Atroposelective Total Synthesis of Darobactin A
You-Chen Lin, Fabian Schneider, Kelly J. Eberle, Debora Chiodi, Hugh Nakamura, Solomon H. Reisberg, Jason Chen, Masato Saito, Phil S. Baran
Abstract
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-based macrocyclizations, 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 an enantiopure form using C-H activation and decarboxylative cross-coupling tactics.