Oxygenated Carbazole Alkaloids

Buchwald-Hartwig amination of p-bromotoluene with m-anisidine affords quantitatively the corresponding diarylamine. While oxidative cyclization using stoichiometric amounts of palladium(II) acetate provides only 36 % yield of 7-methoxy-3-methylcarbazole, up to 72 % yield is obtained using catalytic amounts of palladium(II). The highest turnover for the catalytic cycle is obtained with 

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The reaction of the complex salt 6a with the arylamine 12 affords by regio-selective electrophilic substitution the iron complex 13 [88] (Scheme 11). The oxidative cyclization of complex 13 with very active manganese dioxide provides directly mukonine 14, which by ester cleavage was converted to mukoeic acid 15 [89]. Further applications of the iron-mediated construction of the carbazole framework to the synthesis of 1-oxygenated carbazole alkaloids include murrayanine, koenoline, and murrayafoline A [89]. 

The iron-mediated synthesis of 2-oxygenated carbazole alkaloids is limited and provides only a moderate yield (11%) for the oxidative cyclization to 2-methoxy-3-methylcarbazole using iodine in pyridine as the reagent [90]. Ferricenium hexafluorophosphate is the superior reagent for the iron-mediated arylamine cyclization leading to 3-oxygenated carbazoles (Scheme 12). Electrophilic substitution of the arylamines 16 with the complex salt 6a leads to the iron complexes 17. Oxidative cyclization of the complexes 17 with an excess of ferricenium hexafluorophosphate in the presence of sodium carbonate affords... 

Since the late 1960s, several carbazole alkaloids oxygenated in the 3-position were isolated from diverse natural sources, the majority of which were isolated from different plant sources. However, in 1979, Moore et al. reported the isolation of two unusual, non-basic, 3-oxygenated carbazole alkaloids, hyellazole (245) and chloro-hyellazole (246), from the blue-green marine algae Hyella caespitosa (225). These alkaloids have structures entirely different from those of the carbazole alkaloids isolated from terrestrial plants. 

In 2000, Yenjai et al. reported the anti-plasmodial activity of 2-oxygenated carbazole alkaloids against P. falciparum. In their studies, clausine H (clauszoline-C) (50) (see Scheme 2.11) and heptaphylline (76) (see Scheme 2.15) showed activity with IC50 values of 3.2-6.4 and 5.5-10.7pg/mL, respectively (456). Prior to these studies, a report on the anti-plasmodial activity of 3- and 4-carbazole dialkylaminocarbinols had appeared (457). 

Although a large number of 2-oxygenated tricyclic carbazole alkaloids have been isolated from different natural sources, only a few syntheses of this class of alkaloids were reported. This is mainly due to the lack of general methods, as well as the difficulty associated with the known synthetic methods, to build up the required substitution pattern. Prior to 1990, some total syntheses of 2-oxygenated carbazoles were reported and were covered in the earlier treatises by Kapil (1), Husson (2), and Chakraborty (3) in Volumes 13, 26, and 44 of this series. Since 1990, the only total syntheses which appeared in the literature for this class of carbazole alkaloids were transition metal-mediated or -catalyzed approaches, respectively. These general approaches offered a series of 2-oxygenated carbazole alkaloids (8,10). 

The retrosynthetic analysis of the 2-oxygenated carbazole alkaloids, 2-methoxy-3-methylcarbazole (37) and mukonidine (54), based on an iron-mediated approach, led to the iron-complexed cation 602 and the arylamines 655 and 656 as precursors (Scheme 5.48). 

The retrosynthetic analysis of the 2-oxygenated carbazole alkaloids, 2-methoxy-3-methylcarbazole (37), O-methylmukonal (glycosinine) (38), 2-hydroxy-3-methylcar-bazole (52), and mukonal (53) based on the molybdenum-mediated approach led to the molybdenum-complexed cation (663) and 3-methoxy-4-methylaniline (655) as precursors (Scheme 5.51). The cationic molybdenum complex, dicarbonyl (ri -cyclohexadiene)(r -cyclopentadienyl)molybdenum hexafluorophosphate (663), required for the electrophilic substitution, was easily prepared quantitatively through known literature procedures (586,587). 

Using our palladium(II)-catalyzed approach, we reported the total syntheses of a wide range of 7-oxygenated carbazole alkaloids, including siamenol (89),... 

The relay compound 1025 required for the synthesis of all of these 7-oxygenated carbazole alkaloids was obtained starting from commercially available 4-bromo-toluene (1023) and m-anisidine (840) in two steps and 72% overall yield. Buchwald-Hartwig amination of 4-bromotoluene (1023) with m-anisidine (840) furnished quantitatively the corresponding diarylamine 1024. Oxidative cyclization of 1024 using catalytic amounts of palladium(ll) acetate afforded 3-methyl-7-methoxycarbazole (1025). Oxidation of 1025 with DDQ led to clauszoline-K (98), which, on cleavage of the methyl ether using boron tribromide, afforded 3-formyl-7-hydroxycarbazole (99) (546) (Scheme 5.149). 

One year later, we extended the aforementioned palladium(II)-catalyzed approach to a series of 6-oxygenated carbazole alkaloids, glycozoline (86), glycozolinine (glycozolinol) (91), glycomaurrol (92), micromeline (100), and methyl 6-methoxycarbazole-3-carboxylate (104) (547). The palladium(0)-catalyzed coupling of 4-bromoanisole (670) and p-toluidine (1028), followed by palladium(II)-catalyzed oxidative cyclization, afforded directly glycozoline (86). 

Scheme 15.9 lron(0)-mediated synthesis of 3-oxygenated carbazole alkaloids. 

Clauszoline-K and dausine C (clauszoline-L) have been isolated from the stem bark of the Chinese medidnal plant Clausena excavata [72], Clausine M and dausine N have been found in the root bark of the same plant [73]. The bioassay-guided fractionation of the organic extract of Murraya siamensis, collected in Thailand, led to the isolation of siamenol, which shows HIV-inhibitory activity [74], A simple route to these 7-oxygenated carbazole alkaloids has been developed, based on a highly efficient palladium-catalyzed approach (Scheme 15.21) [75] (Table 15.4). 

Scheme 15.23 Palladium(ll)-catalyzed synthesis of 6-oxygenated carbazole alkaloids.

A series of 7-oxygenated carbazole alkaloids has been synthesized by us for the first time, including clauszoline-K (117), 3-formyl-7-hydroxycarbazole (119), clau-sine M (120), clausine N (121), and siamenol (124) [148]. Clauszoline-K (117) and clauszoline-L (118) have been isolated by Ito et al. from the stem bark of C. excavata [115]. Wu and co-workers had isolated the same compound 118 one year earlier from the same source and named it clausine C (118) [158]. 3-Formyl-7-hydroxycarbazole (119) was obtained from the root bark of Murraya euchrestifolia [159]. Clausine M (120) and clausine N (121) were isolated from the root bark of C. excavata by Wu et al. [116]. Siamenol (124) was isolated from an extract of M. siamensis and proved to have anti-HIV activity [160]. 

Scheme 28 Palladium-catalyzed synthesis of 7-oxygenated carbazole alkaloids...

Scheme 29 Palladium-catalyzed synthesis of 6-oxygenated carbazole alkaloids and the furo[2,3-c]carbazole alkaloid eustifoline-D (132)...

Pityriazole (152) represents an unusual example of a 2-oxygenated carbazole alkaloid since it has an additional indol-3-yl substituent at C-1. This natural product was isolated along with other tryptophan metabolites by Steglich and co-workers from a culture of the human pathogenic yeast Malassezia furfur, which is believed to be responsible for the skin disease pit3riasis versicolor [177]. Due to the strucmral similarity of pityriazole (152) to mukonidine (149) and clausine L (148), we... 

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