CONVERSION OF ALPHA-KETO ESTERS INTO BETA,BETA-DIFLUORO-ALPHA-KETO ESTERS AND CORRESPONDING ACIDS - A SIMPLE ROUTE TO A NOVEL CLASS OF SERINE-PROTEASE INHIBITORS

The preparation of a series of beta,beta-difluoro-alpha-keto esters an d corresponding acids RCF(2)COCO(2)R' (R = Me, Et; i-Pr, Bn, and Ph; R ' = Et and H), designed as potential inhibitors of serine proteases, i s described. The standard procedure developed consists in the initial formation of an alpha,alpha-difluoro ester from an alpha-keto ester, f ollowed by a simple four-step sequence involving the synthesis of hemi acetal, cyanohydrin, and alpha-hydroxy ester difluorinated intermediat es. This method provides an easy route to beta,beta-difluoro-alpha-ket o esters and corresponding acids, via ''formal'' insertion of a difluo romethylene group between the R substituent and the alpha-carbonyl gro up of a generic alpha-keto ester.