Ferrier carbocyclization
Encyclopedia
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
pyran
s to cyclohexanone
s. Typically, this reaction is catalyzed by mercury
salts, specifically mercury(II) chloride
.
Several reviews have been published.
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 anomer
ic 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 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.
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.
derivatives using this reaction. It has also been applied to the synthesis of aminocyclitols in work done by Barton and co-workers. Finally, Amano et al. used the Ferrier conditions to synthesise complex conjugated cyclohexanones in 1998.
Organic reaction
Organic reactions are chemical reactions involving organic compounds. The basic organic chemistry reaction types are addition reactions, elimination reactions, substitution reactions, pericyclic reactions, rearrangement reactions, photochemical reactions and redox reactions. In organic synthesis,...
that was first reported by the carbohydrate
Carbohydrate
A carbohydrate is an organic compound with the empirical formula ; that is, consists only of carbon, hydrogen, and oxygen, with a hydrogen:oxygen atom ratio of 2:1 . However, there are exceptions to this. One common example would be deoxyribose, a component of DNA, which has the empirical...
chemist Robert J. Ferrier in 1979. It is a metal
Metal
A metal , is an element, compound, or alloy that is a good conductor of both electricity and heat. Metals are usually malleable and shiny, that is they reflect most of incident light...
-mediated rearrangement
Rearrangement reaction
A rearrangement reaction is a broad class of organic reactions where the carbon skeleton of a molecule is rearranged to give a structural isomer of the original molecule. Often a substituent moves from one atom to another atom in the same molecule...
of enol ether
Enol ether
An enol ether is an alkene with an alkoxy substituent. The general structure is R_1R_2C=CR_3-O-R_4 with R an alkyl or an aryl group. Enol ethers and enamines are so-called activated alkenes or electron rich alkenes because the oxygen atom donates electrons to the double bond by forming a resonance...
pyran
Pyran
In chemistry, a pyran, or oxine, is a six-membered heterocyclic, non-aromatic ring, consisting of five carbon atoms and one oxygen atom and containing two double bonds. The molecular formula is C5H6O. There are two isomers of pyran that differ by the location of the double bonds...
s to cyclohexanone
Cyclohexanone
Cyclohexanone is the organic compound with the formula 5CO. The molecule consists of six-carbon cyclic molecule with a ketone functional group. This colorless oil has an odor reminiscent of peardrop sweets as well as acetone. Over time, samples assume a yellow color due to oxidation...
s. Typically, this reaction is catalyzed by mercury
Mercury (element)
Mercury is a chemical element with the symbol Hg and atomic number 80. It is also known as quicksilver or hydrargyrum...
salts, specifically mercury(II) chloride
Mercury(II) chloride
Mercury chloride or mercuric chloride , is the chemical compound with the formula HgCl2. This white crystalline solid is a laboratory reagent and a molecular compound. It is no longer used for medicinal purposes Mercury(II) chloride or mercuric chloride (formerly corrosive sublimate), is the...
.
Several reviews have been published.
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
Hemiacetal
Hemiacetals and hemiketals are compounds that are derived from aldehydes and ketones respectively. The Greek word hèmi means half...
. 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 anomer
Anomer
In carbohydrate chemistry, an anomer is a special type of epimer. It is one of two stereoisomers of a cyclic saccharide that differs only in its configuration at the hemiacetal or hemiketal carbon, also called the anomeric carbon. Anomerization is the process of conversion of one anomer to the other...
ic position (carbon-1) results in a mixture of α- and β-anomers. The reaction also works for substituted alkenes (e. g. having an -OAc
Acetyl
In organic chemistry, acetyl is a functional group, the acyl with chemical formula COCH3. It is sometimes represented by the symbol Ac . The acetyl group contains a methyl group single-bonded to a carbonyl...
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
Acetic anhydride
Acetic anhydride, or ethanoic anhydride, is the chemical compound with the formula 2O. Commonly abbreviated Ac2O, it is the simplest isolatable acid anhydride and is a widely used reagent in organic synthesis...
(Ac2O) and pyridine
Pyridine
Pyridine is a basic heterocyclic organic compound with the chemical formula C5H5N. It is structurally related to benzene, with one C-H group replaced by a nitrogen atom...
, 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 bondGlycosidic bond
In chemistry, a glycosidic bond is a type of covalent bond that joins a carbohydrate molecule to another group, which may or may not be another carbohydrate....
). 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
Isopropyl
In organic chemistry, isopropyl is a propyl with a group attached to the secondary carbon. If viewed as a functional group an isopropyl is an organic compound with a propyl group attached at its secondary carbon.The bond is therefore on the middle carbon....
)] worked in the same reaction as a milder version of the Lewis acid
Lewis acid
]The term Lewis acid refers to a definition of acid published by Gilbert N. Lewis in 1923, specifically: An acid substance is one which can employ a lone pair from another molecule in completing the stable group of one of its own atoms. Thus, H+ is a Lewis acid, since it can accept a lone pair,...
, i-Bu3Al, 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
Palladium
Palladium is a chemical element with the chemical symbol Pd and an atomic number of 46. It is a rare and lustrous silvery-white metal discovered in 1803 by William Hyde Wollaston. He named it after the asteroid Pallas, which was itself named after the epithet of the Greek goddess Athena, acquired...
(II) salts, which brought about the same conversion of enol ethers into carbosugars in a more environmentally friendly manner.
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-inositolInositol
Inositol or cyclohexane-1,2,3,4,5,6-hexol is a chemical compound with formula 6126 or 6, a sixfold alcohol of cyclohexane. It exists in nine possible stereoisomers, of which the most prominent form, widely occurring in nature, is cis-1,2,3,5-trans-4,6-cyclohexanehexol, or myo-inositol...
derivatives using this reaction. It has also been applied to the synthesis of aminocyclitols in work done by Barton and co-workers. Finally, Amano et al. used the Ferrier conditions to synthesise complex conjugated cyclohexanones in 1998.