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
Copyright
2013, Souvik Banerjee
Recommended Citation
Banerjee, Souvik, "An Insight Into Asymmetric Synthesis and Bioorganic Applications of Novel Cα- Methyl-Lysine, - Proline, - Nipocotic Acid Analogues" (2013). Dissertations. 224.
https://aquila.usm.edu/dissertations/224