Asymmetric catalysis in the construction of complex molecules: A total synthesis of (+)-lactacystin and development of an enantioselective transannular Diels-Alder reaction

Total synthesis efforts utilizing asymmetric catalytic methods may be undertaken with various goals in mind. Increasingly often, natural product targets are chosen to demonstrate the utility of a previously developed method; in such cases, the demands of a synthesis may require improvements and extensions to the asymmetric catalytic reaction. Alternatively, a disconnection or strategy used successfully in total synthesis may inspire the development of entirely new enantioselective catalytic methodology.; The asymmetric catalytic total synthesis of (+)-lactacystin (1 ) was undertaken with the intention of applying an enantioselective conjugate addition promoted by chiral aluminum salen complex 32. This synthetic effort necessitated the development of a new alpha,beta-unsaturated beta-silyl imide electrophile 39. Use of this substrate afforded a variety of beta-silyl carboxylic acid derivatives, including lactam 45, in high yield and enantiomeric excess. Elaboration of 45 to lactacystin required 11 additional steps and involved an unusual spiro beta-lactone intermediate 61.*; Spiro beta-lactone 61 was found to be a potent inhibitor of the 26S proteasome, while its C-6 epimer 72 displayed very weak activity. Crystallographic studies of these two inhibitors and their interactions with the proteasome's key catalytic N-terminal threonine residue support the hypothesis that the discrepancy in potency is due to differences in the hydrolytic stability of the resulting acyl enzyme complexes.*; Inspired by the many elegant applications of transannular reactions in total synthesis, an asymmetric catalytic version of the transannular Diels-Alder (TADA) reaction was developed that affords polycyclic products in high enantiomeric excess. The optimal catalyst 141f can also alter the inherent diastereoselectivity of cyclizations with chiral macrocyclic substrates. Additionally, this transformation has been utilized as the key step in a total synthesis of the sesquiterpene natural product 11,12-diacetoxydrimane (180).*; *Please refer to dissertation for diagrams.