Bioinspired Total Synthesis of Curtachalasin B and Biosynthetically Related Cytochalasans

We report the first total syntheses of curtachalasin B and a series of biosynthetically related cytochalasans, including ketocytochalasin, xylariasins, brunnesins, zygosporins, arbuschalasins, cytochalasins, and curtachalasin Q, derived from the common precursor zygosporin G. The key intermediate was strategically assembled through an intermolecular Diels–Alder reaction, two Horner–Wadsworth–Emmons (HWE) macrocyclizations, and a late‐stage methyl 1,2‐addition. The highly functionalized 6/6 ring system of curtachalasin B was efficiently constructed through a biosynthetic network analysis inspired transannular cyclization and α‐ketol rearrangement cascade. This unified skeletal reorganization strategy not only accomplished the first total synthesis of fifteen cytochalasans but also provided compelling experimental support for the proposed biosynthetic pathway of curtachalasin B, thereby establishing a chemical link between multiple subclasses of this family.