The Ferrier carbocyclization (or Ferrier II reaction) is an organic reaction that was first reported by the carbohydrate chemist Robert J. Ferrier in 1979.^[1][2] It is a metal-mediated rearrangement of enol ether pyrans to cyclohexanones. Typically, this reaction is catalyzed by mercury salts, specifically mercury(II) chloride.

Several reviews have been published.^[3][4]

Reaction mechanism

Ferrier proposed the following reaction mechanism:

In this mechanism, the terminal olefin undergoes hydroxymercuration to produce the first intermediate, compound 2, a hemiacetal. Next, methanol is lost and the dicarbonyl compound cyclizes through an attack on the electrophilic aldehyde to form the carbocycle as the product. A downside to this reaction is that the loss of CH₃OH at the anomeric position (carbon-1) results in a mixture of α- and β-anomers. The reaction also works for substituted alkenes (e. g. having an -OAc group on the terminal alkene).

Ferrier also reported that the final product, compound 5, could be converted into a conjugated ketone (compound 6) by reaction with acetic anhydride (Ac₂O) and pyridine, as shown below.

Modifications

In 1997, Sinaÿ and co-workers reported an alternative route to the synthesis (shown below) that did not involve cleavage of the bond at the anomeric position (the glycosidic bond).^[5] In this case, the major product formed had maintained its original configuration at the anomeric position.

Sinaÿ proposed this reaction went through the following transition state:

Sinaÿ also discovered that titanium (IV) derivatives such as [TiCl₃(OiPr)] worked in the same reaction as a milder version of the Lewis acid, i-Bu₃Al,^[6] which goes through a similar transition state involving the retention of configuration at the anomeric center.

In 1988, Adam reported a modification of the reaction that used catalytic amounts of palladium (II) salts, which brought about the same conversion of enol ethers into carbosugars in a more environmentally friendly manner.^[7]

Applications

The development of the Ferrier carbocyclization has been useful for the synthesis of numerous natural products that contain the carbocycle group. In 1991, Bender and co-workers reported a synthetic route to pure enantiomers of myo-inositol derivatives using this reaction.^[8] It has also been applied to the synthesis of aminocyclitols in work done by Barton and co-workers.^[9] Finally, Amano et al. used the Ferrier conditions to synthesise complex conjugated cyclohexanones in 1998.^[10]