Formaldehyde-Mediated Hydride Liberation of Alkylamines for Intermolecular Reactions in Hexafluoroisopropanol.

The ability of alkylamines to spontaneously liberate hydride ions is typically restrained, except under specific intramolecular reaction settings. Herein, we demonstrate that this reactivity can be unlocked through simple treatment with formaldehyde in hexafluoroisopropanol (HFIP) solvent, thereby enabling various intermolecular hydride transfer reactions of alkylamines under mild conditions. Besides transformations of small molecules, these reactions enable unique late-stage modification of complex peptides. Mechanistic investigations uncover that the key to these intermolecular hydride transfer processes lies in the accommodating conformation of solvent-mediated macrocyclic transition states, where the aggregates of HFIP molecules act as dexterous proton shuttles. Importantly, negative hyperconjugation between the lone electron pair of nitrogen and the antibonding orbital of amine's α C-H bond plays a critical role in the C-H activation, promoting its hydride liberation.

Construction of Complex Macromulticyclic Peptides via Stitching with Formaldehyde and Guanidine.

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.