C-H functionalization for the post-synthetic modification of peptides

Terrey, M.J., 2019. C-H functionalization for the post-synthetic modification of peptides. PhD, Nottingham Trent University.

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Abstract

Peptidic natural products have been the focus of many recent research projects as they exhibit a variety of biological properties due to the large diversity of amino acid building blocks. Modified peptides have found uses in medicinal chemistry as therapeutics and as tools for the analysis of disease. Through sidechain modification, the conformation, physical properties and hence the function of the peptide can be altered, however, traditional modifications target reactive heteroatoms that may be crucial for peptide function. Post-synthetic modification of peptides enables the manipulation of natural amino acids in a peptide after the sequence has been set.

Palladium-catalysed cross-coupling reactions are a relatively new approach to peptide modification, which enable selective functionalization of the aromatic side chains. However, these reactions require the incorporation of non-natural, halogen-containing amino acids into the peptide sequence. In contrast, direct C-H functionalization is a more efficient strategy for peptide modification, which crucially enables post-synthetic modification of the natural peptide.

When this project started, there had been some research on the C-H functionalization of tryptophan residues in peptides. To expand the opportunities for peptide modification, the primary aim of this investigation was to develop methods for the modification of phenylalanine containing peptides.

The work documented in this thesis describes the development of a new C-H functionalization method for the direct modification of phenylalanine residues in peptides. By employing catalytic palladium, phenylalanine aromatic side chains were modified with alkenes, to produce functionalized side chains in a single step. The methodology was applied to di-, tri and tetrapeptides and also accommodated a range of alkenes. The olefination of phenylalanine appears to be selective; targeting mid sequence and C-terminal residues. Bidentate coordination of the metal catalyst to the peptide backbone is critical for the olefination of phenylalanine residues.

The methodology was successfully applied to tryptophan residues, where the amino acid can be modified throughout a peptide sequence. The installation of a Boc directing group appears crucial for the functionalization of tryptophan residues.

The work described for the modification of phenylalanine and tryptophan residues expands the current methodologies for peptide modification.

Item Type: Thesis
Creators: Terrey, M.J.
Date: September 2019
Rights: This work is the intellectual property of the author. You may copy up to 5% of this work for private study, or personal, non-commercial research. Any re-use of the information contained within this document should be fully referenced, quoting the author, title, university, degree level and pagination. Queries or requests for any other use, or if a more substantial copy is required, should be directed in the owner of the Intellectual Property Rights.
Divisions: Schools > School of Science and Technology
Depositing User: Linda Sullivan
Date Added: 28 May 2020 14:34
Last Modified: 28 May 2020 14:34
URI: http://irep.ntu.ac.uk/id/eprint/39907

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