DFT Study of a Missing Piece in Brasilane-Type Structure Biosynthesis: An Unusual Skeletal Rearrangement.

Brasilane-type sesquiterpenes have been known for a long time, but their biosynthetic pathways and mechanisms remain elusive. Recently, two groups independently characterized a terpene cyclase that produces trichobrasilenol, a brasilane-type sesquiterpene, and a plausible biosynthetic pathway was proposed based on isotopic labeling experiments. In the proposed mechanism, the characteristic brasilane-type 5/6 bicyclic skeleton is synthesized from a 5/7/3 tricyclic intermediate via a complicated concerted reaction, including six chemical events of C-C σ bond metathesis and rearrangements, ring-contraction, π bond formation, and regioselective hydroxylation. However, our density functional theory (DFT) calculations do not support this mechanism. On the basis of DFT calculations, we propose a new pathway for trichobrasilenol biosynthesis, involving a multistep carbocation cascade in which cyclopropylcarbinyl cations in equilibrium with homoallyl cations play a pivotal role. This pathway and mechanism is in good agreement with previous biosynthetic studies on brasilane-type compounds and related terpenoids, including isotope-labeling experiments and byproducts analysis.