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A general route to several styryl-lactone frameworks is presented. Starting from a known enol ether, stereoselective epoxidation and methanolysis yields a series of three distinct hydroxyacetals, each further functionalized by etherification with an allylic vinylsilane fragment. A highly efficient Lewis acid-promoted intramolecular annulation at the tethered oxocarbenium allows direct entry to cis-fused bicyclic ether cores. Further manipulation delivers a variety of additional styryl-lactone motifs and analogs; for example, simple allylic oxidation yields 3-deoxyisoaltholactone, in just five steps overall.

The novel styryl lactone analog (±)-3-deoxyisoaltholactone was synthesized in 5 steps from dihydrofuran. An intramolecular vinylsilane–oxocarbenium condensation thus afforded the central cis-fused bicyclic ether array in near quantitative yield as a single stereoisomer.

Optimization through parallel synthesis of a novel series of hepatitis C virus (HCV) NS5B polymerase inhibitors led to the identification of ( R )-11-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-10-(6-methylpyridine-2-carbonyl)-2,3,4,5,10,11-hexahydro-dibenzo[ b,e ][1,4]diazepin-1-one 11zc and ( R )-11-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-10-(2,5-dimethyloxazol-4-carbonyl)-2,3,4,5,10,11-hexahydro-dibenzo[ b,e ][1,4]diazepin-1-one 11zk as potent (replicon EC 50 = 400 nM and 270 nM, respectively) and selective (CC 50 > 20 μM) inhibitors of HCV replication. These data warrant further lead-optimization efforts.