Conformationally Constrained Amino Acids. Synthesis and Optical Resolution of 3-Substituted Proline Derivatives

Abstract

The literature route to racemic cis- and trans-3-substituted prolines starting from acetamidomalonate and α,β-unsaturated aldehydes has been refined and applied to the synthesis of 3-phenyl- and 3-n-propylproline. A key improvement in the sequence was the acid-catalyzed silane reduction of the initial hydroxylactam Michael adduct 2, which allowed subsequent transformations to proceed cleanly and in high yield. Both the N- and 3-substitutents were found to have an effect on selectivity in the saponification of trans-3-substituted proline esters in the presence of the corresponding cis esters. The trans isomers in each series were resolved via the diastereomeric (S)-α-methylbenzylamides, and the absolute configurations of the resulting pure optical isomers were assigned. © 1990, American Chemical Society. All rights reserved.