Copper-Catalyzed Asymmetric C(sp)-H Benzylation: Stereoselective Synthesis of Unnatural Aromatic Amino Acids.

The general synthesis of chiral unnatural aromatic amino acids has rarely been reported. We herein describe a visible light-promoted copper-catalyzed enantioselective C(sp)-H benzylation of glycine derivatives. The method demonstrated compatibility in coupling various -hydroxyphthalimide (NHP) esters derived from aromatic acids with glycine derivatives, providing a general protocol for synthesizing analogues of phenylalanine, tryptophan, and tyrosine.

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

ConspectusPeptides 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.

Copper-catalyzed asymmetric C(sp)-H cyanoalkylation of glycine derivatives and peptides.

Alkylnitriles play important roles in many fields because of their unique electronic properties and structural characteristics. Incorporating cyanoalkyl with characteristic spectroscopy and reactivity properties into amino acids and peptides is of special interest for potential imaging and therapeutic purposes. Here, we report a copper-catalyzed asymmetric cyanoalkylation of C(sp)-H.

Glycosyl Radical-Based Synthesis of C-Glycoamino Acids and C-Glycopeptides.

Radical-based reactions usually exhibit excellent functional-group compatibilities due to their mild initiation conditions. Glycosyl radical involved C-glycosylation modifications are important strategies to achieve highly regio- and chemoselective constructions of C-glycosidic bonds or C-glycoside linkages of peptides and proteins. In this Concept, we cover recent developments in glycosyl radical-based synthesis of unnatural amino acids and late-stage modification of peptides and proteins, and provide a preliminary outlook on the possible development of this direction in the future.

Visible-Light-Promoted Stereoselective C(sp )-H Glycosylation for the Synthesis of C-Glycoamino Acids and C-Glycopeptides.

The glycosylative modification of peptides could improve the pharmacological properties of peptide drugs and deliver them efficiently to the target sites. Compared with O-/N-glycosides, C-glycosides exhibit more metabolic stability. We here disclose the first example of visible-light-promoted and Cu-catalyzed stereoselective C-glycosylation.

Visible-Light-Promoted C(sp )-H Alkylation by Intermolecular Charge Transfer: Preparation of Unnatural α-Amino Acids and Late-Stage Modification of Peptides.

Disclosed herein is the visible-light-promoted deaminative C(sp )-H alkylation of glycine and peptides using Katritzky salts as electrophiles. Simple reaction conditions and excellent functional-group tolerance provide a general strategy for the efficient preparation of unnatural α-amino acids and precise modification of peptides with unnatural α-amino-acid residues. Mechanistic studies suggest that visible-light-promoted intermolecular charge transfer within a glycine-Katritzky salt electron donor-acceptor (EDA) complex induces a single-electron transfer process without the assistance of photocatalyst.

Cu-Catalyzed cyanoalkylation of electron-deficient alkenes with unactivated alkyl bromides.

We here report the photoinduced Cu-catalyzed cyanoalkylation of electron-deficient alkenes by using alkyl bromides as alkylation reagents. In the reactions, 1°, 2°, and 3° unactivated alkyl bromides with various sensitive functional groups were well tolerated with good yields. Notably, terminal and internal alkenes, as well as alkene-containing peptides, were all tolerated well.

Visible-Light-Driven, Copper-Catalyzed Decarboxylative C(sp )-H Alkylation of Glycine and Peptides.

Despite a well-developed and growing body of work in Cu catalysis, the potential of Cu to serve as a photocatalyst remains underexplored. Reported herein is the first example of visible-light-induced Cu-catalyzed decarboxylative C(sp )-H alkylation of glycine for preparing α-alkylated unnatural α-amino acids. It merits mentioning that the mild conditions and the good functional-group tolerance allow the modification of peptides using this method.

Arylation of benzyl amines with aromatic nitriles.

In the past years, the activations of aromatic nitriles for radical arylations under photoirradiation have been developed. We here report the first example of radical arylations using aromatic nitriles without the assistance of photoirradiation. Importantly, with this method, the direct arylation of C(sp)-H in benzyl amines provided a practical method for the synthesis of diarylmethylamines without the use of precious transition metal catalysts.