title: An Asymmetric Synthesis of L-694,458, a Human Leukocyte Elastase Inhibitor, via Novel Enzyme Resolution of beta-Lactam Esters.
abstract: A convergent synthesis of [S-(R,S)]-2-[4-[(4-methylpiperazin-1-yl)carbonyl]phenoxy]-3,3-diethyl-N-[1-[3,4-(methylenedioxy)phenyl]butyl]-4-oxo-1-azetidinecarboxamide (L-694,458, 1), a potent human leukocyte elastase inhibitor, was achieved via chiral synthesis of key intermediates: (S)-3,3-diethyl-4-[4'-[(N-methylpiperazin-1-yl)carbonylphenoxy]-2-azetidinone (2) and (R)-alpha-propylpiperonyl isocyanate (3). Synthesis of beta-lactam 2 was achieved by a novel enantioselective 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)-ester 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), crystallization as the D-pyroglutamic acid salt (92% yield, 98.2% ee), and isocyanate formation (98% yield) with phosgene.
authors.affiliation: Departments of Process Research and Bioprocess Research and Development, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065.
authors.forename: Raymond J.
authors.initials: RJ
authors.lastname: Cvetovich
authors.forename: Michel
authors.initials: M
authors.lastname: Chartrain
authors.forename: Frederick W.
authors.initials: FW
authors.lastname: Hartner
authors.forename: Christopher
authors.initials: C
authors.lastname: Roberge
authors.forename: Joseph S.
authors.initials: JS
authors.lastname: Amato
authors.forename: Edward J. J.
authors.initials: EJ
authors.lastname: Grabowski