Synthesis and evaluation of stereo-pure a-trifluoromethyl-malic hydroxamates as inhibitors of matrix metalloproteinases

The total synthesis of trifluoromethyl (Tfm) analogs of known nanomolar matrix metalloproteinases (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 ?-Tfm-malic unit. Both the diastereomeric forms of the target ?-Tfm-malic hydroxamates showed micromolar inhibitory potency toward MMP-2 and 9, with a substantial drop with respect to the parent unfluorinated compounds.