Total Synthesis of (±)-Scopadulin

The first total synthesis of (±)-scopadulin, an aphidicolane diterpene, is described. The core structure (A/B/C/D ring system) was constructed by an initial synthesis of the B/C/D ring system by our reported methods and a subsequent A ring cyclization by intramolecular aldol condensation. A highly stereoselective cyanation of the tetracyclic enone by Et<sub>2</sub>AlCN gave a <i>trans</i>-fused A/B ring system with a β-cyanide at C-4. Stereoselective construction of a quaternary carbon at C-4 was achieved by α-alkylation of the cyano group and conversion of the sterically hindered cyano group to a methyl group via our novel reaction for conversion of primary aliphatic amines into alcohols. Finally, the total synthesis of (±)-scopadulin was accomplished by a highly chemo- and stereoselective methylation at C-16 and modification of the C-4 α-functionality. The stereoselectivity observed in the MeTi(O-<i>i</i>-Pr)<sub>3</sub>-mediated methylation for the generation of a tertiary axial alcohol at C-16 is extremely high.