A-Carbolines. synthesis

In a modified Graebe-Ullman reaction, pyridylbenzotriazole 223 was converted to a-carboline 224 in an efficient manner but in moderate yield (Scheme 38) <20060L415>. Microwave irradiation was the energy source for both a-carboline synthesis and the preparation of 223. The advantages of this procedure are that the starting materials are commercially available and lower reaction times are used resulting in fewer undesirable side products. The style of microwave oven, amount of pyrophosphoric acid, power level, and time were all optimized. 

Scheme 51. Pd-catalyzed intramolecular C-N bond formation in a-carboline synthesis...

Pyrido[2,3-h]indoles (a-carbolines), synthesis and reactivity of 84KGS435. 

Pyrido[2,3-h]indoles (a-carbolines), synthesis and reactivity of 84KGS435. Pyrido[2,3-c]indoles (/S-carbolines), biochemistry of 83MIIO. Pyrido[3,2-c]indoles, tetrahydro- (tetrahydro-y-carbolines) 73KGS291. 3//-Pyrrolo[2,3-c]quinolines 78H(9) 1617. 

These formulae explain the scission products of the two alkaloids and the conversion of evodiamine into rutaecarpine, and were accepted by Asahina. A partial synthesis of rutaecarpine was effected by Asahina, Irie and Ohta, who prepared the o-nitrobenzoyl derivative of 3-)3-amino-ethylindole-2-carboxylic acid, and reduced this to the corresponding amine (partial formula I), which on warming with phosphorus oxychloride in carbon tetrachloride solution furnished rutaecarpine. This synthesis was completed in 1928 by the same authors by the preparation of 3-)S-amino-ethylindole-2-carboxylic acid by the action of alcoholic potassium hydroxide on 2-keto-2 3 4 5-tetrahydro-3-carboline. An equally simple synthesis was effected almost simultaneously by Asahina, Manske and Robinson, who condensed methyl anthranilate with 2-keto-2 3 4 5-tetrahydro-3-carboline (for notation, see p. 492) by the use of phosphorus trichloride (see partial formulae II). Ohta has also synthesised rutaecarpine by heating a mixture of 2-keto-2 3 4 5-tetrahydrocarboline with isatoic anhydride at 195° for 20 minutes. 

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

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]. 

In 1969, Szantay and co-workers published a linear synthesis of (+)-yohimbine and (—)-P-yohimbine (75) in full detail (220). Tetracyclic key intermediate 400, obtained from 3,4-dihydro-p-carboline and a properly substituted a,p-unsatu-rated ketone (173), was treated with a proper phosphonoacetic acid derivative to give unsaturated nitrile 401 or unsaturated ester 402. Catalytic reduction of the latter resulted almost exclusively in 404 with normal stereo arrangement, while reduction of 401 supplied a mixture of normal and epialloindolo[2,3-a] quinolizines 403 and 405, respectively. Dieckmann ring closure of diester 404 gave 18a-methoxycarbonylyohimbone (407) as the thermodynamically favored... 

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. 

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... 

A Didemnum sp. from Rota in the northern Mariana Islands contained four new (3-carboline alkaloids, didemnolines A-D (95-98), together with known metabolites [119]. The didemnolines are characterised by substitution at N9 as opposed to Cl. A straightforward synthesis of the didemnolines was reported [120],... 

An important application of the Mannich reaction is the synthesis of 3-dialkylaminoindoles. Intramolecular versions of this reaction are also possible, as illustrated by the formation of the a-carboline (107). 

The Pschorr reaction is valuable in the synthesis of carbolines. The 3-aminopyridine (165) gives the a-carboline (166 78%) under free-radical conditions, but the aniline... 

Various heteroarylenenamines were starting materials in the synthesis of pyridine derivatives. For example, 3-dimethylaminomethylenoxyindole derivatives (168) were used in the preparation of a-carbolines (95MC226). Indolylenamines (169) undergo a facile transformation into y-carbolines... 

Interaction of substituted dienediamines with ethylenediamine yields im-idazo[3,2-n]pyridine derivatives (95JHC477). 3-Arylaminoindoles, with distinct enamine properties, are the starting materials for the synthesis of indolo[3,2-b]quinoline derivatives [96KFZ(7)42]. a-Carboline derivatives can be obtained from enamine-based 3-dimethylamino-2-indolinones [96KFZ(9)35, 96KFZ(10)32], The synthesis and transformation of enamines based on the pyrido[l,2-n]pyrazine ring system into imidazo[l,2-n]pyridine and imidazo[l,2-a]pyrimidine derivatives have been reported... 

Grossularins I (37) and II (38), the first examples of naturally occurring a-carbolines, were obtained from a French solitary tunicate (Dendrodoa grossularia) and were found to be cytotoxic toward L1210 leukemia cells (55). Previously the structure of grossularin I was proposed as 39 (56), which was revised to 37 on the basis of comparison with the structure of grossularin II (38). Structural proof for 38 was unambiguously provided by X-ray analysis. The same tunicate contained 3-indolyl-4//-imidazol-4-one (40), the structure of which was confirmed by synthesis (57). The imidazo-lone compound (40) was devoid of cytotoxicity. 

Stoichiometric palladium-mediated cyclization was used in natural product synthesis by Boger a number of years ago, as was noted in the introduction. More recently, an intramolecular palladium-catalyzed amination of a heteroaromatic halide has been used as a step in the synthesis of an a-carboline natural product analog [146]. As discussed above, the diphenylhydrazone arylation can also be used for nitrogen heterocycle synthesis [140]. 

A partial synthesis of burnamicine (131) from geissoschizine methyl ether (130) takes advantage of the c/D ring cleavage of tetrahydro-/3-carbolines by means of ethyl chloroformate (Scheme 13),79 which simultaneously introduces a function into position 3, thereby facilitating the formation of the 3-oxo-substituent. An exactly analogous route was used for the synthesis of 19,20-dihydroburnamicine (133) from hirsutine (132). 

An extension of Kametani s earlier synthesis has afforded a neat synthesis of rutaecarpine (24) and hortiacine (10-methoxyrutaecarpine).22" In this modification, the presence of a trifluoromethyl group in (23) (instead of hydrogen, as in Kametani s synthesis) increases the electrophilicity of the protonated form, and also provides a useful leaving group for the final stage of the synthesis a dehydrogenation step is therefore unnecessary (Scheme 3). Rutaecarpine has also been synthesized.226 11-Methoxyrutaecarpine has been simply synthesized by condensation of 7-methoxy- 1-oxo-l,2-dihydro-/ -carboline with methyl anthranilate and phosphorus oxychloride.22c... 

Scheme 62. Synthesis of the 10//-benzo[i]-a-carboline ring system (e.g., 377, 378) by Nantka-Namirski and co-workers 136).

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