- An asymmetric synthesis of L-694,458, a human leukocyte elastase inhibitor, via novel enzyme resolution of β-lactam esters
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A convergent synthesis of [S-(R*,S*)]-2-[4-[(4-methylpiperazin-1-yl)carbonyl]phenoxy]-3,3-diet hyl-N-[1-[3,4-(methylenedioxy)phenyl]butyl]-4-oxo-1-azetidinecarboxami de (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-azet idinone (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.
- Cvetovich, Raymond J.,Chartrain, Michel,Hartner Jr., Frederick W.,Roberge, Christopher,Amato, Joseph S.,Grabowski, Edward J. J.
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p. 6575 - 6580
(2007/10/03)
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