The studies described in this proposal explore the role of attractive electrostatic interactions in the conformations and reactions of piperidinium ions. Literature reports indicate that, unlike their neutral piperidine analogs, piperidinium ions substituted by electronegative groups (e.g., OR, Cl, and F) adopt axial conformations. These contrasteric axial preferences have been attributed to through-space electrostatic attractions between the polar N-R (R = H, C) and C-X (X = O, halogen) bonds of these species. This research project aims to develop fundamental understanding of electrostatic effects in piperidinium ions, then to apply this insight to the development of new methodologies for synthesis. Research will proceed in three phases: 1) Experiments will systematically probe the factors that induce axial preferences in piperidinium ions, and will explore the steric limits of these effects. A panel of susbtrates will be prepared and their conformational equilibria in a variety of solvents will be measured by NMR spectroscopy. 2) Studies will aim to establish that attractive electrostatic interactions can be used as elements of stereocontrol in the reactions of piperidinium ions. Diels-Alder reactions, 1,3-dipolar cycloadditions, and conjugate additions will be performed on piperidinium-tethered a,(3-unsaturated ester groups. Bicyclic ammonium ion substrates will be prepared to distinguish between through-space effects and inductive effects. 3) Finally, studies will exploit attractive electrostatic interactions for the stereoselective synthesis of chiral piperidines from acyclic precursors. Sakurai annulations and nucleophilic substitution reactions will be performed, probing the role of attractive electrostatic interactions in the chair-like transition states of these reactions. This final goal is the long-term objective of the research project, as the proposed cyclization reactions represent powerful new methodologies for the synthesis of chiral piperidines. Innumerable therapeutic agents contain piperidine ring structures; these medicines are used to treat Alzheimer's disease, schizophrenia, HIV, diabetes, cancer, and other ailments. The proposed studies will enhance understanding of these drugs by providing information relevant to their three-dimensional structures under physiological conditions. If successful, this research will also provide techniques to make new and existing piperidine-based drugs available at lower costs to the patient and the environment. ? ? ?
| Krumper, Jennifer R; Salamant, Walter A; Woerpel, K A (2009) Correlations between nucleophilicities and selectivities in the substitutions of tetrahydropyran acetals. J Org Chem 74:8039-50 |
| Krumper, Jennifer R; Salamant, Walter A; Woerpel, K A (2008) Continuum of mechanisms for nucleophilic substitutions of cyclic acetals. Org Lett 10:4907-10 |
