Carbazole alkaloids numbering

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. 

Among the large number of carbazole alkaloids that have been isolated from M. koenigii are also many 2-oxygenated derivatives. In 1985, Bhattacharyya et al. isolated 2-methoxy-3-methylcarbazole (37) from the petroleum ether extract of the seeds of M. koenigii (55). The UV spectrum (Tmax 235,255,300, and 328 nm) and the IR... 

In addition to the aforementioned drugs, clinical trials of several other natural pyrido[4,3- 7]carbazole alkaloids and a number of synthetic analogs showed them to be potent inhibitors of several cancerous disorders, but pre-clinical toxicology indicated a number of side effects, including hemolysis and cardiovascular effects (192). 

From the initial discovery till today, biologically active carbazole alkaloids isolated from nature may have quite simple but in some cases also structurally complex substitution patterns. Therefore, a large number of classical and non-classical methods has been developed for the synthesis of the carbazole framework. 

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). 

Among the carbazole alkaloids the most noteworthy is ellipticine (28). It and a number of synthetic analogs exhibit significant antitumor activity. The mechanism of action is believed to involve interaction with DNA (79MI30602). 

Using cationic tricarbonyl(q5-cyclohexadienyl)iron complexes as starting materials, different synthetic routes to a large number of carbazole alkaloids have been developed [51, 58, 67]. The first step is an electrophilic substitution of a substituted arylamine using the cyclohexadienyliron complex and provides the corresponding 5-aryl-substituted cyclohexadiene-iron complexes (Scheme 1.29). 

A number of dimeric carbazole alkaloids have been isolated from various natural sources in recent years, which have been found to exhibit various biological activities including antitumor, anti-inflammatory, and cytotoxic activities. In 1996, clausenamine A was isolated from the stem and root bark of Clausena excavata, which is used in Chinese herbal medicine for detoxification treatment following poisonous snakebites. The first total synthesis of clau-... 

The curry leaf plant is highly valued for its characteristic aroma and medicinal value (Philip, 1981). A number of leaf essential oil constituents and carbazole alkaloids have been extracted from the plant (Mallavarapu et al., 1999). There are a large number of oxygenated mono- and sesquiterpenes present, e.g. c/s-ocimene (34.1%), a-pinene (19.1%), y-terpinene (6.7%) and P-caryophyllene (9.5%), which appear to be responsible for the intense odour associated with the stalk and flower parts of curry leaves (Onayade and Adebajo, 2000). In fresh bay leaves, 1, 8-cineole is the major component, together with a-terpinyl acetate, sabinene, a-pinene, P-pinene, P-elemene, a-terpineol, linalool and eugenol (Kilic et al., 2004). 

The restricted space available for these Reports unfortunately does not allow the discussion of a number of topics of interest to monoterpenoid chemists useful reviews of such topics include monoterpenoid alkaloids/ carbazole alkaloids/ isoprenoids and alkaloids of tobacco/" naturally occurring plant coumarins/ the biosynthesis of aromatic hemiterpenes/ and recent developments in the field of naturally occurring aroma components/ The poor quality of the Chemical Abstracts makes it difficult to assess the significance of a number of reviews of potential industrial interest/ A volume in the Methodicum Chimicum series includes a very brief discussion of some monoterpenoids/"... 

Furoannulated carbazole alkaloids represent a relatively new class of natural products which have been isolated from terrestrial plants [121,122]. The number of members of this family known to date is rather limited. Furoclausine-A (61) along with furoclausine-B was isolated first by Wu and co-workers from the root bark of C. excavata [122]. We have developed an efficient and convergent access to furo [3,2-a]carbazoles via our iron-mediated arylamine cyclization [123, 124]. Retro-synthetic analysis of furoclausine-A (61) suggests 1-methoxycyclohexa-1,4-diene (48) and the arylamine 62 as building blocks (Scheme 16). The latter was obtained by alkylation of 2-methyl-5-nitrophenol (63) with 2-bromo-1,1-diethoxyethane... 

A large number of 2-oxygenated carbazoles has been isolated from natural sources [18, 20]. Mukonidine (149) and clausine L (O-methylmukonidine) (148) have been isolated by Wu et al. from the Chinese medicinal plant C. excavata [173]. 2-Methoxy-3-methylcarbazole (146) was obtained first from the seeds of the Indian medicinal plant Murraya koenigii by Bhattacharyya and co-workers [174]. The isolation of O-methylmukonal (147) was reported by Lange et al. from M. siamen-sis [112]. Two years later, Bhattacharyya found the same compound in the roots of G. pentaphylla and renamed it glycosinine (147) [175]. Clausine V (151), a 2,7-dioxygenated carbazole alkaloid, was extracted from the root bark of C. excavata by Wu and co-workers [116]. 

A large number of alkaloids containing an aromatic carbazole framework have been isolated from plants belonging to the Rutaceae family. These alkaloids can be very simple, for example 3-methyIcarbazole (1), but they frequently have terpenoid units of various length and complexity attached. A selection of Rutaceae carbazole alkaloids is given in Figure 1. 

Table 2. Ultraviolet Absorption Spectra of Some Carbazole Alkaloids (For structures not numbered see Refs //, 19)...

Carbazoles are relatively rare as natural products. There are a number of alkaloids with carbazole rings and these are derived from tryptophan and are closely related biogenetically to the indole alkaloids. 

Of the more than 4500 known naturally occurring organohalogen compounds, a large fraction are alkaloids [1,3]. Most of these halogenated pyrroles, indoles, carbazoles, carbolines, tyrosines, and others have a marine origin. The present chapter surveys the occurrence, structure, and biosynthesis of these fascinating natural products. However, given their sheer number, this review focuses mainly on recent examples. 

Minfiensine (99) [43] exemplifies a variety of indole alkaloids containing the novel l,2,3,4-tetrahydro-9a,4a-(iminoethano)-9/7-carbazole ring skeleton. These include minfiensine (99), vincorine (100) [44], corymine (101) [45], and echitamine (102) [46] (Fig. 4). They exhibit a number of impressive biological activities, including significant anticancer activity [47]. Since the first characterization of the first akuammiline alkaloid member echitamine (102), more than 80 years ago, only a few successful syntheses of this challenging tetracyclic system have been reported. 

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... 

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