Scheme 1. A3-Macrocyclization for azacyclopeptide synthesis

Macrocyclic peptides attract interest for drug development, because they can stabilize active conformers, and improve binding affinity, selectivity, stability and cell-membrane permeability. Diverse macrocyclic peptide chemistry is being explored to provide preclinical candidates with favourable properties. Developing synthetic methods to enhance macrocycle diversity with control over geometry, charge and functional groups to probe structure-activity relationships (SAR) and to improve biological activity, in 2017, we reported synthesis of azacyclopeptides by Cu-catalyzed Mannich addition on azaPra residues using the so-called 'A3-coupling' of aldehyde, alkyne and amine components (Scheme 1). Cyclization was notably favored likely due to the aza-residue promoting turn geometry and the copper catalyst bringing together the acetylene and amine prior to ring closure. Suited for creating diversity, this multicomponent process provides an acetylene that can serve to make related macrocycles, and a tertiary amine that may improve bioavailability and enhance receptor recognition.

Azapeptides &