Ferrier carbocyclization
{{distinguish|text=the Ferrier rearrangement, a reaction discovered by the same chemist}}
The Ferrier carbocyclization (or Ferrier II reaction) is an organic reaction that was first reported by the carbohydrate chemist Robert J. Ferrier in 1979.{{cite journal|last=Ferrier|first=RJ|journal=J. Chem. Soc., Perkin Trans. 1|year=1979|pages=1455–1458|doi=10.1039/p19790001455|title=Unsaturated carbohydrates. Part 21. A carbocyclic ring closure of a hex-5-enopyranoside derivative}}{{cite journal|last1=Blattner|first1=RJ|last2=Ferrier|first2=RJ|journal=Carbohydr. Res.|year=1986|volume=150|pages=151–162|doi=10.1016/0008-6215(86)80012-X|title=Direct synthesis of 6-oxabicyclo[3.2.1]octane derivatives from deoxyinososes}} It is a metal-mediated rearrangement of enol ether pyrans to cyclohexanones. Typically, this reaction is catalyzed by mercury salts, specifically mercury(II) chloride.
File:Ferrier carbocyclization.svg
Several reviews have been published.{{cite journal|last1=Ferrier|first1=RJ|last2=Middleton|first2=S|journal=Chem. Rev.|year=1993|volume=93|pages=2779–2831|doi=10.1021/cr00024a008|title=The conversion of carbohydrate derivatives into functionalized cyclohexanes and cyclopentanes|issue=8}}{{cite journal|last1=Marco-Contelles|first1=J|last2=Molina|first2=Maria T.|last3=Anjum|first3=S|journal=Chem. Rev.|year=2004|volume=104|pages=2857–2900|doi=10.1021/cr980013j|title=Naturally Occurring Cyclohexane Epoxides: Sources, Biological Activities, and Synthesis†|pmid=15186183|issue=6}}
Reaction mechanism
Ferrier proposed the following reaction mechanism:
File:Ferrier carbocyclization mech.svg
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).{{cite journal|last1=Das|first1=SK|last2=Mallet|first2=J-M|last3=Sinaÿ|first3=P|journal=Angew. Chem. Int. Ed.|year=1997|volume=36|pages=493–496|doi=10.1002/anie.199704931|title=Novel Carbocyclic Ring Closure of Hex-5-enopyranosides|issue=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:
File:Sinay transition state.svg
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,{{cite journal|last1=Dalko|first1=PI|last2=Sinaÿ|first2=P|journal=Angew. Chem. Int. Ed.|year=1999|volume=38|pages=773–777|doi=10.1002/(SICI)1521-3773(19990315)38:6<773::AID-ANIE773>3.0.CO;2-N|title=Recent Advances in the Conversion of Carbohydrate Furanosides and Pyranosides into Carbocycles|issue=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.{{cite journal|last=Adam|first=S|title=Palladium(II) promoted carbocyclisation of aminodeoxyhex-5-enopyranosides|journal=Tetrahedron Lett.|year=1988|volume=29|issue=50|pages=6589–6592|doi=10.1016/S0040-4039(00)82404-1}}
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.{{cite journal|last1=Bender|first1=SL|last2=Budhu|first2=RJ|title=Biomimetic synthesis of enantiomerically pure D-myo-inositol derivatives|journal=J. Am. Chem. Soc.|year=1991|volume=113|issue=26|pages=9883–9885|doi=10.1021/ja00026a042}} It has also been applied to the synthesis of aminocyclitols in work done by Barton and co-workers.{{cite journal|last1=Barton|first1=DHR|last2=Camara|first2=J|last3=Dalko|first3=P|last4=Géro|first4=SD|last5=Quiclet-Sire|first5=B|last6=Stütz|first6=P|title=Synthesis of biologically active carbocyclic analogs of N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP)|journal=J. Org. Chem.|year=1989|volume=54|issue=16|pages=3764–3766|doi=10.1021/jo00277a002}} Finally, Amano et al. used the Ferrier conditions to synthesise complex conjugated cyclohexanones in 1998.{{cite journal|last1=Amano|first1=S|last2=Ogawa|first2=N|last3=Ohtsuka|first3=M|last4=Ogawa|first4=S|last5=Chida|first5=N|title=Total synthesis and absolute configuration of FR65814|journal=Chem. Commun.|year=1998|issue=12|pages=1263–1264|doi=10.1039/a802169d}}