Ferrier carbocyclization

Last updated March 31, 2019

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.

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, organic reactions are used in the construction of new organic molecules. The production of many man-made chemicals such as drugs, plastics, food additives, fabrics depend on organic reactions.

Carbohydrate organic compound that consists only of carbon, hydrogen, and oxygen

A carbohydrate is a biomolecule consisting of carbon (C), hydrogen (H) and oxygen (O) atoms, usually with a hydrogen–oxygen atom ratio of 2:1 (as in water) and thus with the empirical formula C_m(H₂O)_n (where m may be different from n). This formula holds true for monosaccharides. Some exceptions exist; for example, deoxyribose, a sugar component of DNA, has the empirical formula C₅H₁₀O₄. The carbohydrates are technically hydrates of carbon; structurally it is more accurate to view them as aldoses and ketoses.

Robert John "Robin" Ferrier FRSNZ, FNZIC, was an organic chemist who invented two chemical reactions, the Ferrier rearrangement and the Ferrier carbocyclization. Originally from Edinburgh, he moved to Wellington, New Zealand, in 1970.

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).

A hemiacetal or a hemiketal is a compound that results from the addition of an alcohol to an aldehyde or a ketone, respectively. The Greek word hèmi, meaning half(semi), refers to the fact that a single alcohol has been added to the carbonyl group, in contrast to acetals or ketals, which are formed when a second alkoxy group has been added to the structure.

An anomer is a type of geometric variation found at certain atoms in carbohydrate molecules. An epimer is a stereoisomer that differs in configuration at any single stereogenic center. An anomer is an epimer at the hemiacetal/acetal carbon in a cyclic saccharide, an atom called the anomeric carbon. The anomeric carbon is the carbon derived from the carbonyl carbon of the open-chain form of the carbohydrate molecule. Anomerization is the process of conversion of one anomer to the other. As is typical for stereoisomeric compounds, different anomers have different physical properties, melting points and specific rotations.

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.

Acetic anhydride, or ethanoic anhydride, is the chemical compound with the formula (CH₃CO)₂O. Commonly abbreviated Ac₂O, it is the simplest isolable anhydride of a carboxylic acid and is widely used as a reagent in organic synthesis. It is a colorless liquid that smells strongly of acetic acid, which is formed by its reaction with moisture in the air.

Pyridine is a basic heterocyclic organic compound with the chemical formula C₅H₅N. It is structurally related to benzene, with one methine group (=CH−) replaced by a nitrogen atom. It is a highly flammable, weakly alkaline, water-soluble liquid with a distinctive, unpleasant fish-like smell. Pyridine is colorless, but older or impure samples can appear yellow. The pyridine ring occurs in many important compounds, including agrochemicals, pharmaceuticals, and vitamins. Historically, pyridine was produced from coal tar. Today it is synthesized on the scale of about 20,000 tonnes per year worldwide.

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.

In chemistry, a glycosidic bond or glycosidic linkage is a type of covalent bond that joins a carbohydrate (sugar) molecule to another group, which may or may not be another carbohydrate.

(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(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]

Palladium is a chemical element with symbol Pd and atomic number 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 by her when she slew Pallas. Palladium, platinum, rhodium, ruthenium, iridium and osmium form a group of elements referred to as the platinum group metals (PGMs). These have similar chemical properties, but palladium has the lowest melting point and is the least dense of them.

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]

Related Research Articles

An enamine is an unsaturated compound derived by the condensation of an aldehyde or ketone with a secondary amine. Enamines are versatile intermediates.

Cyclohexene is a hydrocarbon with the formula C₆H₁₀. This cycloalkene is a colorless liquid with a sharp smell. It is an intermediate in various industrial processes. Cyclohexene is not very stable upon long term storage with exposure to light and air because it forms peroxides.

The Michael reaction or Michael addition is the nucleophilic addition of a carbanion or another nucleophile to an α,β-unsaturated carbonyl compound. It belongs to the larger class of conjugate additions. This is one of the most useful methods for the mild formation of C–C bonds. Many asymmetric variants exist.

The Simmons–Smith reaction is an organic cheletropic reaction involving an organozinc carbenoid that reacts with an alkene to form a cyclopropane. It is named after Howard Ensign Simmons, Jr. and Ronald D. Smith. It uses a methylene free radical intermediate that is delivered to both carbons of the alkene simultaneously, therefore the configuration of the double bond is preserved in the product and the reaction is stereospecific.

The Ferrier rearrangement is an organic reaction that involves a nucleophilic substitution reaction combined with an allylic shift in a glycal. It was discovered by the carbohydrate chemist Robert J. Ferrier.

<i>N</i>-Bromosuccinimide chemical compound

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Diethyl azodicarboxylate chemical compound

Diethyl azodicarboxylate, conventionally abbreviated as DEAD and sometimes as DEADCAT, is an organic compound with the structural formula CH₃CH₂O₂CN=NCO₂CH₂CH₃. Its molecular structure consists of a central azo functional group, RN=NR, flanked by two ethyl ester groups. This orange-red liquid is a valuable reagent but also quite dangerous and explodes upon heating. Therefore, commercial shipment of pure diethyl azodicarboxylate is prohibited in the United States and is carried out either in solution or on polystyrene particles.

Glycal is a name for cyclic enol ether derivatives of sugars having a double bond between carbon atoms 1 and 2 of the ring. The term “glycal” should not be used for an unsaturated sugar that has a double bond in any position other than between carbon atoms 1 and 2.

Nucleophilic conjugate addition is a type of organic reaction. Ordinary nucleophilic additions or 1,2-nucleophilic additions deal mostly with additions to carbonyl compounds. Simple alkene compounds do not show 1,2 reactivity due to lack of polarity, unless the alkene is activated with special substituents. With α,β-unsaturated carbonyl compounds such as cyclohexenone it can be deduced from resonance structures that the β position is an electrophilic site which can react with a nucleophile. The negative charge in these structures is stored as an alkoxide anion. Such a nucleophilic addition is called a nucleophilic conjugate addition or 1,4-nucleophilic addition. The most important active alkenes are the aforementioned conjugated carbonyls and acrylonitriles.

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Cyclic compound Molecule with a ring of bonded atoms

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References

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

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[1] Ferrier, RJ (1979). "Unsaturated carbohydrates. Part 21. A carbocyclic ring closure of a hex-5-enopyranoside derivative". J. Chem. Soc., Perkin Trans. 1: 1455–1458. doi:10.1039/p19790001455.

[2] Blattner, RJ; Ferrier, RJ (1986). "Direct synthesis of 6-oxabicyclo[3.2.1]octane derivatives from deoxyinososes". Carbohydr. Res. 150: 151–162. doi:10.1016/0008-6215(86)80012-X.

[3] Ferrier, RJ; Middleton, S (1993). "The conversion of carbohydrate derivatives into functionalized cyclohexanes and cyclopentanes". Chem. Rev. 93 (8): 2779–2831. doi:10.1021/cr00024a008.

[4] Marco-Contelles, J; Molina, Maria T.; Anjum, S (2004). "Naturally Occurring Cyclohexane Epoxides: Sources, Biological Activities, and Synthesis†". Chem. Rev. 104 (6): 2857–2900. doi:10.1021/cr980013j. PMID 15186183.

[5] Das, SK; Mallet, J-M; Sinaÿ, P (1997). "Novel Carbocyclic Ring Closure of Hex-5-enopyranosides". Angew. Chem. Int. Ed. 36 (5): 493–496. doi:10.1002/anie.199704931.

[6] Dalko, PI; Sinaÿ, P (1999). "Recent Advances in the Conversion of Carbohydrate Furanosides and Pyranosides into Carbocycles". Angew. Chem. Int. Ed. 38 (6): 773–777. doi:10.1002/(SICI)1521-3773(19990315)38:6<773::AID-ANIE773>3.0.CO;2-N.

[7] Adam, S (1988). "Palladium(II) promoted carbocyclisation of aminodeoxyhex-5-enopyranosides". Tetrahedron Lett. 29 (50): 6589–6592. doi:10.1016/S0040-4039(00)82404-1.

[8] Bender, SL; Budhu, RJ (1991). "Biomimetic synthesis of enantiomerically pure D-myo-inositol derivatives". J. Am. Chem. Soc. 113 (26): 9883–9885. doi:10.1021/ja00026a042.

[9] Barton, DHR; Camara, J; Dalko, P; Géro, SD; Quiclet-Sire, B; Stütz, P (1989). "Synthesis of biologically active carbocyclic analogs of N-acetylmuramyl-L-alanyl-D-isoglutamine (MDP)". J. Org. Chem. 54 (16): 3764–3766. doi:10.1021/jo00277a002.

[10] Amano, S; Ogawa, N; Ohtsuka, M; Ogawa, S; Chida, N (1998). "Total synthesis and absolute configuration of FR65814". Chem. Commun. (12): 1263–1264. doi:10.1039/a802169d.