A highly efficient synthesis of fibrinogen receptor antagonist L-734,217 via a novel chemoselective silyl-mediated conjugate addition of δ-lactams to 4-vinylpyridine

John Y.L. Chung, David L. Hughes, Dalian Zhao, Zhiguo Song, David J. Mathre, Guo Jie Ho, James M. McNamara, Alan W. Douglas, R. A. Reamer, Fuh Rong Tsay, Richard Varsolona, James McCauley, Edward J.J. Grabowski, Paul J. Reider

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16 Scopus citations

Abstract

A highly practical chromatography-free six-step synthesis of L-734,217 suitable for large scale preparation is described. The key chiral pyridine acid intermediate (R)-1 was prepared in four steps based on a novel chemoselective silyl-mediated conjugate addition of ethyl (2-oxopiperidin 1-yl)acetate to 4-vinylpyridine and a highly productive, recyclable, kinetic resolution with quinine. Subsequent salt breaking/peptide coupling with benzyl 3-(R)-aminobutyrate (2) in a biphasic system, followed by concomitant hydrogenation of the pyridine ring and debenzylation afforded L-734,217 in 20% overall yield (30% with one recyle) from 2-piperidone. The mechanism of this key conjugate addition to 4-vinylpyridine was studied by 13C NMR.

Original languageEnglish (US)
Pages (from-to)215-222
Number of pages8
JournalJournal of Organic Chemistry
Volume61
Issue number1
DOIs
StatePublished - Jan 12 1996
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Organic Chemistry

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    Chung, J. Y. L., Hughes, D. L., Zhao, D., Song, Z., Mathre, D. J., Ho, G. J., McNamara, J. M., Douglas, A. W., Reamer, R. A., Tsay, F. R., Varsolona, R., McCauley, J., Grabowski, E. J. J., & Reider, P. J. (1996). A highly efficient synthesis of fibrinogen receptor antagonist L-734,217 via a novel chemoselective silyl-mediated conjugate addition of δ-lactams to 4-vinylpyridine. Journal of Organic Chemistry, 61(1), 215-222. https://doi.org/10.1021/jo951214f