Carbazomycins

In contrast to the 1- and 2-oxygenated tricyclic carbazole alkaloids, most of the 3-oxygenated and the 3,4-dioxygenated tricyclic carbazole alkaloids were isolated from Streptomyces (Scheme 2). Their common structural feature is a 2-methylcarbazole, although biosynthetic studies on carbazomycin B have shown that tryptophan is the precursor of the carbazole nucleus [26]. 4-De-... 

Carbazomycin A CH3 H Carbazomycin B H H Carbazomycin C H OCH3 Carbazomycin D CH3 OCH3... 

The total synthesis of the carbazomycins emphasizes the utility of the iron-mediated synthesis for the construction of highly substituted carbazole derivatives. The reaction of the complex salts 6a and 6b with the arylamine 20 leads to the iron complexes 21, which prior to oxidative cyclization have to be protected by chemoselective 0-acetylation to 22 (Scheme 13). Oxidation with very active manganese dioxide followed by ester cleavage provides carbazomycin B 23a [93] and carbazomycin C 23b [94]. The regioselectivity of the cyclization of complex 22b to a 6-methoxycarbazole is rationalized by previous results from deuterium labeling studies [87] and the regiodirecting effect of the 2-methoxy substituent of the intermediate tricarbonyliron-coordinated cyclo-hexadienylium ion [79c, 79d]. Starting from the appropriate arylamine, the same sequence of reactions has been applied to the total synthesis of carbazomycin E (carbazomycinal) [95]. 

Addition of the arylamines 117 to 2-methoxy-3-methyl-l,4-benzoquinone 118 affords regioselectively the 5-arylamino-2-methoxy-3-methyl-l,4-benzo-quinones 119 (Scheme 37). Palladium(II)-catalyzed oxidative cyclization leads to the carbazole-l,4-quinones 28 [135,136],previously obtained by the iron-mediated approach (cf. Scheme 14). Regioselective addition of methyllithium to the quinones 28 provides carbazomycin G 29a and carbazomycin H 29b [96,135]. Reduction of 29a with lithium aluminum hydride followed by elimination of water on workup generates carbazomycin B 23a [135]. Addition of heptylmag-... 

Scheme 37 Palladium(II)-catalyzed synthesis of carbazomycin G 29a, carbazomycin H 29b, and carbazoquinocin C 51...

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. 

The UV spectrum (7max 224, 245, 289, 330, and 340 nm) of carbazomycin B (261) resembled that of carbazomycin A (260), indicating a similar carbazole framework (231). The H-NMR spectrum was similar to that of carbazomycin A, except for the presence of a phenolic hydroxy group at 5 6.21 instead of the C-4 methoxy group at 5 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... 

The UV spectrum Umax 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 carbazoie framework. In the C-NMR spectrum, 12 signals due to the carbazoie nucleus in neocarazostatin A were almost identical to those of the analogous carbons... 

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-l,4-quinol framework and were obtained from Nature in racemic form. Carbazomycin G showed moderate antifungal activity against... 

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