Inter-vs Intramolecular Aldehyde-Alkyne-Amine A3 -Reaction in Solution-phase Peptide Synthesis of Potent Macrocyclic Azapeptide CD36-Modulator

Modern macrocyclic peptides feature unnatural elements that are used to improve activity and pharmacokinetic properties. Chemistry beyond peptide synthesis must however be employed to introduce such elements. Notably, application of the coppercatalyzed aldehyde-alkyne-amine A 3 -reaction in solid-phase peptide synthesis 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 cardio-protective effects. Pursuing a scalable synthesis, inter- and intramolecular A 3 -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 concentration in green solvent. Linear azapeptide and aza-isopeptide precursors were assembled, the latter by intermolecular A 3 -chemistry, from orthogonally protected aza-tripeptide and tetrapeptide fragments, and respectively cyclized by intramolecular A 3 -reaction and lactam formation. A solvent-less, scalable solution-phase peptide synthesis strategy was devised giving access the CD36 modulator in high purity on 100 mg scale without chromatography.