The total synthesis of lupeol was one of the crowning achievements of the Robinson annulation/ reductive alkylation approach to stereocontrolled polycarbocyclic construction developed by Gilbert Stork (J. Am. Chem. Soc. 1971, 93, 4945). It is a measure of the progress of organic synthesis since that time that E. J. Corey of Harvard University could devise (J. Am. Chem. Soc. 2009, 131, 13928) an enantioselective synthesis of (+)-lupeol 3 that could be carried out by a single colleague. The key step in the synthesis was the Lewis acid–mediated cyclization of 1 to 2. The preparation of 1 began with the enantioselective epoxidation of farnesol acetate 4. To this end, asymmetric dihydroxylation delivered the diol 5. Selective mesylation followed by exposure to dilute methoxide effected ring closure to the epoxide, but also removed the acetate, so this had to be reapplied. The synthesis of the aromatic portion of 1 started with the phenol 7. Protection as the very bulky triisopropylsilyl ether was important for the success of the subsequent cyclization, perhaps because it discouraged complexation of the Lewis acid with the aryl ether. Metalation followed by formylation delivered the aldehyde 8, which was reduced and carried on to the bromide 9. The derived Grignard reagent coupled smoothly with 6 under Li2CuCl4 catalysis. The cyclization of 1 to 2 proceeded with remarkable efficiency (43%!), for a reaction in which three new C-C bonds, four rings, and five new stereogenic centers were established. It is particularly noteworthy that the cyclization cleanly set the trans, anti, trans, anti tetra-cyclic backbone of (+)-lupeol 3. To complete the synthesis of 3, the less substituted alkene of 2 was selectively hydrogenated, then CH3 Li was added to give 10. Hydrolysis and dehydration yielded 11, which was reduced and equilibrated to 12. On brief exposure to MsCl/Et3 N, 13 cyclized to (+)-lupeol 3. It is a measure of the remarkable effi ciency of this synthesis of (+)-lupeol 3 that it provided suffi cient material to enable studies of the rearrangement of 3 under acidic conditions to other pentacyclic triterpenes, including, inter alia, germanicol, α -amyrin, δ -amyrin, and taraxasterol 14 .
Stereoselective Synthesis of Highly-Congested Tetralin-Fused Spirooxindoles with Hydroxyl Group: Net Oxygen Atom Induced Hydride Shift/cyclization Process.
