Date of Graduation

12-2011

Document Type

Dissertation

Degree Name

Doctor of Philosophy in Chemistry (PhD)

Degree Level

Graduate

Department

Chemistry & Biochemistry

Advisor

Robert E. Gawley

Committee Member

Bill Durham

Second Committee Member

Neil Allison

Third Committee Member

Matthias McIntosh

Fourth Committee Member

Nan Zheng

Keywords

Pure sciences; Catalytic dynamic resolution; Chiral organolithiums; Dilithiated diaminoalkoxide ligands; Enantiomerization; Medicinal compounds; Piperidine alkaloids

Abstract

One of the most important developments of the last decade has been the emergence of new methods to dynamically resolve racemic organolithiums using stoichiometric amounts of the chiral ligand. When this concept is implemented successfully, it obviates the need for covalently attached chiral auxiliary based methods, asymmetric deprotonation, and asymmetric synthesis of a precursor stannane as ways to access enantioenriched organolithium compounds for use in asymmetric synthesis. Since certain electrophiles consume the chiral ligand, it is desirable to render this process catalytic in the chiral ligand.

As part of a larger study on the amenability of chiral organolithiums to a catalytic dynamic resolution, N-trimethylallyl-2-lithiopyrrolidine, N-Boc-2-lithiopiperidine, and the ethylene ketal of N-Boc-2-lithio-4-oxopiperidine were selected. The barriers to racemization and dynamic thermodynamic resolution (DTR) of these compounds were measured in the presence of various diamine ligands. Using the thermodynamic parameters to guide us, the catalytic dynamic resolution (CDR) was then investigated on both heterocycles at temperatures where racemization is much slower than resolution. Enantiomer ratios as high as 93:7 and 99:1 were achieved for N-trimethylallyl-2-lithiopyrrolidine and N-Boc-2-lithiopiperidine respectively.

The CDR of N-Boc-2-lithiopiperidine using our newly discovered ligands was applied to the highly enantioselective synthesis of several piperidine alkaloids and medicinal compounds such as conhydrine, anabasine, ropivacaine, coniine, pipecolic acid, pelletierine, epipinidinone, lupetidine, and epidihydropinidine.

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