Total synthesis of (+/-)-scopadulin

The first total synthesis of (+/-)-scopadulin, an aphidicolane diterpene, i s 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 s ubsequent A ring cyclization by intramolecular aldol condensation. A highly stereoselective cyanation of the tetracyclic enone by Et2AlCN gave a trans -fused A/B ring system with a beta -cyanide at C-4. Stereoselective constru ction of a quaternary carbon at C-4 was achieved by a-alkylation of the cya no group and conversion of the sterically hindered cyano group to a methyl group via our novel reaction for conversion of primary aliphatic amines int o alcohols. Finally, the total synthesis of (+/-)-scopadulin was accomplish ed by a highly chemo- and stereoselective methylation at C-16 and modificat ion of the C-4 alpha -functionality. The stereoselectivity observed in the MeTi(O-i-Pr)(3)-mediated methylation for the generation of a tertiary axial alcohol at C-16 is extremely high.