Date of Award
Open Access Senior Honors Thesis
Density Functional methods are used to model the tandem aza-Cope rearrangement – Mannich cyclization reaction leading to substituted acylpyrrolidines. The ultimate goal is to determine optimum reaction conditions that maximize stereoselectivity, as only one set of stereoisomers is pharmacologically active. Three aspects of the reaction are investigated. First, we determine the relative size of three rotational barriers in the interconversion of two iminium cation stereoisomers that are precursors to the aza-Cope rearrangement. The lowest energy pathway for the interconversion is identified, as well as the relative stability of the two stereoisomers for two different substituents: diphenyl and methyl. Activation barriers are found to be not much above 10 kcal/mol in all cases and therefore all stereoisomers are expected to be present in solution. We also investigate the relative stability of reactants, intermediates and products for four, differently-substituted iminium cations undergoing the aza-Cope – Mannich tandem reaction. In addition, activation barriers for each step of the reaction are calculated. Regardless of substituent size and position, the energetics of the reaction do not predict either cis or trans acylpyrrolidine product to be favored. Finally, the epimerization of these acylpyrrolidine products is examined by considering two possible mechanisms: keto-enol tautomerism and retro-Mannich - Mannich cyclization. The data suggest that epimerization is not likely to occur via either mechanism, as one of the intermediates common to both pathways is too high in energy.
Lello, Louis Anthony, "Computational Studies of Stereochemical Effects in the Synthesis of Sugar Mimics" (2010). Senior Honors Theses. Paper 240.