Development of SOMO activation technologies and application of organocascade catalysis towards the total synthesis of (+)-aspidospermidine

The design and development of singly occupied molecular orbital (SOMO) activation is described. This new mode of organocatalytic activation is founded upon the mechanistic hypothesis that the one-electron oxidation of a transient enamine intermediate, derived from an aldehyde and chiral amine catalyst, will render a 3pi-electron SOMO-activated species that can readily participate in a range of unique asymmetric bond constructions. The validity of this new concept has been demonstrated with the development of the first direct and highly enantioselective alpha-allylation of aldehydes.We further established SOMO catalysis as a valuable strategy for asymmetric synthesis with the first direct and highly enantioselective alpha-allylation of ketones. This new protocol allows to directly unite simple cyclic ketones and allylsilanes to form alpha-allylated carbonyls, an unprecedented catalytic enantioselective transformation. We also discuss the invention of a new family of organocatalysts that are chemically robust towards oxidative SOMO conditions. These catalysts have allowed the introduction of many new transformations including the direct asymmetric alpha-allylation, alpha-enolation, and alpha-homobenzylation of simple ketones.We also describe a concise, highly stereocontrolled strategy to the Aspidosperma family of indole alkaloids. The strategy is demonstrated by the total synthesis of aspidospermidine, vincadifformine and quebrachamine. To date, this work represents the most effective enantioselective synthesis of aspidospermidine, which is accessible in only 9 steps and 23% overall yield. The basis of this approach was provided by a novel highly enantioselective organocascade reaction. This new transformation utilizes a single chiral imidazolidinone catalyst to mediate two catalytic events and generate a functionalized spiroindoline product. Our approach differs strategically from previous routes and contains built-in flexibility necessary to access many other members belonging to different families of indole alkaloids. The versatility of the synthetic strategy was illustrated through the asymmetric synthesis of the following indole alkaloids: aspisospermidine, vincadifformine, quebrachamine, kopsinine, kopsanone, strychnine, akuammicine and strychnine.