Collective Asymmetric Synthesis of Eudesmane-Type Sesquiterpenoids from (+)-Verbenone: Production of Atractylenolides, Lactam Analogs, and Dimeric Congeners

A generalized and divergent asymmetric approach to the synthesis of eudesmane-type sesquiterpenoids, which exhibit substantial therapeutic potential, has remained elusive. This study reports the collective asymmetric synthesis of 16 eudesmane-type natural products from (+)-verbenone. Specifically, the trans -6/6 bicyclic core was constructed through ring-closing metathesis catalyzed by a second-generation Grubbs catalyst, while the butenolide framework was assembled through TiCl 4 -mediated regioselective γ-lactonization. The Gram-scale synthesis of atractylenolide I (ATL-I; 2 ) facilitated biomimetic diversification to C8-oxygenated and C8-nitrogenated congeners via nucleophilic addition–elimination, while photochemical [2 + 2] cycloaddition of 2 afforded dimeric biepiasreorlid II ( 16 ). Using this platform, cespilamides C ( 13 ), D ( 14 ), and E ( 15 ) were synthesized in good-to-excellent yields (87–93%), and their absolute configurations were revised through optical rotation analysis. Subsequent oxidative elaboration of ATLs II ( 3 ) and III ( 4 ) furnished ATL-IV ( 5 ) and (3 R )-3-hydroxyatractylenolide III ( 6 ), respectively. This study establishes the first scalable and enantioselective route to ATLs I–IV, atractylon, and their lactam analogs from Atractylodes macrocephala . This versatile synthetic platform will facilitate future investigations of the stereochemistry-dependent bioactivities of this pharmacologically valuable natural product family.