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Synthetic studies on Thiomorpholinones for the application in peptide coupling

Monir, D. K. B. (2018) Synthetic studies on Thiomorpholinones for the application in peptide coupling. PhD thesis, University of Reading

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Abstract/Summary

This study addresses synthetic approaches to access a glycine-derived thiomorpholinone template and the application of this template for the production of peptides via C-terminus extension. The first chapter surveys strategies in peptide synthesis, including stepwise elongation and convergent approaches. Several important amino and carboxy protecting groups are described. The development of methodologies in peptide synthesis, beginning with solid phase peptide synthesis (SPPS) towards chemical ligation, native chemical ligation (NCL) and other ligation techniques such as Staudinger ligation and click chemistry, are considered. The racemization problem in peptide synthesis via direct enolization and oxazolone formation are highlighted. Several widely used coupling reagents such as acyl chloride, carbodiimide and phosphonium reagents are discussed. The development of a morpholinone to thiomorpholinone-based peptide synthesis strategy is summarized. Chapter 2 focuses on an alternative synthetic route to obtain glycine-derived thiomorpholinone templates. A seven step synthetic route was successfully developed to access C-3 unsubstituted thiomorpholinones for the first time. The synthesis starts with the nucleophilic ring opening of Boc-protected morpholinone to give an ester. The sulfur introduction was achieved via Mitsunobu reaction, followed by hydrolysis, ring closure with DCC and deprotection to give the desired glycine-derived thiomorpholinone template. Attempts to improve the initially developed method successfully reduced the synthetic sequence to six steps by preparing an ester in a one pot strategy. An attempt at incorporation of a 5-(4-methoxyphenyl) substituent into the thiomorpholinone system was able to give an ester by adapting an improved six step procedure. Chapter 3 concentrates on several other routes investigated with the aim to access the glycine-derived thiomorpholinone template. In a reductive amination approach, benzyl N-Fmoc 2-(4-methoxyphenyl)thioglycine was generated based on a six step procedure requiring two more steps including benzyl removal before ring closing to obtain the more synthetically attractive 5-(4-methoxyphenyl) C-3 unsubstituted thiomorpholinone template. The use of thioacetate as an alternative starting material in this approach successfully led to the thioacid in three steps. A thionation approach was also considered for the conversion of the morpholinone precursor to the thiomorpholinone. Several thionating agents were studied for this purpose, including Lawesson’s reagent, a P4S10–HMDO combination and the P4S10-pyridine complex using Fmoc-protected morpholinone as a starting material. Chapter 4 describes an application of the C-3 unsubstituted thiomorpholinone template in peptide synthesis. This is exemplified by the preparation of a tripeptide derivative ala-gly-ala. The N-terminus peptide extension on the template was carried out using an acid chloride to give a dipeptide adduct ala-gly. The nucleophilic ring opening of N-acylated thiomorpholinone was achieved using a carboxyl protected amino acid under mild conditions to give the ala-gly-ala tripeptide precursor. This study demonstrates that a glycine-derived thiomorpholinone can be used as a template to carry out C-terminus peptide coupling under mild conditions without epimerization as oxazolone formation is prevented. Chapter 5 summarises the main findings in this study including the development and improvement of the synthetic method to access the desired glycine-derived thiomorpholinone template and also the use of this template towards peptide generation. Chapter 6 outlines the experimental procedures and spectroscopic data of the compounds synthesized during the course of these studies.

Item Type:Thesis (PhD)
Thesis Supervisor:Harwood, L.
Thesis/Report Department:School of Chemistry, Food and Pharmacy
Identification Number/DOI:
Divisions:Faculty of Life Sciences > School of Chemistry, Food and Pharmacy
ID Code:88096

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