Tetrahydro-/3-carboline

Activity of P-Carbolines, Tetrahydro-P-Carbolines and Dihydro-P-Carbolines... 

Carbamoyl Chloride Carbodiimide )0-Carboline (tetrahydro) Carbonate Carboxylic Acid... 

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. 

Tetrahydroalstonine gives with the Adamkiewicz test, as modified by Harvey et al., a colour similar to that given by yohimbine, which is taken to indicate the presence of a tetrahydro-/3-carboline ring system. Further, the ultra-violet absorption curves for yohimbine and tetrahydroalstonine... 

This reaction is also a key method for the formation of tetrahydro-P-carbolines 5 from indole bases 4 and aldehydes, ketones, or 1,2-di carbonyl compounds 2. These reactions are similarly acid-catalyzed or thermally-induced and have been utilized in the synthesis of numerous indole alkaloids. 

A few years later, Tatsui developed this process for use with indole bases and prepared l-methyl-l,2,3,4-tetrahydro-P-carboline 11 from tryptamine 9 and acetaldehyde 10 under acid catalysis. ... 

Several factors influence the diastereoselectivity of the Pictet-Spengler condensation to form 1,3-disubstituted and 1,2,3-trisubstituted tetrahydro-P-carbolines (39 and 40, respectively). The presence or absence of an alkyl substituent on the nitrogen of tryptophan has a large influence on the relative stereochemistry of the tetrahydro-P-carboline products formed from a condensation reaction with an aldehyde under various reaction conditions. 

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. ... 

A -sulfinyl chiral auxiliaries have been used to prepare enantiopure tetrahydro-P-carbolines and tetrahydroisoquinolines in good yields under mild reaction conditions. Both enantiomers of V-p-toluenesulfinyltryptamine 46 could be readily prepared from the commercially available Andersen reagents.Compound 46 reacted with various aliphatic aldehydes in the presence of camphorsulfonic acid at -78 °C to give the A-sulfinyl tetrahydro-P-carbolines 47 in good yields. The major diastereomers were obtained after a single crystallization. Removal of the sulfinyl auxiliaries under mildly acidic conditions produced the tetrahydro-P-carbolines 48 as single enantiomers. 

Tryptophan (15) and its substituted derivatives also react with aldehydes to give l,2,3,4-tetrahydro-jS-carboline-3-carboxylic acids (17), Acetaldehyde and benzaldehyde yield the expected products with the amino acid and its A -methyl derivative (abrine). ... 

Depending on conditions, formaldehyde and tryptophan yield either 1,2,3,4 - tetrahydro-jS - carboline-3-carboxylic acid (17 R = H), or the intermediate carbinolamine (16, R = H), which... 

The intense blue color which is obtained when tryptophan, in the presence of an aldehyde, is treated with concentrated sulfuric acid containing an oxidizing agent (Adamkiewicz-Hopkins-Cole reaction) was beheved to involve formation of a tetrahydro-j8-carboline intermediate, since most l,2,3,4-tetrahydro-j8-carbohne derivatives yield a similar color with concentrated sulfuric acid containing an oxidizing agent. The two colors have now been shown to have different absorption spectra. The nature of the carboline-blue color is still obscure. 

The decarboxylated products are obtained directly, however, if condensation of tryptamine with the a-oxo acid is carried out in aqueous solution at elevated temperature. This direct synthesis of a l-substituted-l,2,3,4-tetrahydro-j8-carboline has been carried out with... 

Tryptophan condenses with a-oxo acids at room temperature to yield l,2,3,4-tetrahydro-j8-carboline-l,3-dicarboxylic acids. Both gly-oxylic acid and pyruvic acid yield the expected products. 

Tetrahydro-y-carbolines may be prepared by an internal Mannich-type reaction between 2-j8-aminoethyhndoles and formaldehyde. Kebrle et al. prepared 27 by the reaction of 2-lithio-l-methyl-indole with A-benzyl-A-ethylaminoacetone followed by debenzyl-ation treatment of 27 with formaldehyde led to the formation of the tetrahydro-y-carboline 28. Similarly, when the quaternary salts (30) of the Mannich bases (29) are heated at 100°, 1,2,3,4-tetrahydro-y-carbohnium salts (31) are formed. 

A variety of l,2,3,4-tetrahydro-j8-carbolines have been prepared from 3-piperidone phenylhydrazone derivatives. Used initially to obtain pentacyclic derivatives (35) related to the yohimbe alkaloids, this route was later extended to the synthesis of tetracyclic compounds (36). l-Methyl-5,6,7,8-tetrahydro-j8-carboline (37) was prepared in low yield by heating cyclohexanone 2-methyl-3-pyridylhydrazone with zinc chloride, a synthesis probably based on the similar preparation of the tetracyclic compound 38 starting from the corresponding quinolylhydrazine. Abramovitch and Adams extended this approach to the cyclization of cyclohexanone 3-pyri-dylhydrazone (39) itself. The main product was 6,7,8,9-tetrahydro-8-carboline (40), a smaller amount of the j8-isomer (41) also being obtained. This provides a convenient and readily reproducible route to the otherwise difficultly accessible 8-carboline ring system. The favored attack at carbon-2 over carbon-4 of the pyridine nucleus... 

Variously substituted 1,2,3,4-tetrahydro-y-carbolines (43c) may be obtained readily from 4-piperidone phenylhydrazones (43b). In fact, probably the first appbcation of the Fischer... 

R" = CH20H). The use of sodium borohydride in place of lithium aluminum hydride did not lead to ring closure but to 3-[j8-(A-l,2,3,4-tetrahydroisoquinolyl)ethyl]indole derivatives (53). Reductive cyclization by means of lithium aluminum hydride of the j8-(3-indolyl)ethyl-l-isoquinoline (52) to the pentacyclic tetrahydro-j8-carboline 49 (R = R = R" = H) has been reported. Strong acid alone sufficed to convert 52 into 54, the 0x0 derivative of 49. ... 

In a recent variation of this synthesis of the tetrahydro-j8-carboline system, hexahydro derivatives (65) of the salt 55 were cyclized to fully aromatic j8-carbohne derivatives (66a and 66b) on palladium dehydrogenation, presumably by way of an enamine intermediate. ... 

Tetrahydrocarboline derivatives have recently been synthesized from 2-o-nitroarylated cyclohexanone derivatives. Thus, reductive cyclization of 3-(2,4-dinitrophenyl)-l-methyl-4-piperidone (68) (prepared by the reaction of 2,4-dinitrochlorobenzene with l-methyl-4-A-pyrrolidmo-3-piperideine) gave 7-amino-2-methyl-l,2,3,4-tetrahydro-y-carboline (69). Neither catalytic nor chemical reduction of the... 

Anhydro-bases derived from quaternary )S-carbolinium salts are reduced to p /r-A-substituted-l,2,3,4-tetrahydro-j8-carboline derivatives on hydrogenation over Adams catalyst in methanol solution made alkaline to ensure the presence of anhydro-base. ... 

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