Ferrier carbocyclization

The Ferrier carbocyclization (or Ferrier II reaction) is an organic reaction that was first reported by the carbohydrate chemist Robert J. Ferrier in 1979. 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.

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.

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). 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, which goes through a similar transition state involving the retention of configuration at the anomeric center.

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