What Is Ferrier Glycal Allylic Rearrangement?
The Ferrier rearrangement, formally known as the Ferrier glycal allylic rearrangement or Ferrier type-I reaction, stands as a cornerstone transformation in carbohydrate and synthetic organic chemistry. This reaction provides a direct and versatile route from readily accessible glycals to synthetically valuable 2,3-unsaturated glycosides.
Glycals themselves are 1,2-unsaturated cyclic carbohydrate derivatives, classically obtained from the elimination of suitable pyranoid or furanoid precursors, such as O-protected glycosyl halides. The most renowned member, tri-O-acetyl-D-glucal, is commercially available and serves as a standard substrate for this reaction. The profound significance of the Ferrier rearrangement lies in its ability to forge a new carbon-heteroatom bond at the anomeric center (C1) with concomitant migration of the endocyclic double bond from the 1,2- to the 2,3-position. The resulting 2,3-unsaturated glycosides, often termed "pseudoglycals," are not merely curiosities; they are pivotal chiral intermediates and building blocks for the synthesis of oligosaccharides, C-glycosides, uronic acids, complex natural products, and bioactive glycoconjugates. Their inherent unsaturation offers a strategic handle for further diversification through reactions like hydrogenation, hydroxylation, epoxidation, and dihydroxylation, thereby granting access to a wide array of differentially functionalized sugar motifs.
- Reagents: The reaction is catalyzed by Lewis or Brønsted acids. Common catalysts include BF3·OEt2, SnCl4, FeCl3, Yb(OTf)3, cyanuric chloride (TCT), and montmorillonite K-10 clay. The nucleophile (e.g., alcohol) is typically used as a reagent/solvent or in excess.
- Reactants:
a) A glycal: A 1,2-unsaturated carbohydrate derivative, most commonly a peracetylated glucal or galactal (e.g., tri-O-acetyl-D-glucal).
b) A nucleophile: Typically an alcohol or phenol, but also thiols, azide, and some carbon nucleophiles. - Products: The main product is a 2,3-unsaturated glycoside (pseudoglycal), formed with high α-anomeric selectivity. For example, reaction of tri-O-acetyl-D-glucal with methanol yields methyl 4,6-di-O-acetyl-2,3-dideoxy-α-D-erythro-hex-2-enopyranoside.
- Reaction Type: It is an acid-catalyzed SN2'-type allylic rearrangement.
- Related Reaction: Petasis-Ferrier Rearrangement (or Ferrier Type-II reaction).
Fig 1. Ferrier rearrangement reaction and its mechanism. [1]
Mechanism of Ferrier Rearrangement
- Activation. A Lewis acid or strong Brønsted acid coordinates to the glycal oxygen or to an acyloxy substituent (often at C-3 for acylated glycals), increasing the electrophilicity of the alkene and promoting departure or delocalization to an allylic oxacarbenium species.
- Allylic Oxacarbenium (Delocalized Cation). The key intermediate is best thought of as a delocalized allylic oxacarbenium ion (resonance between C-1 and C-2/C-3 positions). This delocalization controls both regio- and stereochemical outcomes.
- Nucleophilic Capture. An external nucleophile (e.g., ROH, RSH, silyl enol ethers, organosilanes) attacks the cationic center, most commonly at the C-1 position, leading to a substituted product with the double bond relocated (commonly giving a 2,3-unsaturated glycoside). Attack is usually SN1-like and therefore sensitive to the stability and conformation of the intermediate, the nature of the nucleophile, solvent and temperature.
Application Examples of Ferrier Rearrangement
- Example 1: Nianyu Huang et al. achieved the efficient synthesis of α,(Z)-selective C-vinyl glycosides through a tandem intermolecular gold-catalyzed 1,3-acyloxy migration/Ferrier rearrangement, using allene esters as glycosyl acceptors. [2]
- Example 2: Huajun Zhang et al. reported a method for the efficient and stereoselective synthesis of 2,3-unsaturated glycosides under mild conditions. This method utilizes a novel Ferrier rearrangement reaction between a rationally designed glycosyl donor and a C3-adjacent 2,2-dimethoxycarbonylcyclopropylbenzoyl (CCBz) group, using the easily handled and environmentally friendly Cu(OTf)2 or Fe(OTf)3 as a catalyst. [3]
Fig 2. Synthetic examples via Ferrier rearrangement.
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References
- Jie Jack Li. Name Reactions-A Collection of Detailed Mechanisms and Synthetic Applications, Sixth Edition, 2021, 194-196.
- Huang, Nianyu, et al. Organic Letters 20.1 (2018): 16-19.
- Zhang, Huajun, et al. Organic Chemistry Frontiers 11.16 (2024): 4470-4478.
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