Carbazomycin 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]. 

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

The arylamine 780a required for the total synthesis of carbazomycin A (260) was prepared from commercially available 2,3-dimethylphenol (781). The regioselective... 

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-3H-carbazol-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). 

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... 

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 iron-complexed cation 602 with the arylamines 780a and 794. 

Using a one-pot process of oxidative cyclization in air, the arylamine 780a was transformed to the tricarbonyl(ri -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(ri -4b,8a-dihydro-9H-carbazole)iron complex (795). Demetalation of 795, followed by aromatization, led to O-acetylcarbazomycin B (796). 

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 two-step 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... 

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-[(l-ethoxy-carbonyloxy-2-methoxy)ethenyl]-2-(ethoxy-carbonyloxy)indole-l-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-Al 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). lodination 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... 

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). 

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... 

Our palladium(II)-catalyzed approach for the carbazomycins G (269) and H (270) requires the carbazole-l,4-quinones 941 and 981 as precursors (compare the iron-mediated synthesis, see Scheme 5.137). These intermediates should result from oxidative cyclization of the arylamino-l,4-benzoquinones, which in turn are prepared from the arylamines 839 and 984 and 2-methoxy-3-methyl-l,4-benzoqui-none (939) (652) (Scheme 5.138). 

One of the carbazole-l,4-quinones, 3-methoxy-2-methylcarbazole-l,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-l,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-meth-oxyaniline (984) was transformed to 3,6-dimethoxy-2-methylcarbazole-l,4-quinone... 

Hibino et al. reported the total synthesis of carbazomycin G (269) by the regioselective addition of methyllithium onto 3-methoxy-2-methylcarbazole-l,4-quinone (941) (653). The required immediate precursor of carbazomycin G, carbazole-l,4-quinone 941, was obtained from 3-(2-methoxyethenyl)-N-(phenylsul-fonyDindole (986). The benzannulation involves an allene-mediated electrocyclic reaction of a 67t-electron system generated from the 2-propargylindole 989, which was derived from the 3-vinylindole 986 in three steps. 

Scheme 8. Total synthesis of carbazomycin B via a 5-exo-trig cyclization...

The Ziegler group has described a creative approach to mitomycin derivatives and the related alkaloid FR-900482 that involves use of indoles as radical acceptors (Eq. 28) [62]. The key step involves cyclization of aziridinyl bromide 98 to 99 which was carried on to (+)-desmethoxymitomycin A. This reaction surely illustrates the unusual bond constructions that can be accomplished using free-radical chemistry. Interesting approaches to other indole alkaloid substructures have been reported as illustrated in Eqs. (29) [63] and (30) [64]. The former was developed in an approach to lysergic acid while the later is a model study for the synthesis of aspidosperma alkaloids. Neither of these interesting approaches has been brought to fruition. A synthesis of carbazomycin that involves an aryl radical cyclization for construction of the C3-C3a bond of an indole has also been described [65]. 

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. 

In other miscellaneous indole alkaloid syntheses. Joule reported formal syntheses of the makaluvamines <97JOC568> while Lown has developed a new synthesis of the pyrroloquinone nucleus of these alkaloids <97SC2103>. Edstrom reported the synthesis of a fully functionalized 7-aminoaziridinomitosene <97T4549>, and two new approaches to the duocarmycins were reported <97JOC8868,97TL7207>. Finally, Knolker has utilized his iron-mediated construction of carbazoles in the first. synthesis of the antibiotic carbazomycins C and D <97JCS(P1)349>, as well as other carbazole natural products. 

Abstract The occurrence, structure, physiological activities as well as the synthesis of alkaloids having a carbazole skeleton is briefly reviewed. Emphasis is made on the synthesis, in particular on approaches towards girinimbine and the carbazomycines. Some new synthetic approaches based on indoles and 2-vinylindoles, and the use of carbazoles in the synthesis of the cyclopent[b]indole alkaloid yuehchukene will also be discussed. 

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