Synthesis of enantiopure (R,R)- and (S,S)-cis-2,3-propanoprolines

A novel approach to the synthesis of an enantiopure bicyclic proline analogue, hexahydrocyclopenta[b]pyrrole-6a(1H)-carboxylic acid (‘2,3-propanoproline’), has been developed. The method relied on tandem Strecker-nucleophilic cyclization reaction of 2-(2-bromoethyl)cyclopentanone. The overall synthetic scheme included six steps and resulted in 18% overall yield of both enantiomers of the title amino acid.

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(3aR,6aR)-1-((1S)-1-Phenylethyl)-hexahydrocyclopenta[b]pyrrole-6a-carboxylic acid amideC16H22N2OEe = 100%[α]D = −13.9 (c 0.33, MeOH)Source of chirality: (S)-α-phenylethylamineAbsolute configuration: (3aR,6aR,1′S)

(3aS,6aS)-1-((1S)-1-Phenylethyl)-hexahydrocyclopenta[b]pyrrole-6a-carboxylic acid amideC16H22N2OEe = 100%[α]D = −27.6 (c 0.53, MeOH)Source of chirality: (S)-α-phenylethylamineAbsolute configuration: (3aS,6aS,1′S)

(3aS, 6aS)-Hexahydrocyclopenta[b]pyrrole-6a-carboxylic acidC8H13NO2Ee = 100%[α]D = −45 (c 0.4, MeOH)Source of chirality: (S)-α-phenylethylamineAbsolute configuration: (3aS,6aS)

(3aR,6aR)-Hexahydrocyclopenta[b]pyrrole-1,6a-dicarboxylic acid 1-tert-butyl esterC13H21NO4Ee = 100%[α]D = −7.0 (c 0.73, CHCl3)Source of chirality: (S)-α-phenylethylamineAbsolute configuration: (3aR,6aR)