Photoredox Ni-catalyzed peptide C(sp2)-O cross-coupling: from intermolecular reactions to side chain-to-tail macrocyclization

Abstract

Ni/photoredox (4DPAIPN) dual catalysis enabled challenging peptide C(sp²)-O coupling reactions. Successful cross-coupling reactions were demonstrated with highly functionalized alcohols including side chains of amino acids (i.e., serine, threonine, tyrosine), trans-4-hydroxy-l-proline, alkyl alcohols, alkynylated alcohols, and carbohydrates. Coupling reactions between bromobenzoyl-capped peptides containing various side chains and either a protected serine building block or a serine-containing dipeptide also proceeded efficiently. Chemoselective C-O coupling (over C-N) was achieved in intermolecular reactions in the presence of a C-terminal primary amide. Furthermore, by judicious structural design in combination with computational modeling, we demonstrated side chain-to-tail macrocyclization of peptides containing a β-turn motif via C-O coupling. The methodology developed in this work brings new opportunities for late-stage diversification of complex linear and macrocyclic peptides.

Fig. 1. A) Existing synthetic methods in peptide macrocyclization. (B) Examples of C–O bond containing macrocyclic natural products and peptide drugs. (C) Ni-catalyzed photoredox C–O coupling of peptides. PC, photocatalyst.

Fig. 2. Multi-parameter reaction conditions optimization by nanomole-scale high-throughput experimentation. (A) Model reaction for peptide C–O cross-coupling. (B) Heat map showing data from 240 nano-scale reactions analyzed by UPLC-MS.

Fig. 3. Macrocyclization of peptides with a β-hairpin motif (design 2) via Ni-catalyzed photoredox C–O coupling (modeling and experimental results). (A) Two proposed designs for macrocyclization. (B) Key ¹H–¹³C HMBC correlations confirming C (sp²)–O bond formation for 13a. (C) Examples of macrocyclic peptides. Isolated yields are reported after purification using preparative reverse-phase HPLC. General reaction conditions: 0.05 mmol scale, 1 equiv. K₂CO₃, 10 mol% 4DPAIPN, 5 mol% quinuclidine, 20 mol% NiBr₂·glyme, 20 mol% dtbbpy, 2 : 1 MeCN/DMSO (0.005 M), RT, 24 h, 450 nm blue LEDs using MSD photoreactor.