Carboline ester

A more promising approach to a synthesis of vinblastine-type compounds can be derived from the significant observation that reaction of one enantiomer of the carboline ester (-l- )-38 with p-nitrobenzyl chloro-formate and 3-methoxy-A/, A-dimethylaniline, at 25°C, gave a model (-t-)-congener of 39 in 72% yield and 55% enantiomeric excess, thus indicating a conformational retention in the nine-membered cationic intermediate formed on acylation of the carboline ester 38 (37b). 

The preparation of 18-methyIenevincadifformine (384) by H jicek and Troj nek (255) is a straightforward application of Kuehne s synthesis, in which 2-allyl-5-chloropentanal (577) was reacted with the tetrahydro-j8-carboline ester 578, first in boiling toluene, and subsequently in the presence of base. 18-Methylenevincadifformine (384) was thus obtained in essentially a one-pot preparation. 

For the kinetically controlled formation of 1,3-disubstituted tetrahydro-P-carbolines, placing both substituents in equatorial positions to reduce 1,3-diaxial interactions resulted in the cw-selectivity usually observed in these reactions." Condensation reactions carried out at or below room temperature in the presence of an acid catalyst gave the kinetic product distribution with the cw-diastereomer being the major product observed, as illustrated by the condensation of L-tryptophan methyl ester 41 with benzaldehyde. At higher reaction temperatures, the condensation reaction was reversible and a thermodynamic product distribution was observed. Cis and trans diastereomers were often obtained in nearly equal amounts suggesting that they have similar energies."... 

Conversely, when A-alkyl tryptophan methyl esters were condensed with aldehydes, the trans diastereomers were observed as the major products." X-ray-crystal structures of 1,2,3-trisubstituted tetrahydro-P-carbolines revealed that the Cl substituent preferentially adopted a pseudo-axial position, forcing the C3 substituent into a pseudo-equatorial orientation to give the kinetically and thermodynamically preferred trans isomer." As the steric size of the Cl and N2 substituents increased, the selectivity for the trans isomer became greater. A-alkyl-L-tryptophan methyl ester 42 was condensed with various aliphatic aldehydes in the presence of trifluoroacetic acid to give predominantly the trans isomers. ... 

Palladium dehydrogenation of l,2,3,4-tetrahydro-j8-carboline-3-carboxylic acid or its ethyl ester has been reported to take place with loss of the carboxyl or carbethoxyl group, yielding j3-carboline. On the other hand, it has been reported that palladium dehydrogenation of either 1-methyl-1,2,3,4-tetrahydro-j8-carboline-3-carboxylic acid or 1,3-dicarboxyhc acid yields l-methyl-3,4-dihydro-j8-carbohne-3-carboxyhc acid and not l-methyl-jS-carboline. ... 

Methyl-3,4-dihydro-j3-carboline-3-carboxylic acid has been reported to undergo photochemical and pyrolyticoxidation to yield a mixture containing l-methyl-j8-carboline and l-methyl-j8-carboline-3-carboxylic acid. The methyl ester of this 3,4-dihydro-j8-carboline acid appears to be oxidized to methyl l-methyl-j8-carboline-3-carboxylate on alumina chromatography. ... 

Similarly, permanganate oxidation of a number of naturally occurring canthin-6-one derivatives (295) leads to j8-carboline-l-carboxylic acid or its methyl ester.A j8-carboline-l-carboxylic acid... 

Murai, T., Koshikawa, N., Kanayama, T., Takada, K., Tomiyama, K., and Kobayashi, M., Opposite effects of midazolam and beta-carboline-3-carboxylate ethyl ester on the release of dopamine from rat nucleus accumbens measured by in vivo microdialysis, Eur. J. Pharmacol., 261, 65, 1994. 

The tetracyclic /3-carboline derivatives 452-454 have been prepared as sleep disorder therapeutics. The synthesis (Scheme 100) involves the reaction between the enamino ester 451 and acrylic acid derivatives, activated in certain cases with ethyl chloroformate <1997TL8475>. 

The Pictet-Spengler reaction has also seen much use in the synthesis of lavendamycin methyl ester. Both Hibino [31] and Behforouz [32] used it as a key step in their syntheses of this molecule (Fig. 10). In Hibino s synthesis, /i-methyltryptophan ethyl ester 27 was condensed with quinoline aldehyde 28 to give the corresponding lelrahydro- -carbohnc, which was aromatized by heating with palladium on carbon in xylenes, giving /1-carboline 29 in 75% yield. A five-step sequence (which included conversion to the methyl ester for easier comparison with known compounds) yielded bromoquinone 24 in 27% yield for the five steps. This completed Hibino s formal total synthesis of lavendamycin methyl ester, since this was the same intermediate used in Kende s synthesis. 

Behforouz s synthesis employed more highly substituted quinoline aldehyde 30, which, when condensed with ester 21, produced /3-carboline 31 without need of a separate oxidation step. Selective hydrolysis of the acetamide group then provided lavendamycin methyl ester in high yield. A few years later, Behforouz and coworkers reported an improved synthesis of 30, thus boosting the overall yield of their lavendamycin synthesis [33]. 

One of the earliest syntheses of lavendamycin methyl ester, however, did not employ either the Pictet-Spengler or the Bischler-Napieralski reactions for construction of the /J-carboline ring system. Instead, a palladium-promoted ring closure of aryl pyridine 36 (Fig. 12) was used to prepare /1-carboline 37 by Boger and coworkers [35]. Unfortunately, stoichiometric palladium was found to be necessary, in this case 1.5 equivalents of the tetrakis(triphenylphosphine)palladium(0) being used. Friedlander condensation with aldehyde 38 in the presence of benzyltrimethylammonium hydrox-... 

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... 

Banisteriopsis caapi The primary hallucinogenic constituents of B. caapi are the jS-carbolines. These include harmaline, tetrahydroharmine, harmol, harmic acid methyl ester, harmic amide, acetyl norharmine, harmine A/-oxide, harmalinic acid, and ketotetrahydronorharmine (figure 9.8). B. rusbyana also contains DMT, as well as A/-methyltryptamine, 5-methoxy-N,/V-dimethyltryptamine, and 5-hydroxy-N,/V-dimethyltryptamine (bufotenin). /V-methyltetrahydro-jS-carboline is found in trace amounts. 

Unusual amino acids include a class of unnatural a-amino acids such as phenylalanine, tyrosine, alanine, tryptophan, and glycine analogs, and f)-amino acid analogs containing 1,2,3,4-tetrahydroisoquinoline, tetraline, l,2,3,4-tetrahydro-2-carboline, cyclopentane, cyclohexane, cyclohexene, bicyclo[2.2.1]heptane or heptene skeletons. Different selectors were exploited for the separation of unusual amino acids, most of the production being made by Peter and coworkers teicoplanin [41, 56, 84, 90, 93, 124, 141-144], ristocetin A [33, 94, 145, 146], and TAG [56, 147]. Enantiomeric and diastereomeric separations of cyclic -substituted a-amino acids were reported by other authors on a teicoplanin CSP [88, 89], Ester and amide derivatives of tryptophan and phenylalanine were recently analyzed on a Me-TAG CSP [58],... 

In all cases, mixtures of cis and trans diastereoisomers are reported. In terms of experimental observation, it is now possible to prepare 1,3-disubstituted tetrahydro-j8-carbolines and 1-substituted tetrahydro-/3-carbolines of known absolute stereochemistry. For example, if optically active A -benzyltryptophan methyl ester of known chirality reacts with aldehydes in refluxing benzene, the trans derivative is obtained. Arylglycidate was also used in the synthesis instead of aldehydes (78CPB2305). 

For the synthesis of the natural blue pigment trichotomine dimethyl ester, L-Trp-OMe was used as a starting material. The first step of this synthesis was conversion into methyl l-methyl-3,4-dihydro-/8-carboline-3-carboxylate with acetyl chloride in TFA (85JOC3322). An improved method starts from the corresponding thioamides via thioiminium salts which cyclize spontaneously in refluxing solvent (82CPB4226). A-Formyl-tryptophan also cyclized readily with no side reactions (68CJC3404). 

The synthesis of /./-pyridindolol 1064 started by acetonation of glyceric ester 1057 to give 1058, which was converted to the imidazoline 1059 by reaction with l,l-dimethyl-l,2-diaminoethane followed by acetylation. Its methylation gave 1060, which can be reduced to 1061 further reaction with tryptamine or tryptophan ester hydrochloride 1062 gave the respective diastreomeric mixture of carboline 1063 (80H947). Its conversion to racemic alkaloid d,/-pyridindolol 1064 could be readily achieved (79JOC535). 

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