Parallel synthesis of new phenylalanino-2-(phenylthio)pyrrolidin-3-one scaffold-based analogues

Based on the specific PhePro proteolytic cleavage of the HIV-protease, we synthesized short pseudopeptides incorporating a 2-(phenylthio)pyrrolidin-3-one ring. We previously described various analogues based on this scaffold. We report herein a parallel methodology with improved efficiency applied to the synthesis of new derivatives. For this purpose, we selected an intermediate, i.e.8, which can be used as a versatile synthon after simple removal of the N-Boc protecting group of the starting material as the penultimate reaction step. This new route improved the synthesis of these molecules in terms of numbers of reaction and in terms of both reagent and reaction time, and allowed the preparation of a small library focused on the phenylalanino-2-(phenylthio)pyrrolidin-3-one scaffold. A phenylthio group at the 2-position confers on the resulting derivative a high reactivity, which could be unmasked upon hydrolysis, and which led to the release of toxophoric thiophenol as detected by Ellman's reagent. Biological activity of these compounds was analysed towards various representative proteolytic enzymes. Pure diastereoisomers 7(R) and 7(S) displayed potent inhibitory activities against HIV-protease.