Carbazole alkaloid

Carbazole alkaloids have been isolated from a few Rutaceae species, especially Murraya koenigii, the leaves of which have been used in southern India as a flavoring in food. Murrayanine, mukoeic acid, girinimbine, and mahanimbine have been isolated from the leaves. Carbazole alkaloids occur in all parts of this plant. 

Prenylation at the C-2 position of indole followed by cyclization is considered to give 3-methylcarbazole, which is a possible key intermediate in the formation of carbazole alkaloids. 

From Murraya euchretifolia monomeric and bis-type carbazole alkaloids have been obtained (48, 76). 

From the COSY spectrum, the sequence of the members of the four-spin system can usually be established. Given the assignment of the H2 resonance from the COSY spectrum, the assignment of C13a is redundantly confirmed by the Jch coupling pathway shown. 

Jadiffine, Later in 1989, Gamier et al. reported the isolation and structure elucidation of jadiffine (8) from Vinca difformis. The HMQC experiment 

Neocarazostatins. The next reported application of inverse-detected 2D NMR to a terrestrial carbazole alkaloid did not appear until 1991 in the report of Kato et al. A series of free radical scavenging compounds, neocarazostatins A-C, were isolated from a Streptomyces sp. strain. The structure of neocarazostatin-A (9) is shown below. Long-range connectivities from an HMBC spectrum (not referenced) were used in assigning the attachments of the two side chains to the carbazole nucleus. 

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Syntheses of heterocycles, among them carbazole alkaloids, with participation of tricarbonyl(Ti -diene)iron complexes 99CSR151. 

Indolocarbazole glycosides have attracted considerable interest over the years, as most indolo[2,3-fl]pyrrolo[3,4-c]carbazole alkaloids possess this structural feature. These systems are beyond the scope of this review however, there are several studies where glycosides of the parent system 1 have been investigated, in some... 

Vinylindoles have been studied extensively and used in the synthesis of carbazoles, alkaloids and other classes of pharmacologically active compounds. MMX force field calculations have shown that coplanar s-cis and. s-trans conformations of 3-vinylindole (84, Figure 2.11) are the most stable conformers they exhibit only slight differences in their thermodynamic stabilities [86]. 

The Michael addition of the carbanions derived from esters to nitroalkenes followed by reductive cyclization has been used extensively for the preparation of pyrrolidin-2-ones (Eq. 10.76).124 This strategy is used for synthesis of the carbazole alkaloid staurosporine aglycon (K-252c).124c... 

Occurrence, Biological Activity, and Convergent Organometallic Synthesis of Carbazole Alkaloids... 

Occurrence, Classification, and Biological Activity of Carbazole Alkaloids. 116... 

Scheme 1 1-Oxygenated and 2-oxygenated tricyclic carbazole alkaloids...

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-... 

The dimeric carbazole alkaloids often occur along with the corresponding monomeric carbazoles in terrestrial plants [7,62] (Scheme 7). Clausenamine-A was obtained by Wu from the stem bark of Clausena excavata [63]. Clausen-amine-A and its synthetic analogs, like bis(O-demethylmurrayafoline-A), show cytotoxic activities against diverse human cancer cell lines [64] and exhibit moderate antimalarial activity [65,66]. Furukawa isolated l,r-bis(2-hy-droxy-3-methylcarbazole) and bismurrayaquinone-A, the first dimeric car-bazolequinone alkaloid found in nature, from Murraya koenigii [67]. 

A molybdenum-mediated oxidative coupling of aniline 1 with cyclohexene 2a provides carbazole 3. Alternatively, the same overall transformation of aniline 1 to carbazole 3 is achieved by iron-mediated oxidative coupling with cyclo-hexa-1,3-diene 2b or by palladium-catalyzed oxidative coupling with arenes 2c. The use of appropriately substituted anilines and unsaturated six-membered hydrocarbons opens up the way to highly convergent organometallic syntheses of carbazole alkaloids. 

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... 

The total synthesis of the furo[3,2-a]carbazole alkaloid furostifoline is achieved in a highly convergent manner by successive formation of the car-bazole nucleus and annulation of the furan ring (Scheme 15). Electrophilic substitution of the arylamine 30 using the complex salt 6a provides complex 31. In this case, iodine in pyridine was the superior reagent for the oxidative cyclization to the carbazole 32. Finally, annulation of the furan ring by an Amberlyst 15-catalyzed cyclization affords furostifoline 33 [97]. 

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). 

Despite many applications of the iron-mediated carbazole synthesis, the access to 2-oxygenated tricyclic carbazole alkaloids using this method is limited due to the moderate yields for the oxidative cyclization [88,90]. In this respect, the molybdenum-mediated oxidative coupling of an arylamine and cyclohexene 2a represents a complementary method. The construction of the carbazole framework is achieved by consecutive molybdenum-mediated C-C and C-N bond formation. The cationic molybdenum complex, required for the electrophilic aromatic substitution, is easily prepared (Scheme 23). 

Scheme 25 Synthesis of the 2-oxygenated tricyclic carbazole alkaloids 66-69 and l,r-bis(2-hydroxy-3-methylcarbazole) 70...

The molybdenum-mediated arylamine cyclization was also applied to the total synthesis of pyrano[3,2-a]carbazole alkaloids (Scheme 26). Reaction of the 5-aminochromene 71 with the complex salt 62 affords the complex 72, which on oxidative cyclization provides girinimbine 73, a key compound for the transformation into further pyrano[3,2-a] carbazole alkaloids. Oxidation of 73 with DDQ leads to murrayacine 74, while epoxidation of 73 using meta-chloro-perbenzoic acid (MCPBA) followed by hydrolysis provides dihydroxygirinim-bine75 [113]. 

The palladium(II)-mediated oxidative cyclization of Ar,AT-diarylamines is useful for convergent total syntheses of a range of structurally different carbazole alkaloids. Goldberg coupling of 2,3-dimethoxyacetanilide 80 and 2-bromo-5-methylanisole 81 and subsequent alkaline hydrolysis affords the diarylamine 82... 

Knoelker H-J (2005) Occurrence, Biological Activity, and Convergent OrganometaUic Synthesis of Carbazole Alkaloids. 244 115-148 Kolodziejski W (2005) Solid-State NMR Studies of Bone. 246 235-270 Koser GF (2003) C-Heteroatom-Bond Forming Reactions. 224 137-172 Koser GF (2003) Heteroatom-Heteroatom-Bond Forming Reactions. 224 173-183... 

Dineshkumar et al. investigated the antidiabetic efficacy of mahan-imbine (33), a carbazole alkaloid isolated from Murraya koenigii... 

Dineshkumar B, Mitra A, Mahadevappa M. (2010) Antidiabetic and hypolipidemic effects of mahanimbine (carbazole alkaloid) from Murraya koenigii (rutaceae) leaves. Int J Phytomed 2 22-30. 

Malbrancheamide (60) represents a novel type of CaM inhibitors although other natural indole alkaloids such as the unusual indole-carbazole alkaloids from a culture broth of a Nocardiopsis sp, namely K-252a-K252d, the brominated P-carbolines eudistomidins A and C, obtained... 

In this series, three earlier reviews on carbazole alkaloids were published by Kapil (1), Husson (2), and Chakraborty (3) in the Volumes 13,26, and 44, respectively. The present chapter introduces a new classification of carbazole alkaloids and summarizes the recent synthetic efforts. The nomenclature of carbazole alkaloids used in this review is that of Chemical Abstracts. As shown in Scheme 1.1, the conventional tricyclic ring system of carbazole 1 is denoted by A, B, and C, and the numbering starts from ring A. The term carbazole generally refers to a 9H-carbazole. 

Several hypotheses have been proposed for the biogenesis of carbazole alkaloids (see Chapter 3 of this review). However, there is no deep experimental knowledge of the biosynthesis of this class of alkaloids. A comparison of the structural features of carbazole alkaloids isolated from higher plants suggests that 3-methylcarbazole (2) may represent the key intermediate in their biosynthesis (Scheme 1.1). 

In the present review, we summarize the occurrence, biogenesis, biological activity, and the chemistry of carbazole alkaloids, which have been classified based on their natural sources, ring system, and substitution pattern. While a comprehensive overview is given on all carbazole alkaloids isolated from natural sources, only their total syntheses published since 1990 are discussed. 

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