Carbazole-1,4-quinones

The carbazole-l,4-quinones represent an important family of carbazole alkaloids (105,106). Except for clausenaquinone A (112), all carbazole-l,4-quinones isolated from natural sources have a 3-methylcarbazole-l,4-quinone skeleton. The plants of the genus Murray a (Rutaceae) are the major natural source of carbazole-l,4-quinone alkaloids. In 1983, Furukawa et al. reported the first isolation of a carbazole-1, 4-quinone, murrayaquinone A (107), from the root bark of M. euchrestifolia collected in Taiwan (28,29). In subsequent years, the same group reported the isolation of various carbazole-1,4-quinones from the root or stem bark of the same plant murrayaquinone B (108) (28,29), murrayaquinone C (109) (28,29), murrayaquinone D (110) (29), and murrayaquinone E (111) (70) (Scheme 2.21). 

In 1994, Wu et al. described the isolation and structural elucidation of clausenaquinone A (112) from the stem bark of C. excavata (107). This carbazole-1,4-quinone alkaloid exhibited potent inhibitory activity of rabbit platelet aggregation induced by arachidonic acid, as well as cytotoxicity in the HCT-8, RPMI-7951, and TE-671 tumor cells. The UV spectrum (7max 228, 265, 295, and 419 nm) and the IR spectrum (v ax 1600, 1625, 1660, 3260, and 3370 cm ) of clausenaquinone A... 

A palladium-mediated cyclization which provides carbazole-1.4-quinones was improved by development of conditions which require substoichiometirc amounts of Pd(OAc),. /-Butyl hydroperoxide is used for reoxidation of Pd. <95TL1325> The same conditions, however, were only marginally successful (30% yield) for converting diphenylamine to carbazole. 

Most of the early applications of palladium to indole chemistry involved oxidative coupling or cyclization using stoichiometric Pd(II). Akermark first reported the efficient oxidative coupling of diphenylamines to carbazoles 23 with Pd(OAc)2 in refluxing acetic acid [44]. The reaction is applicable to several ring-substituted carbazoles (Br, Cl, OMe, Me, NO2), and 20 years later Akermark and colleagues made this reaction catalytic in the conversion of arylaminoquinones 24 to carbazole-1,4-quinones 25 with ferf-butyUiydroperoxide or oxygen as the oxidant [45]. This oxidative cyclization is particularly useful for the synthesis of benzocarbazole-6, 11-quinones (e.g., 26). 

Figure 9,4 Carbazole-1,4-quinones accessed via intramolecular oxidative Heck cyclizations using stoichiometric palladium.

In 1984, Giibble et al. reported for the first time a novel l,10-bis-(6-methyl-5H-benzo[fc]carbazol-ll-yl)decane (469) which has potential bifunctional nucleic acid intercalating properties (406). To function as anti-tumor active drugs, one of the most important cytostatic mechanisms of action of coplanar annelated polycyclic compounds is their intercalation with DNA (405). Ten years later, Kucklander et al. studied a series of 5H-benzo[ 7]carbazole quinone derivatives for their cytotoxic activity against colon and lung cancer cells, and found that the heteroannelated 5H-benzo[ 7]carbazole quinone derivative 470 was the most active among the various analogs (407) (Scheme 4.2). 

The diquinone 300 has been shown to react with a variety of primary amines producing carbazole quinones 301, a process which presumably involves an intermediate such as 302 formed by Michael-type addition. Alkyl-, aryl-, and heteroarylamines and amino acids have been utilized. The reaction failed with p-nitro- and p-acetylanilines neutral and acidic amino acids required base catalysis. Hydroxyl-... 

Ketcha and Gribble (42) have also used this methodology to convert phthalic anhydride (37) to the benzo[fc]carbazole quinone 38. 

Schane 3 shows some recent carbazoles and carbazole-quinones that were synthesized via the Pd-catalyzed oxidative cycUzalion of diaryl amines [17-21], The so-formed bond is in bold, and the conditions are the typical Pd(OAc)j in refluxing acetic acid. 

The carbazole-3,4-quinone alkaloids were all isolated by Seto from different Streptomyces (Scheme 4). Carbazoquinocin C was obtained from Streptomyces... 

Scheme 3 Carbazole-l,4-quinone and carbazole-l,4-quinol alkaloids...

For the quinone imine cyclization of iron complexes to carbazoles the arylamine is chemoselectively oxidized to a quinone imine before the cyclodehydrogenation [99]. The basic strategy of this approach is demonstrated for the total synthesis of the 3-oxygenated tricyclic carbazole alkaloids 4-deoxycarbazomycin B, hyellazole, carazostatin, and 0-methylcarazostatin (Scheme 17). 

The palladium(II)-mediated oxidative cyclization is also applied to the synthesis of carbazole-l,4-quinone alkaloids. The required arylamino-l,4-benzo-quinones are readily prepared by arylamine addition to the 1,4-benzoquinone and in situ reoxidation of the resulting hydroquinone [131]. 

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-... 

An even more direct approach to carbazole-3,4-quinone alkaloids is provided by the palladium(II)-mediated oxidative coupling of ort/zo-quinones with ary-lamines, which gives access to this class of natural products in a three-step route [137]. 

The ort/zo-quinone cyclization to the carbazole-3,4-quinones carbazoquinocin C 51 and ( )-carquinostatin A ( )-55a is more convergent than the previous approaches to these natural products, which required transformation to the ort/zo-quinone and/or introduction of substituents (prenyl or heptyl) following the carbazole ring formation (cf. Schemes 20,21, and 37). 

The UV spectrum [/Imax 234, 266, and 415 nm] and the IR spectrum (Vmax 1610, 1645,1660, and 3440 cm ) of murrayaquinone D (110) were very similar to those of murrayaquinone C (109), thus indicating the presence of a carbazole-l,4-quinone framework. The H-NMR spectrum confirmed the structural similarity to murrayaquinone C (109), but showed the signal for a hydroxy group (i5 5.52) instead of the signal for a methoxy group. Based on the spectroscopic data, structure 110 was assigned to murrayaquinone D (29). 

In the past decade, Seto et al. reported the isolation of a series of unprecedented carbazoIe-3,4-quinone alkaloids from various Streptomyces species. In 1993, the first example of a carbazole-3,4-quinone alkaloid, carquinostatin A (278) was isolated... 

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