There is a growing interest in constructing multicyclic peptide structures to expand the chemical space of peptides. Conventional strategies for constructing large peptide structures are limited by the typical reliance on the inflexible coupling between premade templates equipped with fixed reactive handles and peptide substrates via cysteine anchors. Herein, we report the development of a facile three-component condensation reaction of primary alkyl amine, formaldehyde, and guanidine for construction of complex macromulticyclic peptides with novel topologies via lysine anchors. Moreover, the reaction sequences can be orchestrated in different anchor combinations and spatial arrangements to generate various macrocyclic structures crosslinked by distinct fused tetrahydrotriazine linkages. The macrocyclization reactions are selective, efficient, versatile, and workable in both organic and aqueous media. Thus, the condensation reaction provides a smart tool for stitching native peptides in situ using simple methylene threads and guanidine joints in a flexible and programmable manner.

A silver-catalyzed intramolecular denitrogenative annulation of pyridotriazole with alkene was reported to achieve the challenging carbene insertion into the vinylic C­(sp2)–H bond. This protocol has enabled the construction of functionalized 1H-indenes with high efficiency and excellent functional group tolerance. Experimental and computational studies suggest a stepwise mechanism involving a water-promoted hydrogen atom transfer with the aid of a silver catalyst.

Metal-catalyzed C–H glycosylation reactions with glycosyl chloride donors have emerged as a useful strategy for the synthesis of C-glycosides. Previously, palladium and nickel complexes were reported to catalyze C–H glycosylation reactions using amide-linked bidentate auxiliaries. Herein, a ruthenium-catalyzed ortho C–H glycosylation reaction of arenes with various glycosyl chloride donors using a monodentate pyridine directing group is developed. Preliminary mechanistic studies indicated that two-electron oxidative addition and reductive elimination of ruthenocycle intermediate led to the glycosylation products.

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