Joshua Hunt

Date Approved

7-14-2016

Degree Type

Open Access Thesis

Degree Name

Master of Science (MS)

Department or School

Chemistry

Committee Member

Cory Emal, Ph.D.

Committee Member

Maria Milletti, Ph.D.

Abstract

We have developed a Lewis-acid catalyzed, diastereoselective aza-Cope rearrangement— Mannich cyclization (ACM) to form acyl pyrrolidines from conformationally mobile substrates. Earlier studies from our lab have shown that substituted acyl pyrrolidines can be synthesized with diastereoselectivity of 50:1 trans to cis, and that unsubstituted pyrrolidines can be synthesized with 13:1 enantioselectivity. This study attempted to observe the stereochemical outcomes of the ACM for disubstituted pyrrolidine systems using oxazolidine starting materials. A proof of concept dimethyl-substituted oxazolidine was subjected to ACM conditions, producing the pyrrolidine with good yields. However, when methyl-phenyl substituted oxazolidine was subjected to ACM conditions, undesired byproduct was formed. We believe that the requisite iminium cation for the ACM reaction is quite stable, causing an unusually high aza- Cope activation barrier and allowing for an undesired pathway to be favored. Destabilization of the iminium cation intermediate via an electron withdrawing group may allow for the reaction to proceed. Enantiomeric control of dimethyl substituted oxazolidine was also observed. Under ACM conditions, 8.5:1 beta to alpha selectivity was observed with good yields. This work emphasizes the ability of the ACM reaction to produce stereoselective pyrrolidine products.

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