Photoinduced C(sp3)–H Functionalization of Glycine Derivatives: Preparation of Unnatural α-Amino Acids and Late-Stage Modification of Peptides

Conspectus Peptides are essential components of living systems and contribute to critical biological processes, such as cell proliferation, immune defense, tumor formation, and differentiation. Therefore, peptides have attracted considerable attention as targets for the development of therapeutic products. The incorporation of unnatural amino acid residues into peptides can considerably impact peptide immunogenicity, toxicity, side effects, water solubility, action duration, and distribution and enhance the peptides’ druggability. Typically, the direct modification of natural amino acids is a practical and effective approach for promptly obtaining unnatural amino acids. However, selective functionalization of multiple C(sp 3 )–H bonds with comparable chemical reactivities in the peptide side chains remains a formidable challenge. Furthermore, chemical modifications aimed at highly reactive (nucleophilic and aromatic) groups on peptide side chains can interfere with the biological activity of peptides. In recent years, the rapid advancement of photoinduced radical reactions has made photoredox radical–radical cross-coupling a practical approach for constructing C(sp 3 )–C(sp 3 ) bonds under mild conditions. Glycine, a naturally occurring amino acid and the fundamental skeleton of all α-amino acids, provides a basis for the alkylated modification of its own α-C(sp 3 )–H bond under mild conditions. This Account describes our recent research endeavors for systematically investigating the photocatalytic α-C(sp 3 )–H alkylation of glycine derivatives via radical–radical coupling between N -aryl glycinate-derived radicals and various alkyl radicals. In 2018, we disclosed the photoinduced Cu-catalyzed decarboxylative α-C(sp 3 )–H alkylation of glycine derivatives. Subsequently, we developed a catalyst-free method for alkylating glycine derivatives and glycine residues in peptides via electron donor–acceptor (EDA)-complex-promoted single electron transfer. Moreover, we developed a photoinduced method for the radical alkylation of N -aryl glycinate α-C(sp 3 )–H bonds using unactivated alkyl chlorides (iodides) under photocatalyst-free conditions. Notably, by building on racemic alkylations of glycine derivatives and glycine-residue-containing peptides, we recently stereoselectively alkylated the N -aryl glycinate α-C(sp 3 )–H bond using a dual-functional Cu catalyst generated in situ for synthesizing a series of unnatural chiral α-amino and C -glycoamino acids. We have developed a series of methods for synthesizing unnatural amino acids through the α-C(sp 3 )–H alkylation of glycine derivatives using photoredox-promoted radical coupling as a key strategy. These methods are efficient and versatile and can be used for the late-stage modification of peptides in various contexts. Our work builds on the fundamental importance of glycine as the basic scaffold of all α-amino acids and highlights the potential of radical-based chemistry for developing chemical transformations in peptide synthesis. These findings have broad implications for chemical biology and may open doors for discovering peptide drugs and developing therapeutics.