AN ASYMMETRIC-SYNTHESIS OF L-694,458, A HUMAN-LEUKOCYTE ELASTASE INHIBITOR, VIA NOVEL ENZYME RESOLUTION OF BETA-LACTAM ESTERS

A convergent synthesis of nedioxy)phenyl]butyl]-4-oxo-1-azetidinecarbo xamide (L-694,458, 1), a potent human leukocyte elastase inhibitor, wa s achieved via chiral synthesis of key intermediates: ethylpiperazin-1 -yl)carbonylphenoxy]-2-azetidinone (2) and (R)-alpha-propylpiperonyl i socyanate (3). Synthesis of beta-lactam 2 was achieved by a novel enan tioselective lipase hydrolysis of ester 5 to produce S)-3,3-diethyl-4- (4'-carboxyphenoxy)-2-azetidinone (6) (60% yield, three cycles, 93% ee ) with isolation, epimerization, and recycling of the undesired (R)-es ter 5. Isocyanate 3 was prepared by chiral addition of Zn(n-Pr)(2) to piperonal (98% yield, 99.2% ee), azide displacement and reduction to ( R)-alpha-propylpiperonylamine (11) (58% yield, 85% ee), crystallizatio n as the D-pyroglutamic acid salt (92% yield, 98.2% ee), and isocyanat e formation (98% yield) with phosgene.