Total Synthesis of Complex Nucleoside Antibiotics Ezomycin A1 and A2

Abstract The complex nucleoside antibiotics ezomycin A1 and A2 have stood as formidable synthetic challenges for half a century due to their density of polar functional groups and unique trans-fused bicyclic framework. Here, we disclose their long-awaited first total synthesis. This convergent and modular strategy is enabled by a stereoselective nickel-catalyzed reductive cross-coupling, a de novo asymmetric carbohydrate synthesis, and a mild (p-Tol)2SO/Tf2O-promoted N-glycosylation. This work not only establishes a unified synthetic route to the ezomycin family but also provides robust methodologies for the precise assembly of sterically demanding, highly functionalized nucleoside natural products.