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

doi:10.1021/jo951214f

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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19 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 language	English (US)
Pages (from-to)	215-222
Number of pages	8
Journal	Journal of Organic Chemistry
Volume	61
Issue number	1
DOIs	https://doi.org/10.1021/jo951214f
State	Published - Jan 12 1996
Externally published	Yes

All Science Journal Classification (ASJC) codes

Organic Chemistry

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10.1021/jo951214f

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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

@article{e10b287b7d1942f4b915a6b473816c9e,

title = "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",

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.",

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

year = "1996",

month = jan,

day = "12",

doi = "10.1021/jo951214f",

language = "English (US)",

volume = "61",

pages = "215--222",

journal = "Journal of Organic Chemistry",

issn = "0022-3263",

publisher = "American Chemical Society",

number = "1",

}

Chung, JYL, Hughes, DL, Zhao, D, Song, Z, Mathre, DJ, Ho, GJ, McNamara, JM, Douglas, AW, Reamer, RA, Tsay, FR, Varsolona, R, McCauley, J, Grabowski, EJJ & Reider, PJ 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, vol. 61, no. 1, pp. 215-222. https://doi.org/10.1021/jo951214f

TY - JOUR

T1 - 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

AU - Chung, John Y.L.

AU - Hughes, David L.

AU - Zhao, Dalian

AU - Song, Zhiguo

AU - Mathre, David J.

AU - Ho, Guo Jie

AU - McNamara, James M.

AU - Douglas, Alan W.

AU - Reamer, R. A.

AU - Tsay, Fuh Rong

AU - Varsolona, Richard

AU - McCauley, James

AU - Grabowski, Edward J.J.

AU - Reider, Paul J.

PY - 1996/1/12

Y1 - 1996/1/12

N2 - 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.

AB - 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.

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ER -

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

Abstract

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