Date of Award

Spring 5-2018

Degree Type

Honors College Thesis


Chemistry and Biochemistry

First Advisor

Matthew Donahue

Second Advisor

Julie Pigza

Advisor Department

Chemistry and Biochemistry


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.