The development of novel methods for the synthesis of histidine-containing peptides

Thesis



The role of the amino-acid histidine in biologically important molecules and the problems encountered in its incorporation whether in protected or unprotected form into peptides, and recent work¹ establishing the importance of the location of the im-protecting group -N(π) being desirable are reviewed in the introduction.

In Chapter 1 the electrolytic deprotection of π-phenacyl-thyroliberin is described: it was found to produce a complex mixture. This and otherdifficulties encountered by co-workers led to the conclusion that π-phenacyl was unsuitable for general use as a histidine protecting group.

In Chapter 2, the investigation of the 1,1,l-trichlorobut-2-enyl group for histidine protection is described. A model compound- NI(1,1,l-trichlorobut-2-enyl)imidazole-was prepared and subjected to screening tests. A number of undesirable side-reactions including cis-trans isomerisation of the double bond were observed indicating that this is not a practical blocking group.

A novel strategy of histidine protection involving reducing the basicity of the imidazole ring by temporary substitution with electronwithdrawing groups is outlined in Chapter 3. A new synthesis of N(α) -protected diiodohistidine derivatives and tests demonstrating their stability to routine conditions encountered in peptide synthesis and deprotection by hydrogenolysis are described. A synthesis of thyroliberin indicated the potential of this strategy.

In Chapter 4 preparations of the corresponding 2,5-dibromoderivatives are described, and a solid phase synthesis of glycyl- L-histidyl-L-phenylalanine and a classical synthesis of thyroliberin are outlined. It was found however that although diiodination inhibited racemisation and dibromination was even more effective that direct blockade of the N(π) was indispensable for its complete prohibition.

A new optimised preparation for N(α) -t-butoxycarbonyl,N(π) - benzyloxymethyl-L-histidine² is described in Chapter 5, this being the first simple three-step synthesis of a N(π)-protected histidine derivative.

In Chapter 6 the use of N(α)-t-butoxycarbonyl ,N(π)-benzyloxymethyl- L-histidine as a protected intermediate in a number of demanding exercises, including the solid phase synthesis of angiotensin II and a solution synthesis of a histidyl-tryptophan dipeptide are demonstrated. No problems due to the histidine derivatives were encountered.

Methods of evaluating the degree of racemisation occurring in activated histidine derivatives are discussed in Chapter 7.

Authors: Richards, J; Richards, John David

• Publication date: 1981
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Subjects: Peptides; Synthesis