Chemoenzymatic Synthesis of ( E,E,Z )-Humulene-Derived Natural Products

Meroterpenoid natural products derived from the 11-membered macrocycle humulene are of great interest due to their potent biological activities and intricate architectures. Whereas molecules derived from the most available (E,E,E)-humulene isomer have been thoroughly investigated, little is known of the chemistry and biological properties of natural products derived from the (E,E,Z)-isomer and derivatives thereof. Herein, we detail the first synthesis of (E,E,Z)-(10S)-hydroxyhumulene through a selective oxidative double-bond isomerization, and using this key building block along with (E,E,Z)-humulene, a suite of complex meroterpenoids was synthesized, including (±)-deoxynoreupenifeldin and neosetophomone B through a chemoenzymatic strategy and pughiinin A through a non-enzymatic route. In addition to gaining synthetic access to a suite of (E,E,Z)-humulene-derived natural products, this work revealed reactivity differences between (E,E,E)-humulene and its (E,E,Z)-isomer. Overall, these efforts culminate in the first total syntheses of three (E,E,Z)-humulene-derived natural products, providing access to this untapped subset of secondary metabolites.