Abstract
Peptides and proteins are becoming increasingly valuable as medicines, diagnostic agents and as tools for biomedical sciences. Much of this has been underpinned by the emergence of new methods for the manipulation and augmentation of native biomolecules. Perfluoroaromatic reagents are perhaps one of the most diverse and exciting tools with which to modify peptides and proteins, due principally to their nucleophilic substitution chemistry, high electron deficiency and the ability for their reactivity to be tuned towards specific nucleophiles. As discussed in this minireview, in recent years, perfluoroaromatic reagents have found applications as protecting groups or activating groups in peptide synthesis and as orthogonal handles for peptide modification. Furthermore, they have applications in chemoselective ‘tagging’, stapling and bioconjugation of peptides and proteins, as well as tuning of ‘drug‐like’ properties. This review will also explore possible future applications of these reagents in biological chemistry.
Highlights
Interest in peptides has increased significantly over recent decades, largely due to recognition of their potential therapeutic applications in combination with a growing tendency for drug-discovery to move away from small flat compounds
Pentafluorophenyl esters are applicable to solid phase peptide synthesis and this was first demonstrated by Atherton and Sheppard in 1985 (Figure 1).[19]
The use of pentafluorophenyl esters of amino acids for peptide synthesis is uncommon, the use of the preformed activated esters provides the advantages of rapid coupling reactions and the avoidance of bringing the growing peptide chain into contact with the activating reagent, to reduce side reactions.[19]
Summary
Interest in peptides has increased significantly over recent decades, largely due to recognition of their potential therapeutic applications in combination with a growing tendency for drug-discovery to move away from small flat compounds. Perfluoroaromatic compounds are well known to undergo aromatic substitution reactions with a variety of nucleophiles.[5] Due to the electron withdrawing nature of several fluorine atoms, the aromatic rings within perfluoroaromatic compounds are extremely electron-poor This lack of electron density in the π framework in combination with the ability of flourines to act as leaving groups means that SNAr processes are highly favoured. This review provides a companion piece to the excellent general reviews of arylation and conjugation of peptides.[10] It presents an up-to-date synopsis of the uses of perfluoroaromatic and perfluoroheteroaromatic compounds in unnatural amino acid synthesis, peptide modification and bioconjugation It looks to highlight a range of synthetic methodologies that have been developed to incorporate perfluoroaryl functionality into peptides and the ways in which perfluoroaryl groups have been used as reactive handles for further peptide modifications.
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