Intramolecular Hydrogen Bonding Enables a Zwitterionic Mechanism for Macrocyclic Peptide Formation: Computational Mechanistic Studies of CyClick Chemistry
Abstract: Macrocyclic peptides have become increasingly important in the pharmaceutical industry. We present a detailed computational investigation of the reaction mechanism of the recently developed “CyClick” chemistry to selectively form imidazolidinone cyclic peptides from linear peptide aldehydes, without using catalysts or directing groups (Angew. Chem. Int. Ed. 2019, 58, 19073–19080). We conducted computational mechanistic to investigate the effects of intramolecular hydrogen bonds (IMHBs) in promoting a kinetically facile zwitterionic mechanism in “CyClick” of pentapeptide aldehyde AFGPA. Our DFT calculations highlighted the importance of IMHB in pre‐organization of the resting state, stabilization of the zwitterion intermediate, and the control of the product stereoselectivity. Furthermore, we have also identified that the low ring strain energy promotes the “CyClick” of hexapeptide aldehyde AAGPFA to form a thermodynamically more stable 15+5 imidazolidinone cyclic peptide product. In contrast, large ring strain energy suppresses “CyClick” reactivity of tetra peptide aldehyde AFPA from forming the 9+5 imidazolidinone cyclic peptide product.
- Location
-
Deutsche Nationalbibliothek Frankfurt am Main
- Extent
-
Online-Ressource
- Language
-
Englisch
- Bibliographic citation
-
Intramolecular Hydrogen Bonding Enables a Zwitterionic Mechanism for Macrocyclic Peptide Formation: Computational Mechanistic Studies of CyClick Chemistry ; day:17 ; month:08 ; year:2023 ; extent:8
Angewandte Chemie / International edition. International edition ; (17.08.2023) (gesamt 8)
- Creator
- DOI
-
10.1002/anie.202307210
- URN
-
urn:nbn:de:101:1-2023081815182360546915
- Rights
-
Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
- Last update
-
14.08.2025, 10:51 AM CEST
Data provider
Deutsche Nationalbibliothek. If you have any questions about the object, please contact the data provider.
Associated
- Shao, Huiling
- Adebomi, Victor
- Bruce, Angele
- Raj, Monika
- Houk, Kendall N.
Other Objects (12)
Intramolecular Hydrogen Bonding Enables a Zwitterionic Mechanism for Macrocyclic Peptide Formation: Computational Mechanistic Studies of CyClick Chemistry
Intramolecular bridges formed by photoswitchable click amino acids
Stereoselective Macrocyclization of Peptides in CyClick Chemistry
Disaccharide-Containing Macrocycles by Click Chemistry and Intramolecular Glycosylation
Intramolecular Glycosidation by Click Reaction Mediated Spacer Generation and Following Spacer Cleavage
Intramolecular chalcogen bonding activated SuFEx click chemistry for efficient organic-inorganic linking
Synthesis of Macrocyclic Amides Using Manganese (III)- Based Intramolecular Cyclization of N-(ω-Alkenyl)-3- oxobutanamides
Klack klack : = Click click
Complete σ* intramolecular aromatic hydroxylation mechanism through O2 activation by a Schiff base macrocyclic dicopper(I) complex
Macrocyclic Alkenylruthenium Complexes
CY
Cy
Intramolecular Hydrogen Bonding Enables a Zwitterionic Mechanism for Macrocyclic Peptide Formation: Computational Mechanistic Studies of CyClick Chemistry
Intramolecular bridges formed by photoswitchable click amino acids
Stereoselective Macrocyclization of Peptides in CyClick Chemistry
Disaccharide-Containing Macrocycles by Click Chemistry and Intramolecular Glycosylation
Intramolecular Glycosidation by Click Reaction Mediated Spacer Generation and Following Spacer Cleavage
Intramolecular chalcogen bonding activated SuFEx click chemistry for efficient organic-inorganic linking
Synthesis of Macrocyclic Amides Using Manganese (III)- Based Intramolecular Cyclization of N-(ω-Alkenyl)-3- oxobutanamides
Klack klack : = Click click
Complete σ* intramolecular aromatic hydroxylation mechanism through O2 activation by a Schiff base macrocyclic dicopper(I) complex
Macrocyclic Alkenylruthenium Complexes
CY
Cy
Intramolecular Hydrogen Bonding Enables a Zwitterionic Mechanism for Macrocyclic Peptide Formation: Computational Mechanistic Studies of CyClick Chemistry
Intramolecular bridges formed by photoswitchable click amino acids
Stereoselective Macrocyclization of Peptides in CyClick Chemistry
Disaccharide-Containing Macrocycles by Click Chemistry and Intramolecular Glycosylation
Intramolecular Glycosidation by Click Reaction Mediated Spacer Generation and Following Spacer Cleavage
Intramolecular chalcogen bonding activated SuFEx click chemistry for efficient organic-inorganic linking
Synthesis of Macrocyclic Amides Using Manganese (III)- Based Intramolecular Cyclization of N-(ω-Alkenyl)-3- oxobutanamides
Klack klack : = Click click
Complete σ* intramolecular aromatic hydroxylation mechanism through O2 activation by a Schiff base macrocyclic dicopper(I) complex
Macrocyclic Alkenylruthenium Complexes
CY