INHIBITION OF HUMAN-LEUKOCYTE ELASTASE BY FUNCTIONALIZED N-ARYL-3,3-DIHALOGENOAZETIDIN-2-ONES - STEREOSPECIFIC SYNTHESIS AND CHIRAL RECOGNITION OF DISSYMMETRICALLY C-3-SUBSTITUTED BETA-LACTAMS

(3R)- and hloromethylphenyl)-3-bromo-3-fluoroazetidin-2-ones 2 were sy nthesized via the separation of diastereoisomeric phenylglycinol deriv atives of the starting 2,3-dibromo-2-fluoropropanoic acid. Acidic hydr olysis of the hydroxyamides led to the chiral trihalogenopropanoic aci ds. Then, an expeditious four step synthesis provided the (3S)- and (3 R)-azetidinones 2, both of which behaved as strictly irreversible inhi bitors of HLE. The configuration of the bromofluorocarbon was shown to have a significant effect on the partition ratio: k(cat)/k(inact)=4.6 and 34.3 for (3S)- and (3R)-2, respectively. (C) 1997 Elsevier Scienc e Ltd.