Theoretical studies of asymmetric aldol reactions catalyzed by proline and catalytic antibodies.

摘要

This dissertation describes theoretical studies aimed at elucidating the mechanism, reactivity, and stereoselectiviy of amine-catalyzed aldol reactions, especially those involving chiral catalysts.; Chapter 1 is an introduction and overview of amine-catalyzed C-C bond forming reactions in biological systems and in organic synthesis. Chapter 2 describes computational studies on the mechanism and reactivity of amine-catalyzed aldol reactions in the gas phase and in solvent cavity models. Chapter 2 has been published as S. Bahmanyar and K. N. Houk, "Transition States of Amine-Catalyzed Aldol Reactions Involving Enamine Intermediates: Theoretical Studies of Mechanism, Reactivity, and Stereoselectivity," J. Am. Chem. Soc. 2001, 123, 11273--11283.; Chapter 3 describes computational studies to understand the origins of stereoselectivity of proline-catalyzed intramolecular aldol reactions. Two possible mechanisms of stereo selectivity and asymmetric induction by the amino acid proline are explored. A model to describe the source of asymmetric induction for the reaction is introduced. A significant portion of Chapter 3 has been published as S. Bahmanyar and K. N. Houk, "The Origin of Stereoselectivity in Proline-Catalyzed Intramolecular Aldol Reactions," J. Am. Chem. Soc. 2001, 123, 12911--12912.; Chapter 4 describes calculations that were carried out to make predictions of proline-catalyzed intermolecular aldol reactions of cyclohexanone with benzaldehyde and isobutyraldehdyde. These predictions were verified subsequently by experiments done by our collaborators Benjamin List and Harry J. Martin at the Scripps Research Institute.; Chapter 5 is a comprehensive computational study of proline-catalyzed aldol reactions of acetaldehyde, acetone, hydroxyacetone, and cyclohexanone with a variety of aldehydes.; Chapter 6 involves the extension of our model for stereoselectivity of proline-catalyzed aldol reactions to understanding the stereoselectivity of the proline-catalyzed Mannich reaction.; Chapter 7 describes our modeling of stereoselective aldol reactions catalyzed by catalytic antibodies 331712 and 38C2. The crystal structure of antibody 331712 is known. This was combined with the transition state structures studied in chapter 1 to model binding, catalysis, and source of stereoselectivity for the antibody-catalyzed aldol reaction.