br MOM N

1519 O

MOM

N

reflux (75%)

N

MOM

H N

O

10% HCl 100°C (72%)

1521

N N H

N 374

Scheme 5.261

H

376

Chemistry and Biology of Carbazole Alkaloids

J. Quinolino[4,3-b]carbazole-1,4-quinone Alkaloids So far this class of carbazole alkaloids contains only two natural products, calothrixin A and its N-deoxy-derivative calothrixin B. These two pentacyclic metabolites with a quinolino[4,3-b]carbazole-1,4-quinone framework displayed potent inhibitory effects on the in vitro growth of both human malarial parasites and human cancer cells and inhibition of RNA polymerase activity. Owing to this pharmaceutical potential, these natural products have attracted the synthetic interest of various research groups (8). Kelly et al. reported the first total synthesis of calothrixins A (377) and B (378) from 3-formyl indole (618) and quinoline-4-carboxylic acid (1523) involving an ortholithiation strategy for the construction of the pentacyclic ring system (861). The MOM-protected 3-formylindole (1522) and the quinoline-4-carboxamide (1523) were prepared in a one-pot operation from the commercially available compounds 618 and 1523, respectively. Lithiation of 1524 using lithium tetramethylpiperidide (LiTMP), followed by coupling with 1522, provided directly the MOM-protected calothrixin B (1529). None of the putative intermediates 1526, 1527, and 1528 shown in Scheme 5.262 was isolated. However, the use of LiTMP as base was crucial for this metalation. Finally, removal of the MOM protecting group of 1529 led to calothrixin B (378) in 74% yield. Selective oxidation of the pyridine nitrogen of calothrixin B (378) with MCPBA afforded calothrixin A (377) in 71% yield (861) (Scheme 5.262).

O H

N O

N H 618 R = H 1522 R = MOM

N

O LiTMP, THF (12%)

N H

R NaH, THF MOMCl

1523 R = OH

SOCl2, Et2NH

1524 R = NEt2

N

O

HO

O

NH2

1526

N

LiTMP

[O] O N Li MOM 1527

NH2

N O MOM 1528 O

O

O

N

N MCPBA

N R

(71%) O

1529 R = MOM 378 R = H

aq. HCl (74%)

N H

O 377

Scheme 5.262

(in situ)

Chemistry of Carbazole Alkaloids

377

Chai et al. reported an alternative synthesis to calothrixin A (377) and B (378) from readily available indole (1170) and the acid chloride 1532. This methodology differs from Kelly’s synthesis in that the pentacyclic ring system is constructed by using Friedel–Crafts acylation and metalation strategies. The acid chloride 1532 was obtained from the corresponding quinoline 1531, which, in turn, is prepared from quinolin-3,4-anhydride (1530). The Friedel–Crafts acylation of indole (1170) with the acid chloride 1532 provided the diaryl ketone 1533 in 90% yield. Compound 1533 was protected as N-MOM derivative 1534. Reaction of 1534 with LiHMDS in the presence of tetramethylethylenediamine (TMEDA), followed by intramolecular nucleophilic substitution of the ester, led to N-MOM-calothrixin B (1529) in 92% yield. Finally, cleavage of the N-MOM group provided calothrixin B (378) (862–864). Conversion of 378 to calothrixin A (377) was then readily achieved by using MCPBA as the oxidant (see Scheme 5.262) (861) (Scheme 5.263). Collet, Guingant, and co-workers reported a convergent synthesis of calothrixin B (378) starting from the commercially available tetrahydro-4H-carbazole-4-one (859) (865,866). This methodology is based on the regioselective hetero-Diels–Alder reaction between 9-bromocarbazole-1,4-dione 1534 and ‘push pull’ 2-aza-1,3-diene 1535 to construct the pentacyclic core structure of calothrixin B (378). Dehydrogenation of tetrahydro-4H-carbazole-4-one (859) on Pd/C afforded carbazol-4-ol 1530, which, on bis-protection with the Cbz group using benzylchloroformate, led to the bis-Cbz carbazole 1531. Chemoselective monodeprotection of 1531 by treatment with aqueous sodium hydroxide led to the N-Cbz-carbazole 1532, which on bromination with NBS in acetonitrile, furnished the corresponding 3-bromocarbazole 1533. O

O

COOMe COOH (COCl) 2

O dry MeOH reflux (70%)

N

(quant.)

N

1530

COOMe COCl N

1531

1532 N

O 1. ZnCl2, MeMgBr

TMEDA, LHMDS

2. quinoline, 1532 (90%)

N H 1170

N R

O

NaH, THF, 0°C MOMCl (90%)

1533 R = H 1534 R = MOM O

O

O

N

N

MCPBA N R

(ref. 861) O

1529 R = MOM 378 R = H

THF, −78°C (92%)

OMe

N H

BBr3, CH2Cl2 NaHCO3, 60°C (85%)

Scheme 5.263

O 377

378

Chemistry and Biology of Carbazole Alkaloids

O

N H

HO

10% Pd/C diphenyl ether

NaH, CbzCl, rt

1,2,5-trimethylbenzene 250°C (90%)

(91%)

N H

859

1530

CbzO

HO NaOH

N Cbz 1531 HO

NBS, MeCN, rt

dioxane/H2O, 40°C (90%)

(94%)

N Cbz 1532 O

Br

Br

PhI(OAc)2 N Cbz 1533

HOAc /TFA, rt (83%)

N Cbz

O

1534

Scheme 5.264

Oxidation of 1533 with diacetoxyiodobenzene [PhI(OAc)2] led to the desired bromoactivated dienophile 1534 (Scheme 5.264). The key [4+2] cycloaddition reaction of 1534 with an excess of 2-aza-1,3-diene 1535 in acetonitrile at 401C afforded the Cbz-deprotected adduct 1536 in 80% yield, along with 5% of the Cbz cycloadduct 1537. The high yield of this cycloadduct is attributed to the electron-acceptor nature of the Cbz protecting group, as well as the removal of the Cbz group with the liberated dimethylamine hydrobromide. Deprotonation of 1536, followed by triflation, afforded a mixture of the enol triflate 1538 and the aryl triflate 1539, which, without separation, were subsequently heated in dioxane in the presence of DDQ to afford the triflate 1539. Finally, exposure of 1539 to palladium(0)-catalyzed reductive elimination conditions completed the synthesis of calothrixin B (378) (865,866) (Scheme 5.265). Execution of this sequence with the benzyl protecting group turned out to be less efficient due to the poor yield in the key cycloaddition step, as well as difficult removal of the N-benzyl protecting group at a later stage of the synthesis (865,866). Hibino et al. reported a new total synthesis of calothrixin B (378) starting from 2-formyl-N-phenylsulfonylindole (1540) (867). The key step in this synthesis is an allene-mediated, electrocyclic reaction of a 6p-electron system involving the indole2,3-bond for the construction of the 4-oxygenated carbazole ring system 1546. The Wittig reaction of 1540 with 2-nitrobenzyltriphenylphosphorane (1541) gave the trans-styrylindole 1542. Treatment of 1541 with 1,1-dichloromethyl methyl ether in the presence of AlCl3 afforded the 3-formylindole 1543. Grignard reaction of 1543 with ethynyl magnesium bromide led to the corresponding propargyl alcohol 1544, which was protected as the methoxymethyl ether 1545. The propargyl ether 1545 was subjected to an allene-mediated electrocyclic reaction by treatment with potassium tert-butoxide (KOt-Bu) in tert-butanol (t-BuOH) and THF at 901C to

Chemistry of Carbazole Alkaloids

NMe2

O

O

N

379

N

N

+1534 MeCN, 40°C

O 1535

N H

N Cbz

O O

1536 (80%) LiHMDS, THF/HMPA, −78°C

O O

1537 (5%)

PhNTf2, THF O

O

N

N Pd(PPh3)4, Et3N

N H

N H

O O Tf

1538

O O Tf

378

HCOOH/dioxane (75%)

1539 DDQ, dioxane, reflux (51% overall)

Scheme 5.265

afford the required 4-oxygenated carbazole 1546. Oxidation of 1546 with DDQ in the presence of lithium perchlorate gave the 3-formyl-4-hydroxy-carbazole 1547 with elimination of the MOM group. Reduction of the nitro group of 1547 with 10% Pd/C, followed by the intramolecular cyclization and subsequent oxidation to the quinone with CAN, afforded calothrixin B (378) in 67% yield (867) (Scheme 5.266). One year later, the same authors reported a biomimetic synthesis to calothrixin B (378) via a hypothetical metabolite, 6-formylindole[2,3-a]carbazole (868). This synthesis is based on an allene-mediated, electrocyclic reaction involving two[b]bonds of indoles and starts from 2-bromoindole-3-carbaldehyde (1548). Suzuki– Miyaura coupling of 1548 with indole-2-boronic acid 1549 gave the bisindole 1550. Cleavage of the N-Boc group in 1550 with TFA, followed by protection of both nitrogen atoms with chloromethyl methyl ether (MOMCl) and NaH, afforded the bis-MOM-bisindole 1551. The Grignard reaction of 1551 with ethynyl magnesium bromide yielded the propargyl alcohol 1552, which was protected with MOMCl to afford the MOM ether 1553. An allene-mediated electrocyclic reaction of 1553 led to the desired indolocarbazole 1554. Oxidation of the 6-methylindolocarbazole 1554 to 6-formylindolocarbazole 1555 was achieved by reaction with DDQ. Further oxidation with CAN led to N-MOM-calothrixin B (1529) involving the quinone imine 1556 and the quinone 1557 as intermediates. Finally, cleavage of the MOM group using Kelly’s method afforded calothrixin B (378) in 65% yield (868) (Scheme 5.267). Bennasar et al. reported a new radical-based route for the synthesis of calothrixin B (378) (869). This synthesis starts from the 2,3-disubstituted N-Boc indole 1558 and uses a regioselective intramolecular acylation of a quinoline ring as the key step for the construction of the calothrixin pentacyclic framework. Chemoselective reaction of in situ-generated 3-lithio-2-bromoquinoline [from 2-bromoquinoline 1559 with LDA] with the 3-formylindole 1558 followed by triethylsilane reduction of the

380

Chemistry and Biology of Carbazole Alkaloids

PPh3Br

NO2

R

1541 CHO BuLi, THF, 0°C N (96%) SO2Ph

(92%)

N PhO2S

1540

HC CMgBr, THF

O2N

1542 R = H 1543 R = CHO

RO

MOMO

Cl2CHOMe, AlCl3 CH2Cl2, −78°C (96%) 1. DDQ, LiClO4 CH2Cl2/H2O, rt

Me

KOt-Bu N PhO2S

t-BuOH, THF (29%)

O2N

1544 R = H 1545 R = MOM HO

MOMCl, i-Pr2NEt CH2Cl2, 50°C (93%)

N H

2. 6 N HCl ethylene glycol THF, 60°C (70% overall)

O2N

1546

O

CHO

N

1. 10% Pd/C, H2, EtOH, rt N H

O2N

2. CAN, MeCN/H2O, 0°C (67% overall)

N H

O 378

1547

Scheme 5.266

resulting carbinol afforded the 2-bromoquinoline 1560 in 65% yield. Reaction of 1560 with tributyltin hydride followed by protection of the indole nitrogen with MOMCl led to the N-MOM methyl ester 1561 in 81% yield. Hydrolysis of 1561, followed by phenylselenation of the intermediate carboxylic acid gave the required selenoester 1562. Treatment of the selenoester 1562 with tri(trimethylsilyl)silane (TTMSS) in the presence of the radical initiator AIBN at 801C led to the pentacyclic phenol 1563. Mild oxidation of the phenol 1563 with molecular oxygen in basic medium furnished a nearly quantitative yield of N-MOM-calothrixin B (1529), a known immediate precursor of calothrixin B (378) (869) (Scheme 5.268). Recently, Moody et al. reported a biomimetic synthesis of calothrixin B (378) by oxidation of Hibino’s 6-formylindole[2,3-a]carbazole 1555 (870). The key intermediate 6-formyl-indole[2,3-a]carbazole was readily obtained in six steps from indigo (1458). Using Somei’s procedure, indigo (1458) was transformed to the cischlorohydrin 1461 in three steps and 50% overall yield (see Scheme 5.247). The reduction of the chlorohydrin 1461 gave 5-hydroxy-indolo[2,3-a]carbazole 1564, and subsequent Vilsmeier formylation delivered the desired 6-formyl-indole[2,3-a]carbazole 1565 in 45% yield. Reaction of hydroxy-indolocarbazole 1565 with an excess of chloromethyl methyl ether (MOMCl) afforded the tris-MOM-protected compound 1555. Following Hibino’s approach, the tris-MOM-protected indolocarbazole 1555

Chemistry of Carbazole Alkaloids

381

CHO

CHO PdCl2(dppf) B(OH)2 2 M Na2CO3, 80°C N (96%) Boc 1549

Br N H 1548

N N H Boc 1550 HO

CHO

1. TFA, 0°C to rt 2. MOMCl, NaH

CH CMgBr

DMF, 0°C to rt (58% overall)

N MOM

THF, 0°C to rt

N MOM

N MOM

(86%)

1551

1552 R = H 1553 R = MOM

MOMO

R

MOMCl, i-Pr2NEt CH2Cl2, 45°C (78%) O

KOt-Bu t-BuOH/THF

N MOM

CHO

CAN

90°C (93%)

N MOM

N MOM

1554 R = Me 1555 R = CHO O

MeOH/H2O, 0°C

1557

N

1556

DDQ, DMF, rt (55%)

CHO O

N MOM

N MOM

(40%)

O H2N

N R 1529 R = MOM 378 R = H

N

O conc. HCl, THF, 55°C (65%)

Scheme 5.267

was transformed to calothrixin B (378) in two steps and 26% overall yield (870) (Scheme 5.269).

K. Miscellaneous Carbazole Alkaloids In this section, we cover the total synthesis of carbazole alkaloids that are not discussed in the previous sections because of their unique substitution pattern. Filimonov et al. reported a synthesis of 3,6-diiodocarbazole (387) by iodination of carbazole (1). For the iodination, the required electrophilic iodine was generated by reacting iodine monochloride (ICl) with silver trifluoroacetate (CF3COOAg) in acetonitrile. Following this procedure, 3,6-diiodocarbazole (387) was obtained in almost quantitative yield (871) (Scheme 5.270). Mu¨llen et al. reported an efficient, two-step synthesis of 2,7-dibromocarbazole (388) starting from 4,4u-dibromobiphenyl (1566). This method uses Cadogan’s

382

Chemistry and Biology of Carbazole Alkaloids

Br CHO

Br

N

N

1. LDA 2. Et3SiH, TFA (65% overall)

COOMe N Boc 1558

N H

COOMe

1559

1560 N

N

1. Bu3SnH, AIBN

1. LiOH

2. MOMCl, NaH (81% overall)

2. PhSeCl PBu3 (80% overall)

N COOMe MOM

N COSePh MOM 1562

1561 O

N

N

NaOH

TTMSS, AIBN (90%)

N OH MOM 1563

acetone, O2 (98%)

N R

1529 R = MOM

O

(ref. 861−863)

378 R = H

Scheme 5.268

O O H N

OH (see Scheme 5.247) (3 steps, 50% overall)

N H

O

N H

N 1461

1458

HO

OH Zn, NH4Cl

CHO

POCl3, DMF

THF, MeOH (55%)

N H

N H

(82%)

1564 MOMO

N N H H 1565

CHO

O

N

(see Scheme 5.267)

MOMCl NaH, DMF (44%)

Cl

N MOM

N MOM

(2 steps, 26% overall)

1555

N H

O 378

Scheme 5.269

Chemistry of Carbazole Alkaloids

I

383

I

CF3COOAg-ICl MeCN, 20°C (98%)

N H 1

N H 387

Scheme 5.270

Br

Br

HOAc, HNO3

Br

100°C (91%)

Br NO2

1566

1567

P(OEt)3, reflux (56%)

Br

Br N H 388

Scheme 5.271

deoxygenative cyclization as the key step for the formation of the carbazole framework. Nitration of the dibromobiphenyl 1566 with concentrated nitric acid gave the corresponding 2-nitro derivative 1567 in 91% yield. Finally, a reductive Cadogan’s ring closure of 1567 by refluxing in triethylphosphite led to 2,7-dibromocarbazole (388) in 56% yield (872) (Scheme 5.271). Over the past few years, the heteroaryl-condensed non-natural carbazoles emerged as a rapidly growing class of compounds because of their broad spectrum of useful biological activities (8,249,873). This relatively new class of non-natural carbazoles with a great variety of heterocyclic systems has been extensively investigated in order to understand the structure activity relationships for the various biological activities (843,874–895).

CH A PT ER

6 Addendum

Pindur et al. reported the synthesis of carazostatin (247) starting from the 2-vinylindole 958, which previously served as the key building block in the total synthesis of carbazoquinocin C (274) (see Scheme 5.130). The 2-vinylindole (958), readily available in four steps starting from N-(phenylsulfonyl)indole (956), was transformed to the indolylacetic acid (1568) by treatment with KCN and paraformaldehyde followed by alkaline hydrolysis. Subsequent acid-catalyzed polar cyclization of 1568 led to carazostatin (247) (648) (Scheme 6.1). Recently, Tripathi et al. reported a new pyrano[3,2-a]carbazole alkaloid, 7-isovaleryloxy-8-methoxygirinimbine (1569) from the leaves of Murraya koenigii (896) (Scheme 6.2). Liu and Larock reported a new total synthesis of mukonine (11) starting from commercially available 4-amino-3-methoxybenzoic acid (1570) (897). This method 1. KCN, (HCO)n Butanol

(see Scheme 5.130) N SO2Ph

N H

956

958 COOH Me

N H 1568

Me 2. 10% NaOH EtOH/H2O C7H15

OH CH3SO3H

Ph

Me N C7H15 H 247 (11% )

Scheme 6.1 Me

O

O

O MeO

N H

Me Me

1569 7-Isovaleryloxy-8-methoxygirinimbine

Scheme 6.2

385

386

Chemistry and Biology of Carbazole Alkaloids

involves a cross-coupling of a 2-iodoaniline with silylaryl triflate and subsequent Pd(0)-catalyzed cyclization as the key step. Reaction of the aminobenzoic acid 1570 with methanol led to the corresponding methyl benzoate 600. Iodination of 600 with iodine monochloride (ICl) in dichloromethane afforded methyl 4-amino-3-iodo-5methoxybenzoate (1571) in 82% yield. Finally, cross-coupling of 1571 with silylaryl triflate in the presence of CsF, followed by Pd(0)-catalyzed intramolecular cyclization, led to mukonine (11) in 95% yield (897) (Scheme 6.3). Ackermann and Althammer reported an efficient synthesis of murrayafoline A (7) starting from the easily accessible 2-methoxy-4-methylaniline (598) (see Scheme 5.33) (898). This methodology involves a Pd(0)-catalyzed domino N–H/C–H bond activation to afford the carbazole framework directly. Thus, in a one-pot operation, 2-chloro-bromobenzene (1573) and the aniline 598 were directly transformed into murrayafoline A (7) in 74% yield by reacting with a catalytic amount of Pd(II) acetate in the presence of K3PO4, PCy3, and N-methylpyrrolidone (NMP). This reaction also proceeds with 1,2-dichlorobenzene, albeit in 72% yield (898) (Scheme 6.4). Lebold and Kerr reported the total synthesis of the eustifolines-A (172), -B (173), C (93), -D (227), and glycomaurrol (92) starting from the readily available quinine imine 1574 and diene 1575 (899). This methodology uses the Diels–Alder reaction of a quinone monoimine 1574 and subsequent Plieninger indolization of the adduct 1576 for the synthesis of the key tetrahydrocarbazole framework. Reaction of the quinine imine 1574 and diene 1575 in refluxing dichloromethane, followed by treatment of the resulting adduct with a catalytic amount of DBU, afforded the desired aromatic compound 1576 as a 1:1 diastereoisomeric mixture in

NH2

NH2

NH2 MeO

MeO

H2SO4

COOH 1570

MeOH, 65°C (98%)

MeO

ICl, CH2Cl2

COOMe

NaHCO3, 30 min (82%)

COOMe

600

TMS 1571 OTf

I

1571

1. CsF, MeOH, rt 2. 5% Pd(OAc)2

COOMe

10% PCy3, 100°C (95%)

1572

N H 11

OMe

Scheme 6.3

Me

Cl Br

Me H2N OMe

1573

Pd(OAc)2, PCy3 K3PO4, NMP (74%)

598

Scheme 6.4

N H 7

OMe

Addendum

387

91% yield. Without separation, both diastereoisomers of the dihydronaphthalene 1576 were transformed to the tetrahydrocarbazole 1577 via an oxidative cleavage of the double bond of the protected phenol (via the diol) followed by treatment of the resulting dicarbonyl with acid. Using this four-step sequence, tetrahydrocarbazole 1577 was obtained in 61% yield. Compound 1577 was transformed to methylcarbazole 1578 in 89% overall yield involving aldehyde reduction, tosyl removal, and dehydrogenation (899) (Scheme 6.5).

Me NTs

Me

1. NaH, TIPSCl, THF, 0˚C 2. NMO, OsO4 THF/t-BuOH/H2O

NHTs 1. CH2Cl2, reflux 2. DBU (91% overall)

O 1574

3. NaIO4, CH2Cl2 4. H2SO4, THF (61% overall)

OH

1575

1576 OH

OHC TIPSO

Me 1. NaBH4, TFA/MeOH

TIPSO

Me

2. Mg, NH4Cl, THF/MeOH 3. Pd/C, mesitylene, reflux

N Ts

N H 1578

(89% overall)

1577

Scheme 6.5

OH TIPSO

Me

1. IBX, EtOAc, reflux

HO

Me

2. i-PrPPh3I, BuLi 3. TBAF, THF (86% overall)

N H 1578

1. IBX, EtOAc, reflux 2. TBAF, THF 3. H2SO4 (53% overall) O

N H 92

1. PhSeCl, CH2Cl2, − 40°C 2. H2O2, CH2Cl2, 0°C (50% overall)

O

Me

Me

N H

N H 227

172

Scheme 6.6

388

Chemistry and Biology of Carbazole Alkaloids

Oxidation of the methylcarbazole 1578 to the corresponding aldehyde, followed by olefination of the crude aldehyde with triphenylphosphonium isopropyl ylide and desilylation, afforded glycomaurrol (92) in 86% yield over three steps. Cyclization of glycomaurrol (92) with PhSeCl, followed by oxidation with hydrogen peroxide (H2O2), afforded eustifoline-A (172) in 50% overall yield over two steps. Eustifoline-D (227) was prepared by oxidizing the 3-methylcarbazole 1578, and subjecting the resulting aldehyde to desilylation, followed by treatment with acid to effect benzofuran formation. This three-step sequence led to eustifoline-D (227) in 53% overall yield (Scheme 6.6).

MeOOC OHC TIPSO

Me

1. H2C CMeMgBr

TIPSO

Me

THF, − 78°C 2. (MeO)3CMe EtCOOH, reflux (85.5% overall)

N Ts 1577

TIPSO

N Ts 1579

Me 1. Mg, NH4Cl THF/MeOH

1. DIBAL, CH2Cl2, −78°C 2. i-PrPPh3I, BuLi THF, 0°C (78% overall)

2. DDQ, dioxane (21% overall)

N Ts 1580

TIPSO

HO

Me

Me

TBAF, THF (64%)

N H 1581

N H 93

O

Me

Pd(OAc)2 THF, 65°C (64%)

N H 173

Scheme 6.7

Addendum

389

Treatment of tetrahydrocarbazole 1577 with isopropenyl magnesium bromide followed by in situ generation of a ketene acetal en route to a Johnson–Claisen rearrangement, led to the formation of ester 1579 with the required E-double bond. Reduction to the aldehyde using DIBAL, and olefination with triphenylphosphonium isopropyl ylide, gave the corresponding tetrahydrocarbazole 1580 with the requisite isopropylidine moiety in 78% overall yield. After N-tosyl removal with magnesium metal in methanolic aqueous ammonium chloride, the corresponding tetrahydrocarbazole was subjected to DDQ-mediated aromatization to afford O-TIPS-eustifoline-C (1581). Desilylation with TBAF furnished eustifoline-C (93) in 64% yield. Oxidative cyclization of eustifoline-C (93) with Pd(II) acetate then generated eustifoline-B (173) in 64% yield (899) (Scheme 6.7).

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410

Chemistry and Biology of Carbazole Alkaloids

[866] D. Sissouma, L. Maingot, S. Collet, and A. Guingant, J. Org. Chem. 71, 8384 (2006). [867] S. Tohyama, T. Choshi, K. Matsumoto, A. Yamabuki, K. Ikegata, J. Nobuhiro, and S. Hibino, Tetrahedron Lett. 46, 5263 (2005). [868] A. Yamabuki, H. Fujinawa, T. Choshi, S. Tohyama, K. Matsumoto, K. Ohmura, J. Nobuhiro, and S. Hibino, Tetrahedron Lett. 47, 5859 (2006). [869] M.-L. Bennasar, T. Roca, and F. Ferrando, Org. Lett. 4, 561 (2006). [870] J. Sperry, C. S. P. McErlean, A. M. Z. Slawin, and C. J. Moody, Tetrahedron Lett. 48, 231 (2007). [871] V. D. Filimonov, E. A. Krasnokutskaya, and Y. A. Lesina, Russ. J. Org. Chem. 39, 875 (2003). [872] F. Dierschke, A. C. Grimsdale, and K. Mu¨llen, Synthesis 2470 (2003). [873] G. H. Kirsch, Curr. Org. Chem. 5, 507 (2001). [874] D. Joseph, L. Martarello, and G. Kirsch, J. Chem. Res. (S) 448 (1995); (M) 2557. [875] N. Haider, J. Heterocycl. Chem. 39, 511 (2002). [876] N. Haider and E. Sotelo, Chem. Pharm. Bull. 50, 1479 (2002). [877] S. Routier, N. Ayerbe, J.-Y. Me´rour, G. Coudert, C. Bailly, A. Pierre´, B. Pfeiffer, D.-H. Caignard, and P. Renard, Tetrahedron 58, 6621 (2002). [878] I. C. F. R. Ferreira, M.-J. R. P. Queiroz, and G. Kirsch, Tetrahedron 58, 7943 (2002). [879] I. C. F. R. Ferreira, M.-J. R. P. Queiroz, and G. Kirsch, Tetrahedron 59, 3737 (2003). [880] I. C. F. R. Ferreira, M.-J. R. P. Queiroz, and G. Kirsch, Tetrahedron Lett. 44, 4327 (2003). [881] M. A. Fousteris, A. I. Koutsourea, E. S. Arsenou, L. Leondiadis, S. S. Nikolaropoulos, and I. K. Stamos, J. Heterocycl. Chem. 41, 349 (2004). [882] M. Chakrabarty, N. Ghosh, and Y. Harigaya, Heterocycles 62, 779 (2004). [883] R. Nagarajan and P. T. Perumal, Synthesis 1269 (2004). [884] G. Desforges, C. Bossert, C. Montagne, and B. Joseph, Synlett 1306 (2004). [885] M. Chakrabarty, N. Ghosh, and Y. Harigaya, Tetrahedron Lett. 45, 4955 (2004). [886] N. Haider and J. Ka¨ferbo¨ck, Tetrahedron 60, 6495 (2004). [887] T. Tsuchimoto, H. Matsubayashi, M. Kaneko, E. Shirakawa, and Y. Kawakami, Angew. Chem. 117, 1360 (2005). [888] H. Bregman, D. S. Williams, and E. Meggers, Synthesis 1521 (2005). [889] D. S. Williams, G. K. Atilla, H. Bregman, A. Arzoumanian, P. S. Klein, and E. Meggers, Angew. Chem. 117, 2020 (2005). [890] S. C. Pelly, C. J. Parkinson, W. A. L. van Otterlo, and C. B. de Koning, J. Org. Chem. 70, 10474 (2005). [891] P. A. Kumar, R. Chakrabarty, and A. K. Saxene, Med. Chem. Res. 15, 112 (2006). [892] H. Bregman, P. J. Carroll, and E. Meggers, J. Am. Chem. Soc. 128, 877 (2006). [893] E. Meggers, G. E. Atilla-Gokcumen, H. Bregman, J. Maksimoska, S. P. Mulcahy, N. Pagano, and D. S. Williams, Synlett 1177 (2007). [894] H. He´non, F. Anizon, B. Pfeiffer, and M. Prudhomme, Tetrahedron 62, 1116 (2006). [895] E. Conchon, F. Anizon, R. M. Golsteyn, S. Le´once, B. Pfeiffer, and M. Prudhomme, Tetrahedron 32, 11136 (2006). [896] B. B. Mishra, V. K. Tiwari, D. D. Singh, A. Singh, and V. J. Tripathi, Med. Chem. Res. 15, 119 (2006). [897] Z. Liu and R. C. Larock, Tetrahedron 63, 347 (2007). [898] L. Ackermann and A. Althammer, Angew. Chem. 119, 1652 (2007). [899] T. P. Lebold and M. A. Kerr, Org. Lett. 9, 1883 (2007).

CUMULATIVE INDEX OF TITLES Aconitum alkaloids, 4, 275 (1954), 7, 473 (1960), 34, 95 (1988) C19 diterpenes, 12, 2 (1970) C20 diterpenes, 12, 136 (1970) Acridine alkaloids, 2, 353 (1952) Acridone alkaloids, 54, 259 (2000) experimental antitumor activity of acronycine, 21, 1 (1983) Actinomycetes, isoquinolinequinones, 21, 55 (1983), 53, 120 (2000) N-Acyliminium ions as intermediates in alkaloid synthesis, 32, 271 (1988) Aerophobins and related alkaloids, 57, 208 (2001) Aerothionins, 57, 219 (2001) Ajmaline-Sarpagine alkaloids, 8, 789 (1965), 11, 41 (1986), 52, 104 (1999), 55, 1 (2001) enzymes in biosynthesis of, 47, 116 (1995) Alkaloid chemistry marine cyanobacteria, 57, 86 (2001) synthetic studies, 50, 377 (1998) Alkaloid production, plant biotechnology of, 40, 1 (1991) Alkaloid structures spectral methods, study, 24, 287 (1985) unknown structure, 5, 301 (1955), 7, 509 (1960), 10, 545 (1967), 12, 455 (1970), 13, 397 (1971), 14, 507 (1973), 15, 263 (1975), 16, 511 (1977) X-ray diffraction, 22, 51 (1983) Alkaloids apparicine and related, 57, 258 (2001) as chirality transmitters, 53, 1 (2000) biosynthesis, regulation of, 49, 222 (1997) biosynthesis, molecular genetics of, 50, 258 (1998) biotransformation of, 57, 3 (2001), 58, 1 (2002) chemical and biological aspects of Narcissus, 63, 87 (2006) containing a quinolinequinone unit, 49, 79 (1997) containing a quinolinequinoneimine unit, 49, 79 (1997) containing an isoquinolinoquinone unit, 53, 119 (2000) ecological activity of, 47, 227 (1995) ellipticine and related, 57, 236 (2001) forensic chemistry of, 32, 1 (1988) histochemistry of, 39, 165 (1990) in the plant, 1, 15 (1950), 6, 1 (1960) of the Menispermaceae, 54, 1 (2000) plant biotechnology, production of, 50, 453 (1998) uleine and related, 57, 247 (2001) Alkaloids from amphibians, 21, 139 (1983), 43, 185 (1993), 50, 141 (1998) ants and insects, 31, 193 (1987) Chinese traditional medicinal plants, 32, 241 (1988) Hernandiaceae, 62, 175 (2005) mammals, 21, 329 (1983), 43, 119 (1993) marine bacteria, 53, 239 (2000), 57, 75 (2001) marine organisms, 24, 25 (1985), 41, 41 (1992)

411

412

Cumulative Index of Titles

medicinal plants of New Caledonia, 48, 1 (1996) mushrooms, 40, 189 (1991) plants of Thailand, 41, 1 (1992) Sri Lankan flora, 52, 1 (1999) Alkyl, aryl, alkylarylquinoline, and related alkaloids, 64, 139 (2007) Allelochemical properties of alkaloids, 43, 1 (1993) Allo congeners, and tropolonic Colchicum alkaloids, 41, 125 (1992) Alstonia alkaloids, 8, 159 (1965), 12, 207 (1970), 14, 157 (1973) Amaryllidaceae alkaloids, 2, 331 (1952), 6, 289 (1960), 11, 307 (1968), 15, 83 (1975), 30, 251 (1987), 51, 323 (1998), 63, 87 (2006) Amphibian alkaloids, 21, 139 (1983), 43, 185 (1983), 50, 141 (1998) Analgesic alkaloids, 5, 1 (1955) Anesthetics, local, 5, 211 (1955) Anthranilic acid derived alkaloids, 17, 105 (1979), 32, 341 (1988), 39, 63 (1990) Antifungal alkaloids, 42, 117 (1992) Antimalarial alkaloids, 5, 141 (1955) Antitumor alkaloids, 25, 1 (1985), 59, 281 (2002) Apocynaceae alkaloids, steroids, 9, 305 (1967) Aporphine alkaloids, 4, 119 (1954), 9, 1 (1967), 24, 153 (1985), 53, 57 (2000) Apparicine and related alkaloids, 57, 235 (2001) Aristolochia alkaloids, 31, 29 (1987) Aristotelia alkaloids, 24, 113 (1985), 48, 191 (1996) Aspergillus alkaloids, 29, 185 (1986) Aspidosperma alkaloids, 8, 336 (1965), 11, 205 (1968), 17, 199 (1979) synthesis of, 50, 343 (1998) Aspidospermine group alkaloids, 51, 1 (1998) Asymmetric catalysis by alkaloids, 53, 1 (2000) Azafluoranthene alkaloids, 23, 301 (1984) Bases simple, 3, 313 (1953), 8, 1 (1965) simple indole, 10, 491 (1967) simple isoquinoline, 4, 7 (1954), 21, 255 (1983) Benzodiazepine alkaloids, 39, 63 (1990) Benzophenanthridine alkaloids, 26, 185 (1985) Benzylisoquinoline alkaloids, 4, 29 (1954), 10, 402 (1967) Betalains, 39, 1 (1990) Biosynthesis in Catharanthus roseus, 49, 222 (1997) in Rauwolfia serpentina, 47, 116 (1995) isoquinoline alkaloids, 4, 1 (1954) pyrrolizidine alkaloids, 46, 1 (1995) quinolizidine alkaloids, 46, 1 (1995) regulation of, 63, 1 (2006) tropane alkaloids, 44, 116 (1993) Bisbenzylisoquinoline alkaloids, 4, 199 (1954), 7, 439 (1960), 9, 133 (1967), 13, 303 (1971), 16, 249 (1977), 30, 1 (1987) synthesis, 16, 319 (1977) Bisindole alkaloids, 20, 1 (1981), 63, 181 (2006) noniridoid, 47, 173 (1995) Bisindole alkaloids of Catharanthus C-20u position as a functional hot spot in, 37, 133 (1990) isolation, structure clucidation and biosynthesis of, 37, 1 (1990), 63, 181 (2006) medicinal chemistry of, 37, 145 (1990) pharmacology of, 37, 205 (1990)

Cumulative Index of Titles

synthesis of, 37, 77 (1990), 59, 281 (2002) therapeutic uses of, 37, 229 (1990) Bromotyrosine alkaloids, marine, 61, 79 (2005) Buxus alkaloids, steroids, 9, 305 (1967), 14, 1 (1973), 32, 79 (1988) Cactus alkaloids, 4, 23 (1954) Calabar bean alkaloids, 8, 27 (1965), 10, 383 (1967), 13, 213 (1971), 36, 225 (1989) Calabash curare alkaloids, 8, 515 (1965), 11, 189 (1968) Calycanthaceae alkaloids, 8, 581 (1965) Calystegines, 64, 49 (2007) Camptothecin and derivatives, 21, 101 (1983), 50, 509 (1998) clinical studies, 60, 1 (2003) Cancentrine alkaloids, 14, 407 (1973) Cannabis sativa alkaloids, 34, 77 (1988) Canthin-6-one alkaloids, 36, 135 (1989) Capsicum alkaloids, 23, 227 (1984) Carbazole alkaloids, 13, 273 (1971), 26, 1 (1985), 44, 257 (1993) biogenesis, 65, 159 (2008) biological and pharmacological activities, 65, 181 (2008) chemistry, 65, 195 (2008) Carboline alkaloids, 8, 47 (1965), 26, 1 (1985) b-Carboline congeners and Ipecac alkaloids, 22, 1 (1983) Cardioactive alkaloids, 5, 79 (1955) Catharanthus alkaloids, 59, 281 (2002) Catharanthus roseus, biosynthesis of terpenoid indole alkaloids in, 49, 222 (1997) Celastraceae alkaloids, 16, 215 (1977) Cephalotaxus alkaloids, 23, 157 (1984), 51, 199 (1998) Cevane group of Veratrum alkaloids, 41, 177 (1992) Chemosystematics of alkaloids, 50, 537 (1998) Chemotaxonomy of Papaveraceae and Fumariaceae, 29, 1 (1986) Chinese medicinal plants, alkaloids from, 32, 241 (1988) Chirality transmission by alkaloids, 53, 1 (2000) Chromone alkaloids, 31, 67 (1987) Cinchona alkaloids, 3, 1 (1953), 14, 181 (1973), 34, 332 (1988) Colchicine, 2, 261 (1952), 6, 247 (1960), 11, 407 (1968), 23, 1 (1984) pharmacology and therapeutic aspects of, 53, 287 (2000) Colchicum alkaloids and allo congeners, 41, 125 (1992) 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 (1967), 29, 287 (1986) Curare-like effects, 5, 259 (1955) Cyclic tautomers of tryptamine and tryptophan, 34, 1 (1988) Cyclopeptide alkaloids, 15, 165 (1975) Cytotoxic alkaloids, modes of action, 64, 1 (2007) Daphniphyllum alkaloids, 15, 41 (1975), 29, 265 (1986), 60, 165 (2003) Delphinium alkaloids, 4, 275 (1954), 7, 473 (1960) C10-diterpenes, 12, 2 (1970) C20-diterpenes, 12, 136 (1970) Dibenzazonine alkaloids, 35, 177 (1989) Dibenzopyrrocoline alkaloids, 31, 101 (1987) Diplorrhyncus alkaloids, 8, 336 (1965) Diterpenoid alkaloids Aconitum, 7, 473 (1960), 12, 2 (1970), 12, 136 (1970), 34, 95 (1988) C20, 59, 1 (2002)

413

414

Cumulative Index of Titles

chemistry, 18, 99 (1981), 42, 151 (1992) Delphinium, 7, 473 (1960), 12, 2 (1970), 12, 136 (1970) Garrya, 7, 473 (1960), 12, 2 (1960), 12, 136 (1970) general introduction, 12, xv (1970) structure, 17, 1 (1979) synthesis, 17, 1 (1979) Eburnamine-vincamine alkaloids, 8, 250 (1965), 11, 125 (1968), 20, 297 (1981), 42, 1 (1992) Ecological activity of alkaloids, 47, 227 (1995) Elaeocarpus alkaloids, 6, 325 (1960) Ellipticine and related alkaloids, 39, 239 (1990), 57, 235 (2001) Enamide cyclizations in alkaloid synthesis, 22, 189 (1983) Enzymatic transformation of alkaloids, microbial and in vitro, 18, 323 (1981) Ephedra alkaloids, 3, 339 (1953) Epibatidine, 46, 95 (1995) Ergot alkaloids, 8, 726 (1965), 15, 1 (1975), 38, 1 (1990), 50, 171 (1998), 54, 191 (2000), 63, 45 (2006) Erythrina alkaloids, 2, 499 (1952), 7, 201 (1960), 9, 483 (1967), 18, 1 (1981), 48, 249 (1996) Erythrophleum alkaloids, 4, 265 (1954), 10, 287 (1967) Eupomatia alkaloids, 24, 1 (1985) Forensic chemistry, alkaloids, 12, 514 (1970) by chromatographic methods, 32, 1 (1988) Galbulimima alkaloids, 9, 529 (1967), 13, 227 (1971) Gardneria alkaloids, 36, 1 (1989) Garrya alkaloids, 7, 473 (1960), 12, 2 (1970), 12, 136 (1970) Geissospermum alkaloids, 8, 679 (1965) Gelsemium alkaloids, 8, 93 (1965), 33, 84 (1988), 49, 1 (1997) Glycosides, monoterpene alkaloids, 17, 545 (1979) Guatteria alkaloids, 35, 1 (1989) Haplophyton cimicidum alkaloids, 8, 673 (1965) Hasubanan alkaloids, 16, 393 (1977), 33, 307 (1988) Hernandiaceae alkaloids, 62, 175 (2005) Histochemistry of alkaloids, 39, 165 (1990) Holarrhena group, steroid alkaloids, 7, 319 (1960) Hunteria alkaloids, 8, 250 (1965) Iboga alkaloids, 8, 203 (1965), 11, 79 (1968), 59, 281 (2002) Ibogaine alkaloids addict self-help, 56, 283 (2001) as a glutamate antagonist, 56, 55 (2001) comparative neuropharmacology, 56, 79 (2001) contemporary history of, 56, 249 (2001) drug discrimination studies with, 56, 63 (2001) effects of rewarding drugs, 56, 211 (2001) gene expression, changes in, 56, 135 (2001) mechanisms of action, 56, 39 (2001) multiple sites of action, 56, 115 (2001) neurotoxicity assessment, 56, 193 (2001) pharmacology of, 52, 197 (1999) review, 56, 1 (2001) treatment case studies, 56, 293 (2001) use in equatorial African ritual context, 56, 235 (2001)

Cumulative Index of Titles

Imidazole alkaloids, 3, 201 (1953), 22, 281 (1983) Indole alkaloids, 2, 369 (1952), 7, 1 (1960), 26, 1 (1985) ajmaline group of, 55, 1 (2001) biomimetic synthesis of, 50, 415 (1998) biosynthesis in Catharanthus roseus, 49, 222 (1997) biosynthesis in Rauvolfia serpentina, 47, 116 (1995) distribution in plants, 11, 1 (1968) sarpagine group of, 52, 103 (1999) simple, 10, 491 (1967), 26, 1 (1985) Reissert synthesis of, 31, 1 (1987) Indole diterpenoid alkaloids, 60, 51 (2003) Indolizidine alkaloids, 28, 183 (1986), 44, 189 (1993) 2,2’-Indolylquinuclidine alkaloids, chemistry, 8, 238 (1965), 11, 73 (1968) In vitro and microbial enzymatic transformation of alkaloids, 18, 323 (1981) Ipecac alkaloids, 3, 363 (1953), 7, 419 (1960), 13, 189 (1971), 22, 1 (1983), 51, 271 (1998) Isolation of alkaloids, 1, 1 (1950) Isoquinoline alkaloids, 7, 423 (1960) biosynthesis, 4, 1 (1954) 13 C-NMR spectra, 18, 217 (1981) simple isoquinoline alkaloids 4, 7 (1954), 21, 255 (1983) Reissert synthesis of, 31, 1 (1987) Isoquinolinequinones, 21, 55 (1983), 53, 120 (2000) Isoxazole alkaloids, 57, 186 (2001) Khat (Catha edulis) alkaloids, 39, 139 (1990) Kopsia alkaloids, 8, 336 (1965) Lead tetraacetate oxidation in alkaloid synthesis, 36, 70 (1989) Local anesthetics, 5, 211 (1955) Localization in the plant, 1, 15 (1950), 6, 1 (1960) Lupine alkaloids, 3, 119 (1953), 7, 253 (1960), 9, 175 (1967), 31, 116 (1987), 47, 1 (1995) Lycopodium alkaloids, 5, 265 (1955), 7, 505 (1960), 10, 306 (1967), 14, 347 (1973), 26, 241 (1985), 45, 233 (1944), 61, 1 (2005) Lythraceae alkaloids, 18, 263 (1981), 35, 155 (1989) Macrocyclic peptide alkaloids from plants, 26, 299 (1985), 49, 301 (1997) Mammalian alkaloids, 21, 329 (1983), 43, 119 (1993) Manske, R.H.F., biography of, 50, 3 (1998) Manzamine alkaloids, 60, 207 (2003) Marine alkaloids, 24, 25 (1985), 41, 41 (1992), 52, 233 (1999) bromotyrosine alkaloids, 61, 79 (2005) Marine bacteria, alkaloids from, 53, 120 (2000) Maytansinoids, 23, 71 (1984) Melanins, 36, 254 (1989) chemical and biological aspects, 60, 345 (2003) Melodinus alkaloids, 11, 205 (1968) Mesembrine alkaloids, 9, 467 (1967) Metabolic transformation of alkaloids, 27, 323 (1986) Microbial and in vitro enzymatic transformation of alkaloids, 18, 323 (1981) Mitragyna alkaloids, 8, 59 (1965), 10, 521 (1967), 14, 123 (1973) Molecular modes of action of cytotoxic alkaloids, 64, 1 (2007) Monoterpene alkaloids, 16, 431 (1977), 52, 261 (1999) glycosides, 17, 545 (1979) Morphine alkaloids, 2, 1 (part 1), 161 (part 2) (1952), 6, 219 (1960), 13, 1 (1971), 45, 127 (1994)

415

416

Cumulative Index of Titles

Muscarine alkaloids, 23, 327 (1984) Mushrooms, alkaloids from, 40, 190 (1991) Mydriatic alkaloids, 5, 243 (1955) a-Naphthophenanthridine alkaloids, 4, 253 (1954), 10, 485 (1967) Naphthylisoquinoline alkaloids, 29, 141 (1986), 46, 127 (1995) Narcotics, 5, 1 (1955) Narcissus alkaloids, 63, 87 (2006) New Caledonia, alkaloids from the medicinal plants of, 48, 1 (1996) Nitrogen-containing metabolites from marine bacteria, 53, 239, (2000), 57, 75 (2001) Non-iridoid bisindole alkaloids, 47, 173 (1995) Nuphar alkaloids, 9, 441 (1967), 16, 181 (1977), 35, 215 (1989) Ochrosia alkaloids, 8, 336 (1965), 11, 205 (1968) Ourouparia alkaloids, 8, 59 (1965), 10, 521 (1967) Oxazole alkaloids, 35, 259 (1989) Oxindole alkaloids, 14, 83 (1973) Oxoaporphine alkaloids, 14, 225 (1973) Papaveraceae alkaloids, 10, 467 (1967), 12, 333 (1970), 17, 385 (1979) pharmacology, 15, 207 (1975) toxicology, 15, 207 (1975) Pauridiantha alkaloids, 30, 223 (1987) Pavine and isopavine alkaloids, 31, 317 (1987) Pentaceras alkaloids, 8, 250 (1965) Peptide alkaloids, 26, 299 (1985), 49, 301 (1997) Phenanthrene alkaloids, 39, 99 (1990) Phenanthroindolizidine alkaloids, 19, 193 (1981) Phenanthroquinolizidine alkaloids, 19, 193 (1981) b-Phenethylamines, 3, 313 (1953), 35, 77 (1989) Phenethylisoquinoline alkaloids, 14, 265 (1973), 36, 172 (1989) Phthalideisoquinoline alkaloids, 4, 167 (1954), 7, 433 (1960), 9, 117 (1967), 24, 253 (1985) Picralima alkaloids, 8, 119 (1965), 10, 501 (1967), 14, 157 (1973) Piperidine alkaloids, 26, 89 (1985) Plant biotechnology, for alkaloid production, 40, 1 (1991), 50, 453 (1998) Plant systematics, 16, 1 (1977) Pleiocarpa alkaloids, 8, 336 (1965), 11, 205 (1968) Polyamine alkaloids, 22, 85 (1983), 45, 1 (1994), 50, 219 (1998), 58, 83 (2002) analytical aspects of, 58, 206 (2002) biogenetic aspects of, 58, 274 (2002) biological and pharmacological aspects of, 46, 63 (1995), 58, 281 (2002) catalog of, 58, 89 (2002) synthesis of cores of, 58, 243 (2002) Pressor alkaloids, 5, 229 (1955) Protoberberine alkaloids, 4, 77 (1954), 9, 41 (1967), 28, 95 (1986), 62, 1 (2005) biotransformation of, 46, 273 (1955) transformation reactions of, 33, 141 (1988) Protopine alkaloids, 4, 147 (1954), 34, 181 (1988) Pseudocinchoma alkaloids, 8, 694 (1965) Pseudodistomins, 50, 317 (1998) Purine alkaloids, 38, 226 (1990) Putrescine and related polyamine alkaloids, 58, 83 (2002) Pyridine alkaloids, 1, 165 (1950), 6, 123 (1960), 11, 459 (1968), 26, 89 (1985)

Cumulative Index of Titles

Pyrrolidine alkaloids, 1, 91 (1950), 6, 31 (1960), 27, 270 (1986) Pyrrolizidine alkaloids, 1, 107 (1950), 6, 35 (1960), 12, 246 (1970), 26, 327 (1985) biosynthesis of, 46, 1 (1995) 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 related to anthranilic acid, 3, 65 (1953), 7, 229 (1960), 17, 105 (1979), 32, 341 (1988) Quinolinequinone alkaloids, 49, 79 (1997) Quinolinequinoneimine alkaloids, 49, 79 (1977) Quinolizidine alkaloids, 28, 183 (1985), 55, 91 (2001) biosynthesis of, 47, 1 (1995) Rauwolfia alkaloids, 8, 287 (1965) biosynthesis of, 47, 116 (1995) Recent studies on the synthesis of strychnine, 64, 103 (2007) Regulation of alkaloid biosynthesis in plants, 63, 1 (2006) Reissert synthesis of isoquinoline and indole alkaloids, 31, 1 (1987) Reserpine, chemistry, 8, 287 (1965) Respiratory stimulants, 5, 109 (1995) Rhoeadine alkaloids, 28, 1 (1986) Salamandra group, steroids, 9, 427 (1967) Sarpagine-type alkaloids, 52, 104 (1999) Sceletium alkaloids, 19, 1 (1981) Secoisoquinoline alkaloids, 33, 231 (1988) Securinega alkaloids, 14, 425 (1973) Senecio alkaloids, see Pyrrolizidine alkaloids Sesquiterpene pyridine alkaloids, 60, 287 (2003) Simple indole alkaloids, 10, 491 (1967) Simple indolizidine alkaloids, 28, 183 (1986), 44, 189 (1993) Simple indolizidine and quinolizidine alkaloids, 55, 91 (2001) Sinomenine, 2, 219 (1952) Solanum alkaloids chemistry, 3, 247 (1953) steroids, 7, 343 (1960), 10, 1 (1967), 19, 81 (1981) Sources of alkaloids, 1, 1 (1950) Spectral methods, alkaloid structures, 24, 287 (1985) Spermidine and related polyamine alkaloids, 22, 85 (1983), 58, 83 (2002) Spermine and related polyamine alkaloids, 22, 85 (1983), 58, 83 (2002) Spider toxin alkaloids, 45, 1 (1994), 46, 63 (1995) Spirobenzylisoquinoline alkaloids, 13, 165 (1971), 38, 157 (1990) Sponges, isoquinolinequinone alkaloids from, 21, 55 (1983) Sri Lankan flora, alkaloids, 52, 1 (1999) Stemona alkaloids, 9, 545 (1967), 62, 77 (2005) Steroid alkaloids Apocynaceae, 9, 305 (1967), 32, 79 (1988) Buxus group, 9, 305 (1967), 14, 1 (1973), 32, 79 (1988) chemistry and biology, 50, 61 (1998), 52, 233 (1999) Holarrhena group, 7, 319 (1960) Salamandra group, 9, 427 (1967) Solanum group, 7, 343 (1960), 10, 1 (1967), 19, 81 (1981) Veratrum group, 7, 363 (1960), 10, 193 (1967), 14, 1 (1973), 41, 177 (1992)

417

418

Cumulative Index of Titles

Stimulants respiratory, 5, 109 (1955) uterine, 5, 163 (1955) Structure elucidation, by X-ray diffraction, 22, 51 (1983) Strychnine, synthesis of, 64, 104 (2007) Strychnos alkaloids, 1, 375 (part 1) (1950), 2, 513 (part 2) (1952), 6, 179 (1960), 8, 515, 592 (1965), 11, 189 (1968), 34, 211 (1988), 36, 1 (1989), 48, 75 (1996) Sulfur-containing alkaloids, 26, 53 (1985), 42, 249 (1992) Synthesis of alkaloids enamide cyclizations for, 22, 189 (1983) lead tetraacetate oxidation in, 36, 70 (1989) Tabernaemontana alkaloids, 27, 1 (1983) Taxol, 50, 509 (1998) Taxus alkaloids, 10, 597 (1967), 39, 195 (1990) Terpenoid indole alkaloids, 49, 222 (1997) Thailand, alkaloids from the plants of, 41, 1 (1992) Toxicology, Papaveraceae alkaloids, 15, 207 (1975) Transformation of alkaloids, enzymatic, microbial and in vitro, 18, 323 (1981) Tremorigenic and non-tremorigenic alkaloids, 60, 51 (2003) Tropane alkaloids biosynthesis of, 44, 115 (1993) chemistry, 1, 271 (1950), 6, 145 (1960), 9, 269 (1967), 13, 351 (1971), 16, 83 (1977), 33, 2 (1988), 44, I (1933) Tropoloisoquinoline alkaloids, 23, 301 (1984) Tropolonic Colchicum alkaloids, 23, 1 (1984), 41, 125 (1992) Tylophora alkaloids, 9, 517 (1967) Uleine and related alkaloids, 57, 235 (2001) Unnatural alkaloid enantiomers, biological activity of, 50, 109 (1998) Uterine stimulants, 5, 163 (1955) Veratrum alkaloids cevane group of, 41, 177 (1992) chemistry, 3, 247 (1952) steroids, 7, 363 (1960), 10, 193 (1967), 14, 1 (1973) Vinca alkaloids, 8, 272 (1965), 11, 99 (1968), 20, 297 (1981) Voacanga alkaloids, 8, 203 (1965), 11, 79 (1968) Wasp toxin alkaloids, 45, 1 (1994), 46, 63 (1995) X-ray diffraction of alkaloids, 22, 51 (1983) Yohimbe alkaloids, 8, 694 (1965), 11, 145 (1968), 27, 131 (1986)

SUBJECT INDEX N-Acetoxymethoxystaurosporine, 122–123 Actinomadura madurae, 98 Actinomadura melliaura, 136 Arctinomadura sp., 127, 130 carbazole alkaloids, 3 6-Acylcarbazole, 189 Aflavazole, 152–154 biogenetic pathway, 177–178 Alkenylstannane, 242–243 N-Alkylamino carbazoles, 191 Alzheimer’s disease, 186, 193 AM-2282, 114 Ancorina sp., 158 Ancorinazole, 157–158 Angiogenesis, 186 2-Anilino-5-methyl-1,4-benzoquinone, 258 Anthracene coal tar, 1, 5 Anthranilic acid, 159–160 Anti-depressants, 191 Anti-inflammatory carbazoles, 190 Anti-malarial carbazoles, 191 Anti-viral carbazoles, 189–190 Antibacterial activity of 6,7-dimethoxy-1hydroxy-3-methylcarbazole, 12 Antibacterial activities arcyriaflavins, 139 AT2433-A1, A2, B1, B2, 136 carbazoles, 188–189 carbazomycin A, B, 100 carquinostatins, 105 clausenal, 10 1-dechloro rebeccamycin, 135 1-formyl-3-methoxy-6-methylcarbazole, 36 glycozolidol, 18 Antibiotic activity epocarbazolin A, B, 99 K-252a, 130–131 Anticancer activity ellipticine, 89, 90, 182–184 imidazo[4,5-a]pyrrolo[3,4-c]carbazole alkaloids, 373 indolo[2,3-a]pyrrolo[3,4-c]carbazole alkaloids, 181 mahanimbine, 181 7-methoxymukonal, 181 pyrayafoline D, 181 pyrido[4,3-b]carbazoles, 181 pyrrolo[2,3-c]carbazole alkaloids, 109 rebeccamycin, 135

Antifeedant activity, of aflavazole, 152 Antifungal activity arcyriaflavins, 139 carbazole alkaloids, 188–189 carbazomycin A, B, 100 carbazomycin G-H, 103 6,7-dimethoxy-1-hydroxy-3methylcarbazole, 12 1-formyl-3-methoxy-6-methylcarbazole, 36 indolo[2,3-a]pyrrolo[3,4-c]carbazole alkaloids, 114 Antihypertensive activity of indolo[2,3-a] pyrrolo[3,4-c]carbazole alkaloids, 114 Antimicrobial activities arcyriaflavin derivatives, 187 indolo[2,3-a]pyrrolo[3,4-c]carbazole alkaloids, 114 ( )-mahanine, 56 murrayanine, 7 Antiostatin A1–B4, 97–98 Antitumor activity AT2433–A1, –B1, 136 clausamine F, 16 indolo[2,3-a]pyrrolo[3,4-c]carbazole alkaloids, 114 Antiyeast activity of carbazomycin A, B, 100 Apocynaceae family, 89 Arcyrflavins, 139–141 Arcyria denudata, 4, 139 Arcyria nutans, 139 Arcyriaflavin A, 174 synthesis from 2,2u-bisindolyl-3,3u-dithiete, 347–348 synthesis from cyclohexene imide, 342 synthesis from indol-3-ylacetic acid, 338–340 synthesis from 2-nitrobenzaldehyde, 369 synthesis from TBS enol ether, 369–370 Arcyriaflavin B synthesis, 357–358, 361 total synthesis from 2-nitrocinnamaldehyde, 337–338 Arcyriaflavin B, 139 Arcyriaflavin C, 139 Arcyriaflavin C, synthesis, 357–358, 361 Arcyriaflavin D, synthesis, 357–358, 361 Arcyriarubin A, 142 synthesis, 347, 349 Arcyriarubin B, 141–142

419

420

Subject Index

Arcyriarubin C, 141–142 Arcyriaverdin C, 141–143 Arcyroxepin A, 141, 143 Arthritis, 193 Aryl hydrocarbons (Ah) receptor protein, 113 Aspergillus sp. carbazole alkaloids, 3 sources of carbazole alkaloids, 4 Aspergillus tubingensis, 152 Aspidosperma australe, 91–92 Aspidosperma longepetiolatum, 91–92 Aspidosperma subincanum, 89 3,4-dihydroellipticine, 92 N-methyltetrahydroellipticine, 91 Aspidosperma ulei, 91 AT2433-A1, 136–137 antibiotic activity, 189 synthesis, 359–361, 363 AT2433-A2, 136–137 AT2433-B1, 136–138 AT2433-B2, 136–138 Atanisatin isolation, 21 structure, 20 ATCC 39243, 135 Atherosclerosis, 192 Bacatecarin, 185 Bacillus cereus, 56 Bacteria. see Antibacterial activity BE-13793C, 138–139 Benzocarbazole alkaloids, 108–109 Bucherer synthesis, 200 Benzodiazepine receptor ligands, 113 Bicyclomahanimbicine, 62 Bicyclomahanimbine, 61–62, 164 Bikoeniquinone-A, 84–85 Bis-2-hydroxy-3-methylcarbazole, 84 biogenetic pathway, 167 1,10-Bis-(6-methyl-5H-benzo[b]carbazol11-yl)decane, 182 Bis-7-hydroxygirinimbine-A, 80–81 Bis-carbazole alkaloids, 69–85 cytotoxicity, 182 sources, 3 synthesis, 295–303 1,1u-Bis(2-hydroxy-3-methylcarbazole), 297 2,3-Bis(indol-3-yl)maleimide alkaloids, 141–143 Bisisomahanine, 82 8,8uu-Biskoenigine, 80 synthesis, 300–301 Bismahanine, 81 Bismurrayafoline-A, 77–78 total synthesis, 297–298 Bismurrayafoline-B, 77–79 Bismurrayafoline-C, 78–79 Bismurrayafoline-D, 78–79

Bismurrayafoline E, 84–85 Bismurrayafolinol, 78 (7)-Bismurrayaquinone-A, 297–299 Bismurrayaquinone-A, 84–85 stereoanalysis, 295–296 total synthesis, 295–296 Bis(O-demethylmurrayafoline A), 80, 167 Bispyrayafoline, 82–83 Bleekeria vitiensis, 89 BMS-250749, 185 Bmy-41950, 127–128 6-Bromogranulatimide, 149–151 Bronchitis, treatment with Clausena lansium roots, 5, 33, 39 Butylated hydroxytoluene, 97 Calothrix cyanobacteria, 151 Calothrixin A synthesis, 376–377 Calothrixin B biomimetic synthesis, 379–382 synthesis, 376–377 synthesis from tetrahydro-4H-carbazole-4one, 377–378 synthesis using radical-based route, 379–380, 382 total synthesis from 2-formyl-Nphenylsulfonylindole, 378–379 Calothrixins A-B, 151–152 biogenetic pathway, 178–180 Cancer. see Anticancer activity; Cytotoxicity Carazolol, 191 Carazostatin, 97, 193 synthesis based on benzannulation of indoles, 230–231 synthesis from 2-vinylindole, 385 total synthesis, 228–229 total synthesis based on iron-mediated annulation, 233–235 total synthesis from N-carbethoxy-2iodoaniline, 232–234 total synthesis using benzannulation strategy, 238–239 Carbalexin A, 23–24 Carbalexin B, 23–24 Carbalexin C, 23–24 Carbazole Chakraborty biogenetic pathway, 162–163 isolation, 3, 5 structure, 5 Carbazole-1,4-quinol alkaloids isolation, 103–104 synthesis, 255–256, 278–283 Carbazole-1,4-quinone alkaloids, 41–43 antibiotic activitiy, 189 synthesis, 291

Subject Index

Carbazole alkaloids biological sources, 4 higher plant sources, 3 nomenclature, 1 nucleus formation, 159 numbering, 1 Carbazolelactone alkaloids, 85–88 Carbazomadurin A, 98–99 direct transformation to epocarbazolin A, 243, 245 total synthesis, 239–244 Carbazomadurin B, 98–99 direct transformation to epocarbazolin B, 243, 245 total synthesis, 239–244 Carbazomarin-A, 16 structure, 17 Carbazomycin A, 100 total synthesis, 244–249 Carbazomycin B bioactivity, 188, 193 biogenesis, 169–171 iron-mediated total synthesis, 247–249 isolation, 100–101 total synthesis based on Diels-Alder reaction, 254 total synthesis using benzeneselenolcatalyzed aryl radical addition, 254–255 Carbazomycin C, 250–251 Carbazomycin D, 250–251 Carbazomycin E, 100–102 Carbazomycin F, 100–102 Carbazomycin G, 281–283 Carbazomycins A-F, 100–103 Carbazomycins G-H, 103–104 total synthesis, 278–282 Carbazoquinocin A, 267–268 Carbazoquinocin B, 268 Carbazoquinocin C retrosynthetic analysis, 273–275 synthesis using thermal o-benzannulation, 278 iron-mediated total synthesis, 268–271 total synthesis from indole 2-carboxylic acid, 276–277 total synthesis from N(phenylsulfonyl)indole, 276 total synthesis using palladium(II)-catalyzed oxidative coupling, 272–273 Carbazoquinocin D enantioselective total synthesis, 267–268 total synthesis, 268 Carbazoquinocin E, 268 Carbazoquinocins A-F, 105–107 9-Carbethoxy-3-methylcarbazole, 6 total synthesis, 285

3-Carboethoxy-9-(3-dimethylaminopropyl)1,2,3,4-tetrahydrocarbazole, 182 3-Carbomethoxy-1-hydroxy-6methoxycarbazole, 15 Carpophilus hemipterus, 152 Carprofen, 190 (7)–Carquinostatin A, 275–276 Carquinostatin A, 104, 107, 193, 252, 254 total synthesis, 269–272 Carquinostatin B, 105, 107 Carvedilol, 191 Cerebellar granule neurons, 15 Chagasu disease, 193 Chlorella vulgaris, 127 3-Chlorocarbazole, 155 6-Chlorohyellazole total synthesis, 231–232, 236–238 total synthesis from diketoindoles, 243–244 Chlorohyellazole, 96–97 Chrestifoline A, 297 Chrestifoline-A-C, 75–77 Chrestifoline-D, 78 Cimicifuga sp., 3 Cimicifuga simplex, 95 Clausamine-A, 85–86 Clausamine-B, 85, 87 Clausamine-C, 85, 87 Clausamine D, 9–11 Clausamine E, 9–11 Clausamine F, 14, 16 Clausamine G, 9–11 Clausanitin, 27, 28 Clausena sp., 30 3-methylcarbazole, 5 carbazole, 3 carbazole alkaloids, 3 sources of carbazole alkaloids, 4 Clausena anisata, 5 clausamine-A-C, 85 clausamine F, 16 clausanitin, 28 mupamine, 46 Clausena excavata, 12 bis-carbazole alkaloids, 69 carbazomarin-A, 16 clausenamine-A, 79–80 clausenaquinone A, 42 clausevatine-D-G, 85–88 clausine A, 28 clausine B, 31 clausine C, 39 clausine D, 13 clausine H, 21 clausine L, 17 clausine M, 39 clausine O, 28

421

422

Subject Index

clausine P, 20 clausine R, 15 clausine V, 95–96 clausine W, 50–51 clauszoline M, 28–29 clauszoline-D, F, 32–33 clauszoline-E, 49–50 clauszoline-G, 48 O-methylmukonal, 17 mukonidine, 22–23 Clausena harmandiana, 27 Clausena heptaphylla, 5, 7, 10 clausenalene, 35 girinimbine, 43–45 heptazolicine, 49 heptazolidine, 48 heptazoline, 30 murrayacine, 47–48, 50 Clausena indica, 5 Clausena lansium, 5, 27 glycozoline, 33 methyl 6-methoxycarbazole-3-carboxylate, 38–40 Clausenal, 9–10 Clausenalene, 34–35 formal synthesis, 289–290 total synthesis, 283–284 (7)-Clausenamine-A, 299–300 Clausenamine-A, 79–80, 299–300 Clausenapin, 7, 8 Clausenaquinone A, 41–43 total synthesis, 260, 262 Clausenatine A, 32–33 spectral characteristics, 33 Clausenine, 7, 9 total synthesis, 214 Clausenol, 12–13 total synthesis, 214 Clausevatine-D-G, 85–87 Clausevatine-E, 87 Clausevatine-F, 87 Clausevatine-G, 88 Clausine A, 28–29 Clausine B, 29, 31 Clausine C, 39 total synthesis, 286 total synthesis using palladium(II)-catalyzed oxidative coupling, 288 Clausine D, 13–14 Clausine E, 12, 14 total synthesis, 216 Clausine F, 14–15 Clausine G, 13–15 Clausine H, 21–22 iron-mediated total synthesis, 225–227 Clausine I, 13–14 Clausine J, 13–15

Clausine K, 21–22 antibiotic activity, 188 antiviral activity, 189 iron-mediated total synthesis, 225–227 Clausine L, 17–18, 22–23 Clausine M, 39 total synthesis, 288 Clausine N, 39 total synthesis, 288 Clausine O, 28–29 iron-mediated total synthesis, 225–227 Clausine P, 20 total synthesis, 226–227 Clausine Q, 9–10 Clausine R, 14–15 Clausine S, 29, 31 Clausine T, 50 Clausine U, 32 Clausine V, 95–96 Clausine W, 50 Clausine Z, 14–15 Clauszoline-A, 64–65 Clauszoline-B, 64–65 biogenetic pathway, 166 Clauszoline-C, 21 Clauszoline-D, 32 Clauszoline-E, 50 Clauszoline-F, 32–33 Clauszoline-G, 48, 50 biogenetic pathway, 166 Clauszoline-H, 64–65 Clauszoline-I, 12 Clauszoline-J, 21 Clauszoline-K, 38 total synthesis, 288 Clauszoline-L, 39 Clauszoline-M, 28–29 Coproverdine, 104 Coriocella nigra, 117 Curryangin, 62 Currayanin, 57 6-Cyano-5-methoxyindolo[2,3-a]carbazole, 144–145 5-Cyano-6-methoxy-11-methylindolo[2,3-a] carbazole, 144–145 synthesis from 2-bromoindolecarboxamide, 372 5-Cyano-6-methoxy-11-methylindolo[2,3-a] carbazole, 363–364 Cyanophyta, sources of carbazole alkaloids, 4 Cycloindole, 191 Cyclomahanimbine, 57–58 in biogenetic pathway, 164–165 Cytotoxicity coproverdine, 104 9-formyl-3-methylcarbazole, 6, 182 girinimbine, 181

Subject Index

koenoline, 7 mahanine, 182 murrayafoline-I, 182 pyrayafoline D, 182 staurosporine aglycone, 114 tubingensin A, 152 UCN-02, 128 1-Dechlororebeccamycin, 135–136 3u-O-Demethyl-4u-N-demethylstaurosporine, 119, 121 4u-Demethylamino-4u-nitrostaurosporine, 122–123 4u-N-Demethyl-N-formyl-Nhydroxystaurosporine, 122–123 4u-N-Demethylstaurosporine, 118, 121 O-Demethylstaurosporine, 115, 116, 172 O-Demethylmurrayanine, 12–14 from total synthesis of mukonine, 216 4u-Deoxime-4u-oxo-epi-TAN-1030A, 124–125 4u-Deoxime-4u-oxo-TAN-1030A, 124–125 4-Deoxycarbazomycin, 188 Diabetes and LY-333531, 187 and pyrrolo[2,3-c]carbazole alkaloids, 109, 193 2,7-Dibromocarbazole, 155–156 synthesis, 381, 383 3,6-Dibromocarbazole, 155–156 1,1-Dichloroarcyriaflavin A, 174 Dictodendrins A-E, 109–112 Dictydiaethalium plumbeum, 139 Dictyodendrilla sp., 109 Dictyodendrilla verongiformis, 109 Dictyodendrin A, 110 Dictyodendrin B, 110–111 synthesis, 312, 314–316 Dictyodendrin C, 111 synthesis, 312, 314–317 Dictyodendrin D, 111 Dictyodendrin E, 111–112 synthesis, 312, 314–318 Didemnimide A, isolation, 149–150 Didemnimide A, synthesis, 373–374 Didemnum, 108 carbazole alkaloids, 3 Didemnum granulatum, 149 Dihydroarcyriarubin B, 141–143 Dihydroarcyriarubin C, 141, 143 Dihydrobenzo[a]carbazoles, 182 3,4-Dihydroellipticine, 92–94 3,4-Dihydroolivacine, 92–93 Dihydrotubingensins A-B, 152, 154 1,7-Dihydroxy-3-formyl-6-methoxycarbazole, 15 Dihydroxygirinimbine, 50–51 3,11-Dihydroxystaurosporine, 116 3,6-Diiodocarbazole, 155–156 synthesis, 381, 383

423

6,7-Dimethoxy-1-hydroxy-3-methylcarbazole, 12–13 2,6-Dimethoxy-3-formylcarbazole, 28 2,7-Dimethoxy-8-formyl-3-methylcarbazole, 20 (7)-N,Nu-Dimethylbismurrayafoline-A, 303 3,4-Dioxygenated tricyclic carbazole alkaloids, 100–103 total synthesis, 244–255 Edotecarin, 185 Ekebergia sp., 3 Ekebergia senegalensis, 10 Ekeberginine, 10 structure, 9 Ellipticine, 89 anticancer activity, 182–184 biogenetic pathway, 168 formal synthesis using 6-benzyl-6Hpyridol[4,3-b]carbazole-5,11-quinone, 327–329 formal total synthesis from 3-formylindole, 333–334 synthesis from 1–(p-methoxybenzyl)–5,6– dihydropyridone, 321–322 synthesis from 9-benzyl-4-methyl-1,2,3,4tetrahydro-9H-carbazole, 322–323 synthesis from indole, 323–324 synthesis from N-Boc indole, 330–331 synthesis from N-(phenylsulfonyl)indole, 324 synthesis using 2,4-dihydropyrrolo[3,4-b] indole, 325–326 total synthesis from 2,4,6trimethoxypyridine, 328–331 total synthesis from 4,7-dimethyl-1H-indene, 336 total synthesis from keto lactam, 319–320 total synthesis from N-benzylindole-2,3dicarboxylic anhydride, 326–328 total synthesis using furoindolone, 332–334 total synthesis using imidoyl radical cascade reaction, 335–336 total synthesis using modified Gribble methodology, 331–333 total synthesis using modified Moody approach, 332 total synthesis using new annulation strategy, 320–321 Epocarbazolin A, 99–100 Epocarbazolin B, 99 Epstein-Barr virus, 11, 16 1-Ethyl-8-n-propyl-1,2,3,4-tetrahydrocarbazole1-acetic acid, 190 Euchrestifoline, 49–50 Euchrestine-A, 26–27 Euchrestine-C, 25 Euchrestine-D, 26–27

424

Subject Index

Flindersia fournieri, 160 3-Formyl-1-methoxycarbazole, 47 1-Formyl-3-methoxy-6-methylcarbazole, 34, 36 9-Formyl-3-methylcarbazole, 6 anticancer activity, 6, 182 total synthesis, 285 3-Formyl-6-methoxycarbazole, 37–38 antibiotic activity, 189 total synthesis, 284–285 3-Formyl-7-hydroxycarbazole, 288 3-Formyl-9-methoxycarbazole, 40 total synthesis, 283, 286–287 3-Formylcarbazole, 5–6 antibiotic activity, 188 occurrence, 5, 159 N-Formylstaurosporine, 122 Free radical activity carbazomycin B, 193 carquinostatin A, 105 Furo[2,3-c]carbazole eustifoline D, 312 Furocarbazole alkaloids, 88–89 total synthesis, 304–312 Furoclausine-A, 88–89 biogenesis, 163–165 total synthesis, 308 Furoclausine-B, 88–89 Furostifoline, 88 biogenesis, 163–165 synthesis by oxidative photocyclization, 308–310 total synthesis, 304–312 total synthesis from indole-3-acetic acid, 308–310 total synthesis from o-cresol, 310–312 total synthesis (iron-mediated), 304–308 total synthesis using new electrocyclic reaction, 309–311

Glycosmis pentaphylla, 5 glycozolicine, 34 glycozoline, 33 glycozolinine, 35 O-methylmukonal, 17 Girinimbilol, 23 biogenesis, 163–165 Girinimbine, 43–45 anticancer activity, 181 biogenesis, 163–165 retrosynthetic analysis, 292–294 Glybomine A, 18–19, 25 Glybomine B, 23, 25 Glybomine C, 23, 25 Glycoborine, 33–34 total synthesis, 286 Glycoborinine, 67 Glycomaurin, 66–67 Glycomaurrol, 34–35 synthesis, 386–388 total synthesis, 288–290 Glycomis pentaphylla, 5 Glycosinine, 17 Glycosmis sp., 3 Glycosmis arborea, 18 Glycosmis mauritiana, 35 Glycosmis pentaphylla, 5 Glycosmis stenocarpa, 6–7 Glycozolicine, 34 Glycozolidal, 20, 28 Glycozolidine, 18 total synthesis, 226–227 Glycozolidol, 18 Glycozoline, 33–34 total synthesis, 288–289 Glycozolinine, 34–35 total synthesis, 288–289 Glycozolinol, 35 Go¨ 6976, 186–187 Graebe-Ullmann synthesis, 199 Granulatimide, 149–150 isomer synthesis, 375 synthesis from 1-methoxyindole, 374–375 total synthesis, 373 Guatambu amarelo, 91 (+)-Guatambuine, 91 (7)-Guatambuine, 333–335 Guatambuine, 93

Glycosmis arborea, 18 glybomine A, 19 glycoborine, 33–34 glycoborinine, 67 Glycosmis mauritiana, 66

Heptaphylline, 29–30, 191 biogenesis, 163–165 Heptazolicine, 49 Heptazolidine, 48–49 Heptazoline, 30

Euchrestine-E, 25–26 Eudistoma sp., 117 Eudistoma toealensis, 118 Eustifoline-A, 66–67 synthesis, 386–389 Eustifoline-B, 66–67 synthesis, 386–389 Eustifoline-C, 34, 36 synthesis, 386–389 Eustifoline-D, 88–89 synthesis, 386–389 Exozoline, 58–59

Subject Index

Heteroarylcarbazoles, 109 Holyrine A, 130–131 Holyrine B, 130–132 Human immunodeficiency virus (HIV) activity of 7-methoxy-O-methylmukonal, 21 activity of siamenol, 34–35 antiviral carbazoles, 189–190 and Go¨ 6976, 187 1-Hydroxy-3-methylcarbazole, 11–12 biogenesis, 163–164 isolation, 11 total synthesis, 214–215 total synthesis from nitro derivative, 217 2-Hydroxy-3-methylcarbazole, 22–23, 163 in biogenetic pathway, 164–166 oxidative dimerization, 167 6-Hydroxy-3-methylcarbazole, 19 3-Hydroxy-3u-O-demethylstaurosporine, 118, 120 11-Hydroxy-4u-N-demethylstaurosporine, 118, 121 3-Hydroxy-4u-N-demethylstaurosporine, 119–120 3-Hydroxy-4u-N-methylstaurosporine, 119–120 2-Hydroxy-7-methyl-9H-carbazole, 95–96 7-Hydroxy-TAN-1030A, 128–129 Hydroxycarquinostatin A, 105 12-Hydroxyellipticine, 89–91 synthesis from Gribble’s ketolactam intermediate, 324–326 9-Hydroxyellipticine, 89–90, 94 total synthesis, 319–320 3-Hydroxymethyl-9-methoxycarbazole, 40 7-Hydroxymurrayazolidine, 59 11-Hydroxystaurosporine, 116–117, 120 3-Hydroxystaurosporine, 118 5u-Hydroxystaurosporine, 118–119 3-Hydroxytetrahydroolivacine, 92–94 Hyella caespitosa, 3 Hyellazole, 96–97 conversion to 6-chlorohyellazole, 238–239 iron-mediated synthesis, 233–239 synthesis based on benzannulation of indoles, 230–231 synthesis based on modified benzannulation of indoles, 231–232 total synthesis, 227–229 total synthesis based on Diels-Alder reaction, 235–236 total synthesis from diketoindoles, 243–244 total synthesis using benzannulation strategy, 238–239 total synthesis using rhodium-catalyzed alkyne cyclotrimerization, 239, 241

(+)-K-252a, 365–368 (7)-K-252a, 356–357, 360 K-252a, 130–133 antibiotic activity, 189 biosynthetic pathway, 172–173 K-252b, 130–133 K-252c, 114–115 biogenetic pathway, 174–175 K-252d, 130–131 Koenidine, 44–45 Koenigicine, 44–45 Koenigine, 44–45 Koeniginequinone A, 41, 43, 258 total synthesis, 263–265 Koeniginequinone B, 41, 43 total synthesis, 263–265 Koenimbidine, 44–45 Koenimbin, 44–45 Koenine, 44–45 Koenoline, 7 total synthesis, 211–212 synthesis from mukonine, 216–218 Kyrtuthrix maculans, 155

Imidazo[4,5-a]pyrrolo[3,4-c]carbazole alkaloids, 149–151, 373–375 Immunosuppression and MLR-52, 126 Indizoline, 9–10

Lansine, 27 antibiotic activity, 188–189 Lavanduquinocin, 105–107 total synthesis, 269–273

425

(+)-Indocarbazostatin C, 131, 133–134 (+)-Indocarbazostatin, 131, 133–134 ( )-Indocarbazostatin B, 131, 133–134 ( )-Indocarbazostatin D, 131, 133–135 Indolo[2,3-a]carbazole alkaloids, 113, 144–149 synthesis, 336–373 Indolo[2,3-a]pyrrolo[3,4-c]carbazole alkaloids, 114–141 anticancer activity, 181 biological activities, 185 Indolocarbazole alkaloids, 3, 114 Insecticidal activities, carbazole alkaloids, 188 Iotrochota sp., 3, 108 Isogranulatimide, 149–150 isomer synthesis, 375 synthesis, 373–374 ( )-Isomahanimbine, 55–56 Isomurrayafoline B, 19–20 Isomurrayazoline, 63–64 6-Isopropoxymethyl-K-252c, 114–115 6-Isopropoxymethyl-TAN-1030A, 124 7-Isovaleryloxy-8-methoxygirinimbine, 385 Janetine, 92–93 JNK pathway, 186

426

Subject Index

Lechevalieria sp., 135 Leukemia, 186 Lipid peroxidation, 97 Loganiaceae family, 89 LY-333531, 187 Lycogalic acid, 174 Mahabinine-A, 83–84 (+)-Mahanimbine, 53 Mahanimbine, 44 anticancer activity, 181 in biogenetic pathway, 164–165 Mahanimbinol, 23–24 in biogenetic pathway, 164–165 ( )-Mahanine, 56–57 (+)-Mahanine, 56–57 Mahanine, 182 Malaria, treatment with C. lansium roots, 33, 39 Malassezia furfur, 3–4, 156, 178 Malasseziazoles A-C, 156–157 Marine sources of carbazole alkaloids, 4 Metatrichia vesparium, 139 N-Methoxy-3-formylcarbazole, 40 1-Methoxy-3-methylcarbazole, 7 2-Methoxy-3-methylcarbazole, 18 molybdenum-mediated total synthesis, 225–226 total synthesis, 222–224 6-Methoxy-3-methylcarbazole, 33 7-Methoxy-3-methylcarbazole-1,4-quinone, 43, 258 3-Methoxy-6-phenylarcyriaflavin A, 369 7-Methoxy-O-methylmukonal, 20–21 antiviral activity, 189 iron-mediated total synthesis, 225–226 9-Methoxyellipticine, 89–90 total synthesis from keto lactam, 319–320 6-Methoxyheptaphylline, 29–30 7-Methoxyheptaphylline, 31 9-Methoxymahanimbicine, 20 6-Methoxymethyl-TAN-1030A, 124 7-Methoxymukonal, 27, 188 anticancer activity, 181 7-Methoxymurrayacine, 48, 50 6-Methoxymurrayanine, 9 9-Methoxyolivacine, 93 Methyl 6-methoxycarbazole-3-carboxylate, 38–40 total synthesis, 288–289 Methyl carbazole-3-carboxylate, 6 antibiotic activity, 188 3u-Methylamino-3u-deoxy-K-252a, 131, 133 1-Methylcarbazole, 155 3-Methylcarbazole, 1, 3, 5–6 biosynthetic pathway, 159–160 Chakraborty biogenetic pathway, 162–163

Chakraborty’s biomimetic hydroxylation studies, 166 Narasimhan biogenetic pathway, 163 as precursor to other carbazole alkaloids, 159, 163–164 4u-N-Methyl-5u-hydroxystaurosporine, 117–119 N-Methylstaurosporine, 120–121 N-Methyltetrahydroellipticine, 91–93 O-Methylmahanine, 56 O-Methylmukonal, 17–18, 20 antiviral activity, 189 molybdenum-mediated total synthesis, 225 O-Methylmurrayamine A, 45–46 7-Methyoxyheptaphylline, 29, 31 Mevalonic acid, 159 Microbial sources of carbazole alkaloids, 4 Micromeline, 38–39 total synthesis, 288–291 Micromelum hirsutum, 37 Micromelum zeylanicum, 44 Micromonospora sp., 118 MLR-52, 126 (+)-MLR-52 total synthesis, 351–357 Mukoeic acid, 7–8 from mukonine, 216 total synthesis, 213 Mukoenine A, 23 as precursor in biogenesis, 163–164 Mukolidine, 37 Mukoline, 37 Mukonal, 22, 27 biogenetic pathway, 166 molybdenum-mediated total synthesis, 225 Mukonicine, 46–47 Mukonidine, 22–23 total synthesis, 222–224 Mukonine, 7–9 total synthesis, 213 total synthesis based on Diels-Alder reaction, 219–220 total synthesis from 3-formylindole, 215–218 total synthesis from 4-amino-3methoxybenzoic acid, 385–386 total synthesis starting with methyl vanillate, 220 transformation into further oxygenated carbazole alkaloids, 217–218 Mupamine, 46–47 Murrafoline-A, 69–70 Murrafoline-B, C, D, G, H, 69–72 Murrafoline-D, 295 Murrafoline-E, 72 Murrafoline-F, 72–73 Murrafoline G, 295 Murranimbine, 82–83 Murrastifoline-A, 300–303 Murrastifoline-A-D, 73–75

Subject Index

Murrastifoline-F, 296–297 Murraya sp., bis-carbazole alkoids, 69 carbazole, 3 carbazole alkaloids, 3 carbazole-1,4-quinones, 41 1-oxygenated carbazole alkaloids, 6 sources of carbazole alkaloids, 4 Murraya euchrestifolia, 5 bis-7-hydroxygirinimbine-A, 80 bis-carbazole alkoids, 69 bismurrayafolinol, 78 cyclomahanimbine, 57–58 dihydroxygirinimbine, 50–51 euchrestifoline, 49 eusrifoline-C, 36 euchrestine-A, B, D, 26 furostifoline, 88 isomurrayafoline B, 19 N-methoxy-3-formylcarbazole, 40 murrafoline-A, 69 murranimbine, 82 murrayaline-C, -D, 29 murrayamine A, 45 murrayamine C, B, 53 murrayamine N, J, 55 murrayamine-E, 63 murrayamine-O, -P, 58–59 murrayaquinone A, 41 oxydimurrayafoline, 77 pyrayafoline A, 51–52 pyrayafoline B, 65–66 Murraya exotica exozoline, 58–59 murrayazolinol, 63–64 Murraya koenigii bis-carbazole alkaloids, 3 8,8uu-biskoenigine, 80 bikoeniquinone-A, 84 bismahanine, 81 bismurrayafoline E, 85 bispyrayafoline, 82 clausine L, 17 curryangin, 62 6,7-dimethoxy-1-hydroxy-3methylcarbazole, 12 euchrestine-B, 26 girinimbine, 43 1-hydroxy-3-methylcarbazole, 11–12 isomurrayazoline, 63 (+)-mahanimbine, 53 mahanimbinol, 24 3-methylcarbazole, 5 O-methylmahanine, 56 O-methylmurrayamine A, 46 mukolidine, 37 mukoline, 37

427

mukonicine, 46 mukonidine, 22–23 mukonine, 8 murrayacine, 47, 50 murrayanine, 1, 7 murrayanol, 20 murrayazolidine, 57 murrayazolinine, 58 3,3u-[oxybis(methylene)]bis-(9-methoxy-9Hcarbazole), 77 2-oxygenated tricyclic carbazole alkaloids, 16 Murraya siamensis, 34–35, 48 7-methoxy-O-methylmukonal, 21 O-methylmukonal, 17 Murrayacine, 47–48, 50 biogenesis, 163–165 retrosynthetic analysis, 292–294 Murrayacinine, 55 Murrayafoline A, 6–7 from mukonine reduction, 216–218 from 1-hydroxy-3-methylcarbazole, 214–216 oxidative dimerization, 166–167 total synthesis based on Diels-Alder reaction, 220 total synthesis by iron-mediated arylamine cyclization, 212–213 total synthesis from N-(N,Ndiarylamino)phthalimide derivative, 218–219 total synthesis from 2-methoxy-4methylaniline, 386 total synthesis by palladium(II)-mediated oxidative double C-H activation, 222 total synthesis using benzannulation strategy, 220–221 Murrayafoline-B, 12–13 Murrayafoline-I, 182 Murrayaline-A, 19–20 Murrayaline-B, 26–27 Murrayaline-C, 29 Murrayaline-D, 29 Murrayamine-A, 45–46 platelet aggregation, 192 Murrayamine-B, 53–54 Murrayamine-C, 53–54 Murrayamine-D, 59–60 Murrayamine-E, 62–63 Murrayamine-F, 59, 61 Murrayamine-G, 59, 61 Murrayamine-H, 59–60 Murrayamine-I, 51–52 Murrayamine-J, 54–55 Murrayamine-K, 51–52 Murrayamine-M, 62 platelet aggregation, 192–193 Murrayamine-N, 54–55

428

Subject Index

Murrayamine-O, 58–60 Murrayamine-P, 58–60 Murrayanine, 1, 7–9 biogenetic pathway, 163–164 from mukonine, 216–218 total synthesis, 211–212 total synthesis based on Diels-Alder reaction, 220 total synthesis using mukonine precursor 213–215 Murrayanine B, 47 Murrayanol, 20 Murrayaquinone A formal synthesis from 2-chloro-3formylindole, 266 formal synthesis from 4-hydroxy-3methylcarbazole, 266–267 formal synthesis from murrayafoline A, 266 iron-mediated formal synthesis, 265–266 pharmacological activity, 192 total synthesis based on anionic [4+2] cycloaddition, 259–260 total synthesis based on bromo-enamino ketone/enamino ester annulation, 263 total synthesis by oxidation of 1-hydroxy-3methylcarbazole, 262–263 total synthesis by palladium(II)-mediated oxidative cyclization, 258 total synthesis from 1,2,3,4tetrahydrocarbazol-4(9H)-one, 259 total synthesis from 3-methylcarbazole, 264–265 total synthesis from arylamine, 264–265 total synthesis by palladium-mediated cyclization, 258 total synthesis using 4-benzyl-1-tertbutyldimethylsiloxy-4H-furo[3,4-b]indole, 258–259 Murrayaquinone A-E, 41–42 Murrayastine, 7–8 Murrayazolidine, 57 (+)-Murrayazoline, 62 Murrayazoline, 62–63 Murrayazolinine, 58 Murrayazolinol, 64 Mycobacterium tuberculosis, 37–38 Nenitzescu carbazole synthesis, 199 Neocarazostatin B, 252–254 Neocarazostatins A-C, 100–103 pharmacological activity, 193 Nerve growth factor inhibition, 133 Neuronal cell protection, 105 Neurotropic properties, 109 Ningalin D, 108–109 Nocardia aerocologenes, 4

Nocardiopsis dassonvillei, 116 Nocardiopsis sp., 114, 130 Ochrosia acuminata, 89 Ochrosia borbonica, 89 Ochrosia elliptica, 89 Ochrosia maculata, 89 Ochrosia moorei, 89, 94 Ochrosia sandwicensis, 89 Olivacine, 91–93 biogenetic pathway, 168–170 formal total synthesis, 320–321 synthesis from 9-benzyl-4-methyl-1,2,3,4tetrahydro-9H-carbazole, 322–323 total synthesis from 2,4,6trimethoxypyridine, 328–330 total synthesis from keto lactam, 319–320 Ovarian cancer, 186 7-Oxo-TAN-1030A, 128–129 1-Oxo-tetrahydrocarbazole derivatives, 188 13-Oxoellipticine, 89–91 7-Oxostaurosporine, 127–128 3,3u-[Oxybis(methylene)]bis-(9-methoxy-9Hcarbazole), 76–77 Oxydimurrayafoline, 76–77 1-Oxygenated tricyclic carbazole alkaloids, 6–16, 211–222 2-Oxygenated tricyclic carbazole alkaloids, 16–33, 222–227 9-Oxygenated tricyclic carbazole alkaloids, 40–41 3-Oxygenated tricyclic carbozole akaloids, 96–100, 227–244 N-Oxy-13-oxoellipticine, 94–95 N-Oxyellipticine, 94 Parkinson’s disease, 186 Pazellipticine, 183 Pentacyclic pyranol[3,2-a]carbazole, 57 Peschiera buchtienii, 92 Pityriazole, 156–157 biogenetic pathway, 178–179 PKC inhibition MLR-52, 126 UCN-02, 128 PKC isoenzyme inhibition, 114 Plasmodium falciparum, 80 Platelet aggregation clausine D, 13 clausine H, 21 clauszoline-I, 12 murrayamine A, 192 staurosporine, 114 Prephenic acid, 159 Protein kinase inhibition pyrrolo[2,3-c]carbazole alkaloids, 109 staurosporine and derivatives, 185–186

Subject Index

Purpurone, 108–109 biomimetic total synthesis, 303–304 Pyrano[3,2-a]carbazole alkaloids, 43–57, 385 Pyranocarbazole-1,4-quinone alkaloids, 68–69 Pyranocarbazole alkaloids, 43–57 synthesis, 291–294 Pyranol[2,3-a]carbazole alkaloids, 64–65 Pyranol[2,3-b]carbazole alkaloids, 65–66 Pyranol[2,3-c]carbazole alkaloids, 66–67 Pyrayafoline A, 51 structure, 52 Pyrayafoline B, 65–66 Pyrayafoline C, 52 structure, 52 Pyrayafoline D, 52–53 anticancer activity, 181–182 structure, 52 Pyrayafoline E, 65–66 Pyrayaquinone-A, 68 total synthesis, 292 Pyrayaquinone-B, 68 total synthesis, 292–293 Pyrayaquinone-C, 68–69 Pyricularia oryzae, 127 Pyridol[4,3-b]carbazole alkaloids, 89–95 anticancer activity, 181–184 total synthesis, 317–336 Pyrrolo[2,3-c]carbazole alkaloids, 109–113, 312–317 and diabetes, 193 Quinolino[4,3-b]carbazole-1,4-quinone alkaloids, 151–152, 376–381 antimalarial activity, 191 Ramatroban, 192 Rebeccamycin, 135–136 anticancer activity, 185 biosynthetic pathway, 171 total synthesis using 1,2-anhydrosugar, 342–344 total synthesis using condensation methodology, 349–351 Retellipticine, 183 Rimcazole, 191 RK-1409B, 126 RK-286C, 125, 351–357 RK-286D, 130–132 Rutaceae family, 3 Saccharothrix aerocolonigenes, 135 Sesquiterpenoid carbazole alkaloids, 152–155 Shikimate pathway, 160–161 Shikimic acid, 159–161 Siamenol, 34–35 antiviral activity, 189 total synthesis, 287–288

429

Staphylococcus aureus, 56 (+)-Staurosporine, 114–116, 130 biosynthesis from L-tryptophan, 171–172, 174–175 total synthesis, 343–346 total synthesis using a-methoxyketone, 351–358 protein kinase C inhibition, 336 Staurosporinone (Staurosporine aglycone), 114–115 synthesis, 337–339, 341, 344–347, 347–348, 364–366, 370 Strellidimine, 94–95 Streptomyces anulatus, 99 Strepromyces chromofuscus, 97 Streptomyces cyaneus, 97 Streptomyces ehimense, 100 Streptomyces exfoliatus, 105 Streptomyces longisporoflavus, 114, 116, 124, 128, 172 Streptomyces platensis, 127 Streptomyces sp., 104 carbazole alkaloids, 3 sources of carbazole alkaloids, 4 TAN-1030A, 123 Streptomyces staurosporeus, 114, 127 Streptomyces tendae, 105 Streptomyces viridochromogenes, 105 Streptoverticillium ehimense, 103 Streptoverticillium mobaraense, 139 Streptoverticillium sp., 100 Strychnos dinklagei, 89 3,4-dihydroellipticine, 92 N-oxy-13-oxoellipticine, 94 Synthetic methods, carbazole alkaloids annulation of a 2,3-disubstituted indole, 200–201 annulations of chromium-carbene complexes, 209 from azidobiphenyls, 196–197 Bucherer synthesis of benzocarbazoles, 200 cyclization of 2,2u-diaminobiphenyls, 197–198 cyclization of arylhydrazones, 198–199 cyclization of b-keto sulfoxides, 200 cyclization of diarylamines, 205–206 deoxygenation of nitrobiphenyls, 195–196 Diels-Alder cycloaddition of vinylindoles, 203–204 Diels-Alder reaction of 2,3-quinodimethanes, 201–203 diverse annulation methods, 199–210 double-N-arylation of primary amines, 209–210 electrocyclic reactions, 204–205 Graebe-Ullmann synthesis, 199 iron-mediated, 206–207 molybdenum-mediated, 207–208 Nenitzescu carbazole synthesis, 199–200

430

Subject Index

palladium-catalyzed annulation of internal alkynes, 209 rhodium-catalyzed, 208 using arylmagnesium reagents, 210 Tabernaemontana psychotrifolia, 92 ( )-TAN-1030A, 351–359 TAN-1030A, 123–124 TAN-999, 115–116 Tedania ignis, 155 2,3,7,8-Tetrachlorodibenzo-p-dioxin, 113 Tetrahydrocarbazole, 188 Tjipanazole B synthesis from nitro derivative, 370–371, synthesis, 372 Tjipanazole D, 144–145 synthesis from nitro derivative, 370–371 total synthesis, 341–342 Tjipanazole E synthesis from nitro derivative, 370–371 synthesis, 372 total synthesis, 341–342 Tjipanazole F1 synthesis, 359, 362 Tjipanazole F2 synthesis, 358–359, 362 Tjipanazole I, 144–146 Tjipanazole J, 138, 145 Tjipanazoles, 138, 144–149 Tolypothrix tjipanasensis, 138, 145 Topoisomerase inhibition, 139, 184–185 Topotecan, 186 L-Tryptophan in biogenetic pathway, 159, 162–163, 168–171, 178–180 and staurosporine biogenesis, 171–172, 174–175

Trichophyton sp., 103 Tricyclic carbazole-1,4-quinol alkaloids, 103–104 Tricyclic carbazole-1,4-quinone alkaloids, 41–43 Tricyclic carbazole-3,4-quinone alkaloids, 104–107 Tricyclic carbazole alkaloids 1-oxygenated tricyclic carbazole alkaloids, 6–16 2-oxygenated tricyclic carbazole alkaloids, 16–33 3-methylcarbazole and non-oxygenated congeners, 5–6 3-oxygenated tricyclic carbazole alkaloids, 96–100 C-Ring oxygenated tricyclic carbazole alkaloids, 33–40 total synthesis, 211–291 Tubingensin A, 152–153 biosynthetic pathway, 176–177 Tubingensin B, 152–153 biogenetic pathway, 176–177 UCN-01, 128–129 UCN-02, 128–130 Uleine, 168 Vasocontraction clausine D, 13 clausine H, 21 clausine K, 21 clauszoline-I, 12 Vasodilators, 191 ZHD-0501, 126–127