School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Victoria, 3010, Australia.
Chem Soc Rev. 2021 Aug 21;50(16):9278-9343. doi: 10.1039/d0cs01441a. Epub 2021 Jul 13.
Peptide modifications can unlock a variety of compounds with structural diversity and abundant biological activity. In nature, peptide modifications, such as functionalisation at the side-chain position of amino acids, are performed using post-translational modification enzymes or incorporation of unnatural amino acids. However, accessing these modifications remains a challenge for organic chemists. During the past decades, selective C-H activation/functionalisation has attracted considerable attention in synthetic organic chemistry as a pathway to peptide modification. Various directing group strategies have been discovered that assist selective C-H activation. In particular, bidentate directing groups that enable tuneable and reversible coordination are now recognised as one of the most efficient methods for the site-selective C-H activation and functionalisation of numerous families of organic compounds. Synthetic peptide chemists have harnessed bidentate directing group strategies for selective functionalisation of the β- and γ-positions of amino acids. This method has been expanded and recognised as an effective device for the late stage macrocyclisation and total synthesis of complex peptide natural products. In this review, we discuss various β-, γ-, and δ-C(sp)-H bond functionalisation reactions of amino acids for the formation of C-X bonds with the aid of directing groups and their application in late-stage macrocyclisation and the total synthesis of complex peptide natural products.
肽修饰可以解锁具有结构多样性和丰富生物活性的各种化合物。在自然界中，肽修饰，如氨基酸侧链位置的功能化，是使用翻译后修饰酶或非天然氨基酸的掺入来完成的。然而，对于有机化学家来说，这些修饰的获得仍然是一个挑战。在过去的几十年中，选择性 C-H 活化/功能化作为一种肽修饰途径，在合成有机化学中引起了相当大的关注。已经发现了各种导向基团策略，以协助选择性 C-H 活化。特别是，能够实现可调谐和可逆配位的双齿导向基团，现在被认为是对许多有机化合物家族进行位点选择性 C-H 活化和功能化的最有效方法之一。合成肽化学家已经利用双齿导向基团策略来选择性地修饰氨基酸的β-和γ-位。这种方法已经得到扩展，并被认为是复杂肽天然产物的后期大环化和全合成的有效手段。在这篇综述中，我们讨论了各种β-、γ-和δ-C(sp)-H 键氨基酸官能化反应，以形成 C-X 键，借助导向基团，并将其应用于后期大环化和复杂肽天然产物的全合成。
