CyClick Chemistry for the Synthesis of Cyclic Peptides. Issue 52 (7th November 2019)

• Record Type: Journal Article
• Authors: Adebomi, Victor; Cohen, Ryan D.; Wills, Rachel; Chavers, Holland Andrew Hays; Martin, Gary E.; Raj, Monika
• Is Part Of: Angewandte Chemie international edition. Volume 58:Issue 52(2019)
• Page Start: 19073
• Page End: 19080
• Publication Date: 2019-11-07
• Subjects: chemoselectivity -- CyClick chemistry -- peptides -- macrocycles -- stereoselectivity; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201911900
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: Here, we report a novel "CyClick" strategy for the macrocyclization of peptides that works in an exclusively intramolecular fashion thereby precluding the formation of dimers and oligomers via intermolecular reactions. The CyClick chemistry is highly chemoselective for the N‐terminus of the peptide with a C‐terminal aldehyde. In this protocol, the peptide conformation internally directs activation of the backbone amide bond and thereby facilitates formation of a stable 4‐imidazolidinone‐fused cyclic peptide with high diastereoselectivity (>99 %). This method is tolerant to a variety of peptide aldehydes and has been applied for the synthesis of 12‐ to 23‐membered rings with varying amino acid compositions in one pot under mild reaction conditions. The reaction generated peptide macrocycles featuring a 4‐imidazolidinone in their scaffolds, which acts as an endocyclic control element that promotes intramolecular hydrogen bonding and leads to macrocycles with conformationally rigid turn structures. Abstract : Exclusively intramolecular : The conformationally induced activation of the amide bond, the idea behind the "CyClick" strategy, is exploited for the macrocyclization of peptides and precludes the formation of dimers or oligomers via intermolecular reactions. This method is tolerant to a variety of peptide aldehydes and has been applied for the synthesis of 12‐ to 23‐membered rings.