Simple indole alkaloids and those with a nonrearranged monoterpenoid unit

Contents

• 1 Introduction

• 2 Simple indole alkaloids
  • 2.1 Non-tryptamines
  • 2.2 Non-isoprenoid tryptamines

• 3 Isoprenoid tryptamines
  • 3.1 Ergot alkaloids

• 4 Bisindole alkaloids
  • 4.1 Indolocarbazoles
  • 4.2 Duocarmycins
  • 4.3 Dimeric β-carbolines

• 5 Peptide alkaloids containing a tryptophan residue

• 6 Indole alkaloids with a nonrearranged monoterpenoid unit

• References

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Abstract

Covering: January 1999 to December 1999. Previous review: 2000, 17, 175.

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Satoshi Hibino

Satoshi Hibino was born in 1945 in Aichi, Japan. He graduated in 1972 from the Graduate School of Pharmaceutical Sciences, Tohoku University and he received his PhD degree from the same university under the supervision of Professor Tetsuji Kametani. After two years of postdoctoral work (1975–1977) with Professor Steven M. Weinreb (Dept. Chem., Penn State U.) at Fordham University, he worked at Tokyo Pharmaceutical University as a faculty member (1977–1982). In 1982 he moved to the Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University and then in 1986 became a full professor. His main research interests are the synthesis of biologically active natural products, especially nitrogen containing heterocyclic compounds based on electrocyclic reactions

Tominari Choshi

Tominari Choshi was born in 1964 in Hiroshima, Japan. He graduated in 1989 from the Graduate School of Pharmaceutical Sciences, Okayama University and then he received his MS Degree. He obtained his PhD degree in 1997 from Tohoku University under the supervision of Professor Keiichiro Fukumoto. He became a faculty member of Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University in 1992. Currently he is a full-time lecturer in organic chemistry. His main research interests are the synthesis of biologically active natural products, especially nitrogen containing heterocyclic compounds based on electrocyclic reactions.

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1 Introduction

This review covers the literature on simple indole alkaloids and those with a nonrearranged monoterpenoid unit from the beginning of 1999 up to the end of 1999. The subject is developed along the lines of our respected predecessors (Saxton, Fukumoto, Ihara, Toyota, Lounasmaa, and Tolvanen). Subheadings along with the title have been established by Lounasmaa and Tolvanen. We applied these subheadings in the review, but a location of a new and/or synthetic alkaloid might be slightly different from that of the former review. Marine natural products have been reviewed in these Reports by Faulkner ¹ and peptide alkaloids have also been surveyed in this series by Lewis.² There will inevitably be some overlap with marine alkaloids and peptide alkaloids containing the indole moiety. New approaches to the total synthesis of manzamine A, ircinal A and related compounds based on a highly efficient Diels–Alder reaction have been reviewed by Nakagawa.³

2 Simple indole alkaloids

2.1 Non-tryptamines

The simple, new indole alkaloid, 3,6-dibromoindole 1 possessing antibacterial activity, has been isolated from the acsidian Distaplia regina.⁴ Two 1H-indole-3-acetonitrile glycosides, capparilosides A 2a and B 2b have been newly isolated from the methanolic extract of the mature fruits of Capparis spinosa.⁵ Their structures were established by spectral analysis and chemical transformation. 3-(3-Indolyl)acrylamide 3a has been found from the acetone extracts of the red algae Chondria atropurpurea together with chondriamide A 3b isolated previously.⁶ An antifungal indole, fistulosin (2-octadecyl-3-hydroxyindole) 4, which shows high activity against Fusarium oxysporum primarily inhibiting protein synthesis, has been found in the roots of Welsh onion (Allium fistulosum L.).⁷

The structures of APHE 1–4 (pyrazolo[1,5-b]isoquinolin-9(1H )-one ring system), produced by actinomycete Streptverticillium griseocarneum, have been reformulated on the basis of the synthesis of pyrazolo[1,5-b]isoquinoline by Kelly ⁸ as pimprinethine 5a, WS-30581 A 5b, pimprinine 5c and WS-30581 B 5d, respectively, which have been isolated from strains of microorganisms ⁹ very similar to the one that produces the APHEs.

Total syntheses of three simple indole alkaloids, 2,4-dimethylindole 6a, 4-(hydroxymethyl)-2-methylindole 6b, and 4-(methoxymethyl)-2-methylindole 6c, isolated from two species of European Basidomycetes (Tricholoma virgatum and Tricholomasciodes),¹⁰ have been accomplished by a palladium-phosphine-catalyzed N-heteroannulation as the key step (Scheme 1).¹¹

Scheme 1 Reagents: i, Pd(OAc)₂, PPh₃, CO, 70 °C, MeCN; ii, DIBAL-H; iii, MeI, KOH.

The total synthesis of polyamine toxin of HO-4166 12, isolated from the venomous spider Hololena curta,¹² has been completed in twelve steps from 1,3-diaminopropane in 41% overall yield by using the 2-nitrobenzenesulfonamide (Ns) as both a protecting and activating group. The deprotection of the Ns group was performed by treatment of a new resin prepared from Merrified resin with p-hydroxytrityl alcohol (Scheme 2).¹³

Scheme 2 Reagents: i, PivCl, Et₃N, CH₂Cl₂, rt; ii, CsCO₃, MeCN, 60 °C; iii, SOCl₂, MeOH, rt; iv, resin, i-Pr₂NEt, CH₂Cl₂, rt; v, HSCH₂CH₂OH, DBU, DMF, rt; vi, TFA, CH₂Cl₂.

Two new batzelline analogues, secobatzellines A 13a and B 13b, have been isolated from a deep-water marine sponge of the genus Batzella. They inhibit the phosphatase activity of calcineuron, and show in vitro cytotoxicity against P-388 and A-549 cell lines. Secobatzelline A also inhibits the peptidase activity of CPP32. These compounds are probable precursors of pyrroloiminoquinone alkaloids.¹⁴

Two new insecticidal agents, nodulisporic acids A₁14a and A₂14b have been isolated from a Nodulisporium sp.¹⁵ They exhibit similar biological profiles to closely related nodulisporic acid A.¹⁶

2.1.1 Indole auxins and phytoalexins. Two new compounds 15a and 15b produced on the surface of Brassica oleracea cv. Botrytis have been isolated. Both novel compounds are closely related to Brassica phytoalexins like brassicanal C.¹⁷ The structures of two new phytoalexins, wasalexins A 16a and B 16b, produced by foliar tissue of wasabi under elicitation by Phoma lingam, Phoma wasabiae or CuCl₂, have been established.¹⁸

2.1.2 Mitomycin C and related compounds. Indole-4,7-quinones are the core of the biological active natural products, such as an antitumor antibiotic mitomycin C. Recently, several routes to assembling the 1,2-aziridinomitosene ring system common to mitomycin derivatives have been published.¹⁹ An enantioselective synthesis of a key compound of the mitomycin antibiotics, 1,2-aziridinomitosene 17 by an intramolecular carbon–hydrogen insertion reaction of metal carbene intermediate using the copper(I) complex (18→19) has been reported (Scheme 3).²⁰ 7-Methoxyaziridinomitosene 20, possessing potent activity against various tumor model systems, has been synthesized in sixteen steps (3.4% overall yield) from the 2,5-dimethylanisole 21 (Scheme 4). The key steps are the syntheses of the intermediate 22 from 21, and the azido-alcohol 25 from 24 with diisopropylvinylsulfonium triflate in the presence of sodium hydride (Scheme 4).²¹

Scheme 3 Reagents: i, NaHMDS, −78 °C; ii, PNBSA, −78 °C to rt; iii, copper(I) triflate; iv, hydrolysis; v, MsCl, Et₃N; vi, DBU, CH₂Cl₂.

Scheme 4 Reagents: i, (COOMe)₂, t-BuOK, Et₂O; ii, SnCl₂, MeOH; iii, H₂, Pd-C, EtOH; iv, Fremy’s salt, 0.2 M NaH₂PO₄, acetone; v, H₂, Pd-C, then TBSCl, imidazole, CH₂Cl₂; vi, DIBAL-H, THF; vii, MnO₂, CH₂Cl₂; viii, diisopropylvinylsulfonium triflate, NaH, THF, 0 °C, then NaN₃, acetone, H₂O; ix, MsCl, Et₃N, CH₂Cl₂; x, POCl₃, DMF; xi, PCC, CH₂Cl₂; xii, NaBH₄, MeOH; xiii, O₂; xiv, phenyl chloroformate, pyridine; xv, NH₃, CH₂Cl₂; xvi, PPh₃, Et₃N, THF, H₂O.

2.1.3 Carbazoles. A new dimeric carbazole alkaloid, bismurrayafoline E 26 has been isolated from the leaves of Murraya koenigii. Its detailed structure, which is that the C-8 of one monomer is linked with the C-8 of the other by a carbon–carbon bond formation, has been elucidated by the inverse-detected HSQC and HMBC NMR experiments.²² Ten new carbazole alkaloids, clausine-M 27a, -N 27b, -O 27c, -P 27d, -Q 27e, -R 27f, -S 27g, -U 27h, -V 27i and clausenatine A 27j, have been isolated and identified from the root bark of Clausena excavata.²³ Their structures have been determined by spectroscopic analyses. A new tetracyclic carbazole alkaloid, designated as glycoboramine 28, has been isolated from the roots of Glycosmis arborea along with two known carbazole alkaloids (glycozoline and glycozolidine). Its structure was elucidated mainly on the basis of its 2D NMR spectral analysis.²⁴

The first synthesis of optically pure biscarbazole has been reported. Optically pure dimeric O-demethylmurrayafoline A 29a and 8,8′-demethylclausenamine-A 29b have been synthesized via resolution of the corresponding camphor sulfonates of the racemates. The absolute configuration of (+)-29a, (+)-29b and (−)-29a, (−)-29b as (aR) and (aS ), respectively, has been established by X-ray crystallographic and CD spectral analyses.²⁵

Improved total synthesis of carbazomycins A 30a and B 30b, isolated from Streptomyces ehimense,²⁶ have been completed. The key steps are a C–C bond formation by electrophilic aromatic substitution at the fully functionalized arylamine 32 with the tricarbonyliron-complexed cyclohexadienyl cation 31 and a subsequent C–N bond formation by oxidative cyclization of the intermediate tricarbonyliron–cyclohexadiene complexes 33 in air (Scheme 5).²⁷ This type of transition metal promoted cyclization procedure for the construction of carbazole framework has been further applied to the synthesis of the marine alkaloid hyellazole 35, isolated from the blue–green alga Hyella caespitosa,²⁸ by the same group.²⁹

Scheme 5 Reagents: i, MeCN, air, 25 °C; ii, Me₃NO, Me₂CO, 56 °C; iii, 10% Pd-C, o-xylene, 145 °C; iv, LiAlH₄, THF, 25 °C.

A concise synthesis of furostifoline 36, isolated from Murraya eucrestifolia,³⁰ has been completed through a five step procedure based on a palladium(0)-catalyzed cross-coupling reaction (Scheme 6).³¹

Scheme 6 Reagents: i, BrCH₂CH(OEt)₂, K₂CO₃, DMF, 100 °C; ii, H₃PO₄, P₂O₅, PhCl, 140 °C; iii, THF, −78 °C, n-BuLi, B(OBu)₃, H₂O; iv, Pd(0), Na₂CO₃, DME, H₂O, reflux; v, P(OEt)₃, reflux.

2.1.4 Indoloquinolines. Indoloquinoline alkaloids isolated from Cryptolepis species have been subject of considerable interest in recent years on the part of several research groups. Cryptolepine (indolo[3,2-b]quinoline) is known to have various biological properties such as antimuscarinic, antibacterial, antiviral, antiplasmodial, and antihyperglycemic activities.³² In the review period, a novel alkaloid 11-isopropylcryptolepine 37 has been found from the root of the West African plant Cryptolepis sanguinolenta. This structure was determined by both homonuclear and heteronuclear 2D NMR shift correlation techniques.³³

Total syntheses of cryptotackieine 38 (also named neocryptolepine, indolo[2,3-b]quinoline ring system) and cryptosanguinolentine 39 (also named isocryptolepine indolo[3,2-c]quinoline ring system), isolated from Cryptolepissanguinolenta,³⁴ have been developed by using the key common compound 40. The intramolecular aza-Wittig reaction of 40 provided cryptotackieine 38. By contrast, cryptosanguinolentine 39 has been obtained by a nitrene insertion process within 40 followed by reduction (Scheme 7).³⁵ Cryptotackieine 38 has also been synthesized by the same group through the aza-Wittig–electrocyclic ring closure strategy.³⁶

Scheme 7 Reagents: i, microwave, nitrobenzene; ii, MeI, DMF, 60 °C; iii, H, Pd/C, rt; iv, NaNH₂, H₂SO₄, H₂O, NaN₃; v, microwave, Me₃P, nitrobenzene; vi, o-xylene; vii, Red-Al, reflux.

The first total synthesis of cryptomisrine 41 (dimeric indolo[3,2-b]quinoline), isolated from Cryptolepis sanguinolenta,³³ has been achieved regioselectively.³⁷ The key step is based on a convergent methodology which involves a new halogen-dance reaction ³⁸ (42→43 and 43→44) in the quinoline ring followed by Suzuki cross-coupling reaction (Scheme 8).

Scheme 8 Reagents: i, LDA, THF, −78 °C, HCOOEt; ii, LDA, THF, −78 °C, 42; iii, Pd(PPh₃)₄, 2 M K₂CO₃, EtOH, toluene, Ar, reflux; iv, MnO₂, toluene, reflux; v, pyridinium chloride, 160 °C, NH₄OH.

2.2 Non-isoprenoid tryptamines

A new N-fatty acyl tryptamine, cheritamine 45, along with thirty-two known compounds have been obtained from the stems of Annona cherimola.³⁹ A further eight tryptamine derived amides, N-palmitoyltryptamine 46a, N-stearoyltryptamine 46b, N-arachidoyltryptamine 46c, N-behenoyltryptamine 46d, N-tricosanoyltryptamine 46e, N-lignoceroyltryptamine 46f, N-pentacosanoyltryptamine 46g, and N-cerotoyltryptamine 46h, have been isolated from the seeds of Rollinia mucosa.⁴⁰ Their structures have been characterized and identified by physical and spectral data. Two new bioactive indole alkaloids, bufobutanoic acid 47a and bufopyramide 47b have been isolated from the Chinese traditional drug Ch’ an Su, prepared from the skin secretions of the local toads such as Bufo bufo garigarizans or Bufo melanostrictus. Both compounds exhibit cytotoxicity against murine P388 lymphocytic leukemia cells with IC₅₀ values of 22 μg mL⁻¹ and 26 μg mL⁻¹, respectively.⁴¹ A sulfur-containing indole alkaloid, glypetelotine 48 has been isolated from the leaves of the endemic Vietnamese plant Glycosmis petelotti. The structure of 48 has been established to be S-methyl N,N-2[(1H )-indol-3-ethyl]methyl thiocarbamate by spectroscopic analysis.⁴²

A new total synthesis of psilocin 49, isolated from the mushroom species Psilocybemexicana ⁴³ as a minor hallucinogenic component, has been achieved by employing the directed regioselective iodination and the Heck-type coupling reaction (50→51) as key steps for the construction of the indole ring (Scheme 9).⁴⁴

Scheme 9 Reagents: i, t-BuLi, Et₂O, −78 °C→25 °C, I₂, THF, −78°→25 °C; ii, 2,5-dihydro-2,5-dimethoxyfuran, Pd(OAc)₂, i-Pr₂NEt, PhCH₂NEt₃Cl, DMF, 80 °C; iii, TFA, CH₂Cl₂, 0 °C→rt.

Two diastereomers that are antipodal at C-7 of 3-oxo-7-hydroxy-3,7-secorhynchophylline 52 isolated from Uncaria attenuata Korth in Thailand, have been prepared, and semi-synthetic 52 has been separated by chiral column chromatography. The absolute configuration at C-7 was elucidated by comparison of the CD spectra with those of the known 3-hydroxy-2-oxotryptophan.⁴⁵ Further the absolute stereochemistry at the C-3′ position of maremycin A 53a and B 53b, isolated from the culture broth of marine Streptomyces, was elucidated to be (S ) and (R), respectively, based on the analysis of their CD spectra.⁴⁵ Subsequently absolute configurations of four 3-hydroxyindole alkaloids, convolutamydines A 54a, B 54b, C, 54c and D 54d, isolated from marine bryozoan by Kamano group,⁴⁶ were suggested to be (R)-form based on a negative Cotton effect in the CD spectra.⁴⁵

An indole alkaloid, racemic convolutamydine A 54a, isolated from marine bryozoan Amathia convoluta,⁴⁶ has been synthesized starting from 4,6-dibromoisatin 55 (Scheme 10).⁴⁷

Scheme 10 Reagents: i, acetone, 15% KOH, EtOH; ii, acetone, PhCH₂N⁺Me₃⁻OH.

(+)-Alantrypinone is a structurally interesting natural product isolated from the fungus Pennicillium thymicola. Total synthesis of the enantiomer 56 of alantrypinone along with its epimer has been established in ten steps, starting from the reaction of isatoic anhydride 57 with (S )-(−)-tryptophan methyl ester 58 (Scheme 11).⁴⁸

Scheme 11 Reagents: i, toluene, reflux; ii, H₂O, CH₂Cl₂, NaHCO₃; iii, PPh₃, I₂, i-Pr₂NEt; iv, [Me₃AlSPh]Li, THF; v, piperidine, THF; vi, m-CPBA, CH₂Cl₂; vii, benzene, PPh₃, reflux; viii, TFA; ix, NBS, TFA; x, Pd-C, H₂, MeOH.

An enantioselective total synthesis of the oxindole alkaloid (−)-horsfiline 59, isolated from Malaysian medicinal plant Horsfilidea superba,⁴⁹ has been developed on the basis of asymmetric nitroolefination (60→62) using the chiral nitro-enamine 61 as the key step (Scheme 12).⁵⁰

Scheme 12 Reagents: i, n-BuLi, toluene, Et₂O, 61; ii, 1 M HCl, MeOH; iii, NaBH₄, dioxane, MeOH; iv, NaH, DMF, PHCH₂Cl; v, NaNO₂, AcOH, DMSO; vi, Et₃N, DPPA, EtOH; vii, O₃, EtOH, −78 °C, Me₂S, NaBH₄, MeOH; viii, Et₃N, MsCl, CH₂Cl₂, NaH, THF; ix, KOH, NH₂NH₂, HOCH₂CH₂OH, HCOOH, HCHO; x, Li, NH₃.

The formal total synthesis of (±)-pedunclarine 63, the principal alkaloid of the Tasmania shurab Aristelia pedunclaris, has been accomplished by the construction of the 6-azabicyclo[3.2.1]octane ring system based on the Cr(0)-promoted higher order cycloaddition as the key step.⁵¹

A cyclized didemnimide alkaloid 64 from the Caribbean Ascidian Didemnumconchyliatum has been isolated.⁵² The structure of this alkaloid was identical with isogranulatimide 64, recently isolated from the ascidian Didemnum granulatum by the Andersen group.⁵³

2.2.1 Piperazinediones. The simple indole alkaloid containing a piperazinedione moiety, dipodazine 65 has been isolated as the major component from Penicillium dipodomyis and Penicillium nalgiovense.⁵⁴ Tardioxopiperazines A 66a and B 66b have been found from the defatted EtOAc extract of an Ascomycete, Micrococus tardifaciens by monitoring the immunosuppressive activity.⁵⁵ Tardioxopiperazine A 66a shows moderate immunosuppressive activity. New okaramines H 67a, I 67b have been isolated from okara fermented with Aspergillus aculeatus KF-428, together with okaramines A and B.⁵⁶ Furthermore, four new okaramines J 68a, K 68b, L 68c and M 68d have been obtained from okara fermented with Penicillium simplicissinum ATCC 90288, together with five known related compounds by the same group.⁵⁷ The new okaramines exhibit no insecticidal activity against the silkworm. A biosynthetic pathway to okaramine has been also proposed.⁵⁶

Total syntheses of amauromine 69 (isolated from Amauroascus sp. 6237 ⁵⁸) and 5-N-acetylardeemin 70 (isolated from the fungus Aspergillus fischerii ⁵⁹) have been completed on the basis of the kinetic stereoselective conversion of 71→72a, followed by the reverse prenylation (conversion of 72a→73) for the construction of the common hexahydropyrrolo[2,3-b]indole 73 (Scheme 13).⁶⁰ Total synthesis of spirotryprostatin A 75, isolated from the fermentation broth of Aspergillus fumigatus,⁶¹ has been accomplished in nine steps. The key step is the oxidative rearrangement of the β-carboline ring 76 to the oxindole 77 by NBS (Scheme 14). The structure activity relations of 75 and its related compounds for cell cycle inhibition has also been described.⁶²

Scheme 13 Reagents: i, N-phenylselenophthalimide, pyridinium toluene-p-sulfonate; ii, MeOTf, 2,6-di(tert-butyl)pridine, prenyltri(n-butyl)stannane, CH₂Cl₂, −78 °C→reflux; iii, separation (cryst); iv, NaOH, THF, MeOH, H₂O, reflux; v, TMSI, MeCN, 0 °C; vi, 74, BOP-Cl, Et₃N, CH₂Cl₂.

Scheme 14 Reagents: i, TFA, 4 Å ms, CH₂Cl₂, 0 °C→rt; ii, NBS, AcOH, H₂O, THF; iii, TFA, CH₂Cl₂; iv, Boc₂O, MeCN, Et₃N, reflux; v, N-Troc-Proline acid chloride, Et₃N, CH₂Cl₂, 0 °C→rt; vi, Zn, THF, MeOH, NH₄Cl; vii, NaIO₄, H₂O, MeOH; viii, toluene, reflux; ix, RhCl₃·3H₂O, EtOH, reflux.

A total synthesis of the acyl-CoA: cholesterol acyltransferase inhibitor gypsetin 78, isolated from N. gypsea var. incurvata IFO9228,⁶³ has been completed on the basis of the introduction of a reversed prenyl group at the 2-position of N-phthaloyltryptophan methyl ester (79→80), followed by the dimethyldioxirane-promoted double-oxidative cyclization of the diketopiperazine (82→78) (Scheme 15).⁶⁴ Total syntheses of deoxybrevianamide E 83, a metabolite of Aspergillus ustus ⁶⁵ and brevianamide E 84, isolated from the culture of Penicilliumbrevicompactum ⁶⁶ have also been achieved from 81.⁶⁴ Furthermore, total synthesis of tryprostatin B 85, isolated from Aspergillus fumigatus,^61a,67 has also been accomplished by the same group, starting from 79 (Scheme 16).⁶⁴

Scheme 15 Reagents: i, t-BuOCl, Et₃N, −78 °C; ii, prenyl 9-BBN, −78 °C; iii, NH₂NH₂, EtOH, rt; iv, 140 °C; v, dimethyldioxirane, CH₂Cl₂, acetone, −78 °C→0 °C; vi, Boc-proline, BOP-Cl, CH₂Cl₂, −78 °C→0 °C; vii, TFA, CH₂Cl₂, rt, then NH₃, MeOH, reflux; viii, dimethyldioxirane, CH₂Cl₂, acetone, −78 °C→0 °C.

Scheme 16 Reagents: i, t-BuOCl; ii, prenyltri(n-butyl)stannane, BCl₃; iii, NH₂NH₂, MeOH, CH₂Cl₂; iv, N-Boc-Proline acid fluoride, CH₂Cl₂, NaHCO₃, H₂O; v, TMSI, MeCN, 0 °C; vi, NH₃, MeOH.

Two new cytotoxic epidithiodioxopiperadine dimers, 11,11′-dideoxyverticillin A 86a and 11′-deoxyverticillin A 86b together with known verticillin A, have been isolated from the mycelium of a marine-derived fungus of the genus Penicillium. A new monomeric bisdethio-bis(methylthio)-dioxopiperazine 87 have also been obtained by extraction of the culture broth. The structures and absolute stereochemistry have been assigned on the basis of NMR and CD spectral experiments. in vitro Cytotoxicity against HCT-116 human colon carcinoma of compounds 86a and 86b has been described (IC₅₀ = 30 ng mL⁻¹).⁶⁸

2.2.2 Physostigmine and related compounds. High-performance liquid chromatography–diode array detection–tandem mass spectrometry analyses has been investigated as a method for the analysis of alkaloids of Amazon Psychotria species. The six known pyrrolidinoindoline alkaloids, (+)-chimonanthine, meso-chimonanthine, hodgkinsine, quadrigemine C, quadrigemine B and psychotridine have been isolated and identified by this method.⁶⁹ The novel pyrrolidinoindoline N_b-desmethyl-meso-chimonanthine 88 has been obtained from New Caledonian, Psychotrialyciiflora, together with the known dimer meso-chimonanthine.⁷⁰ A further three new alkaloids quadrigemine I 89, oleoidine 90, and caledonine 91 have been isolated from Psychotria oleoides along with the five known pyrrolidinoindoline alkaloids, by the same group.⁷⁰ Some of these compounds are the functional antagonists of somatostatin and show a growth hormone-releasing peptide-like activity.

The structure of arumdinine 92, isolated from the perennial giant gross Arundo donax, has recently been elucidated to be pyrrolidinoindoline skeleton having an ether bridge between the two indole units.⁷¹ In addition, the mass-spectrometric fragmentation of 92 has been investigated by high resolution mass spectrometry.⁷²

Total synthesis of the pyrrolidinoindoline alkaloid debromoflustramine B 93, isolated from the marine bryozoan Flustra foliaceae together with closely related alkaloids,⁷³ has been achieved by using the 2-oxofuro[2,3-b]indole 95 derived from the conjugated addition of the prenylmagnesium bromide to the 2-hydroxyindolenine 94 (Scheme 17). Related derivatives, debromoflustramine A and debromoflustramide A, possessing a reverse prenyl group at the 3a-position of hexahydropyrrolo[2,3-b]indole ring have also been synthesized.⁷⁴

Scheme 17 Reagents: i, prenylmagnesium bromide, Et₂O, THF; ii, Al₂O₃ (wet), THF, H₂O; iii, MeONa, MeOH; iv, K₂CO₃, acetone, prenyl bromide; v, MeNH₂, MeOH; vi, LiAlH₄, THF.

The enantiocontrolled total synthesis of (−)-chimonanthine 96, isolated from Idiospermum australiense,⁷⁵ and the stereocontrolled total synthesis of meso-chimonanthine 97, isolated from Psychotria foresteriana,⁷⁶ have been completed (Scheme 18).⁷⁷ The first stereo- and enantioselective route for preparing chiral 3a,3a′-bis(pyrrolo[2,3-b]indolines) has been developed on the basis of a double Heck cyclization as the key step (98→99).

Scheme 18 Reagents: i, LDA, THF, HMPA; ii, LDA, THF, I₂, −78 °C; iii, 2-iodoaniline, Me₃Al, toluene, rt; iv, NaH, BuBr, DMF; v, BCl₃, −78 °C; vi, 2,2-dimethoxypropane, camphorsulfonic acid (H₂O); vii, 10% (PPh₃)₂PdCl₂, Et₃N, DMA, 100 °C; viii, Red-Al, THF, rt→reflux; ix, (PhO)₂P(O)N₃, PPh₃, EtO₂CN[double bond, length half m-dash]NCO₂Et, THF; x, H₂, 10% Pd/C, EtOH; xi, MeOH, 110 °C; xii, HCHO, NaBH(OAc)₃, MeOH; xiii, Na, NH₃.

2.2.3 Indoloiminoquinolines. A new discorhabdin, discorhabdin Q 100 (16,17-dehydrodiscorhabdin B), has been isolated from cytotoxic extracts of the sponge Latrunculia purpurea and Zyzzyamassalis, Z. fuliginosa, and Z. spp.⁷⁸ Its structure has been solved by spectroscopic analysis and comparison to known compounds such as discorhabdin B. Discorhabdin Q 100 exhibits moderate cytotoxic activity (GI₅₀ = 0.5 μg mL⁻¹) possessing essentially a differential cytotoxic profile in a NCI 60 cell line antitumor screen.

Total syntheses of marine alkaloids batzelline A 101a, batzelline B 101b, isobatzelline A 102a, and isobatzelline B 102b, isolated from the genus Batzella,⁷⁹ have been reported. Their tricyclic pyrroloquinoline rings (103 and 104) have been prepared from a quinoline derivative (Scheme 19). Batzelline B 101b has also been synthesized from the pyrroloquinoline 104 in two steps.⁸⁰

Scheme 19 Reagents: i, NiCl₂, NaBH₄, MeOH, acetic formic anhydride; ii, DDQ, CH₂Cl₂, K₂CO₃, MeOH; iii, MeI, NaH, THF; iv, Me₂S, SOCl₂, CH₂Cl₂; v, aq NaOH, CAN, MeCN, H₂O; vi, NH₄Cl, MeOH, Ar, 40 °C; vii, NCS, DMF; viii, DDQ, CH₂Cl₂; ix, BBr₃, CH₂Cl₂, O₂; x, HCl, MeOH.

The first total synthesis of a new type of the pyrroloiminoquinone marine alkaloid veiutamine 105, isolated from the Fijian sponge Zyzzya fuliginosa,⁸¹ has been achieved (Scheme 20).⁸² The key step of this work is regioselective functionalization at the 6-position of pyrroloquinoline nucleus (106→107→108).⁸³ This alkaloid has potent anticancer activity against solid tumors versus leukemia (IC₅₀ = 0.12 μg mL⁻¹ in a 25 cell line panel and IC₅₀ = 0.3 μg mL⁻¹ against the human colon tumor cell line HCT-116).⁸¹

Scheme 20 Reagents: i, t-BuLi, Et₂O, 0 °C, Cl₃CCCl₃; ii, Ac₂O, toluene, 0 °C; iii, Et₂AlCN, toluene, 0 °C; iv, LiAlH₄, benzene, Et₂O, reflux; v, lithium isopropylcyclohexylamide, THF, 0 °C; vi, Boc₂O, reflux; vii, s-BuLi, TMEDA, Et₂O, −78 °C, p-MOMO-C₆H₄-CHO; viii, NaH, THF, 0 °C; ix, H₂, Pd(OH)₂-C, MeOH, AcOEt, rt; x, TBAF, THF, rt; xi, Fremy’s salt, pH = 7.0, 0 °C; xii, NH₄Cl, MeOH, rt, cat. HCl, reflux, NaHCO₃, TFA.

A total synthesis of the marine alkaloid makaluvamine F 109, isolated from the Fijian sponge Zyzzya cf. marsailis and the Indonesian sponge Histodermella sp. (G),⁸⁴ has been completed. The key steps are the formation of the pyrroloiminoquinone nucleus 110, the formation of the dihydrobenzothiophene ring 111, and the preparation of α-azidodihydrobenzothiophene 112 by the hypervalent iodine(III) induced reactions, respectively (Scheme 21).⁸⁵ Makaluvamine F 109 exhibits the potent cytotoxicity towards the human colon tumor cell line HCT-116 (IC₅₀ = 0.17 μM) and the inhibition of topoisomerase II.⁸⁴

Scheme 21 Reagents: i, PIFA-Me₃SiOTf, (CF₃)₂CHOH, H₂O; ii, PIFA, BF₃·Et₂O; iii, aq. MeNH₂; iv, BF₃·Et₂O, EtSH; v, Ac₂O; vi, PhI[double bond, length half m-dash]O, Me₃SiN₃; vii, NaOH, MeOH; viii, H₂, 10% Pd/C, EtOH, TFA; ix, 110, MeOH, rt.

2.2.4 β-Carbolines. A new β-carboline alkaloid, 2-methyl-9H-pyrido[3,4-b]indole-3-carboxylic acid 113 has been isolated from the EtOH extract of Lignopsis spongiosum and characterized by spectral methods.⁸⁶ The two novel trypargimine 114a and 1-carboxytrypargimine 114b have been found from a new Eudistoma sp. ascidian together with the known β-carboline alkaloid trypargine.⁸⁷ A new manzamine congenor, 1,2,3,4-tetrahydromanzamine B 115 has been isolated from a Okinawan marine sponge Amphimedon sp. The absolute stereochemistry of 115 has been established as (1S )-1,2,3,4-tetrahydromanzamine B 115 by CD spectra. This compound 115 exhibits cytotoxicity against L1210 murine leukemia cells and KB human epidermoid carcinoma cells (IC₅₀ = 0.3 and 1.2 μg mL⁻¹, respectively).⁸⁸

Three new β-carboline alkaloids, (−)-isocyclocapitelline 116a, (+)-cyclocapitelline 116b and isocrysotricine 116c together with the known crysotricine (found in Hedyotis crysotricha ⁸⁹), have been isolated from Hedyotis capitellata ⁹⁰ producing capitelline.⁹¹ Further, two new β-carboline alkaloids, hedyocapitelline 117a and hedyocapitine 117b, have been found from Hedyotis capitellata var. molis by the same group.⁹² Species of the genus Hedyotis have been used in the traditional Chinese and Vietnamese medicine.

Isoharmine 118, isolated from the seeds of Perganum harmala,⁹³ has been synthesized by a Pictet–Spengler reaction. Thermolysis of 3-cyanomethyl-2-vinylindole led to indolylacrylonitrile instead of 118.⁹⁴ Total syntheses of N ⁹-substituted β-carboline alkaloids didemnolines A 119a, B 119b, C 120a and D 120b, isolated from the marine ascidian of the genous Didemum,⁹⁵ have been accomplished. Didemnolines A 119a and B 119b have been synthesized by the reaction of β-carboline 121a or 121b with 4-chloromethylimidazole derivative 122. Didemnolines C 120a and D 120b have been derived by oxidation of A 119a and B 119b, respectively (Scheme 22).⁹⁶

Scheme 22 Reagents: i, KOH, DMF; ii, 6 M HCl, 110 °C; iii, NaIO₄, MeOH, H₂O, rt.

Total syntheses of 4,8-dioxygenated β-carboline alkaloids 123a, 123b, 123c, and 123d, isolated from Simarubaceae plants,⁹⁷ have been established.⁹⁸ The key steps are an improved Fischer indolization ⁹⁹ for the synthesis of 7-oxygenated indole 124 and the construction of a 4-methoxy-β-carboline skeleton 125 by an intramolecular C-3-selective cyclization (Scheme 23).

Scheme 23 Reagents: i, Polyphosphoric acid, 70 °C; ii, DIBAL-H, CH₂Cl₂, −78 °C; iii, act MnO₂, CH₂Cl₂; iv, NH₂CH₂CO₂Et, NaBH₃CN, MeOH, rt; v, HCO₂Et, HCO₂H, rt; vi, MsOH, 55 °C; vii, (MeO)₂CMe₂, TsOH, chloranil, benzene, rt; viii, Na-naphthalenide, 0 °C; ix, TMSCH₂N₂, THF, MeOH, rt; x, m-CPBA, CH₂Cl₂, rt; xi, diethylphosphoryl cyanide, Et₃N, Cl(CH₂)₂Cl; xii, HCl, MeOH, reflux.

Manzamine A 127, which exhibits potent antitumor activity in a number of assays,¹⁰⁰ was the first member of this group of alkaloids to be isolated. Enantioselective total syntheses of a biogenetic precursor ¹⁰¹ of manzamine alkaloids ircinal A 126, isolated from the Okinawan marine sponge of Ircinia sp.¹⁰² and the formal total synthesis of manzamine A 127, isolated from the Okinawan marine sponge of the genera Haliclona sp. and Pellina sp.,¹⁰⁰ have been completed. The key steps are a novel strategy for constructing the tricyclic ring core (128→129) by a domino Stille/Diels–Alder reaction and two sequential ring closing metathesis reactions by Grubbs ruthenium catalyst 130 for constructing 13- and 8-membered rings leading to ircinal A 126 (Scheme 24).¹⁰³

Scheme 24 Reagents: i, H₂C[double bond, length half m-dash]CH-SnBu₃, Pd(PPh₃)₄, toluene, reflux; ii, 0.13 equiv. 130, reflux; iii, KOH, MeOH, reflux; iv, H₂C[double bond, length half m-dash]CH(CH₂)₃COCl, Et₃N; v, 1.1 equiv. 130, reflux, then 1 M HCl; vi, DIBAL-H; vii, Dess–Martin periodinane.

An approach to manzamine alkaloids based upon biogenetic considerations has been investigated by reactions of aminopentadienal derivatives with 5,6-dihydropyridinium salts.¹⁰⁴

2.2.5 Canthinones and indolopyridoquinazolines. The canthin-5,6-dione alkaloids, picrasidine L 131a, picrasidine O 131b and euryamine E 131c, isolated from Picrasma quassioides Bennet and Eurycomalongifolia Jack,¹⁰⁵ have been synthesized by a one-step procedure (Scheme 25).¹⁰⁶ The structure of synthetic 131b has been established by X-ray crystallographic analysis. Canthin-5,6-diones exhibit weak antibiotic activity against P-388 murine leukemia cells and PC-6 human lung carcinoma cells. The cytotoxic alkaloid canthin-6-one 132 ¹⁰⁷ has been synthesized from harmalan in six-steps on the basis of a single electron transfer induced radical cationic hetero [4+2]cycloaddition (133→134) as the key step (Scheme 26).¹⁰⁸

Scheme 25

Scheme 26 Reagents: i, Tf₂O, Et₃N, CH₂Cl₂, 0 °C; ii, methyl (E )-3-(N,N-dimethylamino)acrylate, 400 mV, MeCN, CH₂Cl₂, 0.1 M LiClO₄; iii, Na, naphthalene, DME, 0 °C; iv, MnO₂, CH₂Cl₂; v, HCl; vi, Cu, pyridine.

Three known indolopyridoquinazoline alkaloids have been isolated from the fruits of Evodia rutaecarpa by bioassay guided fractionation indicating with the inhibitory activity of cycloxygenase inhibitor (COX-2).¹⁰⁹ A new COX-2 inhibitor has been identified as known rutaecarpine 135,^110a which displays strong COX-2 inhibitory activity (IC₅₀ = 80 ng mL⁻¹). Two other alkaloids have also been identified as known related alkaloids, evodiamine and dehydroevodiamine.^110b

3 Isoprenoid tryptamines

Biosynthesis of the pipecolate moiety of marcfortine A 136, isolated from the culture of Penicillium roqueforti,¹¹¹ has been reported.¹¹² It has been established that the pipecolic acid moiety of 136 is formed from L-lysine with  ¹⁵N-labelled precursors.

A new teleocidin-related metabolite, (−)-14-O-malonylindolactam-V 137, has been isolated from the culture broth of Streptomyces blastmyceticum NA 34-17 which produces a large quantity of (−)-indolactam-V along with a small quantity of (−)-14-O-acetylindolactam-V.¹¹³

3.1 Ergot alkaloids

Pibocin 138, the first representative of marine ergoline alkaloids, has been found in the Far Eastern ascidian Eudistoma sp.¹¹⁴ Its structure and absolute stereochemistry have been established as (8β)-2-bromo-6,8-dimethylergoline on the basis of spectroscopic and X-ray analyses. Pibocin 138 exhibits cytotoxicity against mouse Ehlrich carcinoma cells (ED₅₀ 12.5 μg mL⁻¹). The enantioselective separation method of the semisynthetic ergot alkaloids using the macrocyclic antibiotics, vancomycin and teicomycin as chiral stationary phase in reversed-phase HPLC, has been investigated.¹¹⁵

The first total synthesis of optically active costaclavine 139, isolated from the culture of Agrppyrum or Penicillium type fungi,¹¹⁶ has been accomplished ¹¹⁷ starting from the tricyclic key compound 140 of chanoclavine synthesis.¹¹⁸ The key steps are the formation of the tricyclic ring 140 using palladium(0)-catalyzed intramolecular cyclization and the construction of the tetracyclic ring 141 having cis-conformation (Scheme 27).

Scheme 27 Reagents: i, Pd(0); ii, H₂, Pd/C, MeOH, rt; iii, Tebbe reagent, toluene, THF, pyridine, −20 °C; iv, 10% HCl; v, BF₃·THF, THF, 0 °C, then NaOH, H₂O₂; vi, TsCl, pyridine, DMAP, 50 °C; vii, TFA, CHCl₃, rt; viii, Mg, MeOH, rt.

4 Bisindole alkaloids

Phalarine 142 possessing a novel furanobisindole structure, has been isolated from Phalaris coerulescens.¹¹⁹ Its structure has been determined by mass and NMR spectrometric examinations. Three novel bromoindole sulfonic acids, echinosulfonic acids A 143a, B 143b, and C 143c along with a new sulfone, echinosulfone A 144 have been isolated from the marine sponge Echinodictyum sp. collected in Australia.¹²⁰ The structures assigned to these compounds were on the basis of detailed spectroscopic analysis.

Two new bisindole alkaloids bromodeoxytopsentin 145a and isobromodeoxytopsentin 145b have been isolated from the sponge Spongosorites genitrix together with known deoxytopsentin 145c and bromotopsentin 145d, and their structures have been elucidated by spectroscopic methods.¹²¹ These compounds exhibit moderate cytotoxicity against a human leukemia cell-line K-562 (IC₅₀ = 0.6 and 2.1 μg mL⁻¹, for 145a and 145b, respectively).

Five new asterriquinone analogs 146b, 146c, 146d, 146f and 146g, together with previously identified neoasterriquinone 146a and isoasterriquinone 146e, have been discovered in a fermentation broth of the fungs Aspergillus candidus.¹²² The structures have been determined by 1D and 2D NMR and MS/MS techniques. All seven compounds have shown inhibitory activity against the binding of the Grb-2 adapter to phosphorylated EGF receptor tyrosine kinase.

A new class of bisindole alkaloids iheyamine A 147a and B 147b, exhibiting moderate cytotoxicity, have been isolated from a colonial ascidian Polycitorella sp. collected off the Iheya island of Okinawa.¹²³ Their structures have been established as a new polycyclic heteroaromatic system by interpretation of spectral data, but the absolute stereochemistry of iheyamine B 147b at C-1 and C-2 is still unknown.

The total synthesis of a bisindole alkaloid, hyrtiosin B 148 possessing cytotoxic activity against human epidermoid carcinoma KB cells, found in the Okinawan marine sponge Hyrtios erecta,¹²⁴ has been achieved by a coupling reaction of the zinc metallated indole, prepared from 5-methoxyindole 149, with glyoxylyl chloride 150 as the key step (Scheme 28).¹²⁵

Scheme 28 Reagents: i, (COCl)₂, Et₂O, 0 °C; ii, EtMgBr, Et₂O, rt, ZnCl₂, 150; iii, BBr₃, CH₂Cl₂, −78 °C.

The first total synthesis of a new bisindole alkaloid caulersin 151, isolated from the alga Caulerpa serrulata,¹²⁶ has been achieved by employing a Michael type addition (152→153) and an intramolecular nucleophilic substitution (153→154) (Scheme 29).¹²⁷

Scheme 29 Reagents: i, o-xylene, reflux; ii, methyl vinyl ketone, MeNO₂, BF₃·Et₂O, 0 °C; iii, t-BuOK, t-BuOH, reflux; iv, DDQ, benzene, reflux; v, KOCl, MeOH, rt; vi 6 M HCl, MeOH, reflux.

4.1 Indolocarbazoles

Indolocarbazostatin 155 has been isolated from a culture broth of Streptomyces sp.¹²⁸ The compound 155 inhibits NGF-induced neurite outgrowth from PC12 cells at 6 nM, whereas K252a (158) inhibits at 200 nM under the same assay conditions. The IC₅₀ values of 155 and K252a 158 for protein kinase C from rat brain are 2.0 and 25.0 nM, respectively. Two new indolocarbazole alkaloids, 3-hydroxy-3′-demethoxy-3′-hydroxystaurosporine 156a and 11-hydroxy-4′-N-demethylstaurosporine 156b together with five known staurosporine congeners have been isolated from the marine ascidian Eudistoma toealenis and its predatory flatworm Pseudoceros sp.¹²⁹ The structures have been determined by 1D and 2D homonuclear NMR spectroscopies and from comparison with data of known compounds. A further two new indolocarbazole alkaloids holyrines A 157a and B 157b along with staurosporine, desmethylstaurosporine, and K252d have been isolated from the culture of marine actinomycete obtained from the North Atlantic Ocean,¹³⁰ and their structures have been elucidated by spectroscopic analysis. Holyrines A 157a and B 157b are new members of the indolocarbazole alkaloids having a single attachment of amino sugar to the aromatic aglycon.

The stereocontrolled total synthesis of indolocarbazole alkaloid (+)-K252a 158, isolated from Actinomadura sp. (SF-2370) and Nocardiopsis sp. K252a,¹³¹ has been accomplished in a twenty-three step sequence with an overall yield of 10%. The key steps are the regioselective N-glycosidation of the indole (159→161) and the construction of the indolo[2,3-a]carbazole framework by nonoxidative photocyclization (162→163) (Scheme 30).¹³²

Scheme 30 Reagents: i, allyl bromide, K₂CO₃, DMF, rt; ii, NBS, CCl₄, rt; iii, NaH, MeCN, 160, rt; iv, DBU, MS 4 Å, THF, 60 °C; v, i-Pr₂NEt, hν, CH₂Cl₂, rt; vi, KI, I₂, DBU, THF, rt.

Indolocarbazole glycoside AT2433-B1 164, isolated from the cultures broth of Actinomadura melliaura ATCC39691 ¹³³ and Actinomadura melliaura SCC1655,¹³⁴ has been synthesized by using Mannich cyclization (166→167) for the construction of indolo[2,3-a]carbazole system and the selective N-glycosidation (167→164) (Scheme 31).¹³⁵ The stereochemistry of the amino sugar of 164 has also been revised by CD spectrum analysis.

Scheme 31 Reagents: i, AgClO₄, SnCl₂, THF, −10 °C; ii, H₂ (50 psi), Pd/C, DMF; iii, TFA (neat); iv, 165, MeOH, reflux; v, DDQ, THF; vi, HCl, MeOH.

Improved synthesis of cytotoxic and antiviral 6-cyano-5-methoxy-12-methylindolo[2,3-a]carbazole 168, isolated from blue-green alga Nostoc sphaericum Ex-5-1,¹³⁶ has been achieved starting from indigo 169 in six steps with an overall yield of 59% (Scheme 32).¹³⁷

Scheme 32 Reagents: i, Sn, AcOH, Ac₂O, 64–65 °C; ii, Cl₂CHCOCl, EtOAc, reflux; iii, aq. 1.3% NH₃, MeOH, DMF, rt; iv, Me₂SO₄, K₂CO₃, rt; v, NaCN, DMF, H₂O, 70 °C; vi, CH₂N₂, rt.

4.2 Duocarmycins

CC-1065 and the duocarmycins are the parent members of a class of potent naturally occurring antitumor antibiotics which derive their biological properties through the sequence selective alkylation of duplex DNA. 1,2,9,9a-Tetrahydrocyclopenta[c]-benzoindol-4-one (CBI) analogs 170a and 170b incorporating the natural CPI alkylation subunit of CC-1065, have been synthesized and evaluated for their antitumor activity by Boger group.¹³⁸ A new antibiotic gilvusmycin 171 has been isolated from the culture broth of Streptomyces sp. QM16.¹³⁹ The structure has been related to CC-1065 and determined by NMR spectral analysis. Gilvusmycin 171 exhibits antitumor activity against murine leukemia P388 invivo.

4.3 Dimeric β-carbolines

A total synthesis of a dimeric β-carboline alkaloid ochrolifuanine A 172, isolated from Apocynaceae,¹⁴⁰ has been completed in seven steps by Michael type condensation of ethyl acrylate and tryptamine as the key step (Scheme 33).¹⁴¹

Scheme 33 Reagents: i, THF, rt; ii, 10% HCl; iii, NaHCO₃, H₂O, EtOH, Et₂O; iv, ethyl α-formylbutyrate, Et₂O, reflux; v, NaH, benzene, reflux; vi, NaH, triethylphosphonoacetate, DME, rt; vii, H₂, 10% Pd-C, EtOH, rt; viii, DIBAL-H, toluene, −73 °C; ix, tryptamine, 0.2 M phosphate buffer, 40 °C.

5 Peptide alkaloids containing a tryptophan residue

A new antibiotic zelkovamycin 173 has been isolated from the fermentation broth of Streptomyces sp. K96-0670.¹⁴² Zelkovamycin 173 is a cyclic peptide containing a thiazole ring and a modified tryptophan residue, and the structure has been established by spectroscopic studies including ¹H–¹H COSY, ¹³C–¹H COSY, ¹³C–¹H HMQC, ¹³C–¹H HMBC, ¹⁵N–¹H HMQC and ¹⁵N–¹H HMBC NMR experiments.

Two jaspamide derivatives B 174a and C 174b along with jaspamide have been newly isolated from the marine sponge Jaspis splendans collected in Vanuatu.¹⁴³ Their structures have been determined by 1D and 2D NMR experiments and MS data. These two compounds inhibit the growth of the NSCLC-N6 human tumor cell lines in vitro with IC₅₀ values of 3.3 μg mL⁻¹ and 1.1 μg mL⁻¹, respectively.

A novel 14-membered cyclopeptide alkaloid Waltherine-C 175 has been isolated, together with four known cyclopeptide alkaloids from the bark of Waltheria douradinha (Sterculiaceae).¹⁴⁴ The structure has been elucidated on the basis of 2D NMR spectral data, such as ¹H–¹H COSY, NOESY, HMQC and HMBC experiments, and FAB mass spectrum.

Two new peptides, tylopeptins A 176a and B 176b, have been isolated from the methanol extract of the fruiting body of the mushroom, Tylopilus neofelleus.¹⁴⁵ Compounds 176a and 176b were determined to be linear peptides possessing an acetylated N-terminal residue, fourteen amino acids, and leucinol as C-terminal amino alcohol by FAB mass spectroscopy and two dimensional techniques (COSY and HOHAHA). These peptides exhibit antimicrobial activity against some Gram-positive bacteria.

Three new cyclic heptapeptides, cyclomarins A–C (177a–177c), have been isolated from the extract of a cultured marine bacterium collected in the vicinity of San Diego.¹⁴⁶ The structure of the major component, cyclomarin A 177a contained three common and four unusual amino acids, and was determined using 1D and 2D NMR methods. Futhermore, the stereochemistry of the diacetate derivative of 177a has been determined by X-ray analysis. The structures of cyclomarins B 177b and C 177c have been assigned by comparison with spectral data for 177a. Cyclomarin A 177a shows antiinflammatory activity in both in vivo and in vitro assays.

The total synthesis of semi-synthetic cyclic heptapeptide dihydro-WIN67689 178c, isolated from Aspergillus flavipes ¹⁴⁷ has been completed, and the stereochemistry of the β-hydroxy group of the isoprenyltyrosine moiety in 178a–c has been established as R-configuration (Scheme 34).¹⁴⁸ Substance P antagonist activity of 178c is 70 times more potent than WIN66306 178a and the same potent as WIN67689 178b, isolated from the same species.

Scheme 34 Reagents; i, (R)-Schöllkopf ’s reagent, BuLi, −78 to −20 °C; ii, 0.25 M TFA; iii, H₂, Pd/C, MeOH; iv, Cbz-Gly-Val-Gly-OH, HOBt, EDCI, iPr₂NEt, CH₂Cl₂; v, LiOH, MeCN; vi, TFA, Gly-Trp-Pro-Obn, HOBt, EDCI, iPr₂NEt, CH₂Cl₂; vii, H₂, Pd/C, MeOH; viii, pentafluorophenyl diphenylphosphinate, DMF, iPr₂NEt.

The first total synthesis of cyclic heptadepsipeptide HUN-7293 180, isolated from a fungal broth during a screen for potent inhibitors of inducible cell adhesion molecule expression and from a different fungal species based on a screen for anti-HIV compounds,¹⁴⁹ has been achieved by the Boger group.¹⁵⁰ The approach is based on a Mitsunobu esterification between tetrapeptide 181 and tripeptide 182 followed by macrocyclization (183→180) (Scheme 35). It has been confirmed by biological evaluation that synthetic HUN-7293 180 is indistinguishable from the naturally occurring cyclodepsipeptide.

Scheme 35 Reagents; i, Ph₃P, DIAD, toluene; ii, TFA, anisole; iii, HATU, collidine.

The first total synthesis of keramamide J 184, isolated from an Okinawan marine sponge Theonella sp.,¹⁵¹ has been established.¹⁵² The synthesis has been achieved by using four fragment amides 185, 186, 187 and 190 which are assembled from the appropriate amino acid constituents (Scheme 36). The structure of synthetic keramamide J 184 was not identical with that of natural keramamide J.

Scheme 36 Reagents; i, HCl, Et₂O; ii, DCC, HOBt, iPr₂NEt; iii, Pd(PPh₃)₄, dimedone; iv, DCC, HOBt, iPr₂NEt; v, Pd(PPh₃)₄, dimedone; vi, Et₂NH; vii, (PhO)₂PON₃, NaHCO₃; viii, HCl, MeOH; ix, HATU, 2,4,6-collidine; x, o-iodoxybenzoic acid, DMSO; xi, Amberlite IR-120.

A synthetic approach to a 23-membered cyclic hexapeptide, microsclerodermines A 191a and B 191b, isolated from the lithistid marine sponge Microscleroderma sp.,¹⁵³ has been reported by Shioiri group.¹⁵⁴

6 Indole alkaloids with a nonrearranged monoterpenoid unit

Three new alkaloids, 3-hydroxywelwitindolinone C isonitrile 192a, 3-hydroxy-N-methylwelwitindolinone C isothiocyanate 192b, and N-methylwelwitindolinone D isonitrile 192d together with 3-hydroxy-N-methylwelwitindolinone C formamide 192c and known welwitindolinones ¹⁵⁵ have been isolated from two terrestrial Fischerella spp. belonging to the Stigonemataceae.¹⁵⁶ The compound 192a is readily converted to 3-hydroxy-N-methylwelwitindolinone C formamide 192c by hydration during the isolation procedure. The compound 192d is a novel cyclic ether of welwitindolinones.

References

1. (a) D. J. Faulkner, Nat. Prod. Rep., 2000, 17, 1; (b) D. J. Faulkner, Nat. Prod. Rep., 2000, 17, 7.
2. J. R. Lewis, Nat. Prod. Rep., 2000, 17, 57.
3. M. Nakagawa, Y. Torisawa, H. Uchida and A. Nishida, J. Synth. Org. Chem. Jpn., 1999, 57, 1002.
4. A. Qureshi and D. J. Faulkner, J. Nat. Prod., 1999, 13, 59.
5. I. Çalis, A. Kuruüzüm and P. Rüedi, Phytochemistry, 1999, 50, 1205.
6. L. Suescun, R. A. Mariezcurrena, A. W. Mombrú, D. Davyt and E. Monta, Acta Crystallogr., Sect. A, Fundam. Crystallogr., 1999, 55, 211.
7. N. Phay, T. Higashiyama, M. Tsuji, H. Matsuura, Y. Fukushi, A. Yokota and F. Tomita, Phytochemistry, 1999, 52, 271.
8. T. R. Kelly, Y. Fu and R. L. Xie, Tetrahedron Lett., 1999, 40, 1857.
9. (a) Y. Koyama, R. Yokose and L. J. Dolby, J. Agric. Biol. Chem., 1981, 45, 1285; (b) M. Noltemeyer, G. M. Sheldrick, H.-U. Hoppe and A. Zeeck, J. Antibiot., 1982, 35, 549; (c) K. Umehara, K. Yoshida, M. Okamoto, M. Iwami, H. Tanaka, M. Kohsaka and H. Imanaka, J. Antibiot., 1984, 37, 1153; (d) D. S. Bhate, R. K. Hulyalkar and S. K. Menon, Experientia, 1966, 16, 504; (e) B. S. Joshi, W. I. Taylor, D. S. Bhate and S. S. Karmarkar, Tetrahedron, 1963, 19, 1437.
10. L. Garlaschelli, Z. Pang, O. Sterner and G. Vidari, Tetrahedron, 1994, 50, 3541.
11. B. C. Söderberg, A. G. Chisnell, S. N. O’Neil and J. A. Shriver, J. Org. Chem., 1999, 64, 9731.
12. G. B. Quistad, C. C. Reuter, W. S. Skinner, P. A. Dennis, S. Suwanrumpha and E. W. Fu, Toxicon, 1991, 29, 329.
13. Y. Hida, T. Kan and T. Fukuyama, Tetrahedron Lett., 1999, 40, 4711.
14. S. P. Gunasekera, P. J. McCarthy, R. E. Longley, S. A. Pomponi and A. E. Wright, J. Nat. Prod., 1999, 62, 1208.
15. O. D. Hensens, J. G. Ondeyka, A. W. Dombrowski, D. A. Ostlind and D. L. Zink, Tetrahedron Lett., 1999, 40, 5455.
16. J. G. Ondeyka, G. L. Helms, O. D. Hensens, M. A. Goetz, D. L. Zink, A. Tsipouras, W. L. Shoop, L. Slayton, A. W. Dombrowski, J. D. Polishook, D. A. Ostlind, N. N. Tsou, R. G. Ball and S. B. Singh, J. Am. Chem. Soc., 1997, 119, 8809.
17. J. Hurter, T. Ramp, B. Patrian, E. Städler, P. Roessingh, R. Baur, R. de Jong, J. K. Niersen, T. Winkler, W. J. Richter, D. Müller and B. Ernst, Phytochemistry, 1999, 51, 377.
18. M. S. C. Pedras, J. L. Sorensen, F. I. Okanga and I. L. Zaharia, Bioorg. Med. Chem. Lett., 1999, 9, 3015.
19. (a) S. J. Danishefsky and J. M. Schkeryantz, Synlett, 1995, 475; (b) Z. Wang and L. S. Jimenez, Tetrahedron Lett., 1996, 37, 6049and related references cited therein..
20. S. Lee, W.-M. Lee and G. A. Sulikowski, J. Org. Chem., 1999, 64, 4224.
21. W. Dong and L. S. Jimenez, J. Org. Chem., 1999, 64, 2520.
22. M. T. H. Nutan, C. M. Hasan and M. A. Rashid, Fitoterapia, 1999, 70, 130.
23. T.-S. Wu, S.-C. Huang, P.-L. Wu and C.-S. Kuoh, Phytochemistry, 1999, 52, 523.
24. A. K. Chakravarty, T. Sarkar, K. Masuda and K. Shiojima, Phytochemistry, 1999, 50, 1263.
25. G. Lin and A. Zhang, Tetrahedron Lett., 1999, 40, 341.
26. M. Kaneda, T. Naid, T. Kitahara, S. Nakamura, T. Hirata and T. Suga, J. Antibiot., 1988, 41, 602 and related references cited therein..
27. H.-J. Knölker and W. Fröhner, Tetrahedron Lett., 1999, 40, 6915.
28. J. H. Cardellina II, M. P. Kirkup, R. E. Moore, J. S. Mynderse, K. Seff and C. J. Simmons, Tetrahedron Lett., 1979, 4915.
29. H.-J. Knölker, E. Baum and T. Hopfmann, Tetrahedron, 1999, 55, 10391.
30. C. Ito and H. Furukawa, Chem. Pharm. Bull., 1990, 38, 1548.
31. T. Soós, G. Timári and G. Hajós, Tetrahedron Lett., 1999, 40, 8607.
32. (a) H. W. Rauwald, M. Kobar, E. Mutschler and G. Lambrecht, Planta Med., 1992, 58, 486; (b) K. Cimanga, T. De Bruyne, A. Lasure, B. Van Poel, L. Pieters, M. Claeys, D. Vanden Berghe, K. Kambu, L. Tona and A. J. Vlietinck, Planta Med., 1996, 62, 22; (c) K. Cimanga, T. De Bruyne, L. Pieters and A. J. Vlietinck, J. Nat. Prod., 1997, 60, 688; (d) D. E. Bierer, D. M. Fort, C. D. Mendez, J. Lou, P. A. Imbach, L. G. Dubenko, S. D. Jolad, R. E. Gerber, J. Litvak, Q. Lu, P. Zhang, M.-J. Reed, N. Waldeck, R. C. Bruening, B. K. Noamesi, R. F. Hector, T. J. Carlson and S. R. King, J. Med. Chem., 1998, 41, 894.
33. C. E. Hadden, M. H. M. Sharaf, J. E. Guido, R. H. Robins, A. N. Tackie, C. H. Phoebe Jr., P. L. Schiff Jr. and G. E. Martin, J. Nat. Prod., 1999, 62, 238.
34. (a) J. L. Pousset, A. Jossag and B. Bock, Phytochemistry, 1995, 39, 735; (b) K. Cimanga, T. De Bruyne, L. Pieters, M. Claeys and A. Vlietinck, Tetrahedron Lett., 1996, 37, 1703; (c) M. H. M. Sharaf, P. L. Schiff Jr., A. N. Tackie, C. H. Phoebe Jr. and G. E. Martin, J. Heterocycl. Chem., 1996, 33, 239.
35. P. M. Fresneda, P. Molina and S. Delgado, Tetrahedron Lett., 1999, 40, 7275.
36. P. Molina, P. M. Fresneda and S. Delgado, Synthesis, 1999, 326.
37. E. Arzel, P. Rocca, F. Marsais, A. Godard and G. Quéguiner, Tetrahedron, 1999, 55, 12149.
38. (a) E. Arzel, P. Rocca, F. Marsais, A. Godard and G. Quéguiner, Tetrahedron Lett., 1998, 39, 6465; (b) P. Rocca, C. Cochennec, F. Marsais, L. Thomas-dit-Dumont, M. Mallet, A. Godard and G. Quéguiner, J. Org. Chem., 1993, 58, 7832.
39. C.-Y. Chen, F.-R. Chang, C.-M. Teng and Y.-C. Wu, J. Chin. Chem. Soc., 1999, 46, 77.
40. D. Chávez, L. A. Acevedo and R. Mata, J. Nat. Prod., 1999, 62, 1119.
41. Y. Kamano, H. Morita, R. Takano, A. Kotake, T. Nogawa, H. Hashima, K. Takeya, H. Itokawa and G. R. Pettit, Heterocycles, 1999, 50, 499.
42. N. M. Cuong, W. C. Taylor and T. V. Sung, Phytochemistry, 1999, 52, 1711.
43. (a) A. Hofmann, R. Heim and H. Kobel, Experientia, 1958, 14, 107; (b) A. Hofmann, R. Heim, A. Brack, H. Kobel, A Frey, H. Ott, T. Petrzilka and F. Troxler, Helv. Chim. Acta, 1959, 42, 1557; (c) T. J. Petcher and H. P. Weber, J. Chem. Soc., Perkin Trans. 2, 1974, 946.
44. H. Sakagami and K. Ogasawara, Heterocycles, 1999, 51, 1131.
45. H. Takayama, T. Shimizu, H. Sada, Y. Harada, M. Kitajima and N. Aimi, Tetrahedron, 1999, 55, 6841.
46. (a) Y. Kamano, H. Zhang, Y. Ichihara, H. Kizu, K. Komiyama and G. R. Pettit, Tetrahedron Lett., 1995, 36, 2783; (b) H. Zhang, Y. Kamano, Y. Ichihara, H. Kizu, K. Komiyama, H. Itokawa and G. R. Pettit, Tetrahedron, 1995, 51, 5523.
47. (a) G. K. Jnaneshwar and V. H. Deshpande, J. Chem. Res. (S ), 1999, 632; (b) G. K. Jnaneshwar, A. V. Bedekar and V. H. Deshpande, Synth. Commun., 1999, 29, 3627.
48. D. J. Hart and N. Magomedov, Tetrahedron Lett., 1999, 40, 5429.
49. A. Jossang, P. Jossang, H. A. Hadi, T. Sevenet and B. Bodo, J. Org. Chem., 1991, 56, 6527.
50. G. Lakshmaiah, T. Kawabata, M. Shang and K. Fuji, J. Org. Chem., 1999, 64, 1699.
51. J. H. Rigby and J. H. Meyer, Synlett, 1999, 860.
52. H. C. Vevoort, W. Fenical and P. A. Keifer, J. Nat. Prod., 1999, 62, 389.
53. R. G. S. Berlinck, R. Britton, E. Piers, L. Lim, M. Roberge, R. M. da Rocha and R. J. Andersen, J. Org. Chem., 1998, 63, 9850.
54. D. Sørensen. T. O. Larsen, C. Cristophersen, P. H. Nielsen and U. Anthoni, Phytochemistry, 1999, 51, 1181.
55. H. Fujimoto, T. Fujimaki, E. Okuyama and M. Yamazaki, Chem. Pharm. Bull., 1999, 47, 1426.
56. H. Hayashi, K. Furutsuka and Y. Shiono, J. Nat. Prod., 1999, 62, 315.
57. Y. Shiono, K. Akiyama and H. Hayashi, Biosci. Biotechnol. Biochem., 1999, 63, 1910.
58. J. E. Hochlowski, M. M. Mullaly, S. G. Spanton, D. N. Whittern, P. Hill and J. B. McAlpine, J. Antibiot., 1993, 46, 380.
59. (a) S. Takase, M. Iwami, T. Ando, M. Okamoto, K. Yoshida, H. Horiai, M. Kohsaka, H. Aoki and H. Imanaka, J. Antibiot., 1984, 37, 1320; (b) S. Takase, Y. Kawai, I. Uchida, H. Tanaka and H. Aoki, Tetrahedron, 1985, 41, 3037.
60. K. M. Depew, S. P. Marsden, D. Zatorska, A. Zatorski, W. G. Bornmann and S. J. Danishefsky, J. Am. Chem. Soc., 1999, 121, 11953.
61. (a) C.-B. Cui, H. Kakeya, G. Okada, R. Onose and H. Osada, J. Antibiot., 1996, 49, 527; (b) C.-B. Cui, H. Kakeya and H. Osada, Tetrahedron, 1997, 53, 59; (c) T. Usui, M. Kondoh, C.-B. Cui, T. Mayumi and H. Osada, Biochem. J., 1998, 333, 543.
62. (a) S. Edmondson, S. J. Danishefsky, L. Sepp-Lorenzino and N. Rosen, J. Am. Chem. Soc., 1999, 121, 2147; (b) S. Edmondson and S. J. Danishefsky, Angew. Chem., Int. Ed., 1998, 37, 1138.
63. (a) C. Shinohara, K. Hasumi, Y. Takei and A. Ando, J. Antibiot., 1994, 47, 163; (b) B. Nuber, F. Hansske, C. Shinohara, S. Miura, K. Hasumi and A. Ando, J. Antibiot., 1994, 47, 168.
64. (a) J. M. Schkeryantz, J. C. G. Woo, P. Siliphaivanh, K. M. Depew and S. J. Danishefsky, J. Am. Chem. Soc., 1999, 121, 11964; (b) K. M. Depew, S. J. Danishefsky, N. Rosen and L. Sepp-Lorenzino, J. Am. Chem. Soc., 1996, 118, 12463.
65. (a) P. S. Steyn, Tetrahedron Lett., 1971, 3331; (b) P. S. Steyn, Tetrahedron, 1973, 29, 107.
66. (a) A. J. Birch and J. J. Wright, J. Chem. Soc., Chem. Commun., 1969, 644; (b) A. J. Birch and J. J. Wright, Tetrahedron, 1970, 26, 2329.
67. (a) C.-B. Cui, H. Kakeya, G. Okada, R. Onose, M. Ubukata, I. Takahashi, K. Isono and H. Osada, J. Antibiot., 1995, 48, 1382; (b) C.-B. Cui, H. Kakeya and H. Osada, J. Antibiot., 1996, 49, 534.
68. B. W. Son, P. R. Jensen, C. A. Kauffman and W. Fenical, Nat. Prod. Lett., 1999, 13, 213.
69. L. Verotta, F. Peterlongo, E. Elisabetsky, T. T. Amador and D. S. Nunes, J. Chromatogr. A, 1999, 841, 165.
70. V. Jannic, F. Guéritte, O. Laprévote, L. Serani and M.-T. Martin, J. Nat. Prod., 1999, 62, 838.
71. I. Zhalolov, V. U. Khuzhaev, B. Tashkhodzhaev, M. G. Levkovich, S. F. Aripova and N. D. Abdullaev, Chem. Nat. Compd., 1998, 34, 706.
72. I. Zhalolov, V. U. Khuzhaev, U. A. Abdullaev and S. F. Aripova, Chem. Nat. Compd., 1999, 35, 221.
73. C. Christophersen, Acta Chem. Scand., Ser. B, 1985, 39, 517.
74. M. S. Morales-Ríos, O. R. Suárez-Castille and P. Joseph-Nathan, J. Org. Chem., 1999, 64, 1086.
75. R. K. Duke, R. D. Allan, G. A. R. Johnston, K. N. Mewett, A. D. Mitrovic, C. C. Duke and T. W. Hambley, J. Nat. Prod., 1995, 58, 1200.
76. Y. Adjibade, B. Weniger, J. C. Quirion, B. Kuballa, P. Cabalion and R. Anton, Phytochemistry, 1992, 31, 317.
77. L. E. Overman, D. V. Paone and B. A. Stearns, J. Am. Chem. Soc., 1999, 121, 7702.
78. M.-G. Dijoux, W. R. Gamble, Y. F. Hallock, J. H. Cardellina II, R. van Soest and M. R. Boyd, J. Nat. Prod., 1999, 62, 636.
79. (a) H. H. Sun, S. Sakemi, N. Burres and P. McCarthy, J. Org. Chem., 1990, 55, 4964; (b) S. Sakemi, H. H. Sun, C. W. Jefford and G. Bernadinelli, Tetrahedron Lett., 1989, 30, 2517.
80. (a) M. Alvarez, M. A. Bros and J. A. Joule, Eur. J. Org. Chem., 1999, 1173; (b) M. Alvarez, M. A. Bros and J. A. Joule, Tetrahedron Lett., 1998, 39, 679.
81. D. A. Vanables, L. R. Barrows, P. Lassota and C. M. Ireland, Tetrahedron Lett., 1997, 38, 721.
82. Y. Moro-oka, T. Fukuda and M. Iwao, Tetrahedron Lett., 1999, 40, 1713.
83. (a) M. Iwao, O. Motoi, T. Fukuda and F. Ishibashi, Tetrahedron, 1998, 54, 8999; (b) W. F. Bailey and S. C. Longstaff, J. Org. Chem., 1998, 63, 432.
84. (a) D. C. Radisky, E. S. Radisky, L. R. Barrows, B. R. Copp, R. A. Kramer and C. M. Ireland, J. Am. Chem. Soc., 1993, 115, 1632; (b) L. R. Barrows, D. C. Radisky, B. R. Copp, D. S. Swaffer, R. A. Kramer, R. L. Warters and C. M. Ireland, Anti-Cancer Drug Des., 1993, 8, 333.
85. (a) Y. Kita, M. Egi, T. Takada and H. Tohma, Synthesis, 1999, 885; (b) Y. Kita, M. Egi and H. Tohma, Chem. Commun., 1999, 143.
86. G. M. Cabrera and A. M. Seldes, J. Nat. Prod., 1999, 62, 759.
87. R. M. Van Wagoner, J. Jompa, A. Tahir and C. M. Ireland, J. Nat. Prod., 1999, 62, 794.
88. M. Tsuda, D. Watanabe and J. Kobayashi, Heterocycles, 1999, 50, 485.
89. J. N. Peng, X. Z. Feng, Q. T. Zheng and X. T. Liang, Phytochemistry, 1997, 46, 1119.
90. N. M. Phuang, T. V. Sung, A. Porzel, J. Schmidt, K. Merzweiler and G. Adam, Phytochemistry, 1999, 52, 1725.
91. N. M. Phuang, T. V. Sung, J. Schmidt, A. Porzel and G. Adam, Nat. Prod. Lett., 1998, 11, 93.
92. N. M. Phuang, T. V. Sung, A. Porzel, J. Schmidt and G. Adam, Planta Med., 1999, 65, 761.
93. M. T. Ayoub and L. J. Rashan, Phytochemistry, 1991, 30, 1046.
94. J. Sapi, D. Patigny and J.-Y. Lorenze, Heterocycles, 1999, 51, 361.
95. R. W. Schumacher and B. S. Davidson, Tetrahedron, 1995, 51, 10125.
96. R. W. Schumacher and B. S. Davidson, Tetrahedron, 1999, 55, 935.
97. (a) T. Ohmoto, K. Koike, T. Higuchi and K. Ikeda, Chem. Pharm. Bull., 1985, 33, 3356; (b) T. Ohmoto and K. Koike, Chem. Pharm. Bull., 1985, 33, 3847; (c) C. Souleles and E. Kokkalou, Planta Med., 1989, 55, 286and related references cited therein..
98. H. Suzuki, M. Unemoto, M. Hagiwara, T. Ohyama, Y. Yokoyama and Y. Murakami, J. Chem. Soc., Perkin Trans. 1, 1999, 1717.
99. Y. Murakami, Y. Yokoyama, C. Aoki, H. Suzuki, K. Sakurai, T. Shinohara, C. Miyagi, Y. Kimura, T. Takahashi, T. Watanabe and T. Ohmoto, Chem. Pharm. Bull., 1991, 39, 2189.
100. (a) R. Sakai, T. Higa, C. W. Jefford and G. Bernardinelli, J. Am. Chem. Soc., 1986, 108, 6404; (b) H. Nakamura, S. Deng, J. Kobayashi, Y. Ohizumu, Y. Tomotake, T. Matsuzaki and Y. Hirata, Tetrahedron Lett., 1987, 28, 621; (c) N. Matzanke, R. Gregg and S. Weinreb, Org. Prep. Proc. Int., 1998, 30, 1; (d) E. Magnier and Y. Langlois, Tetrahedron, 1998, 54, 6201.
101. (a) J. E. Baldwin and R. C. Whitehead, Tetrahedron Lett., 1992, 33, 2059; (b) J. E. Baldwin, T. D. W. Claridge, A. J. Culshaw, F. A. Heupel, V. Lee, D. R. Spring, R. C. Whitehead, R. J. Boughtflower, I. M. Mutton and R. J. Upton, Angew. Chem., Int. Ed., 1998, 37, 2661; (c) M. Tsuda and J. Kobayashi, Heterocycles, 1997, 46, 765.
102. K. Kondo, H. Shigemori, Y. Kikuchi, M. Ishibashi, T. Sasaki and J. Kobayashi, J. Org. Chem., 1992, 57, 2480.
103. S. F. Martin, J. M. Humphrey, A. Ali and M. C. Hillier, J. Am. Chem. Soc., 1999, 121, 866.
104. K. Jakubowicz, K. B. Abdeljelil, M. Herdemann, M.-T. Martin, A. Gateau-Olesker, A. A. Mourabit, C. Marazano and B. C. Das, J. Org. Chem., 1999, 64, 7381.
105. (a) T. Ohmoto and K. Koike, Chem. Pharm. Bull., 1982, 30, 1204; (b) T. Ohmoto and K. Koike, Chem. Pharm. Bull., 1985, 33, 3847; (c) T. Ohmoto and K. Koike, Chem. Pharm. Bull., 1985, 33, 4901; (d) K. Matsunaga, K. Koike, T. Sawaguchi and T. Ohmoto, Phytochemistry, 1994, 35, 799.
106. K. Koike, H. Yoshino and T. Nikaido, Heterocycles, 1999, 51, 315.
107. (a) T. Ohmoto, R. Tanaka and T. Nikaido, Chem. Pharm. Bull., 1976, 24, 1532; (b) T. Ohmoto, K. Koike and Y. Sakamoto, Chem. Pharm. Bull., 1981, 29, 390; (c) T. Ohmoto and K. Koike, Chem. Pharm. Bull., 1984, 32, 170; (d) H. F. Haynes, E. R. Nelson and J. R. Price, Aust. J. Sci. Res., 1952, 5, 385; (e) J.-H. Li and J. K. Snyder, Tetrahedron Lett., 1994, 35, 1485.
108. U. Rößler, S. Blechert and E. Steckhan, Tetrahedron Lett., 1999, 40, 7075.
109. S. S. Kang, J. S. Kim, K. H. Son. H. P. Kim and H. W. Chang, Nat. Prod. Sci., 1999, 5, 65.
110. (a) H. Itokawa, M. Inamatsu and K. Takeya, Shoyakugaku Zasshi, 1990, 44, 135; (b) A. Haji, Y. Momose, R. Takeda, S. Nakanishi, T. Horiuch and M. Arisawa, J. Nat. Prod., 1994, 57, 387.
111. J. Polonsky, M.-A. Merrien, T. Prange and C. J. Pascard, J. Chem. Soc., Chem. Commun., 1980, 601.
112. M. S. Kuo, D. A. Yurek, S. A. Mizsak, J. I. Cialdella, L. Baczynskyj and V. P. Marshall, J. Am. Chem. Soc., 1999, 121, 1763.
113. K. Irie, S. Tomimatsu, Y. Nakagawa, H. Ohigashi and H. Hayashi, Biosci. Biotechnol. Biochem., 1999, 63, 1669.
114. T. N. Makarieva, S. G. Ilyin, V. A. Stonik, K. A. Lyssenko and V. A. Denisenko, Tetrahedron Lett., 1999, 40, 1591.
115. E. Tesarová, K. Záruba and M. Flieger, J. Chromatogr. A, 1999, 844, 137.
116. (a) M. Abe, S. Yamatodani, T. Yamano and M. Kusumoto, Bull. Agric. Chem. Soc. Jpn., 1956, 20, 59; (b) S. Yamatodani and M. Abe, J. Agric. Chem. Soc. Jpn., 1960, 34, 366.
117. K. Osanai, Y. Yokoyama, K. Kondo and Y. Murakami, Chem. Pharm. Bull., 1999, 47, 1587.
118. Y. Yokoyama, K. Kondo, M. Mitsuhashi and Y. Murakami, Tetrahedron Lett., 1996, 37, 9309.
119. N. Anderton, P. A. Cockrum, S. M. Colegate, J. A. Edgar, K. Flower, D. Gardner and R. I. Willing, Phytochemistry, 1999, 51, 153.
120. S. P. B. Ovenden and R. J. Capon, J. Nat. Prod., 1999, 62, 1246.
121. J. Shin, Y. Seo, K. W. Cho, J.-R. Rho and C. J. Sim, J. Nat. Prod., 1999, 62, 647.
122. K. A. Alvi, H. Pu, M. Luche, A. Rice, H. App, H. Dare and B. Margolis, J. Antibiot., 1999, 52, 215.
123. T. Sasaki, I. I. Ohtani, J. Tanaka and T. Higa, Tetrahedron Lett., 1999, 40, 303.
124. J. Kobayashi, T. Murayama, M. Ishibashi, S. Kosuge, M. Takamatsu, Y. Ohizumi, H. Kobayashi, T. Ohta, S. Nozoe and T. Sasaki, Tetrahedron, 1990, 46, 7699.
125. J. Bergman, T. Janosik and A.-L. Johnsson, Synthesis, 1999, 580.
126. J.-Y. Su, Y. Zhu, L.-M. Zeng and X.-H. Xu, J. Nat. Prod., 1997, 66, 1043.
127. P. M. Fresneda, P. Molina and M. A. Saez, Synlett, 1999, 1651.
128. M. Ubukata, N. Tamehiro, N. Matsuura and N. Nakajima, J. Antibiot., 1999, 52, 921.
129. P. Schupp, C. Eder, P. Proksch, V. Wray, B. Schneider, M. Herderich and V. Paul, J. Nat. Prod., 1999, 62, 959.
130. D. E. Williams, V. S. Bernan, F. V. Ritacco, W. M. Maiese, M. Greenstein and R. J. Andersen, Tetrahedron Lett., 1999, 40, 7171.
131. (a) M. Sezaki, T. Sasaki, T. Nakazawa, U. Takeda, M. Iwata, T. Watanabe, M. Koyama, F. Kai, T. Shomura and M. Kojima, J. Antibiot., 1985, 38, 1439; (b) H. Kase, K. Iwahashi and Y. Matsuda, J. Antibiot., 1986, 39, 1059.
132. Y. Kobayashi, T. Fujimoto and T. Fukuyama, J. Am. Chem. Soc., 1999, 121, 6501.
133. J. Golik, T. W. Doyle, B. Krishnan, G. Dubay and J. A. Matson, J. Antibiot., 1989, 42, 1784.
134. J. A. Matson, C. Claridge, J. A. Bush, J. Titus, W. T. Bradner, T. W. Doyle, A. C. Horan and M. Patel, J. Antibiot., 1989, 42, 1547.
135. J. D. Chisholm, J. Golik, B. Krishnan, J. A. Matson and D. L. Van Vranken, J. Am. Chem. Soc., 1999, 121, 3801.
136. G. Knübel, L. K. Larsen, R. E. Moore, I. A. Levine and G. M. L. Patterson, J. Antibiot., 1990, 43, 1236.
137. H. Hayashi, Y. Suzuki and M. Somei, Heterocycles, 1999, 51, 1233.
138. D. L. Boger, C. W. Boyce, R. M. Garbaccio, M. Searcey and Q. Jin, Synthesis, 1999, 1505.
139. Y. Tokoro, T. Isoe and K. Shindo, J. Antibiot., 1999, 52, 263.
140. N. Peube-Locou, M. Koch, M. Plat and P. Potier, C. R. Acad. Sci., 1971, 905, 273.
141. I. P. Malhotra and N. Malhotra, J. Serb. Chem. Soc., 1999, 64, 155.
142. H. Zhang, H. Tomoda, N. Tabata, M. Oohori, M. Shinose, Y. Takahashi and S. Omura, J. Antibiot., 1999, 52, 29.
143. A. Zampella, C. Giannini, C. Debitus, C. Roussakis and M. V. D’Auria, J. Nat. Prod., 1999, 62, 332.
144. A. F. Morel, A. Flach, N. Zanatta, E. M. Ethur, M. A. Mostardeiro and I. T. S. Gehrke, Tetrahedron Lett., 1999, 40, 9205.
145. S.-J. Lee, B.-S. Yun, D.-H. Cho and I.-D. Yoo, J. Antibiot., 1999, 52, 998.
146. M. K. Renner, Y.-C. Shen, X.-C. Cheng, P. R. Jensen, W. Frankmoelle, C. A. Kauffman, W. Fenical, E. Lobkovsky and J. Clardy, J. Am. Chem. Soc., 1999, 121, 11273.
147. (a) C. J. Barrow, M. S. Doleman, M. A. Bobko and R. Cooper, J. Med. Chem., 1994, 37, 356; (b) C. J. Barrow, D. M. Sedlock, H. H. Sun, R. Cooper and A. M. Gillum, J. Antibiot., 1994, 47, 1182.
148. Y.-Q. Li, K. Sugase and M. Ishiguro, Tetrahedron Lett., 1999, 40, 9097.
149. (a) U. Hommel, H.-P. Weber, L. Oberer, H. U. Naegeli, B. Oberhauser and C. A. Foster, FEBS Lett., 1996, 379, 69; (b) H. Itazaki, T. Fujiwara, A. Sato, Y. Kawamura and K. Matsumoto, Jpn Pat., Kokai Tokkyo Koho 07109299, 1995, Appl. 93/255592, 13 Oct. 1993; Chem. Abstr., 1995, 123, 110270.
150. D. L. Boger, H. Keim, B. Oberhauser, E. P. Shreiner and C. A. Foster, J. Am. Chem. Soc., 1999, 121, 6197.
151. J. Kobayashi, F. Itagaki, H. Shigemori, T. Takao and Y. Shimonishi, Tetrahedron, 1995, 51, 2525.
152. J. A. Sowinski and P. L. Toogood, Chem. Commun., 1999, 981.
153. C. A. Bewley, C. Debitus and D. J. Faulkner, J. Am. Chem. Soc., 1994, 116, 7631.
154. S. Sasaki, Y. Hamada and T. Shioiri, Tetrahedron Lett., 1999, 40, 3187.
155. (a) K. Startmann, R. E. Moore, R. Bonjouklian, J. B. Decter, G. M. Patterson, S. Shaffer, C. D. Smith and T. A. Smitka, J. Am. Chem. Soc., 1994, 116, 9935; (b) D. Klein, D. Daloze, J. C. Braekman, L. Hoffmann and V. Demoulin, J. Nat. Prod., 1995, 58, 1781.
156. J. I. Jimenez, U. Huber, R. E. Moore and G. M. L. Patterson, J. Nat. Prod., 1999, 62, 569.

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