Enantiospecific Formation of Trans 1,3-Disubstituted Tetrahydro-β-carbolines by the Pictet−Spengler Reaction and Conversion of Cis Diastereomers into Their Trans Counterparts by Scission of the C-1/N-2 Bond

Abstract

The factors which effect the stereoselective formation of trans-1-alkyl-2-benzyl-3-(alkoxycarbonyl)-1,2,3,4-tetrahydro-beta-carbolines and trans-3-(alkoxycarbonyl)-1-alkyl-2-(diphenylmethyl)-1,2,3,4-tetrahydro-beta-carbolines by the Pictet-Spengler cyclization were examined by heating tryptophan derivatives with aldehydes of varied steric bulk under aprotic and acidic conditions, followed by determination of the ratio of cis to trans diastereomers so formed. The presence of a benzyl group at the N(b)-nitrogen atom alters the diastereochemical outcome of this condensation to provide 100% trans stereoselectivity when the cyclization is carried out with cyclohexanecarboxaldehyde. Furthermore, when N(b)-(diphenylmethyl)tryptophan isopropyl ester was condensed with aldehydes of any size, trans diastereomers are formed with 100% stereoselectively. The trans N(b)-substituted diastereomers are thermodynamically more stable than their cis congeners as shown by equilibration experiments in TFA. Conversion of the cis diastereomers into the more stable trans diastereomers is believed to occur under acidic conditions by cleavage of the carbon (C-1)-nitrogen (N-2) bond with complete retention of configuration at the C-3 stereocenter. Evidence from deuterium exchange experiments as well as optical rotations support this model for epimerization. In addition, when cis diastereomer 66a was allowed to stir in CF(3)COOD, the trans isomer 66b was isolated in 90% yield, while treatment of cis 66a with CF(3)COOH/NaBH(4) provided a mixture of the ring cleaved [scission across C(1)-N(2) bond] product 67 and the trans isomer 66b. Treatment of 66b (control experiment) with NaBH(4)/CF(3)COOH under the same conditions returned only starting trans 66b in excellent yield. The Pictet-Spengler reaction of substrates with sufficiently large substituents, followed by treatment with acid, permits the 100% enantiospecific formation of trans-1,3-disubstituted-1,2,3,4-tetrahydro-beta-carbolines for alkaloid total synthesis.

The Pictet–Spengler Reaction in Nature and in Organic Chemistry

“…[109] Detailed examination of the reaction conditions allowed thermodynamic trans stereocontrol by application of the N bbenzylalkyl esters of tryptophan. [108,[110][111][112] A mixture of isomers of 1,2,3-trisubstituted tetrahydro-bcarbolines was formed when small aliphatic aldehydes were used under acidic and non-acidic aprotic conditions (Table 3). Selective formation of the trans diastereomer was observed for cyclohexanecarboxaldehyde.…”

“…[4b, 108,111,112] The diastereomers can usually be separated by flash chromatography. The thermodynamically more-stable trans isomer could be obtained exclusively from the cis/trans mixture by epimerization of the N b -substituted cis isomer under acidic conditions (trifluoroacetic acid; Scheme 16).…”

The Chiral Pool in the Pictet–Spengler Reaction for the Synthesis of β-Carbolines

“…In fact, since 1979, Cook and co-workers studied the reaction of these compounds with aldehydes [14][15][16][17][18]. Thus, they found that the steric bulk of the carbonyl compounds, and the substituents either at the Nb nitrogen atom or at the ester group governed the diastereoselectivity of the PSR, leading preferentially to trans-1,2,3-trisubstituted tetrahydro-β-carbolines under thermodynamic stereocontrol (Scheme 3).…”

Aliphatic aldehydes in the synthesis of carbo- and heterocycles: Part II. Synthesis of six- and seven-membered rings, bicyclic compounds, and macrocycles

“…Among the latter, many compounds are important drugs, including benzyltetrahydroisoquinoline alkaloids which are synthesized via enzymatic Pictet-Spengler reaction, i.e., condensation of aldehydes with 2-arylethanamines 58 with formation of tetrahydroisoquinolines 57 (Scheme 15). The amine component may be derivatives of phenylalkanamines [47][48][49][50][51] [52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67], amines of the naphthalene series [68], and aminoalkyl derivatives of heterocyclic compounds [69,70]. If X = O, the corresponding 1,2-oxazines, 1,2-oxazepines, and 1,2-oxazocines are obtained [71].…”