Synthesis of Proline-Valine Pseudodipeptide Enol Lactones, Serine Protease Inhibitors

Article abstract of DOI:10.1021/jo00008a011

Pseudodipeptides of proline-valine that incorporate protio or halo enol lactone moieties have been synthesized from common acetylenic acid precursors; in each case, two diastereomers were prepared in enantiomerically pure form.The preparation began with isomeric propargylic alcohols derived from L-prolinal, which are further elaborated into the methyleneoxy valine pseudodipeptide analogues via an oxalactam intermediate.Stereochemical assignments were made by comparisons of nuclear Overhauser enhancement factors.The pseudodipeptide acetylenic acids could by cyclized to the protio enol lactones by mercuric salts and could be eleborated to tetrapeptide analogues either before or after cyclization.The relative stability of the two diastereomeric enol lactone systems toward intramolecular acyl transfer could be rationalized by molecular mechanics energy calculations on ground-state and tetrahedral intermediates believed to be involved in the reaction.While the halo enol lactones derived from the pseudotetrapeptides proved to be very unstable, they could be prepared from the n-butyl carbamate derivatives of the dipeptide.An evaluation of these protio and halo enol lactone systems as inhibitors of serine proteases will be discussed elsewhere.