Peptide modification by combining C-H functionalization and sulfur(vi)-fluoride exchange; developing new peptide cyclization methods

Holmes, A., 2022. Peptide modification by combining C-H functionalization and sulfur(vi)-fluoride exchange; developing new peptide cyclization methods. PhD, Nottingham Trent University.

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Abstract

Chemically modified peptides often display improved biological activity and pharmacological properties when compared with their native equivalents. In contrast to their linear counterparts, conformationally constrained peptides demonstrate higher structural rigidity and improved pharmacokinetic properties.

Whilst there are many synthetic techniques that could be employed to cyclize peptides, these often rely upon polar side chains, heteroatoms or unnatural amino acids, which can detract from peptide function and contribute to poor atom economy. Methods focussed on alternative strategies to achieve cyclization are therefore crucial for maximising versatility and enabling a broader scope for constrained peptide application. Click chemistry reactions are well suited to cyclization due to their tolerance for other functional groups and high yields. Recently, sulfur(VI)-fluoride exchange (SuFEx) has been described as the "next generation click reaction" however, it is yet to be fully explored as a technique in peptide modification. Methods of introducing SuFEx-able hubs to amino acids and particularly peptide substrates are lacking.

This body of work describes the development of a new cyclization method involving the CH functionalization of ethenesulfonyl fluorides (ESF) onto linear peptides to install a reactive arylvinylsulfonyl fluoride (aryl VSF) at phenylalanine, an otherwise unreactive residue. The protocol then subjects the modified peptide to sulfur(VI)-fluoride exchange (SuFEx) chemistry in order to facilitate the synthesis of further diversified structures, including cyclic peptides through intramolecular SuFEx transformations. The results show that a broad scope of linear, short-chained peptides containing phenylalanine residues can be modified with ESF to form aryl VSFs in good yields. The modified peptides were then exposed to developed conditions in order to facilitate SuFEx transformations generating diverse new structures. SuFEx reactions were carried out successfully with primary amine, secondary amine and silyl ether nucleophiles. The power of the technique was demonstrated by the generation of cyclic peptides from their linear counterparts.

Item Type:	Thesis
Creators:	Holmes, A.
Contributors:	Name Role NTU ID ORCID Cross, W. Thesis supervisor SST3CROSSW orcid.org/0000-0001-6277-400X Perry, C. Thesis supervisor CHP3HARRICC orcid.org/0000-0003-1517-468X
Date:	September 2022
Rights:	The copyright in this work is held by 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 to the author.
Divisions:	Schools > School of Science and Technology
Record created by:	Linda Sullivan
Date Added:	08 Nov 2023 09:40
Last Modified:	08 Nov 2023 09:40
URI:	https://irep.ntu.ac.uk/id/eprint/50312

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