Biomimetic Cationic Tail-to-Head Cyclizations of Linear Sesquiterpenols Enabled by Stabilizing the Cationic Intermediates with 1,1,1,3,3,3-Hexafluoroisopropanol (HFIP)

In nature, cationic tail-to-head cyclizations of the diphosphates of a few linear sesquiterpenols generate a vast array of structurally diverse polycyclic sesquiterpenes. However, in normal organic solvents, cationic cyclizations of linear sesquiterpenols stop after the first ring closure and give mainly elimination product bisabolenes. We found that in 1,1,1,3,3,3-hexafluoroisopropanol (HFIP), β-hydrogen elimination of the carbocation intermediates formed during tail-to-head cyclization could be minimized. In HFIP, the bisabolyl cation generated by the first cyclization of (2<i>Z</i>,6<i>E</i>)-farnesol could rearrange and then cyclize completely to produce polycyclic sesquiterpenes such as α-cedrenes, isocalamenenes, and 6-<i>epi</i>-amorphadiene.