Total Synthesis of (+)-Mutilin: A Transannular [2+2] Cycloaddition/Fragmentation Approach.

A new and enantioselective total synthesis of the diterpenoid (+)-mutilin is described. Following a Claisen rearrangement approach to construct the 6,9-bicycle, a transannular [2+2] photocycloaddition and the ensuing ring-opening reaction were implemented to forge the characteristic 5-6-8 propellane-like skeleton. Subsequent late-stage alkylations and reduction completed the synthesis.

Total Syntheses of (-)-Hibiscone C and Lysergine: A Cyclization/Fragmentation Strategy.

The first asymmetric total synthesis of (-)-hibiscone C and a concise synthesis of ergot alkaloid lysergine are described. Both syntheses were achieved using the radical cyclization/fragmentation strategy. This cascade reaction enabled the application of the strained bicycle as a synthon for the synthesis of highly substituted decalins in an efficient and stereoselective manner.

Synthesis of (+)-Lysergol and Its Analogues To Assess Serotonin Receptor Activity.

An efficient synthesis of ergot alkaloid lysergol and its analogues is described, providing compounds for functional evaluation at the human 5-HT1A, 5-HT2A, 5-HT2B, or 5-HT2C receptors. Key features of the synthesis include the development of a tandem reaction to construct the multifunctionalized piperidine skeleton and use of a rhodium-catalyzed [3 + 2] annulation in the late-stage indole formation.

Enantioselective Total Syntheses of Various Amphilectane and Serrulatane Diterpenoids via Cope Rearrangements.

Ampilectane and serrulatane natural products are structurally and stereochemically complex compounds that display various potent pharmacological activities ranging from anti-inflammatory to antituberculosis. A general synthetic route toward this family of natural products has been developed, which accomplished a number of amphilectane and serrulatane natural products. The key step employed a stereoselective Cope rearrangement either promoted by gold catalysis or thermal conditions, while a regioselective gold-catalyzed 6-endo-dig cyclization was optimized to afford a precursor. The preparation of the chiral ß-ketoester as a starting material was established via an optimized asymmetric 1,4-addition followed by trapping with Mander's reagent, and this initially installed stereogenic center provided good control in the subsequent introduction of all the other stereocenters. A rarely investigated one-pot conversion of α-pyrone into phenol was also examined to enable the syntheses. DFT calculations explain the high stereoselectivity of the Cope rearrangement of the intermediate that eventually led to amphilectolide and caribenol A.

Enantioselective synthesis of Iboga alkaloids and vinblastine via rearrangements of quaternary ammoniums.

An efficient and novel strategy for the enantioselective syntheses of various iboga alkaloids has been developed. The salient features include a gold-catalyzed oxidation of a terminal alkyne followed by cyclization, a Stevens rearrangement and a tandem sequence that combines the gold-catalyzed oxidation, cyclization and [1,2]-shift. The catharanthine analogs provided by our approach were further converted to the vinca alkaloid vinblastine and its analogs, which confirmed the remarkable sensitivity of the cytotoxicity to the C20' substituent of vinblastine.