2- Hydroxycarbazole

The 4-(2,3-apoxypropoxy)carbazole used as starting material is prepared as follows. A solution of 16.3 g 4-hydroxycarbazole in a mixture of 190 ml dioxan and 98 ml 1 N sodium hydroxide is, after the addition of 66 ml epichlorohydrin, stirred for 2 hours at 40°C to 45°C. The reaction mixture is then diluted with water and shaken out with methylene chloride. The methylene chloride phase is washed with water, dried over anhydrous sodium sulfate and evaporated. There are obtained 16.8 g 4-(2,3-epoxypropoxy)carbazole. 

The transformation of carbazole has been examined, and naphthalene 1,2-dioxygenase activity was induced in Pseudomonas sp. strain NCIB 9816-4 and in Beijerinckia sp. strain B8/36 (Resnick et al. 1993). The 3-hydroxycarbazole that was formed could have resulted from two pathways (a) from the initial production of ciy-3,4-dihydro-3,4-dihydroxycarbazole followed by dehydration or (b) by monooxygenation that cannot be excluded since monooxygenase activity can be mediated by naphthalene 1,2-dioxygenase (Gibson et al. 1995). 

Resnick SM, DS Torok, DT Gibson (1993) Oxidation of carbazole to 3-hydroxycarbazole by naphthalene 1,2-dioxygenase and biphenyl 2,3-dioxygenase. FEMS Microbiol Lett 113 297-302. 

The UV spectrum (7max 225,242,253,276,289, and 351 nm) of clausine D (29) was similar to that of O-demethylmurrayanine (24), which also represents a 3-formyl-l-hydroxycarbazole framework. The presence of a hydroxy group and a conjugated aldehyde group was further supported by strong absorptions at 3380 and 1655 cm in the IR spectrum. The H-NMR spectrum was very similar to that of O-demethylmurrayanine, except for the presence of a prenyl group ( 1.65,... 

In 1992, Furukawa et al. reported the isolation of 3-formyl-7-hydroxycarbazole (99) from the root bark of M. euchrestifolia (104). The UV spectrum [2max 233,245 (sh), 273, 288, and 326 nm] and the IR spectrum (v ax 1673 and 3336 cm ) of 3-formyl-7-hydroxycarbazole were very similar to those of clauszoline-K (98), indicating a 3-formylcarbazole framework. The H-NMR spectrum confirmed the structural similarity to clauszoline-K, and showed the presence of a hydroxy group instead of the methoxy group. All of the spectroscopic data supported the structure of 3-formyl-7-hydroxycarbazole (99) (Scheme 2.19). 

In 1993, Kusano et al. isolated 2-hydroxy-7-methyl-9H-carbazole (243) from the aerial parts of Cimicifuga simplex Wormsk. ex DC. (224). Six years later, Wu et al. reported the isolation of clausine V (244) from the root bark of C. excavata (43) (Scheme 2.60). The UV spectrum (/max 236, 261, and 305 nm) of 2-hydroxy-7-methyl-9H-carbazole (243) indicated a 2-hydroxycarbazole. This assignment was supported by the IR spectrum [Vmax 1611 (aromatic system), 2700-3000 (OH), and 3400 (NH) cm ]. The presence of a hydroxy function was confirmed by transformation into the corresponding 0-acetate and comparison with 2-hydroxy-7-methyl-9H-carbazole. 

As an extension of the Nenitzescu indole synthesis, p-benzoquinone (521) was condensed with various electron-withdrawing anilines 522 in the presence of trifluoroacetic acid (TFA) to give 6-hydroxycarbazoles 523. Besides the low )deld of... 

The key step in this synthesis is an intramolecular nucleophilic attack on the electron-rich indole nucleus by the carbocation derived from the p-keto sulfoxide in the presence of acid. Finally, the intermediate tetrahydrocarbazole aromatizes by elimination of methanethiol under the conditions of the reaction to produce the hydroxycarbazole (511) (Scheme 5.12). 

The thermal cyclization of 3-(l,3-butadienyl)indoles 692 in refluxing cis-decalin afforded the carbazoles 698. Selective hydrolysis of the 3-carbonate ester, methylation of the corresponding 3-hydroxycarbazoles 699 with methyl iodide in the presence of... 

Duval and Cuny reported the total syntheses of hyellazole (245) and 6-chlorohyellazole (246) starting from diketoindoles 777a and 777b (606). In this methodology, the key step is the base-catalyzed intramolecular aldol condensation of the ketoindoles to fully functionalized 3-hydroxycarbazoles. 

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). 

Murakami et al. reported (575) a total synthesis of murrayaquinone A (107) by oxidation of l-hydroxy-3-methylcarbazole (23) with Fremy s salt, as previously described by Martin and Moody (632). The hydroxycarbazole 23 required for this synthesis was obtained via the Fischer indolization of the O-methanesulfonyl phenylhydrazone 614 (575) (see Scheme 5.38). The oxidation of l-hydroxy-3-methylcarbazole (23) with Fremy s salt afforded murrayaquinone A (107) as the major product, along with a 5% yield of isomeric carbazole-l,2-quinone 876 (575) (Scheme 5.108). 

In addition to the aforementioned syntheses of various carbazole-l,4-quinone alkaloids, many formal syntheses for this class of carbazole alkaloids were also reported. These syntheses involve the oxidation of the appropriate 1- or 4-oxygenated-3-methylcarbazoles using Fremy s salt (potassium nitrosodisulfonate), or PCC (pyridinium chlorochromate), or Phl(OCCXI F3)2 [bis(trifluoroacetoxy)iodo]-benzene. Our iron-mediated formal synthesis of murrayaquinone A (107) was achieved starting from murrayafoline A (7) (see Scheme 5.34). Cleavage of the methyl ether in murrayafoline A (7) and subsequent oxidation of the resulting intermediate hydroxycarbazole with Fremy s salt provided murrayaquinone A (107) (574,632) (Scheme 5.113). 

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