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Title: Morpholinone based peptide synthesis incorporating N- and C-terminus chain xtension
Author: Yan, Ran
ISNI:       0000 0004 2717 2048
Awarding Body: University of Reading
Current Institution: University of Reading
Date of Award: 2006
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The research contained herein is concerned with morpholinone based peptide synthesis incorporating N- and C-terminus chain extension. Chapter 1 firstly considers the bio-significance of peptides, the conformation of the peptide bond, local restriction of peptide chains and the reactivity of peptide bonds. Three general problems in peptide synthesis including chemoselectivity, racemization and yield are discussed. Subsequently, several important coupling systems such as dicyclohexylcarbodiimide, acid chlorides, acid fluorides, acid azides, phosphonium salts and uronium reagents are considered. The process of solid phase peptide synthesis is described and the total synthesis of a cyclic heptapeptide, hymenamide C, is given as an example of a successful solid phase synthesis. A recently developed protein synthesis methodology that employs a chemical ligation strategy is also presented. Synthetic strategies for the construction of small cyclic peptides are also described. Various methods for the aminolysis of lactones and N-debenzylation of amides are reviewed. Finally, previous morpholinone-based amino acid and peptide analogue syntheses are reviewed. The first part of the "Results and Discussion" chapter concentrates on the N-acylation of the 3-alkylsubstituted morpholinone templates. It was found that Fmoc acid chlorides are very powerful coupling reagents for the N-terminus extension of the hindered secondary amines. In the second part of this chapter, the investigation of the C-terminus extensions of the 3-alkylsubstituted morpholinone dipeptide derivatives is described, wherein dimethyl aluminium amides were found to be the ideal lactone aminolysis reagents. The third part of the chapter focuses on the synthesis and C- terminus extension of the five membered oxazolidinone dipeptide derivatives. Next, several amide N-debenzylation methods were tried leading ultimately to the successful synthesis of tri-L-alanine and L-D-L-alanine using lithium in liquid ammonia in the presence of t-butanol at -78°C. The synthesis of cyclic peptides based on 3-methyl morpholinone was attempted but was unsuccessful and this led us to construct the potentially more reactive thiamorpholinone templates. A universal three step synthesis of thiamorpholinones was developed and the expected high electrophilicity of these compounds was observed during the reduction process. A brief investigation of the thiamorpholinone N,C-termini extensions was carried out. It was found that the proline derived thiamorpholinone could be aminolyzed by a secondary amine under very mild conditions. The N-terminus extension of thiamorpholinones was also achieved using the method developed in the morpholinone series in good yields. However, the C-terminus extension of these dipeptide derivatives could not be observed under mild conditions. Suggestions for future C-terminus extension of thiamorpholinone dipeptide derivatives and a new pathway to the synthesis of non-proteinogenic amino acid residue containing thiamorpholinones are made.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available