Electrochemical Synthesis of Peptide Aldehydes Via C‒N Bond Cleavage of Cyclic Amines

Overview

Journal Nat Commun

Specialty Biology

Date 2024 Jun 18

PMID 38890290

Authors

Xinyue Fang

Yong Zeng

Yawen Huang

Zile Zhu

Shengsheng Lin

Wenyan Xu

Chengwei Zheng

Xinwei Hu

Youai Qiu

Zhixiong Ruan

Affiliations

Soon will be listed here.

Abstract

Peptide aldehydes are crucial biomolecules essential to various biological systems, driving a continuous demand for efficient synthesis methods. Herein, we develop a metal-free, facile, and biocompatible strategy for direct electrochemical synthesis of unnatural peptide aldehydes. This electro-oxidative approach enabled a step- and atom-economical ring-opening via C‒N bond cleavage, allowing for homoproline-specific peptide diversification and expansion of substrate scope to include amides, esters, and cyclic amines of various sizes. The remarkable efficacy of the electro-synthetic protocol set the stage for the efficient modification and assembly of linear and macrocyclic peptides using a concise synthetic sequence with racemization-free conditions. Moreover, the combination of experiments and density functional theory (DFT) calculations indicates that different N-acyl groups play a decisive role in the reaction activity.

References

Gao P, Weng X, Wang Z, Zheng C, Sun B, Chen Z . Cu /TEMPO-Catalyzed Enantioselective C(sp )-H Alkynylation of Tertiary Cyclic Amines through Shono-Type Oxidation. Angew Chem Int Ed Engl. 2020; 59(35):15254-15259. DOI: 10.1002/anie.202005099. View

Kim Y, Heo J, Kim D, Chang S, Seo S . Ring-opening functionalizations of unstrained cyclic amines enabled by difluorocarbene transfer. Nat Commun. 2020; 11(1):4761. PMC: 7506026. DOI: 10.1038/s41467-020-18557-8. View

Osberger T, Rogness D, Kohrt J, Stepan A, White M . Oxidative diversification of amino acids and peptides by small-molecule iron catalysis. Nature. 2016; 537(7619):214-219. PMC: 5161617. DOI: 10.1038/nature18941. View

Weng Y, Xu X, Chen H, Zhang Y, Zhuo X . Tandem Electrochemical Oxidative Azidation/Heterocyclization of Tryptophan-Containing Peptides under Buffer Conditions. Angew Chem Int Ed Engl. 2022; 61(41):e202206308. DOI: 10.1002/anie.202206308. View

Long H, Huang C, Zheng Y, Li Z, Jie L, Song J . Electrochemical C-H phosphorylation of arenes in continuous flow suitable for late-stage functionalization. Nat Commun. 2021; 12(1):6629. PMC: 8616953. DOI: 10.1038/s41467-021-26960-y. View

Soro D, Roque J, Rackl J, Park B, Payer S, Shi Y . Photo- and Metal-Mediated Deconstructive Approaches to Cyclic Aliphatic Amine Diversification. J Am Chem Soc. 2023; 145(20):11245-11257. PMC: 10214453. DOI: 10.1021/jacs.3c01318. View

Taylor R, MacCoss M, Lawson A . Rings in drugs. J Med Chem. 2014; 57(14):5845-59. DOI: 10.1021/jm4017625. View

Depienne S, Alvarez-Dorta D, Croyal M, Temgoua R, Charlier C, Deniaud D . Luminol anchors improve the electrochemical-tyrosine-click labelling of proteins. Chem Sci. 2022; 12(46):15374-15381. PMC: 8635215. DOI: 10.1039/d1sc04809k. View

Jiao K, Xing Y, Yang Q, Qiu H, Mei T . Site-Selective C-H Functionalization via Synergistic Use of Electrochemistry and Transition Metal Catalysis. Acc Chem Res. 2020; 53(2):300-310. DOI: 10.1021/acs.accounts.9b00603. View

10.

Tay N, Lehnherr D, Rovis T . Photons or Electrons? A Critical Comparison of Electrochemistry and Photoredox Catalysis for Organic Synthesis. Chem Rev. 2021; 122(2):2487-2649. PMC: 10021920. DOI: 10.1021/acs.chemrev.1c00384. View

11.

Driggers E, Hale S, Lee J, Terrett N . The exploration of macrocycles for drug discovery--an underexploited structural class. Nat Rev Drug Discov. 2008; 7(7):608-24. DOI: 10.1038/nrd2590. View

12.

Rockl J, Pollok D, Franke R, Waldvogel S . A Decade of Electrochemical Dehydrogenative C,C-Coupling of Aryls. Acc Chem Res. 2019; 53(1):45-61. DOI: 10.1021/acs.accounts.9b00511. View

13.

Hou X, Kaplaneris N, Yuan B, Frey J, Ohyama T, Messinis A . Ruthenaelectro-catalyzed C-H acyloxylation for late-stage tyrosine and oligopeptide diversification. Chem Sci. 2022; 13(12):3461-3467. PMC: 8943857. DOI: 10.1039/d1sc07267f. View

14.

Aho A, Sulkanen M, Korhonen H, Virta P . Conjugation of Oligonucleotides to Peptide Aldehydes via a pH-Responsive -Methoxyoxazolidine Linker. Org Lett. 2020; 22(17):6714-6718. DOI: 10.1021/acs.orglett.0c01815. View

15.

Hayashi Y, Hirose T, Iwatsuki M, O Mura S, Sunazuka T . Synthesis of the Antimalarial Peptide Aldehyde, a Precursor of Kozupeptin A, Utilizing a Designed Hydrophobic Anchor Molecule. Org Lett. 2019; 21(20):8229-8233. DOI: 10.1021/acs.orglett.9b02966. View

16.

Zhu C, Ang N, Meyer T, Qiu Y, Ackermann L . Organic Electrochemistry: Molecular Syntheses with Potential. ACS Cent Sci. 2021; 7(3):415-431. PMC: 8006177. DOI: 10.1021/acscentsci.0c01532. View

17.

Yan M, Kawamata Y, Baran P . Synthetic Organic Electrochemical Methods Since 2000: On the Verge of a Renaissance. Chem Rev. 2017; 117(21):13230-13319. PMC: 5786875. DOI: 10.1021/acs.chemrev.7b00397. View

18.

Sato S, Matsumura M, Kadonosono T, Abe S, Ueno T, Ueda H . Site-Selective Protein Chemical Modification of Exposed Tyrosine Residues Using Tyrosine Click Reaction. Bioconjug Chem. 2020; 31(5):1417-1424. DOI: 10.1021/acs.bioconjchem.0c00120. View

19.

Ackermann L . Metalla-electrocatalyzed C-H Activation by Earth-Abundant 3d Metals and Beyond. Acc Chem Res. 2019; 53(1):84-104. DOI: 10.1021/acs.accounts.9b00510. View

20.

Chen W, Ma L, Paul A, Seidel D . Direct α-C-H bond functionalization of unprotected cyclic amines. Nat Chem. 2018; 10(2):165-169. PMC: 5942596. DOI: 10.1038/nchem.2871. View