Asymmetric Synthesis of cis-2,5-Disubstituted Pyrrolidine, the Core Scaffold of β3‑AR Agonists
A practical, enantioselective synthesis of cis-2,5-disubstituted pyrrolidine is described. Application of an enzymatic DKR reduction of a keto ester, which is easily accessed through a novel intramolecular N→C benzoyl migration, yields syn-1,2-amino alcohol in >99% ee and >99:1 dr. Subsequent...
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| Veröffentlicht in: | Organic letters 2013-03, Vol.15 (6), p.1342-1345 |
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| container_title | Organic letters |
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| creator | Xu, Feng Chung, John Y. L Moore, Jeffery C Liu, Zhuqing Yoshikawa, Naoki Hoerrner, R. Scott Lee, Jaemoon Royzen, Maksim Cleator, Ed Gibson, Andrew G Dunn, Robert Maloney, Kevin M Alam, Mahbub Goodyear, Adrian Lynch, Joseph Yasuda, Nobuyashi Devine, Paul N |
| description | A practical, enantioselective synthesis of cis-2,5-disubstituted pyrrolidine is described. Application of an enzymatic DKR reduction of a keto ester, which is easily accessed through a novel intramolecular N→C benzoyl migration, yields syn-1,2-amino alcohol in >99% ee and >99:1 dr. Subsequent hydrogenation of cyclic imine affords the cis-pyrrolidine in high diastereoselectivity. By integrating biotechnology into organic synthesis and isolating only three intermediates over 11 steps, the core scaffold of β3-AR agonists is synthesized in 38% overall yield. |
| doi_str_mv | 10.1021/ol400252p |
| format | Article |
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By integrating biotechnology into organic synthesis and isolating only three intermediates over 11 steps, the core scaffold of β3-AR agonists is synthesized in 38% overall yield.</description><subject>Adrenergic beta-3 Receptor Agonists - chemical synthesis</subject><subject>Adrenergic beta-3 Receptor Agonists - chemistry</subject><subject>Adrenergic beta-3 Receptor Agonists - pharmacology</subject><subject>Amino Alcohols - chemistry</subject><subject>Catalysis</subject><subject>Hydrogenation</subject><subject>Imines - chemistry</subject><subject>Molecular Structure</subject><subject>Oxidation-Reduction</subject><subject>Pyrrolidines - chemical synthesis</subject><subject>Pyrrolidines - chemistry</subject><subject>Pyrrolidines - pharmacology</subject><subject>Stereoisomerism</subject><issn>1523-7060</issn><issn>1523-7052</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo90EtOwzAQBmALgWgpLLgA8gaJRQMeO06cZVSeUiUQhXXkJDa4SuISO4vsuAJX4SAcgpOQqqWrGY2-GY1-hE6BXAKhcGWrkBDK6WoPjYFTFsSE0_1dH5EROnJuSQgMk-QQjSgLOYhEjJFMXV_XyremwIu-8e_KGYetxoVxAZ3y4Nq4Lnfe-M6rEj_1bWsrU5pGTfGA8cy2Ci8KqbWtyvXezzf7_fxKn3H6ZhvjvDtGB1pWTp1s6wS93t68zO6D-ePdwyydBxJ45IOYaRqJhAMQIXUUKgqhjigkSc61FDKSUomk5GEh1WCAihx4WWiaM54UTLIJutjcXbX2o1POZ7Vxhaoq2SjbuQwYxIKFMYeBnm1pl9eqzFatqWXbZ_-xDOB8A2ThsqXt2mb4PAOSrePOdnGzP9Imb-0</recordid><startdate>20130315</startdate><enddate>20130315</enddate><creator>Xu, Feng</creator><creator>Chung, John Y. 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L</au><au>Moore, Jeffery C</au><au>Liu, Zhuqing</au><au>Yoshikawa, Naoki</au><au>Hoerrner, R. Scott</au><au>Lee, Jaemoon</au><au>Royzen, Maksim</au><au>Cleator, Ed</au><au>Gibson, Andrew G</au><au>Dunn, Robert</au><au>Maloney, Kevin M</au><au>Alam, Mahbub</au><au>Goodyear, Adrian</au><au>Lynch, Joseph</au><au>Yasuda, Nobuyashi</au><au>Devine, Paul N</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Asymmetric Synthesis of cis-2,5-Disubstituted Pyrrolidine, the Core Scaffold of β3‑AR Agonists</atitle><jtitle>Organic letters</jtitle><addtitle>Org. Lett</addtitle><date>2013-03-15</date><risdate>2013</risdate><volume>15</volume><issue>6</issue><spage>1342</spage><epage>1345</epage><pages>1342-1345</pages><issn>1523-7060</issn><eissn>1523-7052</eissn><abstract>A practical, enantioselective synthesis of cis-2,5-disubstituted pyrrolidine is described. Application of an enzymatic DKR reduction of a keto ester, which is easily accessed through a novel intramolecular N→C benzoyl migration, yields syn-1,2-amino alcohol in >99% ee and >99:1 dr. Subsequent hydrogenation of cyclic imine affords the cis-pyrrolidine in high diastereoselectivity. By integrating biotechnology into organic synthesis and isolating only three intermediates over 11 steps, the core scaffold of β3-AR agonists is synthesized in 38% overall yield.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>23451898</pmid><doi>10.1021/ol400252p</doi><tpages>4</tpages></addata></record> |
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| subjects | Adrenergic beta-3 Receptor Agonists - chemical synthesis Adrenergic beta-3 Receptor Agonists - chemistry Adrenergic beta-3 Receptor Agonists - pharmacology Amino Alcohols - chemistry Catalysis Hydrogenation Imines - chemistry Molecular Structure Oxidation-Reduction Pyrrolidines - chemical synthesis Pyrrolidines - chemistry Pyrrolidines - pharmacology Stereoisomerism |
| title | Asymmetric Synthesis of cis-2,5-Disubstituted Pyrrolidine, the Core Scaffold of β3‑AR Agonists |
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