Late‐Stage Modification of Oligopeptides by Nickel‐Catalyzed Stereoselective Radical Addition to Dehydroalanine

Abstract

Radical addition to dehydroalanine (Dha) represents an appealing, modular strategy to access noncanonical peptide analogues for drug discovery. Prior studies on radical addition to the Dha residue of peptides and proteins have demonstrated outstanding functional group compatibility, but the lack of stereoselectivity has limited the synthetic utility of this approach. Herein, we address this challenge by employing chiral nickel catalysts to control the stereoselectivity of radical addition to Dha on oligopeptides. The conditions accommodate a variety of primary and secondary electrophiles to introduce polyethylene glycol, biotin, halo-tag, and hydrophobic and hydrophilic side chains to the peptide. The reaction features catalyst control to largely override substrate-based control of stereochemical outcome for modification of short peptides. We anticipate that the discovery of chiral nickel complexes that confer catalyst control will allow rapid, late-stage modification of peptides featuring nonnatural sidechains.

Kinetic Resolution of Epimeric Proteins enables Stereoselective Chemical Mutagenesis

“…License: CC BY-NC-ND 4.0 Chemical mutagenesis via Dha is particularly versatile due to the diversity and yields of the products generated. 8 However, with a few notable exceptions relying on stereoselective protein refolding, 25 or modification with chiral Ni-complexes at peptide level, 44 this method is restricted due to a loss of stereochemical integrity at the modification site. Here we provide an elegant solution to this problem, enabling us to generate stereoselectively modified proteins via a kinetic resolution step, catalysed by alkaline D-peptidase (AD-P).…”

Selective Hydrofunctionalization of Alkenyl Fluorides Enabled by Nickel-Catalyzed Hydrogen Atoms and Group Transfer: Reaction Development and Mechanistic Study

“…Motivated by this chemistry, we hypothesized that such a radical transfer process would provide a viable approach for the selective functionalization of alkenyl fluorides under mild conditions without the need for defluorination . As a continuation of our research interest in nickel-catalyzed radical asymmetric functionalization of alkenes, precisely, we speculated that nickel-catalyzed HAT , or group transfer of alkyl radicals to alkenyl fluorides would generate α-fluoro radical/Ni cage pair, which could engage in stereoselective protometalation or cross-couplings with organohalides in the presence of chiral nickel complexes . If successful, this innovative strategy would not only enable efficient and facile access to fluorinated sp 3 stereocenters from planar alkenyl fluorides, but it would also complement the previously well explored nickel-hydride-catalyzed asymmetric hydroalkylation of alkenes (which is predominantly limited to primary and secondary alkyl electrophiles), , with distinct selectivity and an expanded reservoir of alkyl halides.…”