An Asymmetric Synthesis of L-694,458, a Human Leukocyte Elastase Inhibitor, via Novel Enzyme Resolution of β-Lactam Esters

• Published in: Journal of organic chemistry Vol. 61; no. 19; pp. 6575 - 6580
• Main Authors: Cvetovich, Raymond J, Chartrain, Michel, Hartner, Frederick W, Roberge, Christopher, Amato, Joseph S, Grabowski, Edward J. J
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 20.09.1996; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Organic; Physical Sciences; Science & Technology; ALCOHOLS; ACCESS; EMPHYSEMA
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo960618k

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)-α-propylpiperonyl isocyanate (3). Synthesis of β-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)-α-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.