Amino acids and peptides play an important role in nature, as well as in organic and pharmaceutical chemistry. Therefore, the easy, straightforward and versatile access of biogenic and unnatural derivatives is still highly demanding. This micro‐review intends to provide to the reader the current state of the art on site‐selective C–H bond functionalization technology applied on α‐amino acids and peptides, focusing on the different C–H positions that can successfully be addressed to date. It is structured in two main parts implying i) the α‐C–H functionalization at the peptide backbone and ii) the modification of the side‐chain. Herein, metal‐catalyzed C–H activation, oxidative C–H functionalization, as well as light mediated approaches, are discussed considering the challenges in reactivity and selectivity. The great potential of these transformations is also depicted with the derivatization and macrocyclization of complex peptides leading to products of pharmaceutical importance.

A versatile photoredox‐catalyzed synthesis of unnatural amino acids and peptides is presented. Commercially available Ru(bpy)3(PF6)2 was efficiently used as visible light photocatalyst in combination with a broad number of different types of radical precursors in the coupling with several dehydrogenated amino acid residues. This method provides new entries to the mild, selective and direct modification of both simple and complex peptide‐like compounds towards novel structures with improved or unusual properties. Hence, (fluorinated)alkyl halides, arylsulfonyl chlorides or various N‐(acyloxy)phthalimides (NHPI esters) were effectively reacted with a series of natural and unnatural α,β‐dehydroamino acids and dipeptides. Moreover, the applicability of the process was also proved by the late stage functionalization of the naturally occurring peptide thiostrepton.

Over the past few years, the development of oxidative methodologies towards efficient and selective direct Csp-H bond functionalization processes has attracted tremendous attention from synthetic chemists. However, only a little attention has been given to the key role of the nature of the oxidant. This review aims at providing a brief summary of the recent advances in mild and more benign oxidative Csp-H bond functionalization reactions, which are classified according to the type of oxidation system employed.