1 Département de Chimie, Université de Montréal, Complexe des Sciences, Montreal, Quebec H2V 0B3, Canada.
2 Faculté de Pharmacie, Université de Montréal, Montreal, Quebec H3C 3J7, Canada.
3 Department of Chemistry and Biochemistry, Department of Chemical and Materials Engineering, Concordia University, Montréal, Quebec H4B 1R6, Canada.
4 Department of Pharmacology, Université de Montréal, Montreal, Quebec H3T 1J4, Canada.
5 Studio Bioscience Inc., Verdun, Quebec H3E 1L4, Canada.

Modern macrocyclic peptides feature unnatural elements that are used to improve the activity and pharmacokinetic properties. Chemistry beyond peptide synthesis must, however, be employed to introduce such elements. Notably, application of the copper-catalyzed aldehyde-alkyne-amine A³-reaction in solid-phase peptide synthesis (SPPS) enabled a diversity-oriented approach for macrocyclization and furnished the azapeptide cluster of differentiation-36 receptor (CD36) modulator 298 which exhibits potent anti-inflammatory and cardioprotective effects. Pursuing a scalable synthesis, inter- and intramolecular A³-reaction sequences were compared in convergent solution-phase approaches to the cyclic azapeptide. Peptide building blocks were synthesized by resonant acoustic mixing (RAM) at high concentrations in a green solvent. Linear azapeptide and aza-isopeptide precursors were assembled, the latter by intermolecular A³-chemistry, from orthogonally protected aza-tripeptide and tetrapeptide fragments, and, respectively, cyclized by intramolecular A³-reaction and lactam formation. The latter afforded a solventless, scalable solution-phase peptide synthesis strategy that gave access to the CD36 modulator in high purity on a 100 mg scale with minimal chromatography.