Solution/solid-phase synthesis of partially modified retro-psi [NHCH(CF3)]-peptidyl hydroxamates

The synthesis of a novel family of partially-modified (PM) retropeptidyl hy droxamates incorporating a [CH(CF3)CH2CO] unit as a surrogate of the conven tional malonyl group, has been accomplished both in solution and in solid-p hase. The key step is the Michael-type N-addition of free or polymer bound alpha -amino hydroxamates to 3-(E-enoyl)-1,3-oxazolidin-2-ones, which takes place very effectively, although with low stereocontrol. A number of tri- and tetra-peptidyl hydroxamates were obtained either in diastereomerically pure form (by solution-phase synthesist after chromatographic purification) , or as mixtures of two epimers in very good chemical purity (by solid-phas e, after release from the resin), demonstrating that this method is suitabl e for preparing combinatorial libraries of PM retro-psi [NHCH(CF3)]-peptidy l hydroxamates for screening as metalloprotease inhibitors. (C) 2001 Elsevi er Science Ltd. All rights reserved.