Towards the stereoselective synthesis of α-methylated (2S,3aS,7aS)-octahydroindole-2-carboxylic acid

A high yielding and remarkably stereoselective α-methylation reaction of the (2S,3aS,7aS)-stereoisomer of octahydroindole-2-carboxylic acid, (S,S,S)-Oic, suitably protected is described. The severe steric hindrance imposed by the fused cyclohexane ring, which prevents the application of Seebach’s self-reproduction of chirality methodology, accounts for the formation of (S,S,S)-(αMe)Oic with high selectivity and retention of configuration.

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Methyl (2S,3aS,7aS)-N-(tert-butoxycarbonyl)octahydroindole-2-carboxylateC15H25NO4Ee >98%[α]D = −31.8 (c 0.48, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2S,3aS,7aS)

Methyl (2S,3aS,7aS)-N-(tert-butoxycarbonyl)-2-methyloctahydroindole-2-carboxylateC16H27NO4Ee >98%[α]D = +9.5 (c 0.95, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2S,3aS,7aS)

Methyl (2S,3aS,7aS)-2-methyloctahydroindole-2-carboxylate hydrochlorideC11H20NO2ClEe >98%[α]D = −47.7 (c 0.56, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2S,3aS,7aS)

(2S,3aS,7aS)-N-(tert-Butoxycarbonyl)-2-methyloctahydroindole-2-carboxylic acidC15H25NO4Ee >98%[α]D = −21.0 (c 0.49, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2S,3aS,7aS)