Asymmetric synthesis of unusual amino acids for peptide molecular design and molecular recognition studies.

Abstract

Asymmetric synthetic organic chemistry of amino acids is of fundamental importance for the study of peptide and protein molecular design and molecular recognition. The designed unusual amino acids can provide unique conformational and topographical properties that are crucial for molecular recognition processes between peptide ligands and specific receptors, receptor subtypes, and the related signal transduction processes. It is necessary to design and synthesize optically pure unusual amino acids to meet different stereochemical requirements for different receptors and the various active sites on receptors. The Evans-type auxiliary has played an important role in the asymmetric synthesis of optically pure amino acids in the past decade. However, a lot of theoretical and practical research aspects in this field which are related to sensitive chiral enolates, new methodologies and new synthetic procedures need to be investigated. This thesis will present some new tactics for peptide molecular design, for asymmetric synthesis of β-branched α-amino acids and for the related mechanistic organic chemistry which include: a one-pot tandem Michael-like addition/electrophilic bromination reaction and its application to the total asymmetric synthesis of four individual four individual isomers of 2', β-di-methyl tyrosine; an efficient mono- and di-demethylation procedure for aryl-methyl ethers of unusual amino acids; 1,2-asymmetric cis electrophilic induction in allylic-strained boron enolates and its potential application for the asymmetric synthesis of unusual amino acids; a new strategy for the total synthesis of the four individual isomers of β-methylphenylalanine by using 4-phenyl-oxazolidinone as a new chiral resolution reagent and simultaneously as a chiral auxiliary which can provide complete stereoselectivities; a concise method to separate racemic Boc-amino acids, including Boc-unusual amino acids, and a new chiral resolution reagent for HPLC and NMR analysis; a mechanistic study of the asymmetric Michael-like addition reaction by using 4-phenyl-oxazolidinone as a chemical probe (and a potential probe to study biological processes in the future when this motif is incorporated into biologically active molecules). In the last part of the thesis, a new method for the synthesis of the peptide Biphalin, which is perhaps the most potent antinociceptive molecule examined thus far, by solution phase procedures which greatly accelerates the synthetic process and the structure-activity relationships study of Biphalin from the new uses of β-constrained unusual amino acids. Finally, some new strategies for peptide molecular design are discussed.