Date of Award

1994

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

First Advisor

Mark L. McLaughlin

Abstract

$\alpha$-Amino acids serve a central role in biology and chemistry. With the advance of a variety of sophisticated spectroscopic and computational methods to elucidate the relationships between amino acid sequence, protein conformation, and their chemical, physical, and biological properties, a tremendous level of interest has been generated in the de novo design and synthesis of unnatural amino acids for the purposes of imparting enzyme-inhibitory, antimetabolite, protease resistance, and unique conformational properties to peptides and derivatives. The goal of this research work was to synthesize tryptophan and tyrosine derivatives, which are conformationally constrained, with fixed side-chain to prevent $\alpha$-$\beta$ and/or $\alpha$-$\beta$ bonds from rotating. The constrained derivative of tryptophan, 2-amino-1,2-dihydro-cyclopenta (b) indole-2-carboxylic acid, with a five-membered ring fused to the indole ring, was synthezised. All the intermediates in the reaction were characterized spectroscopically, and the structure proof was made by X-ray crystallographic determination. The constrained tyrosine derivative, methyl 2-benyoxycarbonamido-2-(5-methoxyindanylidene)carboxylate, with alanyl side chain fused to five-membered ring, was prepared by coupling three small molecules first, then ring-closure with Heck reaction. Progress made towards the derivative of tryptophan with the same approach is reported. Progress made towards the derivatives of tryptophan and tyrosine with a cyclopropane ring at $\alpha$-$\beta$ bonds of the amino acids is reported. The tryptophan and tyrosine derivatives are potential intrinsic fluorescence probes. Also these conformationally constrained derivatives could be useful in the bioactive peptide synthesis to change their primary structure as well as secondary structure in order to closely study structure-bioactivity relationships.

Pages

127

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