Murrayaquinone

Scheme 36 Palladium(II)-catalyzed synthesis of murrayaquinone A116a, koeniginequinone A 116b, and koeniginequinone B 116c...

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). 

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). 

The UV spectrum (/max 225, 252, 291, and 392 nm) of bismurrayaquinone-A (215) resembled that of murrayaquinone A (107) (see Scheme 2.21) indicating a similar carbazole unit. The IR spectrum showed a strong band at Vmax 1650 cm . The H-NMR spectrum was also similar to that of murrayaquinone A, except for the lack of a signal for H-2 (H-2 ). The spectroscopic data confirmed structure 215 for bismurrayaquinone-A (82) (Scheme 2.52). 

Murrayaquinone A (107) (see Scheme 2.21) was found to produce a triphasic inotropic response of guinea-pig papillary muscle. This triphasic inotropic response is not mediated through a receptor mechanism, but through a mechanism involving ATP production (473). 

Furukawa et al. reported the total synthesis of murrayaquinone A (107) by a palladium(II)-mediated oxidative cyclization of the corresponding 2-arylamino-5-methyl-l,4-benzoquinones. 2-Anilino-5-methyl-l,4-benzoquinone (842) was prepared starting from 2-methyl-l,4-benzoquinone 841 and aniline 839, along with the regio-isomeric 2-anilino-6-methyl-l,4-benzoquinone (844). The oxidative cyclization of 2-anilino-5-methyl-l,4-benzoquinone (842) with stoichiometric amounts of palla-dium(ll) acetate provided murrayaquinone A (107) in 64% yield. This method was also applied to the synthesis of 7-methoxy-3-methylcarbazole-l,4-quinone (113) starting from 3-methoxyaniline (840) (623). Seven years later, Chowdhury et al. reported the isolation of 7-methoxy-3-methylcarbazole-l,4-quinone (113) from the stem bark of Murraya koenigii and named it koeniginequinone A (113) (49) (Scheme 5.101). 

Miki and Hachiken reported a total synthesis of murrayaquinone A (107) using 4-benzyl-l-ferf-butyldimethylsiloxy-4fT-furo[3,4-f>]indole (854) as an indolo-2,3-quinodimethane equivalent for the Diels-Alder reaction with methyl acrylate (624). 4-Benzyl-3,4-dihydro-lfT-furo[3,4-f>]indol-l-one (853), the precursor for the 4H-furo[3,4-f>]indole (854), was prepared in five steps and 30% overall yield starting from dimethyl indole-2,3-dicarboxylate (851). Alkaline hydrolysis of 851 followed by N-benzylation of the dicarboxylic acid with benzyl bromide and sodium hydride in DMF, and treatment of the corresponding l-benzylindole-2,3-dicarboxylic acid with trifluoroacetic anhydride (TFAA) gave the anhydride 852. Reduction of 852 with sodium borohydride, followed by lactonization of the intermediate 2-hydroxy-methylindole-3-carboxylic acid with l-methyl-2-chloropyridinium iodide, led to the lactone 853. The lactone 853 was transformed to 4-benzyl-l-ferf-butyldimethylsiloxy-4H-furo[3,4- 7]indole 854 by a base-induced silylation. Without isolation, the... 

Hanaoka et al. reported a total synthesis of murrayaquinone A (107) based on an anionic [4+2] cycloaddition of the indole ester 864 with phenyl p-tiimethylsilylvinyl sulfone (865) (631). The reaction of the MOM-protected indole 864 with phenyl... 

Akermark et al. applied (548) a catalytic version of Furukawa s palladium-mediated (stoichiometric) cyclization of 2-anilino-5-methyl-l,4-benzoquinone (842) to a total synthesis of murrayaquinone A (107) (see Scheme 5.101) (623). In this cyclization, only 5mol% of palladium(ll) acetate and an excess of TBHP as reoxidant were used (548). Subsequently, a catalytic cyclization of 842 to murrayaquinone A (107), using oxygen for the reoxidation of palladium, was reported (549) (Scheme 5.107). 

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). 

Chowdhury et al. reported a synthesis of murrayaquinone A (107) starting from... 

Recently, we reported two-step total syntheses of murrayaquinone A (107), koeniginequinone A (113), and koeniginequinone B (114) starting from the commercially available arylamines 839, 840, and 889, respectively (635). In these syntheses, catalytic amounts of palladium(II) acetate were used for the key transformations of the 2-arylamino-5-methyl-l,4-benzoquinones 842, 843, and 890 to the corresponding 3-methylcarbazole-l,4-quinones 107,113, and 114. The required... 

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). 

Hibino et al. reported a formal synthesis of murrayaquinone A (107) starting from 2-chloro-3-formylindole (891) by an allene-mediated electrocyclic reaction involving the indole 2,3-bond. The 4-hydroxy-3-methylcarbazole (858), a known precursor for murrayaquinone A (107), and required for this formal synthesis was obtained in seven steps, and 26% overall yield, starting from the 2-chloro-3-formylindole (891) (636,637) (Scheme 5.114). 

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... 

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