| Description |
Given the potential for opposite enantiomers of a chiral molecule to have different biological effects, access to a single enantiomer of a compound is desirable. Asymmetric catalysis is a powerful method for the synthesis of enantiomerically enriched chiral building blocks, and a mechanistic understanding of the relationship between catalyst structure and selectivity has the potential to advance the field. Additionally, mechanistic investigation provides insight about the nature of reactive intermediates, which allows one to imagine new ways to obtain or intercept such intermediates in the pursuit of new reaction development. Herein are described studies of two catalytic systems with a focus on mechanistic understanding. In the first system, a modular catalyst structure was used to systematically evaluate the effects of catalyst acidity in a hydrogen bond-catalyzed hetero Diels-Alder reaction. Linear free energy relationships between catalyst acidity and both rate and enantioselectivity were observed, where greater catalyst acidity leads to increased activity and selectivity. A relationship between reactant electronic nature and rate was also observed, although there is no such correlation to enantioselectivity, indicating the system is under catalyst control. In the second study, a unique approach to alkene difunctionalization was taken based on a mechanistic hypothesis of a quinone methide intermediate in a related reaction. Substrates containing an alkene adjacent to an ortho-phenol and a tethered nucleophile were prepared, allowing for the regioselective addition of two distinct nucleophiles. A key improvement to the catalytic system was achieved using a ligated copper cocatalyst, leading to improved reactivity without a detrimental effect on enantioselectivity. The reaction was applied to the dioxygenation and aminooxygenation of alkenes, resulting in the enantioselective formation of heterocyclic compounds bearing two adjacent chiral centers. The mechanism of the alkene difunctionalization reaction was studied using physical organic chemistry techniques. The proposed quinone methide intermediate was trapped in a Diels Alder reaction. Kinetic analysis provided evidence of rate limiting attack of this intermediate and for copper involvement in more than solely catalyst turnover. Through examination of substrate electronic effects a Jaffé relationship was observed correlating rate to electronic perturbation at two positions of the phenol. Ligand effects were evaluated to provide evidence of rapid ligand exchange and a direct correlation between ligand electronic nature and enantioselectivity. |
