Investigating Imidazolidinone Catalysts: Enantioselective Organocatalytic Diels-Alder Reactions, Conjugate Additions to Access Non-Natural ∝-Amino Acids, and Bimodal Catalyst Activation for the Development of Organo-Cascade Reactions

Citation

Larsen, Catharine Hoàng-Mai (2006) Investigating Imidazolidinone Catalysts: Enantioselective Organocatalytic Diels-Alder Reactions, Conjugate Additions to Access Non-Natural ∝-Amino Acids, and Bimodal Catalyst Activation for the Development of Organo-Cascade Reactions. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/2WS6-B577. https://resolver.caltech.edu/CaltechETD:etd-10142005-105810

Abstract

The MacMillan group focuses on the development of new strategies that harness the power of simple organic compounds to catalyze asymmetric reactions. To this end, we have designed amine catalysts which activate alpha,beta-unsaturated aldehydes via the reversible formation of chiral iminium ions (in analogy to LUMO-lowering activation by reversible metal-substrate complexation). Kinetic studies highlight the importance of the acid co-catalyst and identified a more reactive imidazolidinone catalyst complex, which improved enantioselectivities and vastly expanded the substrate scope of the first highly enantioselective organocatalytic Diels–Alder reaction. Exploration of the crucial components of catalyst architecture led to the development of the second-generation imidazolidinone that not only catalyzes cycloadditions, but a variety of other reactions of aldehydes with excellent selectivity.

Complementary to the 1,2-addition observed with Lewis acids, the alternative mode of activation offered by iminium catalysis allows for 1,4-addition of heterocycles to alpha,beta-unsaturated aldehydes. Using a chiral amine catalyst, the first asymmetric conjugate addition of oxazoles generates protected quaternary alpha-amino acids with an adjacent tertiary stereocenter, a widely applicable motif in biology, materials science, and medicine. Finally, having demonstrated that imidazolidinones can activate both electrophiles (LUMO-lowering) and nucleophiles (HOMO-raising), these iminium and enamine catalysis cycles can be linked for tandem nucleophilic addition/electrophilic trapping of enals. In a single synthetic operation, this enantioselective conjugate addition/alpha-halogenation sequence takes achiral starting materials and selectively connects them, creating multiple stereocenters across the newly formed bonds.

Thesis Files