Highly stereoselective transformation of (1S,3S)-cis-1,3-disubstituted tetrahydro-β-carbolines into (1S,3R)-trans-1,3-disubstituted tetrahydro-β-carbolines: an improved asymmetric synthesis of tadalafil from l-tryptophan

An efficient and general method for the highly stereoselective transformation of (1S,3S)-cis-1,3-disubstituted 1,2,3,4-tetrahydro-β-carbolines (THBCs) into (1S,3R)-trans-1,3-disubstituted THBCs is described. The method contains the following three steps: the enantiomerically pure (1S,3S)-cis-1,3-disubstituted THBCs 1 were first converted into (1S,3S)-cis-1,2,3-trisubstituted THBCs 2 by N-1-naphthylmethylation/benzylation; (1S,3S)-cis-1,2,3-trisubstituted THBCs2 were then converted into (1S,3R)-trans-1,2,3-trisubstituted THBCs 3 in high yields and with high stereoselectivities via a base-catalyzed epimerization at C-3; (1S,3R)-trans-1,2,3-trisubstituted THBCs 3 were subsequently converted into (1S,3R)-trans-1,3-disubstituted THBCs 4 after reductive removal of the 1-naphthylmethyl/benzyl group. In addition, as an application of this method, an improved and highly stereoselective synthesis of the PDE5 inhibitor tadalafil (Cialis®) starting from natural and less expensive l-tryptophan was developed.

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(1S,3S)-Methyl 1-(benzo[d][1,3]dioxol-5-yl)-2-(naphthalen-1-yl-methyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC31H26N2O4[α]D20=-83.4 (c 1.00, CH3OH)Source of chirality: l-TryptophanAbsolute configuration: (1S,3S)

(1S,3S)-Methyl 1-(benzo[d][1,3]dioxol-5-yl)-2-benzyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC27H24N2O4[α]D20=-87.0 (c 1.60, CHCl3)Source of chirality: l-TryptophanAbsolute configuration: (1S,3S)

(1S,3S)-Ethyl 1-(benzo[d][1,3]dioxol-5-yl)-2-(naphthalen-1-yl-methyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC32H28N2O4[α]D20=-69.4 (c 1.00, CH3OH)Source of chirality: l-TryptophanAbsolute configuration: (1S,3S)

C30H25FN2O2(1S,3S)-Methyl 1-(4-fluorophenyl)-2-(naphthalen-1-ylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate[α]D20=-98.7 (c 1.00, CH3OH)Source of chirality: l-TryptophanAbsolute configuration: (1S,3S)

(1S,3S)-Ethyl 2-(naphthalen-1-ylmethyl)-1-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC34H34N2O5[α]D20=-67.0 (c 1.05, CH3OH)Source of chirality: l-TryptophanAbsolute configuration: (1S,3S)

(1S,3S)-Methyl 1-(3-hydroxyphenyl)-2-(naphthalen-1-ylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC30H26N2O3[α]D20=-77.3 (c 1.00, CH3OH)Source of chirality: l-TryptophanAbsolute configuration: (1S,3S)

(1S,3S)-Methyl 1-phenyl-2-(naphthalen-1-ylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC30H26N2O2[α]D20=-43.9 (c 1.00, CHCl3)Source of chirality: l-TryptophanAbsolute configuration: (1S,3S)

(1S,3S)-Methyl 1-(3,4-dimethoxyphenyl)-2-(naphthalen-1-ylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC32H30N2O4[α]D20=-77.2 (c 1.00, CHCl3)Source of chirality: l-TryptophanAbsolute configuration: (1S,3S)

(1S,3S)-Methyl 1-(4-ethoxy-3-methoxy-phenyl)-2-(naphthalen-1-ylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC33H32N2O4[α]D20=-68.1 (c 3.00, CHCl3)Source of chirality: l-TryptophanAbsolute configuration: (1S,3S)

(1S,3S)-Methyl 1-methyl-2-(naphthalen-1-ylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC25H24N2O2[α]D20=-22.5 (c 1.10, CH3OH)Source of chirality: l-TryptophanAbsolute configuration: (1S,3S)

(1S,3S)-Methyl 2-benzyl-1-methyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC21H22N2O2[α]D20=-6.1 (c 2.6, CH3OH)Source of chirality: l-TryptophanAbsolute configuration: (1S,3S)

(1S,3S)-Methyl 1-ethyl-2-(naphthalen-1-ylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC26H26N2O2[α]D20=-42.2 (c 1.02, CH3OH)Source of chirality: l-TryptophanAbsolute configuration: (1S,3S)

(1S,3S)-Methyl 2-(naphthalen-1-ylmethyl)-1-propyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC27H28N2O2[α]D20=-33.2 (c 1.00, CHCl3)Source of chirality: l-TryptophanAbsolute configuration: (1S,3S)

(1S,3S)-Methyl 1-hexyl-2-(naphthalen-1-ylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC30H34N2O2[α]D20=-60.4 (c 1.10, CH3OH)Source of chirality: l-TryptophanAbsolute configuration: (1S,3S)

(1S,3R)-Methyl 1-(benzo[d][1,3]dioxol-5-yl)-2-(naphthalen-1-yl-methyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC31H26N2O4[α]D20=+67.3 (c 1.20, CH3OH)Source of chirality: l-TryptophanAbsolute configuration: (1S,3R)

(1S,3R)-Methyl 1-(benzo[d][1,3]dioxol-5-yl)-2-benzyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC27H24N2O4[α]D20=+91.4 (c 1.00, CHCl3)Source of chirality: l-TryptophanAbsolute configuration: (1S,3R)

(1S,3R)-Ethyl 1-(benzo[d][1,3]dioxol-5-yl)-2-(naphthalen-1-yl-methyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC32H28N2O4[α]D20=+71.7 (c 1.00, CH3OH)Source of chirality: l-TryptophanAbsolute configuration: (1S,3R)

(1S,3R)-Methyl 1-(4-fluorophenyl)-2-(naphthalen-1-ylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC30H25FN2O2[α]D20=+67.5 (c 1.07, CH3OH)Source of chirality: l-TryptophanAbsolute configuration: (1S,3R)

(1S,3R)-Ethyl 2-(naphthalen-1-ylmethyl)-1-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC34H34N2O5[α]D20=+44.3 (c 1.00, CH3OH)Source of chirality: l-TryptophanAbsolute configuration: (1S,3R)

(1S,3R)-Methyl 1-(3-hydroxyphenyl)-2-(naphthalen-1-ylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC30H26N2O3[α]D20=+67.1 (c 1.06, CH3OH)Source of chirality: l-TryptophanAbsolute configuration: (1S,3R)

(1S,3R)-Methyl 1-phenyl-2-(naphthalen-1-ylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC30H26N2O2[α]D20=+127 (c 1.00, CHCl3)Source of chirality: l-TryptophanAbsolute configuration: (1S,3R)

C32H30N2O4(1S,3R)-Methyl 1-(3,4-dimethoxyphenyl)-2-(naphthalen-1-ylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate[α]D20=+102 (c 1.00, CHCl3)Source of chirality: l-TryptophanAbsolute configuration: (1S,3R)

(1S,3R)-Methyl 1-(4-ethoxy-3-methoxy-phenyl)-2-(naphthalen-1-ylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC33H32N2O4[α]D20=+100 (c 1.50, CHCl3)Source of chirality: l-TryptophanAbsolute configuration: (1S,3R)

(1S,3R)-Methyl 1-methyl-2-(naphthalen-1-ylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC25H24N2O2[α]D20=-27.4 (c 1.00, CH3OH)Source of chirality: l-TryptophanAbsolute configuration: (1S,3R)

(1S,3R)-Methyl 2-benzyl-1-methyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC21H22N2O2[α]D20=-18.4 (c 1.10, CHCl3)Source of chirality: l-TryptophanAbsolute configuration: (1S,3R)

(1S,3R)-Methyl 1-ethyl-2-(naphthalen-1-ylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC26H26N2O2[α]D20=-29.2 (c 1.60, CH3OH)Source of chirality: l-TryptophanAbsolute configuration: (1S,3R)

(1S,3R)-Methyl 2-(naphthalen-1-ylmethyl)-1-propyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC27H28N2O2[α]D20=-42.9 (c 1.30, CHCl3)Source of chirality: l-TryptophanAbsolute configuration: (1S,3R)

(1S,3R)-Methyl 1-hexyl-2-(naphthalen-1-ylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC30H34N2O2[α]D20=-34.7 (c 1.00, CH3OH)Source of chirality: l-TryptophanAbsolute configuration: (1S,3R)

(1S,3R)-Methyl 1-(benzo[d][1,3]dioxol-5-yl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC20H18N2O4[α]D20=+33.0 (c 1.00, CHCl3)Source of chirality: l-TryptophanAbsolute configuration: (1S,3R)

(1S,3R)-Ethyl 1-(benzo[d][1,3]dioxol-5-yl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC21H20N2O4[α]D20=+33.2 (c 1.50, CH3OH)Source of chirality: l-TryptophanAbsolute configuration: (1S,3R)

(1S,3R)-Methyl 1-(4-fluorophenyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC19H17FN2O2[α]D20=+30.8 (c 1.05, CH3OH)Source of chirality: l-TryptophanAbsolute configuration: (1S,3R)

(1S,3R)-Ethyl 2-(naphthalen-1-ylmethyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC23H26N2O5[α]D20=+27.3 (c 1.60, CH3OH)Source of chirality: l-TryptophanAbsolute configuration: (1S,3R)

(1S,3R)-Methyl 1-(3-hydroxyphenyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC19H18N2O3[α]D20=+35.5 (c 1.00, CH3OH)Source of chirality: l-TryptophanAbsolute configuration: (1S,3R)

(1S,3R)-Methyl 1-phenyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC19H18N2O2[α]D20=+44.5 (c 1.00, CHCl3)Source of chirality: l-TryptophanAbsolute configuration: (1S,3R)

(1S,3R)-Methyl 1-(3,4-dimethoxyphenyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC21H22N2O4[α]D20=+26.0 (c 1.90, CHCl3)Source of chirality: l-TryptophanAbsolute configuration: (1S,3R)

(1S,3R)-Methyl 1-(4-ethoxy-3-methoxy-phenyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC22H24N2O4[α]D20=+17.9 (c 2.00, CHCl3)Source of chirality: l-TryptophanAbsolute configuration: (1S,3R)

(1S,3R)-Methyl 1-methyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC14H16N2O2[α]D20=-16.4 (c 1.10, CH3OH)Source of chirality: l-TryptophanAbsolute configuration: (1S,3R)

(1S,3R)-Methyl 1-ethyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC15H18N2O2[α]D20=-27.5 (c 1.00, CH3OH)Source of chirality: l-TryptophanAbsolute configuration: (1S,3R)

(1S,3R)-Methyl 1-propyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylateC16H20N2O2[α]D20=-4.5 (c 3.0, CHCl3)Source of chirality: l-TryptophanAbsolute configuration: (1S,3R)

C19H26N2O2(1S,3R)-Methyl 1-hexyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxylate[α]D20=-21.6 (c 1.00, CH3OH)Source of chirality: l-TryptophanAbsolute configuration: (1S,3R)