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

Yuxuan Ding; Simon Steffen Pedersen; Haofan Wang; Baorui Xiang; Yixian Wang; Zhi Yang; Yuxiang Gao; Emilia Morosan; Matthew R. Jones; Han Xiao; Zachary Ball

doi:10.1002/anie.202405344

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

Yuxuan Ding, Simon Steffen Pedersen, Haofan Wang, Baorui Xiang, Yixian Wang, Zhi Yang, Yuxiang Gao, Emilia Morosan, Matthew R. Jones, Han Xiao, Zachary Ball^*

^*Corresponding author for this work

Interdisciplinary Nanoscience Center - INANO-Kemi, iNANO-huset

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

1 Citation (Scopus)

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.

Original language	English
Article number	e202405344
Journal	Angewandte Chemie International Edition
Volume	63
Issue	30
Number of pages	8
ISSN	1433-7851
DOIs	https://doi.org/10.1002/anie.202405344
Publication status	Published - 22 Jul 2024

Keywords

ex situ gaseous reagent
lysine-lysine crosslinking
lysine-tyrosine crosslinking
multicomponent reactions
peptide macrocyclization

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title = "Selective Macrocyclization of Unprotected Peptides with an Ex Situ Gaseous Linchpin Reagent",

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 = "ex situ gaseous reagent, lysine-lysine crosslinking, lysine-tyrosine crosslinking, multicomponent reactions, peptide macrocyclization",

author = "Yuxuan Ding and Pedersen, {Simon Steffen} and Haofan Wang and Baorui Xiang and Yixian Wang and Zhi Yang and Yuxiang Gao and Emilia Morosan and Jones, {Matthew R.} and Han Xiao and Zachary Ball",

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month = jul,

day = "22",

doi = "10.1002/anie.202405344",

language = "English",

volume = "63",

journal = "Angewandte Chemie International Edition",

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Selective Macrocyclization of Unprotected Peptides with an Ex Situ Gaseous Linchpin Reagent. / Ding, Yuxuan; Pedersen, Simon Steffen; Wang, Haofan et al.
In: Angewandte Chemie International Edition, Vol. 63, No. 30, e202405344, 22.07.2024.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Selective Macrocyclization of Unprotected Peptides with an Ex Situ Gaseous Linchpin Reagent

AU - Ding, Yuxuan

AU - Pedersen, Simon Steffen

AU - Wang, Haofan

AU - Xiang, Baorui

AU - Wang, Yixian

AU - Yang, Zhi

AU - Gao, Yuxiang

AU - Morosan, Emilia

AU - Jones, Matthew R.

AU - Xiao, Han

AU - Ball, Zachary

PY - 2024/7/22

Y1 - 2024/7/22

N2 - 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.

AB - 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.

KW - ex situ gaseous reagent

KW - lysine-lysine crosslinking

KW - lysine-tyrosine crosslinking

KW - multicomponent reactions

KW - peptide macrocyclization

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U2 - 10.1002/anie.202405344

DO - 10.1002/anie.202405344

M3 - Journal article

C2 - 38753429

SN - 1433-7851

VL - 63

JO - Angewandte Chemie International Edition

JF - Angewandte Chemie International Edition

IS - 30

M1 - e202405344

ER -

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

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Keywords

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