Progress and perspectives on directing group-assisted palladium-catalysed C–H functionalisation of amino acids and peptides

Abstract

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(sp³)–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.