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.

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含氟氨基酸和多肽的合成研究进展

由于氨基酸在生命中的重要作用，氨基酸、多肽和蛋白质的位点选择性修饰一直是有机合成、药物化学和化学生物学中的热门话题。在已开发的方法中，将氟官能团选择性引入氨基酸和肽已成为改变其理化和生物学特性的有用方法。随着生命科学需求的增加，蛋白质的直接氟化/氟烷基化也受到越来越多的关注，因为氟原子的独特性质可以改变蛋白质结构，增加其亲脂性，并使氟作为生物示踪剂的功能或用于化学生物学研究的探针。在这篇专题文章中，我们总结了氟化氨基酸和多肽合成的最新进展，其中讨论了两种策略。一类是基于含氟结构单元制备结构多样的含氟氨基酸和多肽，包括含氟亚胺的转化和烯烃与溴二氟乙酸及其衍生物的镍催化双碳功能化；另一种是氨基酸、肽和蛋白质的直接氟化/氟烷基化，其中丝氨酸、苏氨酸、酪氨酸、色氨酸和半胱氨酸上的官能团的选择性转化导致广泛的氟化α-氨基酸、肽、和蛋白质，具有合成方便和生物大分子后期修饰的特点。这两种策略相辅相成，