CyClick Chemistry for the Synthesis of Cyclic Peptides

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.

Secondary Amino Alcohols: Traceless Cleavable Linkers for Use in Affinity Capture and Release

“…This imine is spontaneously hydrolyzed, affording a primary amine on the C‐terminal fragment ( C ) and an aldehyde on the N‐terminal fragment ( D ). Aldehydes could represent a handle for further functionalization . However, aldehydes suppress MS signals, in particular hindering MS/MS sequencing.…”

Peptide Cyclization at High Concentration

“…To achieve this goal, a new CyClick methodology was developed that involves the reaction between peptide aldehydes and the N-terminal amine (Figure 1, E). 29 The aldehyde reacts with the N-terminus to form a reversible cyclic imine intermediate. This promotes conformational preorganization followed by trapping of the cyclic imine with the amidic nitrogen at the second position to generate a stable 4-imidazolidinone cyclic peptide (Figure 2).…”

“…This promotes conformational preorganization followed by trapping of the cyclic imine with the amidic nitrogen at the second position to generate a stable 4-imidazolidinone cyclic peptide (Figure 2). 29 The unique feature of this approach is that it works in an exclusively intramolecular fashion. This method was tested to prove its exclusive intramolecular nature with two different experiments.…”

“…was observed by using the CyClick method (right HPLC trace, Figure 3A). 29 However, the reductive amination approach at 25 mM concentration resulted in both linear and cyclic dimers as byproducts (left HPLC trace, Figure 3A).…”

Reinvestigation of a Critical Reductive Amination Step Leads to an Optimized Protocol for the Synthesis of N-2-Hydroxybenzylcysteine Peptide Crypto-Thioesters

“…Related reactions were recently exploited by Francis and Raj groups for protein immobilization on polymeric supports and for the synthesis of conformationally rigid macrocycles through chemo-and diastereoselective cyclization ("CyClick chemistry"), respectively. [43] Scheme 5: Mechanistic hypotheses for imidazolidinones 10a-d formation.…”