Recent advances in phosphono- and phosphinopeptide synthesis

Abstract

Phosphopeptides have been described as protease inhibitors as well as haptens for the preparation of abzymes exhibiting esterase activity. Phosphono- or phosphinopeptides have previously been prepared by solution synthesis, starting from the fully protected phosphoester dipeptide analogue. We have compared the reactivity of phosphonic versus carboxylic acid using BOP- or PyBOP-mediated activation. These reagents have been efficiently used for the preparation of mixed phosphonate diesters in the presence of an alcohol by phosphonic acid activation. We demonstrate their efficiency for solid phase synthesis of phosphonopeptides (or phosphinopeptides) in the presence of an amine by carboxy acid activation, starting from an unprotected phosphodipeptide analogue. In contrast, the efficient BroP-mediated monoesterification of α-amino-phosphonic acid is not suitable for phosphonopeptide preparation by SPPS.