The late-stage modification of structurally complex peptides bears great potential for drug discovery, crop protection, and the pharmaceutical industry, among others. Whereas traditional approaches largely rely on prefunctionalizations, C-H activation catalysis has in recent years emerged as an increasingly powerful tool for post-translational peptide modifications in a step-economic manner. Herein, we summarize recent progress in organometallic C-H activation on peptides until June 2018, including position- and chemoselective palladium-, ruthenium-, and manganese-catalyzed processes.

A mild, general, and highly efficient catalytic etherification protocol for chloroheteroarenes was developed using the Pd/PTABS catalytic system. The protocol is selective for the etherification of chloroheteroarenes using a large variety of electron-rich and electron-deficient phenol bearing synthons which include inter alia biologically and commercially important estrone, estradiol, tyrosine, and several other molecules. The mildness of the new protocol is expected to be beneficial for the synthesis of complex drugs and drug intermediates offering late-stage modification of bioactive compounds.

Synthesis of α,β-unsaturated-γ-lactams continue to attract attention due to the importance of this structural motif in organic chemistry. Herein, we report the development of a visiblelight-induced excited-state copper-catalyzed [4 + 1] annulation reaction for the preparation of a wide range of γ-H, −OH, and −OR-substituted α,β-unsaturated-γ-lactams using acrylamides as the 4-atom unit and aroyl chlorides as the 1-atom unit. This modular synthetic protocol features mild reaction conditions, broad substrate scope, and high functional group tolerance. The reaction is amenable to late-stage diversification of complex molecular architectures, including derivatives of marketed drugs. The products of the reaction can serve as versatile building blocks for further derivatization. Preliminary mechanistic studies suggest an inner-sphere catalytic cycle involving photoexcitation of the Cu(BINAP) catalyst, single-electron transfer, and capture of radical intermediates by copper species, followed by reductive elimination or protonation to give the desired γ-functionalized α,βunsaturated-γ-lactams.

A highly efficient and mild protocol for the aminocarbonylation of a nucleoside is developed by employing palladium/(1,3,5-triaza-7-phosphaadamantan-1-ium-1-yl)butane-1-sulfonate (Pd/PTABS) as the catalytic system. The developed aminocarbonylation methodology employs CO gas at a relatively low temperature of 60 °C and is suitable for a wide range of amines, including (heteroaryl)benzylic, aliphatic acyclic, alicyclic and secondary amines. This protocol is also utilized for the synthesis of a sangivamycin precursor by carrying out the Pd-catalyzed amination and aminocarbonylation simultaneously. The utility of this protocol is further demonstrated by the synthesis of the drugs moclobemide and nikethamide.