Article, 2024

Selective Macrocyclization of Unprotected Peptides with an Ex Situ Gaseous Linchpin Reagent

Angewandte Chemie, ISSN 1521-3757, 0044-8249, Volume 136, 30, 10.1002/ange.202405344

Contributors

Ding, Yuxuan 0000-0002-4201-2689 [1] Pedersen, Simon S [1] [2] Wang, Haofan [1] Xiang, Baorui [1] Wang, Yixian 0009-0004-3093-6835 [1] Yang, Zhi [1] Gao, Yuxiang [1] Morosan, Emilia 0000-0002-6076-9204 [1] Jones, Matthew R [1] Xiao, Han- 0000-0002-4311-971X [1] Ball, Zachary Thomas 0000-0002-8681-0789 (Corresponding author) [1]

Affiliations

  1. [1] Rice University
    2. [NORA names: United States; America, North; OECD];
  2. [2] Aarhus University
    3. [NORA names: AU Aarhus University; University; Denmark; Europe, EU; Nordic; OECD]

Abstract

Abstract Peptide cyclization has dramatic effects on a variety of important properties, enhancing metabolic stability, limiting conformational flexibility, and altering cellular entry and intracellular localization. The hydrophilic, polyfunctional nature of peptides creates chemoselectivity challenges in macrocyclization, especially for natural sequences without biorthogonal handles. Herein, we describe a gaseous sulfonyl chloride derived reagent that achieves amine–amine, amine–phenol, and amine–aniline crosslinking through a minimalist linchpin strategy that affords macrocyclic urea or carbamate products. The cyclization reaction is metal‐mediated and involves a novel application of sulfine species that remains unexplored in aqueous or biological contexts. The aqueous method delivers unique cyclic or bicyclic topologies directly from a variety of natural bioactive peptides without the need for protecting‐group strategies.

Keywords

Abstract, amine-phenol, applications, aqueous method, bioactive peptides, biological context, biorthogonal handle, carbamate, carbamate product, cellular entry, challenges, chemoselectivity, chloride, conformational flexibility, context, crosslinking, cyclization, cyclization reaction, enhanced metabolic stability, entry, flexibility, handling, intracellular localization, localization, macrocycle, macrocyclic ureas, metabolic stability, metal-mediated, method, natural bioactive peptides, natural sequence, nature of peptides, peptide, peptide cyclization, polyfunctional nature, production, properties, protecting-group strategy, reaction, reagents, sequence, species, stability, strategies, sulfonyl chlorides, topology, unprotected peptides, urea

Funders

  • Welch Foundation
  • NordForsk
  • Danish National Research Foundation
  • Innovation Fund Denmark
  • National Institute of General Medical Sciences
  • Directorate for Mathematical & Physical Sciences

Data Provider: Digital Science

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