Carbazole-1,4-quinone alkaloids synthesis

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]. 

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). 

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.

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... 

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). 

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). 

Prior to the discovery of the aryl-Heck reaction (Chapter 72), the direct Pd-promoted oxidative cyclization of diaryl amines to carbazoles was well known. In 1975 Akennark reported this reaction (Scheme 1, eqnation 1) [1], In addition, A -phenylanthranUic acid gave carbazole-l-carboxylic acid (60%). Miller and Moock used Pd(OAc)j to cyclize 6-anilino-5,8-dimethylisoquinoIine to eUipticine in low yield [2]. The second advance in this chemistry was reported independently by Bittner [3] and Furukawa [4], who described the Pd-mediated (stoichiometric) oxidative conversion of 2-anilino-l,4-benzoquinones and 2-anilino-l,4-naphthoquinones to the corresponding carbazole-l,4-diones and benzo[ ]carbazole-l,6-diones (equations 2, 3). Furukawa s studies included syntheses of several carbazolequinone alkaloids. In 1995 Akermark and colleagues developed catalytic versions (i.e., using tert-butyl hydrogen peroxide [TBHP] or oxygen) of this cyclization (equation 3) [5,6], which elevated the importance of this palladium oxidative cyclization, mainly because of the expense of Pd(OAc)2. Somewhat earlier, Knbiker used cupric acetate as a reoxidant in a synthesis of carbazole-l,4-quinones [7]. 

A key step in a synthesis of the carbazole alkaloid murraya-quinone-B (132) is the concomitant indole ring formation and regio-selective Claisen rearrangement from the azide (129), which on... 

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