| Inspired by the potential for a concise total synthesis of (-)-tubulosine (1), an enantioselective, aminothiourea-catalyzed formal aza-Diels-Alder reaction was developed for the formation of chiral, polycyclic tetrahydroisoquinolines such as ketone 4. From ketone 4, the total synthesis of (-)-tubulosine was achieved in five steps and in 18% overall yield. The substrate scope of this transformation was broadened to include the formation of variously substituted polycyclic tetrahydroisoquinoline and tetrahydro-beta-carboline products.*;The aminothiourea-catalyzed aza-Diels-Alder reaction was further applied towards an enantioselective, catalytic total synthesis of (+)-reserpine ( 41). Catalyst 39 was used to effect the diastereoselective coupling of imine 80 and chiral enone 79 with a high degree of catalyst control, setting the C3 and C20 stereogenic centers. Enone 79 was obtained in six steps from enantioenriched secondary alcohol 83, the product of a cobalt(oligosalen)-catalyzed kinetic resolution. In four steps, ketone 78 was elaborated to pentacycle 97, the transformation of which to the natural product is under investigation.*;The total synthesis of (+)-peloruside A (111) was completed, culminating an ongoing effort to apply asymmetric catalytic methods to the total synthesis of a complex polyketide. Seco-acid 173, available in four steps from the reductive aldol adduct of enone 165 and aldehyde 174, was identified as a successful macrolactonization precursor. The syntheses of fragments 165 and 174 from enantioenriched terminal epoxides, obtained via cobalt(salen)-catalyzed kinetic resolutions, were optimized to incorporate the successful protecting group scheme.*;*Please refer to dissertation for diagrams. |
