Convergent Solution-Phase Synthesis of a Cyclic Azapeptide CD36 Modulator

Cyclic azapeptide cluster of differentiation-36 receptor (CD36) modulator 298 has exhibited biomedical potential for treating diseases implicating macrophage-driven inflammation.^1,2 Previously, azapeptide 298 was prepared in mg amounts using a linear solid-phase peptide synthesis approach featuring an A³-macrocyclization on resin prior to cleavage and deprotection.^3,4 Towards scale-up, a solution-phase synthesis of azapeptide 298 has now been achieved using a fragment coupling strategy. Employing phosgene-free semicarbazide synthesis, orthogonal protection, and A³ macrocyclization in solution, the convergent approach minimizes chromatographic purification to effectively afford the cyclic azapeptide. Our presentation discloses the features of this promising means for delivering the potent CD36 modulator for preclinical investigations