In the (salen)Co(III)-catalyzed hydrolytic kinetic resolution (HKR) of terminal epoxides, the rate- and stereoselectivity-determining epoxide ring-opening step occurs by a cooperative bimetallic mechanism with one Co(III) complex acting as a Lewis acid and another serving to deliver the hydroxide nucleophile. In this paper, we analyze the basis for the extraordinarily high stereoselectivity and broad substrate scope observed in the HKR. We demonstrate that the stereochemistry of each of the two (salen)Co(III) complexes in the rate-determining transition structure is important for productive catalysis: a measurable rate of hydrolysis occurs only if the absolute stereochemistry of each of these (salen)Co(III) complexes is the same. Experimental and computational studies provide strong evidence that stereochemical communication in the HKR is mediated by the stepped conformation of the salen ligand, and not the shape of the chiral diamine backbone of the ligand. A detailed computational analysis reveals that the epoxide binds the Lewis acidic Co(III) complex in a well-defined geometry imposed by stereoelectronic, rather than steric effects. This insight serves as the basis of a complete stereochemical and transition structure model that sheds light on the reasons for the broad substrate generality of the HKR.

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.

We describe the rational design of a linked, bis-thiourea catalyst with enhanced activity relative to monomeric analogs in a representative enantioselective anion-abstraction reaction. Mechanistic insights guide development of this linking strategy to favor substrate activation though the intramolecular cooperation of two thiourea subunits while avoiding nonproductive aggregation. The resulting catalyst platform overcomes many of the practical limitations that have plagued hydrogen-bond donor catalysis and enables use of catalyst loadings as low as 0.05 mol %. Computational analyses of possible anion-binding modes provide detailed insight into the precise mechanism of anion-abstraction catalysis with this pseudo-dimeric thiourea.

We provide here a detailed mechanistic characterization of the electrophile-activation step in a representative thiourea-catalyzed enantioselective reaction proposed to involve generation of ion-pair intermediates. Comparison of catalyst-promoted substrate epimerization with catalytic alkylation points to the participation of a common intermediate in both pathways and provides conclusive evidence for anion abstraction via an SN1-like pathway involving the cooperative action of two catalyst molecules.

Chiral, neutral H-bond donors have found widespread use as catalysts in enantioselective reactions involving ion-pair intermediates. Herein, a systematic mechanistic study of a prototypical anion-binding reaction, the thiourea-catalyzed enantioselective alkylation of α-chloroethers, is detailed. This study reveals that the catalyst resting state is an inactive dimeric aggregate that must dissociate and then reassemble to form a 2:1 catalyst–substrate complex in the rate-determining transition structure. Insight into this mode of catalyst cooperativity sheds light on the practical limitations that have plagued many of the H-bond donor-catalyzed reactions developed to date and suggests design strategies for new, highly efficient catalyst structures.