Carbazole-1,4-quinone alkaloids

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... 

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

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]. 

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 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 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... 

To date, several syntheses have been reported for the natural 1,4-quinone alkaloids and their analogs. In 1994, Furukawa published a review on the isolation and synthesis of natural carbazole-l,4-quinones (105). Six years later. Pillion et al. published a comprehensive review with the coverage of various synthetic approaches towards natural and non-natural carbazole-l,4-quinones (106). In this section, we cover only the total syntheses of the natural carbazole-l,4-quinone alkaloids which have appeared since 1990. In contrast to other sections, this section also includes the formal total syntheses. 

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). 

A common precursor, the 6-bromocarbazole derivative 927, required for the total synthesis of the carbazole-3,4-quinone alkaloids (+ )-carquinostatin A K )-278] (641) and (+ )-lavanduquinocin [( )-280] (642), was prepared by iron-mediated one-pot C-C and C-N bond formation. Recently, the same methodology was adopted for the first enantioselective total synthesis of carquinostatin A (278) (643) and lavandu-quinocin (280) (644). 

Furukawa et al. reported a palladium(II)-mediated intramolecular cyclization of arylamino-l,4-benzoquinones to carbazole-l,4-quinones (623). Previously, this facile synthetic approach was applied to various 3-methylcarbazole-l,4-quinone alkaloids (623) (see Schemes 5.101 and 5.102). As an extension, this methodology was further... 

The carbazoquinodns are carbazole-3,4-quinone alkaloids and have been isolated from Streptomyces violaceus 2942-SVS3 [61]. They are strong antioxidative agents and thus represent potential drugs for the treatment of diseases initiated by oxygen-derived free radicals. We have developed an effident synthesis of carbazoquinodn C using palladium(II)-catalyzed oxidative cydization as the key step (Scheme 15.17, Table 15.2) [62]. 

Scheme 15.18 Palladium(ll)-catalyzed synthesis of carbazole-l,4-quinone alkaloids.

Because of their promising pharmacological properties, the carbazole-l,4-quinone alkaloids became attractive synthetic targets [30,63]. Murrayaquinone A has been isolated from the root bark of the Chinese medicinal plant Murraya euchrestifilia and shows cardiotonic activity [64], The koeniginequinones A and B have been obtained from the... 

A number of studies on the palladium(n)-mediated oxidative cyclization of aniUno-quinones later appeared. Some of the compounds produced via this protocol are depicted in Figure 9.4. Bittner et al. [37b] and Furukawa and coworkers [37c] both described the application of the intramolecular cyclization chemistry toward the synthesis of analogues of the carbazole-l,4-quinone alkaloids. Furukawa and coworkers [37c] also reported the synthesis of murrayaquinone A (79) using this chemistry. Knolker and O Sullivan [37d,e] later demonstrated the utility of the palladium(ll)-mediated cycUzation in the synthesis of 83, which was initially anticipated to be a prekinamycin analogue precursor. In all... 

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). 

In the past decade, a few examples of benzoannulated carbazole ring systems were found in nature as marine products. In 1993, Chan et al. reported a novel marine benzocarbazole alkaloid, purpurone (281) from the marine sponge lotrochota sp. in its racemic form. Purpurone, as indicated by its name, is purple in color. This represents the first example of a benzocarbazole alkaloid with a biphenylene quinone methide functionality. The isolate showed ATP-citrate lyase (ACL) inhibitory activity (247). 

In 1999, Rickards et al. reported the isolation of calothrixins A (377) and B (378) from photoautrophic cultures of Calothrix cyanobacteria (345). These two, novel, pentacyclic carbazole alkaloids contain a quinolino[4,3-fc]carbazole-l,4-quinone framework. Calothrixins A and B inhibit the growth of a chloroquin-resistant strain of the malaria parasite P. falciparum and human HeLa cancer cells (345). 

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). 

The tricyclic carbazolequinones represent an important class of carbazole alkaloids with a quinone moiety in the A-ring of the carbazole nucleus. This family of... 

So far this class of carbazole alkaloids contains only two natural products, calothrixin A and its N-deoxy-derivative calothrixin B. These two pentacyclic metabolites with a quinolino[4,3- 7]carbazole-l,4-quinone framework displayed potent inhibitory effects on the in vitro growth of both human malarial parasites and human cancer cells and inhibition of RNA polymerase activity. Owing to this pharmaceutical potential, these natural products have attracted the synthetic interest of various research groups (8). 

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