Date of Award

Summer 8-2017

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

Vijay Rangachari

Committee Member 2 Department

Chemistry and Biochemistry

Committee Member 3

Wujian Miao

Committee Member 3 Department

Chemistry and Biochemistry

Committee Member 4

Julie Pigza

Committee Member 4 Department

Chemistry and Biochemistry

Committee Member 5

Paige Buchanan

Abstract

In the field of chemistry there is a growing demand for small molecule organocatalysts such as amino acids, more specifically proline and its analogues, which could catalyze various key chemical reactions in the synthesis of several biologically important molecules. Even though natural proline is reported to catalyze various chemical reactions, its use as organocatalyst is limited mainly due to the solubility issues in the reaction media and high catalyst loadings, which is not very ideal for bulk scale manufacturing. To address these limitations we planned to develop unnatural analogues of proline that could catalyze the reactions with lower catalyst loadings and expanded solvent choice. Herein we disclose a novel synthetic route that utilizes enzyme porcine liver esterase and a novel stereoselective cyclization strategy, developed in our lab, to prepare two diastereomers of 5-benzyl substituted Cα-methyl-β-Proline in their optically pure forms. These two diastereomers were tested for their activities in both Aldol and Mannich reactions, an important class of carbon-carbon bond forming reactions between carbonyl compounds. Among them, only one diastereomer proved to be an excellent organocatalyst in the Mannich Reaction providing anti-selective products with ee of up to 99%. The catalyst also catalyzed the Aldol reaction between acetone and 4-nitrobenzaldehyde in water yielding racemic mixture of Aldol product.

PLE isoenzyme studies were conducted on two malonate diesters 4b and 4c with different groups in the side chain. Isoenzymes 1 and 2 did not show any reactivity towards both diester substrates. Isoenzyme 5 did not show reactivity with substrate 4b. Whereas isoenzymes 3 and 4 showed reversal of diastereoselectivity with the diester 4c.

A concise synthetic methodology, for the preparation of orthogonally protected Cα-Methyl cysteine has been developed. Curtius rearrangement of enantiomerically enriched malonate halfester from PLE hydrolysis followed by Fmoc protection using Titanium (IV) Isopropoxide is the key step in the synthesis of NH-Fmoc-S-Trityl-Cα-Methyl Cysteine. The synthesized amino acid is currently under investigation for its effect when incorporated into a biologically active polypeptide.

ORCID ID

0000-0002-8157-9688

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