| This dissertation describes a combination of studies by experimental and computational methods directed towards understanding the origins of diastereo- and enantioselectivity of different processes, from the relatively simple amine catalyzed addition of chiral alcohols to ketenes used by Merck in the synthesis of arylpropionic acids (NSAIDs), to an antibody-catalyzed Diels-Alder reaction.;Chapter 1 provides an introduction to the relevance of chirality in synthesis and biology.;Chapter 2 describes the asymmetric syntheses of the enantiomerically pure exo-(3S,4S) and endo-(3R,4S) Diels-Alder adducts and the experiments designed to determine their absolute stereochemistry. The second section in chapter 2 explains how, using these enantiomerically pure synthetic compounds, we determined the enantioselectivity of the Diels-Alder reaction between 4-carboxybenzyl trans-1,3-butadiene-1-carbamate (diene 1) and N,N-dimethylacrylamide, catalyzed by antibodies 13G5, 4D5 and other catalytic antibodies elicited simultaneously. This second section contains details about the biological and analytical experiments carried out during my internship at the Scripps Research Institute. Chapter 3 is dedicated to the quantum mechanical modeling of the addition of diene 1 to N,N-dimethylformamide and the quantum mechanical study of the effect of different arrangements of catalytic residues on the structure and energies of the possible transition states. It also provides the results of flexible docking of these transition states in the antibody active site followed by molecular dynamical studies of the resulting complexes that allowed us to explain the origins of catalysis and enantioselectivity.;Chapter 4 describes the extensive high level computations performed to explain the origins of enantioselectivity in the addition of chiral alcohols to ketenes. We have explored the complete potential energy surface of this reaction with quantum mechanical calculations and provided a quantitative model that accounts for the origin of stereoselectivity and all of the experimental observations made on this reaction. Depending on the chiral alcohol used, the unusual 1,4-asymmetric induction is a consequence of the high atroposelectivity in the addition of the chiral alcohol to the ketene, or the result of steering of enolate protonation by electrostatic and hydrogen-bonding interactions involving the carbonyl oxygen at the stereogenic center and the trialkyammonium ion that protonates the enolate carbon. The discovery of this new type of hydrogen bond, +N-C-H ....O=C, important in stabilizing preferentially one transition state over its diastereoisomeric competing transition states, has led to new computations, described in Chapter 5, designed to quantify the magnitude of these interactions in model systems in the gas phase and in solution. These results are useful in explaining the outcome of other asymmetric reactions and processes. |
