Late-stage stitching enabled by manganese-catalyzed C─H activation: Peptide ligation and access to cyclopeptides

Abstract

Bioorthogonal late-stage diversification of structurally complex peptides bears enormous potential for drug discovery and molecular imaging. Despite major accomplishments, these strategies heavily rely on noble-metal catalysis. Herein, we report on a manganese(I)-catalyzed peptide C─H hydroarylation that enabled the stitching of peptidic and sugar fragments, under exceedingly mild and racemization-free conditions. This convergent approach represents an atom-economical alternative to traditional iterative peptide synthesis. The robustness of the manganese(I) catalysis regime is reflected by the full tolerance of a plethora of sensitive functional groups. Our strategy enabled an expedient access to challenging cyclic peptides by a modular late-stage macrocyclization of structurally complex peptides.

Fig. 1. Late-stage stitching and macrocyclization toward molecular complexity.

A versatile approach toward site-selective peptide modifications via a ligation and macrocyclization of complex precursors, catalyzed by Earth-abundant manganese.

Fig. 2. Small peptide assembly by manganese catalysis.

(A) Synthesis of dipeptides via a C─H peptidic coupling. (B) Disubstituted alkynes 2e and 2f as coupling partner. (C) Synthesis of tripeptides via a C─H peptidic coupling featuring various functional groups. (D) Ligation of brevianamide F and fellutanine A analogs.

Fig. 3. Synthesis of complex hydrid molecules via C─H hydroarylation.

(A) Synthesis of complex via a C─H coupling strategy. (B) C─H stitching of biomolecules toward hydrid architectures.

Fig. 4. Synthetic applications of the C─H hydroarylation.

(A) Gram-scale synthesis. (B) Late-stage manipulation on the hydroarylated peptides.

Fig. 5. Manganese-catalyzed macrocyclization and removal of the directing group.

(A) Access to cyclic peptides of various ring sizes using the native C terminus, N terminus, and the serine side chain. (B) Selective methylation/hydrogenation protocol for the traceless removal of the directing group. wt %, weight %.

Fig. 6. Anticancer activity of cyclic peptides 10j and 10h against HCT116 cells.

**P < 0.01 and ***P <0.001. ns, not significant. A.U., arbitrary units.