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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| Veröffentlicht in: | Journal of organic chemistry 1996-01, Vol.61 (1), p.215-222 |
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| container_title | Journal of organic chemistry |
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| 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 |
| format | Article |
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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</creator><creatorcontrib>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</creatorcontrib><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. 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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><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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| source | ACS Publications |
| 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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