Date of Award

Fall 12-2013

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry and Biochemistry

School

Mathematics and Natural Sciences

Committee Chair

Douglas Masterson

Committee Chair Department

Chemistry and Biochemistry

Committee Member 2

Karl Wallace

Committee Member 2 Department

Chemistry and Biochemistry

Committee Member 3

Wujian Miao

Committee Member 3 Department

Chemistry and Biochemistry

Committee Member 4

Vijayaraghavan Rangachari

Committee Member 4 Department

Chemistry and Biochemistry

Committee Member 5

Anthony Bell

Committee Member 5 Department

Chemistry and Biochemistry

Abstract

Prochiral malonic diesters consisting of a quaternary carbon center have been successfully converted into a different set of tBoc-Fmoc-α2,2-methyllysine-OH analogues through chiral malonic half-ester intermediates achieved via enzymatic (Pig Liver Esterase, PLE) hydrolysis. The selection of chiral half-ester intermediates, which vary from 1 to 6 methylene units in the side chain, are achieved in high optical purity (92% - 97% ee) and in good yields (65% - 72%). The PLE hydrolysis of malonic diesters with a variety of side chain lengths observed to obey the Jones’s PLE model as evidenced from the stereochemical configurations of the resulting chiral half-esters. The optimized synthetic strategy allows the construction of both enantiomers of α2,2-methyllysine analogues, and a (S)-β2,2-methyllysine analogue from a common synthon by straightforward exploitation of protecting groups. Two different straightforward synthetic strategies are illustrated for the synthesis of α2,2-methyllysine analogues. The described strategies should find significant usefulness in preparing novel peptide libraries with unnatural lysine analogues. A Vapreotide analogue incorporating (S)-α2,2-methyllysine was constructed. However, the Vapreotide analogue with (S)-α-methyl-α-lysine is found to lose its specific binding to somatostatin receptor subtype 2 (SSTR2). In an additional project, a stereoselective and enantiodivergent cyclization strategy for the preparation of γ/δ-lactams is exhibited. The cyclization strategy exploits chiral malonic esters prepared from enantiomerically enriched (92% ee - 97% ee) mono esters of disubstituted malonic acid. The cyclization takes place with the selective departure of a substituted benzyl alcohol as the leaving group. A Hammett study demonstrates that the cyclization is under electronic control. The resulting γ/δ-lactam was readily converted into a novel proline/nipecotic acid analogue.

ORCID ID

0000-0002-7811-2577

Included in

Chemistry Commons

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