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. 2021 Feb 26;7(9):eabe6202.
doi: 10.1126/sciadv.abe6202. Print 2021 Feb.

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

Nikolaos Kaplaneris  1 , Felix Kaltenhӓuser  1 , Giedre Sirvinskaite  1 , Shuang Fan  2 , Tiago De Oliveira  2 , Lena-Christin Conradi  2 , Lutz Ackermann  3   4   5
Affiliations

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

Nikolaos Kaplaneris et al. Sci Adv. .

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.

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Figures

Fig. 1
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
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
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
Fig. 4. Synthetic applications of the C─H hydroarylation.
(A) Gram-scale synthesis. (B) Late-stage manipulation on the hydroarylated peptides.
Fig. 5
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
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.
See this image and copyright information in PMC

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