Person:

Ford, David Dearborn

In asymmetric catalysis, interactions between multiple molecules of catalyst can be important for achieving high catalyst activity and stereoselectivity. In Chapter 1 of this thesis, we introduce catalyst-catalyst interactions in the context of the classic Kagan nonlinear effect (NLE) experiment, and present examples of the strengths and drawbacks of the NLE experiment. For the remainder of the thesis, we explore catalyst-catalyst interactions in the context of two different reactions. First, in Chapter 2, we apply a combination of reaction kinetics and computational chemistry to a reaction that is well known to require the cooperative action of two molecules of catalyst: the (salen)Co(III)-catalyzed hydrolytic kinetic resolution (HKR) of terminal epoxides. In our investigation, we demonstrate that stereoselectivity in the HKR is achieved through catalyst-catalyst interactions and provide a model for how high selectivity and broad substrate scope are achieved in this reaction. In Chapter 3, we focus our attention on the thiourea-catalyzed enantioselective alkylation of alpha-chloroethers with silyl ketene acetal nucleophiles, a reaction that was not known to require the cooperative action of two molecules of catalyst at the outset of our investigation. By using a wide range of physical organic chemistry tools, we established that the resting state of the optimal thiourea catalyst is dimeric under typical reaction conditions, and that two molecules of catalyst work cooperatively to activate the alpha-chloroether electrophile. The implications of this mechanism for catalyst design are discussed.

The (salen)Co(III)-catalyzed hydrolytic kinetic resolution (HKR) of terminal epoxides is a bimetallic process with a rate controlled by partitioning between a nucleophilic (salen)Co–OH catalyst and a Lewis acidic (salen)Co–X catalyst. The commonly used (salen)Co–OAc and (salen)Co–Cl precatalysts undergo complete and irreversible counterion addition to epoxide during the course of the epoxide hydrolysis reaction, resulting in quantitative formation of weakly Lewis acidic (salen)Co–OH, and severely diminished reaction rates in the late stages of HKR reactions. In contrast, (salen)Co–OTs maintains high reactivity over the entire course of HKR reactions. We describe here an investigation of catalyst partitioning with different (salen)Co–X precatalysts, and demonstrate that counterion addition to epoxide is reversible in the case of the (salen)Co–OTs. This reversible counterion addition results in stable partitioning between nucleophilic and Lewis acidic catalyst species, allowing highly efficient catalysis throughout the course of the HKR reaction.