Atroposelective Total Synthesis of Darobactin A

A concise, modular synthesis of the novel antibiotic darobactin A is disclosed. The synthesis successfully forges the hallmark strained macrocyclic ring systems in a sequential fashion. Key transformations include two atroposelective Larock-macrocylizations, one of which proceeds with exquisite regioselectivity despite bearing an unprotected alkyne. The synthesis is designed with medicinal chemistry considerations in mind, appending key portions of the molecule at a late-stage. Requisite unnatural amino acid building blocks are easily prepared in enantiopure form using C–H activation and decarboxylative cross-coupling tactics.