Synthesis of an Inhibitor of HCV Polymerase

Significance

N-Acylpyrrolidine J is a potent inhibitor of the hepatitis C virus (HCV). In enzymatic assays it inhibits the RNA-dependent RNA polymerase (NS5B) and in cell-based replicon assays it inhibits viral RNA replication. The synthesis depicted has been performed on a multi kilogram scale and features an asymmetric [3+2] cycloaddition catalyzed by a cinchona alkaloid and silver acetate to form pyrrolidine D with good diastereo- and enantioselectivity. All isolated intermediates were highly crystalline.