Cobalt-catalyzed selective α-alkylation and α-heteroarylation processes of α-amino esters and peptide derivatives are described. These cross-dehydrogenative reactions occur under mild conditions and allow for the rapid assembly of structurally diverse α-amino carbonyl compounds. Unlike enolate chemistry, these methods are distinguished by their site-specificity, occur without racemization of the existing chiral centers, and exhibit total selectivity for aryl glycine motifs over other amino acid units, hence providing ample opportunities for peptide modifications.

We report the first diastereo- and enantioselective formal Mannich reaction of 2-pyridyl acetates which gives rise to α- and β-functionalized 2-substituted pyridines. Key for success is the previous azaarene N-oxide formation enabling α-carbon deprotonation by a mild bifunctional Brønsted base and subsequent reaction with N-Boc imines under almost perfect stereocontrol.

An efficient ligand-free Fe-catalyzed oxidative Ugi-type reaction toward the assembly of α-amino amides and short peptides is described. The reaction proceeds through the α-C(sp)-H oxidation of N,N-dimethylanilines and further nucleophilic attack of the resulting iminium species by isocyanides. Additive screening showed that judicious choice of the carboxylic acid could lead to the formation of α-amino imides via a 3-component reaction. The process occurs with operational simplicity and is compatible with a variety of sensitive functional groups.

A novel Pd-catalyzed δ-C(sp2)–H functionalization reaction with readily available aldehydes towards the assembly of non-proteogenic acylated Phe-containing oligopeptides is presented.

A novel Pd-catalyzed C–H acylation reaction with readily available aldehydes under an aqueous environment towards the assembly of non-protegenic acylated Tyr-containing oligopeptides is presented.

The Cu I -catalyzed selective a-alkylation of a-aminoa cid and peptided erivatives with 2-alkyl-1,3-dioxolanes is reported.T his oxidative coupling is distinguished by its site-specificity, high diastereoselectivity,a nd chirality preservation and exhibits absolute chemoselectivity for N-aryl glycine motifs over other amino acid units.C ollectively,t he methoda llows for the assembly of challenging quaternary centers, as well as compounds derived from natural products of high structuralc omplexity,w hich may provide ample opportunities for late-stage functionalization of peptides.Scheme1.CDCs with ethers and a-amino acid derivatives.[a] M.

The functionalization of typically unreactive C(sp3)–H bonds holds great promise for reducing the reliance on existing functional groups while improving atom-economy and energy efficiency. As a result, this topic is a matter of genuine concern for scientists in order to achieve greener chemical processes. The site-specific modification of α-amino acid and peptides based upon C(sp3)–H functionalization still represents a great challenge of utmost synthetic importance. This short review summarizes the most recent advances in ‘Cross-Dehydrogenative Couplings’ of α-amino carbonyl compounds and peptide derivatives with a variety of nucleophilic coupling partners.1 Introduction2 C–C Bond-Forming Oxidative Couplings2.1 Reaction with Alkynes2.2 Reaction with Alkenes2.3 Reaction with (Hetero)arenes2.4 Reaction with Alkyl Reagents3 C–Heteroatom Bond-Forming Oxidative Couplings3.1 C–P Bond Formation3.2 C–N Bond Formation3.3 C–O and C–S Bond Formation4 Conclusions

A radical α−C−H alkylation of a collection of N‐picolinamide amino acid derivatives with ethers and cycloalkanes as chemical feedstock is described. This cross‐dehydrogenative coupling is distinguished by its reliable scalability and removable auxiliary group, and enables the assembly of a variety of tri‐ and tetrasubstituted amino acid compounds.