Date of Award

Fall 12-2013

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry and Biochemistry

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.

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Chemistry Commons

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