Syntheses of chiral 1,3-disubstituted tetrahydro-β-carbolines via CIAT process: highly stereoselective Pictet–Spengler reaction of d-tryptophan ester hydrochlorides with various aldehydes

A highly stereoselective Pictet–Spengler reaction of d-tryptophan methyl ester hydrochloride 1-HCl with various aldehydes via a CIAT (crystallization-induced asymmetric transformation) process is described. It was revealed that the CIAT process should be performed in a mixed solvent of nitromethane and toluene, and a fine tuning of the ratio of nitromethane and toluene for each epimer mixture of 2-HCl was necessary in order to get as high yields and stereoselectivities as possible. Enantiomerically pure cis (or trans) 1,3-disubstituted tetrahydro-β-carbolines 2a–2v were obtained by recrystallization or flash chromatography after neutralization of the corresponding hydrochloride salts cis-2-HCl or trans-2-HCl.

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(1R,3R)-Methyl 1-hexyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC19H26N2O2[α]D20=+57.8 (c 1.6,CHCl3)Source of chirality: d-tryptophanAbsolute configuration: (1R,3R)

(1R,3R)-Methyl 1-(2-methoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC20H20N2O3[α]D20=-14.1 (c 1.5, CHCl3)Source of chirality: d-tryptophanAbsolute configuration: (1R,3R)

(1R,3R)-Methyl 1-(2-ethoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC21H22N2O3[α]D20=+1.6 (c 4.1, CHCl3)Source of chirality: d-tryptophanAbsolute configuration: (1R,3R)

(1R,3R)-Methyl 1-(2-chlorophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC19H17N2O2Cl[α]D20=-20.6 (c 0.9, CHCl3)Source of chirality: d-tryptophanAbsolute configuration: (1R,3R)

(1R,3R)-Methyl 1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC14H16N2O2[α]D20=+93.6 (c 2.5, CHCl3)Source of chirality: d-tryptophanAbsolute configuration: (1R,3R)

(1R, 3R)-Methyl 1-ethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC15H18N2O2[α]D20=+9.8 (c 1.6, CHCl3)Source of chirality: d-tryptophanAbsolute configuration: (1R,3R)

(1S,3R)-Methyl 1-(4-acetoxy-3-methoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC22H22N2O5[α]D20=+30.4 (c 1.2, CHCl3)Source of chirality: d-tryptophanAbsolute configuration: (1S,3R)

(1R,3R)-Methyl 1-(4-benzoyloxy-3-methoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC27H24N2O5[α]D20=+8.1 (c 1.4, CHCl3)Source of chirality: d-tryptophanAbsolute configuration: (1R,3R)

(1R,3R)-Ethyl 1-(3,4,5-trimethoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC23H26N2O5[α]D20=+20.5 (c 0.4, CHCl3)Source of chirality: d-tryptophanAbsolute configuration: (1R,3R)

(1S,3R)-Ethyl 1-(3,4-dimethoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC22H24N2O4[α]D20=+26.0 (c 1.9, CHCl3)Source of chirality: d-tryptophanAbsolute configuration: (1S,3R)

(1S,3R)-Methyl 1-(3,4,5-trimethoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC22H24N2O5[α]D20=+11.3 (c 1.3, CHCl3)Source of chirality: d-tryptophanAbsolute configuration: (1S,3R)

(1S,3R)-Ethyl 1-(4-methoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC21H22N2O3[α]D20=+49.7 (c 0.3, CHCl3)Source of chirality: d-tryptophanAbsolute configuration: (1S,3R)

(1R,3R)-Ethyl 1-(benzo[d][1,3]dioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC21H20N2O4[α]D20=+32.2 (c 1.0, EtOAc)Source of chirality: d-tryptophanAbsolute configuration: (1R,3R)

C22H22N2O4(1R,3R)-Propyl 1-(benzo[d][1,3]dioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate[α]D20=+36.2 (c 1.0, EtOAc)Source of chirality: d-tryptophanAbsolute configuration: (1R,3R)

(1R,3R)-Methyl 1-(3,4-dimethoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC21H22N2O4[α]D20=+21.9 (c 1.6, CHCl3)Source of chirality: d-tryptophanAbsolute configuration: (1R,3R)

(1S,3R)-Methyl 1-phenyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC19H18N2O2[α]D20=+44.5 (c 1.0, CHCl3)Source of chirality: d-tryptophanAbsolute configuration: (1S,3R)

(1S,3R)-Methyl 1-deutero-1-(3,4-dimethoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC21H21DN2O4[α]D20=+24.5 (c 1.0, CHCl3)Source of chirality: d-tryptophanAbsolute configuration: (1S,3R)

(R)-Methyl 2-amino-3-(2-(3,4-dimethoxybenzyl)-1H-indol-3-yl)propanoateC21H24N2O4[α]D20=+17.3 (c 1.2, CHCl3)Source of chirality: d-tryptophanAbsolute configuration: (R)

(1S,3R)-Methyl 1-(3,4-dimethoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC21H22N2O4[α]D20=+25.4 (c 1.7, CHCl3)Source of chirality: d-tryptophanAbsolute configuration: (1S,3R)

(1S,3R)-Methyl 1-(4-methoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC20H20N2O3[α]D20=+44.0 (c 2.0, CHCl3)Source of chirality: d-tryptophanAbsolute configuration: (1S,3R)

(1R,3R)-Methyl 1-phenyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC19H18N2O2[α]D20=+14.2 (c 1.5, CHCl3)Source of chirality: d-tryptophanAbsolute configuration: (1R,3R)

(1R,3R)-Methyl 1-(4-hydroxy-3-methoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC20H20N2O4[α]D20=+39.8 (c 1.1, CHCl3)Source of chirality: d-tryptophanAbsolute configuration: (1R,3R)

(1R,3R)-Methyl 1-(4-hydroxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC19H18N2O3[α]D20=+34.2 (c 1.0, acetone)Source of chirality: d-tryptophanAbsolute configuration: (1R,3R)

(1R,3R)-Methyl 1-(4-nitrophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC19H17N3O4[α]D20=+5.4 (c 1.0,CHCl3)Source of chirality: d-tryptophanAbsolute configuration: (1R,3R)

(1S,3R)-Methyl 1-isopropyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC16H20N2O2[α]D20=-53.4 (c 1.6, CHCl3)Source of chirality: d-tryptophanAbsolute configuration: (1S,3R)

(1R,3R)-Methyl 1-(2-nitrophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylateC19H17N3O4[α]D20=+22.6 (c 6.6,CHCl3)Source of chirality: d-tryptophanAbsolute configuration: (1R,3R)