Practical access to the proline analogs (S,S,S)- and (R,R,R)-2- methyloctahydroindole-2-carboxylic acids by HPLC enantioseparation

Abstract

An efficient methodology for the preparation of the α- tetrasubstituted proline analog (S,S,S)-2-methyloctahydroindole-2-carboxylic acid, (S,S,S)-(αMe)Oic, and its enantiomer, (R,R,R)-(αMe)Oic, has been developed. Starting from easily available substrates and through simple transformations, a racemic precursor has been synthesized in excellent yield and further subjected to HPLC resolution using a cellulose-derived chiral stationary phase. Specifically, a semipreparative (250 mm × 20 mm ID) Chiralpak® IC column has allowed the efficient resolution of more than 4 g of racemate using a mixture of n-hexane/tert-butyl methyl ether/2-propanol as the eluent. Multigram quantities of the target amino acids have been isolated in enantiomerically pure form and suitably protected for incorporation into peptides. © 2011 Wiley-Liss, Inc.