Chemoenzymatic synthesis of (E,E,Z)-humulene derived natural products

Among the >300 skeletally distinct products derived from farnesyl pyrophosphate (FPP) reported to date, meroterpenoids derived from the humulene core are of great interest due to their potent biological activities. Whereas the most available (E,E,E)-humulene core and derivatives thereof have been well-studied, comparatively little is known of the chemistry and biological properties of the related (E,E,Z)-core and natural products derived from this humulene isomer. Herein, we detail the first synthesis of (E,E,Z)-(10S)-hydroxyhumulene and elaborate this macrocycle through a chemoenzymatic route to (±)-deoxyeupenifeldin and neosetophomone B, and further accomplish the chemical synthesis of pughiinin A. The (E,E,Z)-(10S)-hydroxyhumulene was accessed via a selective oxidative double-bond isomerization from the (E,E,E)-humulene core. Additionally, when studying this macrocycle in subsequent hetero-Diels Alder (hDA) cycloadditions, it was observed that the (E,E,Z)-core imparted more biased diastereoselectivity when compared to previous studies of the corresponding (E,E,E)-core. Our findings demonstrate scalable access to (E,E,Z)-(10S)-hydroxyhumulene and the ability to build meroterpene natural products from this humulene isomer.