Effects of ring contraction on the conformational preferences of a-substituted proline analogs

Abstract

The structural consequences derived from the incorporation of either a methyl or a phenyl group at the a carbon of proline were recently investigated by quantum mechanical calculations (J Org Chem 2008, 73, 3418). In this work, the effect produced by contraction of the pyrrolidine ring on such a-substituted proline analogs has been explored using the same computational methods. Specifically, the intrinsic conformational preferences of the N-acetyl-N 0 -methylamide derivatives of the lower proline homolog L-azetidine-2-carboxylic acid (Aze), characterized by a four- instead of a fivemembered ring, and its a-methyl (aMeAze) and aphenyl (aPhAze) derivatives have been determined using quantum mechanical calculations and compared to those observed before for the proline counterparts. Replacement of the pyrrolidine ring by an azetidine cycle leads to a reduction of the conformational flexibility, especially for the Aze and aMeAze derivatives, which should be attributed to the quasi-planar geometry of the fourmembered ring. Furthermore, the azetidine nitrogen shows pyramidalization, which depending on the peptide backbone conformation favors the formation of an attractive N–H N interaction or alleviates a severe steric hindrance. Calculations on different environments predict that the tendency of aMeAze to adopt g-turns is higher than that of unsubstituted Aze and amethylproline, this feature being in full agreement with the experimental observations available