A Practical Asymmetric Synthesis of the Antiviral Agent Lobucavir, BMS-180194
Organic Process Research & Development1998Vol. 2(6), pp. 393–399
Citations Over Time
Janak Singh, Gregory S. Bisacchi, Saleem Ahmad, Jollie D. Godfrey, Thomas P. Kissick, Toomas Mitt, Octavian Kocy, Truc Chi Vu, Chris G. Papaioannou, Michael K. Y. Wong, James E. Heikes, Robert Zahler, Richard H. Mueller
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%.
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