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

Conspectus Peptidesare essential components of livingsystems and contributeto critical biological processes, such as cell proliferation, immunedefense, tumor formation, and differentiation. Therefore, peptideshave attracted considerable attention as targets for the developmentof therapeutic products. The incorporation of unnatural amino acidresidues into peptides can considerably impact peptide immunogenicity,toxicity, side effects, water solubility, action duration, and distributionand enhance the peptides' druggability. Typically, the directmodification of natural amino acids is a practical and effective approachfor promptly obtaining unnatural amino acids. However, selective functionalizationof multiple C(sp(3))-H bonds with comparable chemicalreactivities in the peptide side chains remains a formidable challenge.Furthermore, chemical modifications aimed at highly reactive (nucleophilicand aromatic) groups on peptide side chains can interfere with thebiological activity of peptides. In recent years, the rapidadvancement of photoinduced radicalreactions has made photoredox radical-radical cross-couplinga practical approach for constructing C(sp(3))-C(sp(3)) bonds under mild conditions. Glycine, a naturally occurringamino acid and the fundamental skeleton of all & alpha;-amino acids,provides a basis for the alkylated modification of its own & alpha;-C(sp(3))-H bond under mild conditions. This Account describesour recent research endeavors for systematically investigating thephotocatalytic & alpha;-C(sp(3))-H alkylation of glycinederivatives via radical-radical coupling between N-aryl glycinate-derived radicals and various alkyl radicals. In 2018,we disclosed the photoinduced Cu-catalyzed decarboxylative & alpha;-C(sp(3))-H alkylation of glycine derivatives. Subsequently,we developed a catalyst-free method for alkylating glycine derivativesand glycine residues in peptides via electron donor-acceptor(EDA)-complex-promoted single electron transfer. Moreover, we developeda photoinduced method for the radical alkylation of N-aryl glycinate & alpha;-C(sp(3))-H bonds using unactivatedalkyl chlorides (iodides) under photocatalyst-free conditions. Notably,by building on racemic alkylations of glycine derivatives and glycine-residue-containingpeptides, we recently stereoselectively alkylated the N-aryl glycinate & alpha;-C(sp(3))-H bond using a dual-functionalCu catalyst generated in situ for synthesizing aseries of unnatural chiral & alpha;-amino and C-glycoaminoacids. We have developed a series of methods for synthesizingunnaturalamino acids through the & alpha;-C(sp(3))-H alkylationof glycine derivatives using photoredox-promoted radical couplingas a key strategy. These methods are efficient and versatile and canbe used for the late-stage modification of peptides in various contexts.Our work builds on the fundamental importance of glycine as the basicscaffold of all & alpha;-amino acids and highlights the potential ofradical-based chemistry for developing chemical transformations inpeptide synthesis. These findings have broad implications for chemicalbiology and may open doors for discovering peptide drugs and developingtherapeutics.

Automated summary

Peptides play essential roles in biological processes and are attractive targets for therapeutic development. Incorporating unnatural amino acid residues into peptides can greatly impact their properties. Recent advancements in photoinduced radical reactions have enabled the construction of C(sp(3))-C(sp(3)) bonds under mild conditions. This study focuses on the α-C(sp(3))-H alkylation of glycine derivatives using radical-radical coupling reactions.