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

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...

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Bibliographic Details
Published in:Journal of organic chemistry 1996-01, Vol.61 (1), p.215-222
Main Authors: Chung, John Y. L, Hughes, David L, Zhao, Dalian, Song, Zhiguo, Mathre, David J, Ho, Guo-Jie, McNamara, James M, Douglas, Alan W, Reamer, R. A, Tsay, Fuh-Rong, Varsolona, Richard, McCauley, James, Grabowski, Edward J. J, Reider, Paul J
Format: Article
Language:English
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Summary: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.
ISSN:0022-3263
1520-6904
DOI:10.1021/jo951214f