Author

John A. Hood

Date of Award

5-2018

Degree Type

Honors College Thesis

Department

Chemistry and Biochemistry

First Advisor

Matthew Donahue, Ph.D

Second Advisor

Julie Pigza, PhD.

Advisor Department

Chemistry and Biochemistry

Abstract

The nitrogen heterocycles are shared amongst 59% of Food and Drug Administration (FDA) approved small molecule pharmaceuticals with the six-membered piperidine representing the most common moiety. Given the versatility and potential to yield derivatives with broad biological activities, the discovery of new chemical methods to generate these heterocycles in a more time and cost-efficient manner is desired. While there are existing racemic methods to access this class of molecule, the objective of this research is to pioneer a new novel six-step method to generate 2,4,6-trisubstituted piperidines with stereoselective control.

The first step is a condensation between a nonenolizable aldehyde and (R)-2-methylpropane-2-sulfinamide to create the Ellman N-sulfinyl imine. Carbons C3-C5 of the nascent ring can be installed at the si face of the imine via stereoselective allylation that is coordinated by transition metals such as magnesium, indium, or zinc to generate a homoallylic amine. The sulfinyl group is then removed via acidic conditions to afford the primary amine that is subsequently acylated with succinic anhydride to access an N-succinimide via a thermal condensation. A reduction of the cyclic imide via DIBAL-H accesses the N-acyl aminal. The ring closure is initiated by acidic activation of the enamine to the N-sulfinyl iminium ion. This positions the substrate into a kinetically favorable six-membered chair conformation that places the nucleophilic alkene to intercept the iminium carbon stereoselectively affording the tri-substituted piperidine. We are investigating this strategy as a tunable method to prepare a variety of stereochemically diverse piperidines.

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