Synthesis and evaluation of stereopure α-trifluoromethyl-malic hydroxamates as inhibitors of matrix metalloproteinases

The total synthesis of trifluoromethyl (Tfm) analogs of known nanomolar matrix metalloprotein ases (MMPs) inhibitors has been performed. The synthetic protocol is based on a moderately stereoselective aldol reaction of trifluoropyruvate with an N-acyl-oxazolidin-2-thione for the construction of the core alpha-Tfm-malic unit. Both the diastereomeric forms of the target alpha-Tfm-malic hydroxamates showed micromolar inhibitory potency toward MMP-2 and 9, with a substantial drop with respect to the parent unfluorinated compounds. (C) 2004 Elsevier Ltd. All rights reserved.