Total Synthesis of Orberryamides A, D and Their Biological Evaluation as Macrophage Differentiation Inhibitors

We report the total synthesis of orberryamides <b>A</b> and <b>D</b> and their biological evaluation as macrophage differentiation inhibitors. Both compounds were synthesized from readily available natural amino acids through a series of reactions, including condensation coupling, hydrolysis, acidification, and hydrogenation. A macrocyclic intermediate was formed by selecting a long linear chain with minimal head-tail steric hindrance, followed by mild esterification and acidification to yield orberryamide <b>A</b>, which was achieved in 21 steps, while orberryamide <b>D</b> was done in 8 steps. Biological assays indicated that orberryamides <b>A</b> and <b>D</b> may regulate the M2 phenotype of macrophages by inhibiting the expression of arginase-1 in vitro.