Carbazomycin iron-mediated total synthesis

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]. 

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 0-acetyl derivative... 

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 the carbazomycins G (269) and H (270) based on our iron-mediated 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). 

In 1989 we reported an iron-mediated route for the construction of the tricyclic carbazole skeleton [72, 73]. This convergent method was applied to the total synthesis of the naturally occurring alkaloid carbazomycin A [72]. Key steps of our iron-mediated approach are the consecutive C C bond formation and oxidative cyclization (formation of the C N bond) between an electrophilic tricarbonyl(ri -cyclohexadienyhum)iron complex salt 30 and an arylamine 31 (Scheme 10). Subsequent oxidation and demetalation provides the aromatized carbazole 32. 

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