An Enzymatic Route to the Synthesis of Tricyclic Fused Hexahydrofuranofuran P2-Ligand for a Series of Highly Potent HIV-1 Protease Inhibitors.

We describe a stereoselective synthesis of an optically active (1 R , 3aS, 5 R , 6 S , 7 aR )-octahydro-1,6-epoxy-isobenzo-furan-5-ol derivative. This stereochemically defined heterocycle serves as a high-affinity ligand for a variety of HIV-1 protease inhibitors. The key synthetic steps involve a highly enantioselective enzymatic desymmetrization of meso -1,2(dihydroxymethyl)cyclohex-4-ene and conversion of the resulting optically active alcohol to a methoxy hexahydroisobenzofuran derivative. A substrate controlled stereoselective dihydroxylation afforded syn -1,2-diols. Oxidation of diol provided the substituted 1,2-diketone and L-Selectride reduction provided the corresponding inverted syn -1,2-diols. Acid catalyzed cyclization furnished the ligand alcohol in optically active form.