Bio-inspired total synthesis of daphnepapytone A

Abstract

Daphnepapytone A (1) is an unprecedented guaiane-derived sesquiterpene characterized by a bridged and highly substituted cyclobutane. We describe its total synthesis through a bio-inspired sequence of skeleton construction and late-stage oxidation. After the Eschenmoser–Tanabe fragmentation of (R)-carvone epoxide, the allenylation of the resulting aldehyde was followed by an allenic Pauson–Khand reaction with distal regioselectivity in the presence of [Rh(CO)₂Cl]₂ to give the guaiane skeleton. Oleodaphnone (3) was identified as a key intermediate of this strategy and was engaged in a biomimetic [2 + 2]-photocycloaddition, leading to the bridged cyclobutane of the title compound. Finally, a late-stage C–H oxidation chemoselectively released a triketone intermediate (15), which was reduced in a remarkably chemo- and stereoselective manner to furnish target compound 1. During this work, complex rearrangements of the bridged skeleton were observed. Beside the total synthesis of daphnepapytone A, this paper also describes the total synthesis of three guaiane natural products (oleodaphnone, diarthroncha C, daphnenicillata W), one of them being structurally revised.