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Title: Studies in peptide synthesis
Author: Warnke, Jonathan Gordon
ISNI:       0000 0001 3563 5231
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 1974
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The preparation of polypeptide and protein analogues by conventional or fragment condensation synthesis is often a complex and time-consuming procedure. The combination of protected natural peptide fragments, isolated by enzymatic cleavage, and synthetic peptides could give these analogues more rapidly and conveniently than before. A semisynthetic approach is therefore an alternative approach for effective introduction of amino acid substitutions in enzymes and proteins. Insulin offers an excellent opportunity in which this approach can be investigated as tryptic cleavage removes the B-chain C-terminal octapeptide to give des-octapeptide insulin. This thesis reports the synthesis of protected B-chain C-terminal peptides that could be coupled to a similarly protected des-octapeptide insulin. Complete deprotection would then yield a semisynthetic insulin. The intended use of acid labile groups such as t-butoxycarbonyl and benzhydryl esters for the final protected fragments imposed severe restrictions on planning and synthesising the protected fragments. The syntheses were therefore devised such that fully protected peptides could be prepared by conventional strategy and then converted to a much milder protected form suitable for coupling. The 4-picolyl ester method [R. Gamble, R. Garner and G. T. Young, Nature, Lond. 217, 247 (1967)] was used to synthesise the fully protected natural octapeptide (1) using the t-butoxycarbonyl group for α-amino protection, except for the ultimate glycine residue which was incorporated as its benzyloxycarbonyl derivative, piperidino-oxycarbonyl for ε-amino lysine protection and benzyl ethers for threonine and tyrosine hydroxyl group protection. The use of these groups was such that by a series of deprotection-reprotection steps the mildly protected derivative (2) could be prepared and this would be in a form ready for coupling. The synthetic route for the preparation of (1) is outlined in Figure 1. The combination of N, N'-dicyclohexylcarbodi-imide and 1-hydroxybenzotriazole for coupling reactions was employed throughout the synthesis due to its advantages with regard to speed, simplicity of use and absence of racemisation.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available