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

Abstract

Metrics & MoreArticle Recommendations 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 Naryl 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. T...

Organo-Photoredox Catalyzed gem-Difluoroallylation of Glycine and Glycine Residue in Peptides

“…Notwithstanding these advantages, the direct C­(sp 3 )–H functionalization of glycine or glycine residue in a peptide for the synthesis of unnatural amino acids and site-specific late-stage modification of peptides is still in its infancy . In the past decade, radical-mediated reactions have emerged as mild and efficient approaches to forge unnatural amino acids and peptides via direct C­(sp 3 )–H functionalization of glycine derivatives . These reactions involve either imine ion Int-A via dehydrogenative oxidation or α-carbon radical intermediate Int-B via single-electron oxidation of glycine derivatives followed by deprotonation and 1,2-hydrogen shift (Scheme a).…”

Visible-Light-Driven α-C(sp3)–H Bond Functionalization of Glycine Derivatives

“…Various arylated unnatural amino acids and peptides could be synthesized successfully in a green and sustainable manner via this reaction. In contrast with the redox-neutral alkylation mentioned above, the arylation always proceeded via aerobic visible-light-driven oxidation and nucleophilic addition [87][88][89][90][91][92]. In 2012, Rueping et al reported the first application of visible-light photo redox catalysis in the α-C(sp 3 )-H arylation of glycine derivatives and peptides with indoles as the aryl source.…”

Visible Light-Driven Flexible Synthesis of α-Alkylated Glycine Derivatives Catalyzed by Reusable Covalent Organic Frameworks

“…Glycine is the most elementary α-amino acid. Its direct derivatization and modification hold significant relevance in synthesizing unnatural amino acid-containing bioactive peptides and pharmaceuticals. , Past decades have witnessed a booming interest in functionalizing glycine derivatives. − Among them, visible light-driven α-C­(sp 3 )–H bond alkylation of glycine derivatives is outstanding as it could deliver diverse alkylated glycine derivatives precisely and efficiently in a green and sustainable manner. − Regarding the photocatalysts involved in initiating the reaction, reported visible light-driven approaches toward this objective can be categorized into the following three types (Scheme a): (1) the external photocatalyst (PC) needed visible light-driven C­(sp 3 )–H bond alkylation, in which transition-metal complexes, organic dyes, or quantum dots acted as photocatalysts to absorb visible light and initiate the reaction. − (2) photocatalyst-free visible light-driven C­(sp 3 )–H bond alkylation, in which electron donor–acceptor (EDA) complexes always formed and served as internal photocatalysts. − (3) visible light-driven C­(sp 3 )–H bond asymmetric alkylation, in which transition-metal asymmetric catalysis and photocatalysis merged to fulfill the synthesis of C­(sp 3 )-alkylated glycine derivatives stereo selectively. − The protocols above have demonstrated significant advancements concerning reaction efficiency, selectivity, and the range of applicable substrates. Nevertheless, substantial room exists for further enhancement in various facets of environmentally benign characteristics, including but not limited to catalyst reusability, reaction flexibility, and simplification of postreaction workup procedures.…”