A-carboline

Like peganine a laboratory synthesis of rutaecarpine (51a) under physiological conditions has been realized by condensation of o-aminobenzaldehyde with a -carboline (Scheme 16). 

According to the Ring Index, the system is classified as pyrido-indole and numbered as in 6 (harmine = 7-methoxy-1-methyl-9 -pyrido[3,4-fc]indole). This is the nomenclature adopted by Chemical Abstracts, according to which a-carboline (5) is 9 -pyrido[2,3-6]indole, jS-carboline (6) is 9jy-pyrido[3,4-6]indole, y-carboline (7) is pyrido[4,3-6]indole, and S-carbohne (8) is 5jy-pyrido[3,2-fc]indole. 

Chemical Abstracts), and a-carboline is sold commercially under the name 1-azacarbazole. The trivial norharman nomenclature, in conjunction with numbering as in 1 or as in 6, is still to be found in recent papers. Other systems of numbering, as well as some incorrect systems of nomenclature, are to be found and add to the confusion. 

Homoesermetol (1,4a,9-trimethyl-6-methoxy-1,2,3,4,4a, 9a-hexa-hydro-a-carboline (89 R = CH3, R = OCH3) may be prepared in a manner analogous to that used for the preparation of eseroline. Thus, when the 3-y-oxindolylpropylamine 88 (R = CH3, R = OCH3) is reduced with sodium in butanol, homoesermetol is obtained. Reductive cycbzation of 88 (R = R = H) with lithium aluminum hydride has recently been reported. 

Preliminary experiments indicate that a-carboline is the major isomer formed in the reaction. The preparation of a mixture of a-(81.5%) and y-carboline (18.5%) from 3-o-nitrosophenylpyridine... 

Hey et al. also cyclized (21) to the a-carboline (22) with copper powder the yield, however, was low, the main product being a salt whose cation was formulated as (23) and which was presumably formed by an ionic reaction. ... 

Although a-carbolines (in particular, 2-amino-a-carboline) are perhaps better known as mutagens [89], some a-carbolines have been found to possess antitumor properties. For example, there has been much interest in the synthesis of natural products grossularine-1 133 and grossularine-2 134 (Fig. 38) since the report of their activity as antitumor agents at the 10 ng/mL level [90]. 

Synthetic a-carbolines have also attracted interest as antitumor agents. For example, Chen and coworkers [97] prepared a series of indolo[2,3-fr] quinoline derivatives, the most active of which was 154, which had a mean GI50 value against three cancer cell lines of 0.78 iM. This compound was prepared by methylation of 153 with dimethyl sulfate (Fig. 43), and was isolated in 12% yield, along with isomeric 155, which was isolated in 40% yield, but had significantly lower cytotoxicity. Precursor 153 itself was found to be inactive. 

Qudguiner s group enlisted a combination of directed metalation and a Pd-catalyzed crosscoupling reaction for the construction of heteroaryl natural products [49]. One example was the total synthesis of bauerine B (64), a -carboline natural product [50], Or/fio-lithiation of 2,3-dichloro-A-pivaloylaminobenzene (61) was followed by reaction with trimethylborate to provide boronic acid 62 after hydrolysis. The Suzuki reaction between 62 and 3-fluoro-4-iodopyridine led to the desired biaryl product 63 contaminated with the primary amine (ca. 30%), both of which were utilized in the total synthesis of bauerine B (64). Another p-carboline natural product, the antibiotic eudistomin T (65), and a few other hydroxy p-carbolines have also been synthesized in the same fashion [3,51]. 

A synergistic combination of Pd-catalyzed amination and arylation was the central operation of Sakamoto s synthesis of carbolines [147]. Diarylamine 187 was first installed via the Buchwald-Hartwig amination protocol. Subsequent intramolecular Heck-like arylation of 187 provided a novel route to a-carboline 188. 

Excitation of o-nitrodiphenylamine (111) and 3-nitro-2-phenylaminopyridine (112)64 causes the common intramolecular hydrogen abstraction, as the initial step, but subsequent steps involve the elimination of HNO2 and cyclization to give carbazole and a-carboline (113 and 114) in equation 55. 

Methods were described for HPLC determination of the mutagenic and carcinogenic a-carbolines (56,57), y-carbolines (58,59)155 160, and other products of amino acid pyrolysis found in cigarette smoke, diesel exhaust and cooked foods and phenazines (60, 61) present as impurities of certain pesticides161. These compounds were also determined in human plasma, urine and bile161,162. 

Indole oximes are widely used in the synthesis of a-, /3- and y-carbolines. Synthesis of a-carbolines 302 was easily realized from 0-2,4-dinitrophenyl-substituted oximes 301... 

One of the rare examples, where the palladium catalyzed closure of a six membered ring leads to an aromatic heterocycle is presented in 4.18. Intramolecular transformation of the 2-bromoindole derivative in the presence of a palladium-BINAP catalyst led to the formation of the a-carboline (pyrido[2,3- ]indole) skeleton. The ring closure was accompanied by the oxidation of the intermediate dihydrocarboline derivative.21... 

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