Collect. Czech. Chem. Commun. 2003, 68, 202-210

On the Concerted Ring Opening of Protonated Squalene Oxide and A-Ring Formation in the Biosynthesis of Lanosterol

B. Andes Hess, Jr.

Department of Chemistry, Vanderbilt University, Nashville, TN 37235, U.S.A.


Density functional calculations were performed on a model system of squalene oxide to study the mechanism of the formation of ring A in the biosynthesis of lanosterol from squalene. When (2Z)-6,7-epoxy-3,7-dimethyloct-2-ene was protonated, it was calculated to undergo a very facile ring opening of the oxirane in concert with the formation of the six-membered ring of the 4-(hydroxymethyl)-1,2,3,3-tetramethy1cyclohexyl cation. A study of the reaction pathway (IRC) indicates a very early transition structure in which the carbon- carbon double bond participates anchimerically in the ring-opening of the protonated oxirane. It is suggested that the primary role of the enzyme in this first step of the biosynthesis of lanosterol is protonation of the oxirane ring along with holding the substrate in the proper conformation for the concerted ring-closure to occur. The similarity between this mechanism and that recently proposed for concerted C-ring expansion and D-ring formation in the biosynthesis of lanosterol is discussed.

Keywords: Steroids; Terpenoids; Biosynthesis; DFT calculations; Ab initio; Reaction mechanism; Epoxides; Cyclizations.

References: 18 live references.