Ferrier carbocyclization explained

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.

(Bn = benzyl, i-Bu = isobutyl)

Sinaÿ proposed this reaction went through the following transition state:

Sinaÿ also discovered that titanium (IV) derivatives such as [TiCl₃(O[[isopropyl|''i''Pr]])] 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]

Notes and References

1. Ferrier. RJ. J. Chem. Soc., Perkin Trans. 1. 1979. 1455–1458. 10.1039/p19790001455. Unsaturated carbohydrates. Part 21. A carbocyclic ring closure of a hex-5-enopyranoside derivative.
2. Blattner. RJ. Ferrier. RJ. Carbohydr. Res.. 1986. 150. 151–162. 10.1016/0008-6215(86)80012-X. Direct synthesis of 6-oxabicyclo[3.2.1]octane derivatives from deoxyinososes.
3. Ferrier. RJ. Middleton. S. Chem. Rev.. 1993. 93. 2779–2831. 10.1021/cr00024a008. The conversion of carbohydrate derivatives into functionalized cyclohexanes and cyclopentanes. 8.
4. Marco-Contelles. J. Molina. Maria T.. Anjum. S. Chem. Rev.. 2004. 104. 2857–2900. 10.1021/cr980013j. Naturally Occurring Cyclohexane Epoxides: Sources, Biological Activities, and Synthesis†. 15186183. 6.
5. Das. SK. Mallet. J-M. Sinaÿ. P. Angew. Chem. Int. Ed.. 1997. 36. 493–496. 10.1002/anie.199704931. Novel Carbocyclic Ring Closure of Hex-5-enopyranosides. 5.
6. Dalko. PI. Sinaÿ. P. Angew. Chem. Int. Ed.. 1999. 38. 773–777. 10.1002/(SICI)1521-3773(19990315)38:6<773::AID-ANIE773>3.0.CO;2-N. Recent Advances in the Conversion of Carbohydrate Furanosides and Pyranosides into Carbocycles. 6.
7. Adam. S. Palladium(II) promoted carbocyclisation of aminodeoxyhex-5-enopyranosides. Tetrahedron Lett.. 1988. 29. 50. 6589–6592. 10.1016/S0040-4039(00)82404-1.
8. Bender. SL. Budhu. RJ. Biomimetic synthesis of enantiomerically pure D-myo-inositol derivatives. J. Am. Chem. Soc.. 1991. 113. 26. 9883–9885. 10.1021/ja00026a042.
9. Barton. DHR. Camara. J. Dalko. P. Géro. SD. Quiclet-Sire. B. Stütz. P. Synthesis of biologically active carbocyclic analogs of N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP). J. Org. Chem.. 1989. 54. 16. 3764–3766. 10.1021/jo00277a002.
10. Amano. S. Ogawa. N. Ohtsuka. M. Ogawa. S. Chida. N. Total synthesis and absolute configuration of FR65814. Chem. Commun.. 1998. 12. 1263–1264. 10.1039/a802169d.