Date of Award

Fall 12-2015

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

Anthony Bell Jr.

Committee Member 2 Department

Chemistry and Biochemistry

Committee Member 3

Wujian Miao

Committee Member 3 Department

Chemistry and Biochemistry

Committee Member 4

Vijay Rangachari

Committee Member 4 Department

Chemistry and Biochemistry

Committee Member 5

Karl Wallace

Committee Member 5 Department

Chemistry and Biochemistry

Abstract

Cα-methyl-γ- and δ-unnatural amino acids (UAAs) are important class of biomolecules used extensively as structural scaffolds, peptidomimetics, and in the development of pharmaceuticals. Due to steric congestion surrounding the quaternary center, asymmetric preparation of α,α-disubstituted UAAs are synthetically challenging. Herein, two methods for the synthesis of chiral synthons to prepare Cα-methyl-γ- and -δ-UAAs are reported. A crucial step in both strategies includes an enzymatic hydrolysis of prochiral malonic esters with pig liver esterase (PLE). The first method utilizes the Meyer Schuster rearrangement to prepare α,β-unsaturated diesters synthons, but the preparation of the precursor propargyl alcohol decomposes into uncontrollable retro-aldol products. Alternatively, synthons 3-(hydroxymethyl)-3-methylpyrrolidin-2-one and piperidin-2-one, are prepared via a phthalimide deprotection and stereoselective cyclization of the free amine toward an activated ester. This cyclization strategy allows for the preparation of both enantiomers through steric or electronic controls. Conversion of intermediate γ- or δ-lactams into mesylates, nucleophilic substitution, and ring opening led to the formation of γ2,2 and δ2,2-serine, -azido, and -cysteine analogues. General application of the cyclization strategy was found to be limited by sterics imposed by the neopentyl intermediate resulting in longer reaction times and inability to substitute some nucleophiles.

The esterification of oxidized glutathione with thionyl chloride and various alcohols was monitored for completeness using electrospray ionization mass spectrometry. Oxidized glutathione was found to be highly compatible with an excess of methanol and ethanol, but slow and incomplete with 2-propanol. The thionyl chloride esterification was applied to other small peptides to evaluate the limitations with various amino acid side chains. The results show incompatibilities with peptides containing both serine and cysteine but well tolerated with the remaining natural amino acids.

ORCID ID

0000-0002-7819-0014

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