Computational Studies on the Mechanism and Stereochemistry of Lewis Acid-Catalyzed Aldol Condensations and Other Molecular Modeling Studies

Mukaiyama aldol reactions are an efficient way to construct carbon-carbon bonds and form products with multiple stereocenters in one step. However, mechanistic explanations for stereoselectivity thus far have only been qualitative. This thesis includes the first computational study of stereoselectivity in Mukaiyama aldol reactions;Computational modeling is presented that builds upon previous models and allows for a more quantitative description of Mukaiyama aldol diastereoselectivity. A model for diastereoselectivity in the Lewis acid-catalyzed Mukaiyama aldol reaction is presented based on computational scans of the Mukaiyama aldol reaction potential energy surface and optimized transition structures. The modeling study indicates the importance of the Lewis acid to be near the silyl enol ether α-hydrogen to relieve steric repulsion in the stereodetermining transition state. In contrast to previous reports, not all transition states for this reaction have a staggered geometry. Furthermore, evidence is provided suggesting that pro-syn pathways disfavor an antiperiplanar transition state configuration. The modeling work is successfully validated by comparison to several experimental examples from the literature and expanded to more complex reactants. These results lead to a more quantitative understanding of causes of diastereoselectivity in Mukaiyama aldol reactions.An enantioselective Lewis acid-catalyzed Mukaiyama aldol reaction is investigated. A combination of quantum mechanical calculations and force field development describes the chiral (acylox)borane-catalyzed Mukaiyama aldol reaction's transition state. Force fields are developed using the quantum-guided molecular mechanics (Q2MM) method to create a classical force field based on quantum mechanical data. This study highlights the ability of Q2MM to be used to allow for a transition state conformational search. Starting with essentially no available information about the reasons for enantioselectivity in these borane-catalyzed reactions, a detailed model of the reaction?s transition state is provided. By combining insights about the transition state regarding preferred torsion angles, the preferred configuration of the stereocenter at the boron atom, and the preferred coordination geometry of the catalyst relative to the aldehyde, transition state conformational analysis is simplified.Squaraine rotaxane endoperoxides are modeled to support experimental results from another group regarding their stereochemistry. The results of the calculations support a stereochemical revision of these structures in which the endoperoxide initially forms as an unstable external stereoisomer. This stereochemistry leads to a mechanistic hypothesis in which squaraine rotaxane endoperoxides can isomerize to the more stable internal stereoisomer or release molecular oxygen to relieve steric strain.A homology model for the c-subunit ring of V-ATPase is developed. The model is built using the crystal structure of a comparable ring of V-type Na+-ATPase from Enterococcus hirae as a template. The model is compared to mutagenesis studies in the literature to suggest the general location and structure of a binding site for known inhibitors, such as iejimalide. The suggested binding site location is in agreement with mutagenesis data in the literature.