Synthesis of a novel class of peptide mimics derived from N-acylisatins

Abstract

The primary aim of this thesis was to synthesize a new class of peptide mimics derived from N-acylisatins and to investigate various methodologies for their synthesis.

N-Acetylisatin 15 and its derivatives 39 and 40 were found to undergo facile nucleophilic ring-opening with amino acid esters yielding a range of 2-acetamidophenylglyoxylamide derivatives in moderate to good yields. This type of reaction was also found to work for di- and tripeptide methyl ester hydrochlorides leading to a range of N-glyoxylamide peptide mimics. The methodology of the reaction conditions was further extended to N,N′-oxalyl bisisatins 17 and 134, and 1,3,5-tris(2,3-dioxoindoline-1-carbonyl)benzene 168 substrates and their reaction with amino acid esters gave a new range of C,C′-linked-bis-glyoxylamide peptide mimics and C,C′,C′′-linked tris-glyoxylamide peptide mimics respectively. Meanwhile, reactions of N-acylisatins with 1,10-diaminodecane 155 and tris(2-aminoethyl)amine 167 gave the corresponding bis and tris-glyoxylamides.

In the event of introducing amino acids at the N-1 position of isatin 9, a range of NH protecting groups for the synthesis of N-protected amino acid acyl isatins 193 were examined. It was found that the phthalamido group, e.g. phthaloylglycine 197, was the best protecting group for the introduction of a glycine unit at the N-1 position of isatin 9. Additionally, a viable and interesting alternative approach utilizing N-succinyl acylisatin 158 as the starting material was also demonstrated. In continuation of our interest in the peptidomimetic approach, a new class of cyclic peptide mimics using Grubbs ring-closing metathesis approach was also successfully synthesized. A range of bis-O-allyl substrates 237, 240, 242 and 246 were prepared from reaction of the corresponding N-acylisatins with L-valine allyl ester hydrochloride 236 and 1,10- diaminodecane 155 respectively. High conversion yields of the target macrocyclic systems 238, 241 and 243 were observed when the bis-Oallyl substrates were irradiated with Hoveyda-Grubb catalyst in a microwave reactor.

These latter studies will provide a synthetically versatile platform for the future design of potential new drugs candidates against Gram-positive bacterial infections