A Versatile Enantioselective Strategy Toward L-C-Nucleosides: A Total Synthesis of L-Showdomycin

Strategies for the synthesis of nucleosides that can provide either L or D isomers become more important as a result of the increasing number of such compounds that are therapeutically useful. The lower toxicity and reduced susceptibility toward metabolism of the L isomers make them particularly interesting. A strategy toward the C-nucleoside analogues has been explored in the context of the synthesis of L-showdomycin. The route involves an asymmetric desymmetrization using palladium catalysis of cis-2,5-diacyloxy-2,5-dihydrofurans available in one step from furan, with carbon nucleophiles. Nucleophilic synthons for a maleimide unit and a methoxycarbonyl unit have been designed. Two sequential palladium-catalyzed reactions introduce both substituents with excellent chemo-, regio-, diastereo-, and enantioselectivity. The presence of a double bond in this doubly alkylated compound at C-3 and C-4 allows easy structural variation. The use of an ester as a hydroxymethyl precursor also introduces a diversity element as well as having importance in its own right. The successful completion of a synthesis of L-showdomycin validates this approach as a viable strategy to C-nucleosides.