| Summary: | This thesis describes the application of computational chemistry to understand the origins of the regioselectivity and stereoselectivity in reactions involving the opening and formation of cyclic species. In particular, we have used transition state modeling to gain quantitative insight into an area of organic chemistry where previous understanding has been heavily unfluenced by empirical observations. Our work provides a basis to understand regioselective ring-opening of epoxides in systems controlled by subtrate- or solvent effects. We have also studied enantioselective catalysis using phosphoric acids, which promote enol ether spirocyclizations and the desymmetrization of meso epoxides and aziridines. In Chapter 2 we investigate the unusual 6-endo-tet selectivity of epoxide-opening cyclizations, which form a tetrahydropyran motif found in several marine natural products. Through DFT calculations we have established the stereoelectronic effect of neighboring groups in weakening the adjacent C-O bond, which directs the nucleophilic attack at this position. We also discover that the role of a template provides a thermodynamic bias towards the pyran product, but that it also influences charge separation in the competing transition state structures. The 5-exo-tet pathway suffers from greater charge separation, and entropically unfavorable solvation effects. In Chapters 3 and 4 we turn to enantioselective catalysis with chiral phosphoric acids. Here we investigated the origins of enantioselective enol ether spiroketalization. We have established that selectivity arises in a concerted, but asynchronous step in which the enol ether is protonated, and the developing oxonium is quickly intercepted. The computations are able to account for the sense and level of enantioselectivity based on this mechanistic model. We then focus on the desymmetrization of meso epoxide and aziridines using the same class of catalyst: again a bifunctional mechanism emerges from our studies in which ring opening and nucleophilic attack are promoted by the phosporic acid in a single step. A model for enantioselectivity has been developed to account for the sense of selectivity for this synthetic transformation.
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