Division of Chemical Biology and Medicinal Chemistry Eshelman School of Pharmacy, and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Org Biomol Chem. 2019 Apr 10;17(15):3653-3669. doi: 10.1039/c8ob03155j.
α,β-Dehydroamino acids (dhAAs) are noncanonical amino acids that are found in a wide array of natural products and can be easily installed into peptides and proteins. dhAAs exhibit remarkable synthetic flexibility, readily undergoing a number of reactions, such as polar and single-electron additions, transition metal catalyzed cross-couplings, and cycloadditions. Because of the relatively mild conditions required for many of these reactions, dhAAs are increasingly being used as orthogonal chemical handles for late-stage modification of biomolecules. Still, only a fraction of the chemical reactivity of dhAAs has been exploited in such biorthogonal applications. Herein, we provide an overview of the broad spectrum of chemical reactivity of dhAAs, with special emphasis on recent efforts to adapt such transformations for biomolecules such as natural products, peptides, and proteins. We also discuss examples of enzymes from natural product biosynthetic pathways that have been found to catalyze many similar reactions; these enzymes provide mild, regio- and stereoselective, biocatalytic alternatives for future development. We anticipate that the continued investigation of the innate reactivity of dhAAs will furnish a diverse portfolio dhAA-based chemistries for use in chemical biology and drug discovery.
α,β-去氢氨基酸（dhAAs）是一种非典型的氨基酸，广泛存在于各种天然产物中，可以轻松地被引入到肽和蛋白质中。dhAAs 表现出显著的合成灵活性，容易进行多种反应，如极性和单电子加成、过渡金属催化交叉偶联以及环加成反应。由于许多这些反应所需的条件相对温和，dhAAs 越来越多地被用作生物分子后期修饰的正交化学接头。尽管如此，在这些双正交应用中，dhAAs 的化学反应性仅有一部分得到了利用。本文概述了 dhAAs 的广泛的化学反应性，特别强调了最近为适应天然产物、肽和蛋白质等生物分子而进行的此类转化的努力。我们还讨论了天然产物生物合成途径中的酶的例子，这些酶被发现可以催化许多类似的反应；这些酶为未来的发展提供了温和、区域和立体选择性的生物催化替代方案。我们预计，对 dhAAs 固有反应性的持续研究将提供一系列基于 dhAA 的化学方法，用于化学生物学和药物发现。
