Inhibition of human leukocyte elastase by functionalized N-aryl-3,3-dihalogenoazetidin-2-ones. Stereospecific synthesis and chiral recognition of dissymmetrically C 3-substituted β-lactams

Abstract

(3 R)- and (3 S)- N-(2-chloromethylphenyl)-3-bromo-3-fluoroazetidin-2-ones 2 were synthesized via the separation of diastereoisomeric phenylglycinol derivatives of the starting 2,3-dibromo-2-fluoropropanoic acid. Acidic hydrolysis of the hydroxyamides led to the chiral trihalogenopropanoic acids. Then, an expeditious four step synthesis provided the (3 S)- and (3 R)-azetidinones 2, both of which behaved as strictly irreversible inhibitors 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 (3 S)- and 3 R)- 2, respectively.