Synthesis of Novel Amino Acids and Peptidomimetics as Tools for Drug Discovery

Abstract

This doctoral thesis describes the synthesis of novel amino acids and peptidomimetics for use as tools for drug discovery. The first part of this study focuses on the preparation of modified tyrosine analogues using metal-catalysed coupling reactions and the incorporation of these novel amino acid building blocks into biotin-R8ERY* peptidomimetics using Fmoc SPPS. The second part deals with an investigation towards the development of a new method for the synthesis of optically active α–amino acids. The aim of the first part of this research project was the synthesis of small libraries of biotin-R8ERY peptidomimetics for use as a treatment for autoimmune diseases. Due to its ability to specifically block the invasion of leukocytes into inflamed tissues in the brain and in the gut, biotin-R8ERY represents a potential cure for multiple sclerosis and Crohn’s disease. In this work, a structure-activity relationship study with biotin-R8ERY-containing side-chain modified tyrosine building blocks (including substituted biphenylalanines, 4-heteroarylphenylalanines and O-arylated tyrosines) was carried out. The preparation of a series of Boc and methyl ester protected substituted biphenylalanines (3a-j) involved the palladium-catalysed Suzuki-Miyaura coupling of a tyrosine triflate intermediate 8 with various organoboron reagents, while the preparation of the Boc and methyl ester protected 4-heteroarylphenylalanines (3k-o) required Suzuki coupling of a boronophenylalanine intermediate 16 with structurally diverse heteroaryl halides. The final Boc and methyl ester protected O-arylated tyrosine series (3p-u) was prepared using the copper-catalysed Evans-Chan-Lam reaction between a protected tyrosine residue 2 and substituted phenylboronic acids. The Fmoc protected non-proteinogenic amino acids 4a-u required for use in Fmoc SPPS were obtained through protecting group exchange. The biotin-R8ERY* peptidomimetics 5 were prepared by Fmoc solid phase peptide synthesis and tested for their ability to inhibit the binding of α47 integrins on the surface of leukocytes to their receptor MAdCAM-1 on the surface of specific inflamed tissues. The synthetic methodology for the preparation of the three series of biotin-R8ERY* peptidomimetics is outlined in Scheme 1. Scheme 1. Synthetic scheme summarising the preparation of the three series of biotin-R8ERY* peptidomimetics. The second part of this thesis focused on a project conceived to answer the problems associated with the lack of an efficient method to readily access novel α-amino acids and benefitted from a collaboration with Dr. Craig Harris at the AstraZeneca Research Centre (Reims, France). The knowledge of Dr. Harris in the field of Mitsunobu alkylation allowed the development of an original strategy for the preparation of racemic amino acids by direct alkylation of an achiral glycine scaffold with stable alcohol electrophiles using modified Mitsunobu reagents. This unprecedented methodology was then employed to synthesise a library of 21 racemic amino acid derivatives 123a-v. Furthermore, by combining the expertise developed inside Prof. Brimble’s group towards the synthesis of enantiopure amino acids using the Belokon’s nickel complex chemistry with the knowledge acquired at AstraZeneca, a practical route for the preparation of a large range of structurally diverse optically active amino acids from readily available alcohols was implemented. Finally, this new method was applied to the synthesis of a library of 12 chiral α-amino acids 143a-l. This new, simple method provides facile access to a wide variety of novel unnatural amino acids that are valuable tools for drug discovery.