Brominated carbolines

Unlike carbazoles, haiogenated (3-carbolines are abundant in nature [1[. For example, the simple eudistomin O (7-bromo-(3-carboline) (40) is a ubiquitous marine ascidian metabolite [44[. Indeed, the tunicate genus Eudistoma has furnished most of the extant haiogenated (3-carbolines, some of which have significant antiviral (polio, herpes) and microbial activity. The Caribbean Eudistoma olivaceum produces at least 15 brominated carbolines [1[. A study of Eudistoma gilboverde uncovered the new eudistomins 41-43[45[, and the Australian ascidian Pseudodistoma aureum has... 

The bromination of 7-methoxy-l-methyl-j8-carboline (harmine) was studied by Fischer. He obtained a compound, Ci3Hi2Br4N20, which he called tetrabromoharmine, by the action of bromine water on a dilute sulfuric acid solution of harmine. The bromination of harmine was reinvestigated by Hasenfratz, who found that two products (both hydrobromides) could be isolated when harmine was treated with bromine in aqueous acetic acid. The major component formed colorless needles and was called bromoharmine hydrobromide (free base colorless needles, m.p. 275°), while the product obtained in lesser amount was a canary-yellow dihydrate which was named isobromoharmine hydrobromide (free base colorless needles, m.p. 

Most of the substitution reactions of di-, tetra, and hexa-hydro-carbolines and of their oxo derivatives are similar to those of the parent indole or indolenine derivatives. Nitration and bromination of harma-line (l-methyl-3,4-dihydro-j8-carbolme) are referred to in Section IV, A, 1. Sulfonation and azO COupling ° proceed as expected for indole derivatives. The preparation of chlorinated and iodinated derivatives of 6-nitroharmaline has been reported,but their structures have not been established. 

Malbrancheamide (60) represents a novel type of CaM inhibitors although other natural indole alkaloids such as the unusual indole-carbazole alkaloids from a culture broth of a Nocardiopsis sp, namely K-252a-K252d, the brominated P-carbolines eudistomidins A and C, obtained... 

This section and the section on alkaloids in the first survey (7) are artificially small since many halogenated alkaloids are presented in the sections on pyrroles, indoles, carbolines, tyrosines, and other nitrogen heterocycles. It might be noted that the very large number of brominated alkaloids that are obviously tyrosine-derived are now included in Sect. 3.22.3 (Tyrosines). 

Amongst the more complex brominated p-carboline alkaloids are the fascaply-sins and related metabolites from the tunicate Didemnum sp. and the sponge Pascaplysinopsis reticulata [50,51]. Several examples of each type are illustrated as 53-63. 

Finally, it might be noted that several brominated tetrahydro- and dihydro-p-carbolines are known, for example woodinine (64) [52,53] and 19-bromoisoeudisto-min U (65) [54], both from Eudistoma spp. The tunicate Pseudodistoma arborescens has yielded arboresddine A (66) a brominated derivative of the well-known indolo[2,3-a]quinolizidine alkaloid ring system [55]. 

Brevicarine (7) and brevicolline (8) have been interrelated by bromination of brevicarine, which affords 6,8-dibromobrevicarine, T,6,8-tribromobrevicarine, and 6-bromobrevicolline (9), also obtainable by the direct bromination of brevicolline. " The total synthesis of Na-methylbrevicolline (10) takes advantage of an ingenious new method for the synthesis of 4-substituted tetrahydro-j3-carbolines (Scheme... 

Biogenetic work to date has concerned only those 3-carbolines which have a 5-membered N-containing ring substituted at Cl. Although the biogenesis of eudistomidin A (141) was speculated to be from condensation of tryptophane with glutamate [116], biosynthetic studies with eudistomins H (138) and I (136) indicate a more direct route from tryptophane and proline [117,118]. Data which indicate a proposed order for bromination and decarboxylation of tryptophane have also been presented. 

Adesanya, S. A., Chbani, M., Pais, M., Debitus, C., (1992). Brominated P-carbolines from the marine tunieate Eudistoma album. J. Nat. Prod. 55, 525-527. 

Dibromo-l-methyl-4-pyridone has been prepared from Mmethyl-4-pyridone by modifications of an earber procedure. 7V- /i-Butyl)-2,6-di-methyl-4-pyridone is also brominated in acetic acid to the 3,5-derivative. 3-Nitro-4-pyridone and 2,6-dbnethyl-3-nitro-4-pyridone are halogenated at the 5-position to give 5-bromo- and 5-chloro-2,6-dimethyl-3-nitro-4-pyridone, which have been converted to the corresponding 4-chloropyridines for use in 7-carboline synthesis. 

The eudistomins constitute a broad family of P-carboline alkaloids which are found mainly in the genus Eudistoma (mostly from E. olivaceum) but also in a few species of Lissoclinum (eudistomine U, isolated from L. vareau see above) and in Ritterella (see below), which all belong to the order Aplousobranchia. This series of alkaloids was discovered in 1978 during the same expedition of the American vessel Alpha Helix that led to the discovery of the didemnins. The 30 eudistomins currently known are almost all brominated and may be divided into four structural types, which are presented in Figure 28.19. 

Most alkaloids of dictyoceratid sponges are indole alkaloids or related bis-indolic derivatives, derivatives of tryptophan, with or without a bromine atom, and of P-carboline. This finding is not specific to Dictyoceratida, or even to sponges. Some atypical structures, such as derivatives of imidazole, guanidine or pyridine, have also been characterized in some species. 

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