HIGHLY EFFICIENT SYNTHESIS OF FIBRINOGEN RECEPTOR ANTAGONIST L-734,217 VIA A NOVEL CHEMOSELECTIVE SILYL-MEDIATED CONJUGATE ADDITION OF DELTA-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 pyr idine acid intermediate (R)-1 was prepared in four steps based on a no vel chemoselective silyl-mediated conjugate addition of ethyl (2-oxopi peridin-1-yl)acetate to 4-vinylpyridine and a highly productive, recyc lable, kinetic resolution with quinine. Subsequent salt breaking/pepti de coupling with benzyl 3-(R)-aminobutyrate (2) in a biphasic system, followed by concomitant hydrogenation of the pyridine ring and debenzy lation afforded L-734,217 in 20% overall yield (30% with one recyle) f rom 2-piperidone. The mechanism of this key conjugate addition to 4-vi nylpyridine was studied by C-13 NMR.