Recent advances in the synthesis of fluorinated amino acids and peptides.

ABSTRACT

The site-selective modification of amino acids, peptides, and proteins has always been an intensive topic in organic synthesis, medicinal chemistry, and chemical biology due to the vital role of amino acids in life. Among the developed methods, the site-selective introduction of fluorine functionalities into amino acids and peptides has emerged as a useful approach to change their physicochemical and biological properties. With the increasing demand for life science, the direct fluorination/fluoroalkylation of proteins has also received increasing attention because of the unique properties of fluorine atom(s) that can change the protein structure, increase their lipophilicity, and enable fluorine functionality as a biological tracer or probe for chemical biology studies. In this feature article, we summarized the recent advances in the synthesis of fluorinated amino acids and peptides, wherein two strategies have been discussed. One is based on the fluorinated building blocks to prepare fluorinated amino acids and peptides with diversified structures, including the transformations of fluorinated imines and nickel-catalyzed dicarbofunctionalization of alkenes with bromodifluoroacetate and its derivatives; the other is direct fluorination/fluoroakylation of amino acids, peptides, and proteins, in which the selective transformations of the functional groups on serine, threonine, tyrosine, tryptophan, and cysteine lead to a wide range of fluorinated α-amino acids, peptides, and proteins, featuring synthetic convenience and late-stage modification of biomacromolecules. These two strategies complement each other, wherein transition-metal catalysis and new fluoroalkylating reagents provide powerful tools to selectively access fluorinated amino acids, peptides, and proteins, showing the prospect of medicinal chemistry and chemical biology.