A PRACTICAL ASYMMETRIC-SYNTHESIS OF THE ANTIVIRAL AGENT LOBUCAVIR, BMS-180194

A practical synthesis of the antiviral agent lobucavir, [1R(1 alpha,2 beta,3 alpha)] -[2,3-bis(hydroxymethyl)cyclobutyl]-6H-purin-6-one (BMS -180194), is described. The key chiral intermediate, [1S-(1 alpha,2 be ta,3 alpha)]-3-hydroxy-1,2-cyclobutanedimethanol, dihenzoate ester, wa s made by an asymmetric [2 + 2] cycloaddition of dimenthyl fumarate wi th ketene dimethyl acetal followed by sequential diester reduction, be nzoylation, deketalization, and stereoselective ketone reduction. Regi oselective N9-alkylation of the tetra-n-butylammonium salt of 2-amino- 6-iodopurine with the derived cyclobutyltriflate furnished the purinec yclobutyl dibenzoate. Methanolysis followed by acid hydrolysis produce d lobucavir in a 35% overall yield with an ee, 99%.