Dioxygenated Carbazole Alkaloids

The family of 2,7-dioxygenated carbazole alkaloids has been isolated from different terrestrial plants. Prior to our work this group of natural products was synthetically completely unexplored. 7-Methoxy-O-methylmukonal has been isolated from the 

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Retrosynthetic analysis of the 2,7-dioxygenated carbazole alkaloids, 7-methoxy-O-methylmukonal (48), clausine H (clauszoline-C) (50), clausine K (clauszoline-J) (51), and clausine O (72), based on an iron-mediated approach, led to 2-methoxy-substituted iron complex salt 665 and 3-methoxy-4-methylaniline (655) as precursors (588) (Scheme 5.53). 

Scheme 15.13 I ron(0)-mediated synthesis of 2,7-dioxygenated carbazole alkaloids.

A large number of 2-oxygenated carbazoles has been isolated from natural sources [18, 20]. Mukonidine (149) and clausine L (O-methylmukonidine) (148) have been isolated by Wu et al. from the Chinese medicinal plant C. excavata [173]. 2-Methoxy-3-methylcarbazole (146) was obtained first from the seeds of the Indian medicinal plant Murraya koenigii by Bhattacharyya and co-workers [174]. The isolation of O-methylmukonal (147) was reported by Lange et al. from M. siamen-sis [112]. Two years later, Bhattacharyya found the same compound in the roots of G. pentaphylla and renamed it glycosinine (147) [175]. Clausine V (151), a 2,7-dioxygenated carbazole alkaloid, was extracted from the root bark of C. excavata by Wu and co-workers [116]. 

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. 

Over the past 15 years, we developed three procedures for the iron-mediated carbazole synthesis, which differ in the mode of oxidative cyclization arylamine cyclization, quinone imine cyclization, and oxidative cyclization by air (8,10,557,558). The one-pot transformation of the arylamine-substituted tricarbonyl(ri -cyclohexadiene) iron complexes 571 to the 9H-carbazoles 573 proceeds via a sequence of cyclization, aromatization, and demetalation. This iron-mediated arylamine cyclization has been widely applied to the total synthesis of a broad range of 1-oxygenated, 3-oxygenated, and 3,4-dioxygenated carbazole alkaloids (Scheme 5.24). 

Scheme 30 Palladium-catalyzed synthesis of 1,6-dioxygenated carbazole alkaloids...

The 2,6-dioxygenated carbazole alkaloid glycozolidine (170) was isolated first by Chakraborty et al. from the root bark of G. pentaphylla in 1966 [182]. Glyco-zolidal (171) and glycozolidol (175) were obtained from the same natural source by Bhattacharyya et al. [183, 184]. Carbalexin C (179) represents a stress-induced phytoalexin generated in the leaves of G. pentaphylla and Glycosmis parviflora... 

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-... 

Scheme 2 3-Oxygenated and 3,4-dioxygenated tricyclic carbazole alkaloids...

In 1996, Ito et al. reported the isolation of clauszoline-A (167) and clauszoline-B (168) from the acetone extract of the stem bark of C. excavata collected in Singapore (74). These alkaloids represented the first, naturally occurring 2,8-dioxygenated-3-formylcarbazole alkaloids with a dimethylpyran ring fused to C-7 and C-8 of the carbazole nucleus. The extracts of the leaves and bark of this tree have been used in traditional medicine for the treatment of snakebites and abdominal pain (74). One year later, the same group isolated another pyrano[2,3-fl]carbazole alkaloid, clauszoline-H (169), from the roots of the same natural source in Japan (47) (Scheme 2.34). 

In 1991, Furukawa et al. reported the isolation of pyrayafoline B (170) from the stem bark of M. euchrestifolia collected in May in Taiwan (87). In the same year, the same group isolated a further pyrano[2,3- ]carbazole alkaloid, pyrayafoline E (171), from the stem bark of M. euchrestifolia. Pyrayafoline E was isolated from Nature in racemic form (70). These alkaloids are the first members of the naturally occurring 2,7-dioxygenated-3-methylcarbazole alkaloids having a dimethyl pyran ring fused to C-6 and C-7 of the carbazole nucleus (70,87) (Scheme 2.35). 

While 1- and 2-oxygenated tricyclic carbazole alkaloids were isolated primarily from higher plants, various tricyclic carbazole alkaloids, which are 3-oxygenated or 3,4-dioxygenated, were obtained from alternative natural sources, such as microbial, marine, and mammalian sources. 

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