A Practical Asymmetric Synthesis of the Antiviral Agent Lobucavir, BMS-180194
A practical synthesis of the antiviral agent lobucavir, [1R-(1α,2β,3α)]-2-amino-9-[2,3-bis(hydroxymethyl)cyclobutyl]-6H-purin-6-one (BMS-180194), is described. The key chiral intermediate, [1S-(1α,2β,3α)]-3-hydroxy-1,2-cyclobutanedimethanol, dibenzoate ester, was made by an asymmetric [2 + 2] cycloa...
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| Veröffentlicht in: | Organic process research & development 1998-11, Vol.2 (6), p.393-399 |
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| container_title | Organic process research & development |
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| creator | Singh, Janak Bisacchi, Gregory S Ahmad, Saleem Godfrey, Jollie D Kissick, Thomas P Mitt, Toomas Kocy, Octavian Vu, Truc Papaioannou, Chris G Wong, Michael K Heikes, James E Zahler, Robert Mueller, Richard H |
| description | A practical synthesis of the antiviral agent lobucavir, [1R-(1α,2β,3α)]-2-amino-9-[2,3-bis(hydroxymethyl)cyclobutyl]-6H-purin-6-one (BMS-180194), is described. The key chiral intermediate, [1S-(1α,2β,3α)]-3-hydroxy-1,2-cyclobutanedimethanol, dibenzoate ester, was made by an asymmetric [2 + 2] cycloaddition of dimenthyl fumarate with ketene dimethyl acetal followed by sequential diester reduction, benzoylation, deketalization, and stereoselective ketone reduction. Regioselective N9-alkylation of the tetra-n-butylammonium salt of 2-amino-6-iodopurine with the derived cyclobutyltriflate furnished the purinecyclobutyl dibenzoate. Methanolysis followed by acid hydrolysis produced lobucavir in a 35% overall yield with an ee > 99%. |
| doi_str_mv | 10.1021/op970214+ |
| format | Article |
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The key chiral intermediate, [1S-(1α,2β,3α)]-3-hydroxy-1,2-cyclobutanedimethanol, dibenzoate ester, was made by an asymmetric [2 + 2] cycloaddition of dimenthyl fumarate with ketene dimethyl acetal followed by sequential diester reduction, benzoylation, deketalization, and stereoselective ketone reduction. Regioselective N9-alkylation of the tetra-n-butylammonium salt of 2-amino-6-iodopurine with the derived cyclobutyltriflate furnished the purinecyclobutyl dibenzoate. 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Process Res. Dev</addtitle><description>A practical synthesis of the antiviral agent lobucavir, [1R-(1α,2β,3α)]-2-amino-9-[2,3-bis(hydroxymethyl)cyclobutyl]-6H-purin-6-one (BMS-180194), is described. The key chiral intermediate, [1S-(1α,2β,3α)]-3-hydroxy-1,2-cyclobutanedimethanol, dibenzoate ester, was made by an asymmetric [2 + 2] cycloaddition of dimenthyl fumarate with ketene dimethyl acetal followed by sequential diester reduction, benzoylation, deketalization, and stereoselective ketone reduction. Regioselective N9-alkylation of the tetra-n-butylammonium salt of 2-amino-6-iodopurine with the derived cyclobutyltriflate furnished the purinecyclobutyl dibenzoate. 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Process Res. Dev</addtitle><date>1998-11-01</date><risdate>1998</risdate><volume>2</volume><issue>6</issue><spage>393</spage><epage>399</epage><pages>393-399</pages><issn>1083-6160</issn><eissn>1520-586X</eissn><abstract>A practical synthesis of the antiviral agent lobucavir, [1R-(1α,2β,3α)]-2-amino-9-[2,3-bis(hydroxymethyl)cyclobutyl]-6H-purin-6-one (BMS-180194), is described. The key chiral intermediate, [1S-(1α,2β,3α)]-3-hydroxy-1,2-cyclobutanedimethanol, dibenzoate ester, was made by an asymmetric [2 + 2] cycloaddition of dimenthyl fumarate with ketene dimethyl acetal followed by sequential diester reduction, benzoylation, deketalization, and stereoselective ketone reduction. Regioselective N9-alkylation of the tetra-n-butylammonium salt of 2-amino-6-iodopurine with the derived cyclobutyltriflate furnished the purinecyclobutyl dibenzoate. Methanolysis followed by acid hydrolysis produced lobucavir in a 35% overall yield with an ee > 99%.</abstract><pub>American Chemical Society</pub><doi>10.1021/op970214+</doi><tpages>7</tpages></addata></record> |
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| title | A Practical Asymmetric Synthesis of the Antiviral Agent Lobucavir, BMS-180194 |
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