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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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
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cited_by cdi_FETCH-LOGICAL-a297t-83248b63aee3ac28b705fc3c8ddcd13ba351c81b7ddd38dbe597bf6765b471193
cites cdi_FETCH-LOGICAL-a297t-83248b63aee3ac28b705fc3c8ddcd13ba351c81b7ddd38dbe597bf6765b471193
container_end_page 222
container_issue 1
container_start_page 215
container_title Journal of organic chemistry
container_volume 61
creator 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
description 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.
doi_str_mv 10.1021/jo951214f
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A</creatorcontrib><creatorcontrib>Tsay, Fuh-Rong</creatorcontrib><creatorcontrib>Varsolona, Richard</creatorcontrib><creatorcontrib>McCauley, James</creatorcontrib><creatorcontrib>Grabowski, Edward J. J</creatorcontrib><creatorcontrib>Reider, Paul J</creatorcontrib><collection>Istex</collection><collection>CrossRef</collection><jtitle>Journal of organic chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chung, John Y. L</au><au>Hughes, David L</au><au>Zhao, Dalian</au><au>Song, Zhiguo</au><au>Mathre, David J</au><au>Ho, Guo-Jie</au><au>McNamara, James M</au><au>Douglas, Alan W</au><au>Reamer, R. A</au><au>Tsay, Fuh-Rong</au><au>Varsolona, Richard</au><au>McCauley, James</au><au>Grabowski, Edward J. J</au><au>Reider, Paul J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>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</atitle><jtitle>Journal of organic chemistry</jtitle><addtitle>J. Org. Chem</addtitle><date>1996-01-12</date><risdate>1996</risdate><volume>61</volume><issue>1</issue><spage>215</spage><epage>222</epage><pages>215-222</pages><issn>0022-3263</issn><eissn>1520-6904</eissn><notes>ark:/67375/TPS-ZNJSH630-N</notes><notes>istex:4461F564F1FF57E6CCE1917097DCACAC2500D274</notes><notes>Abstract published in Advance ACS Abstracts, November 15, 1995.</notes><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.</abstract><pub>American Chemical Society</pub><doi>10.1021/jo951214f</doi><tpages>8</tpages></addata></record>
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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
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