Ferrier carbocyclization reaction

The Ferrier carbocyclization reaction, meanwhile, is another iii5)ortant carbohydrate-based transformation in organic synthesis. The reaction is highly effective for the conversion of readily available aldohexoses into enantiomerically pure cyclohexanones. Chiral and highly functionalized cyclohexanones obtained by the Ferrier carbocyclization are potentially useful chiral building blocks, so the reaction has been frequently employed in the synthesis of structurally complex natural products containing a cyclohexane unit. In this chapter, we will focus on the Ferrier carbocyclization reaction and its applications to natural product S5mthesis. 

Two synthetically in iortant variants of the Ferrier carbocyclization reaction have been reported. One is a rearrangement of enol acetate 24 (Scheme 12.7). Reaction of 24 with a stoichiometric amount of Hg salt afforded an organomercurial intermediate 25, which was then treated with NaCl to induce the cyclization affording inosose derivatives 26a and 26b with good stereoselectivity. As biologically inportant myo-inositol derivatives, such as d-myo-inositol phosphates, are optically active, the enol-acetate version of the Ferrier carbocyclization would be effective for the preparation of enantiomerically pure inositol derivatives. 

If the Ferrier carbocyclization reaction could be applied to 4-enofuranoside substrates, the corresponding cyclopentanones, which are useful chiral building blocks in natural product synthesis, would be obtained. However, it has been reported that the attempted Ferrier carbocyclization of furanoside 34 with a stoichiometric amount of Hg(OAc)2 gave no... 

The Ferrier carbocyclization reaction is a reliable transformation of 5-enopyranosides into carbocycles. As shown in Scheme 12.12 (the carbon numberings in substrates and products have been changed the numbering of substrates is based on the nomenclature of carbohydrates, and the numbering of products is that of cyclohexanones), irrespective of the kinds of substituents and patterns of stereochemistry in the substrates, the rearranged products (15 and 42-46) were obtained in moderate to good yields with relatively high diastereoselectivity. An exception is a reaction of a 4-deoxy-5-enopyranoside derivative, which resulted in a low yield of product 47. 

The proposed mechanism of the Ferrier carbocyclization reaction is oudined in Scheme 12.13. First, oxymercuration of the exo-olefin in 48 affords mercurial-hemiacetal 49, whose aglycon moiety (-OMe) eliminates to give mercurial-aldehyde derivative 50. This mercurial intermediate 50 was isolable when a stoichiometric amount of Hg salt was employed at low temperature. Intramolecular aldol-type cyclization of 50 provides product 51. 

The true mechanism of the cyclization process as well as the origin of the diastereoselectivity in the Ferrier carbocyclization reaction has not been fully clarified at present. More detailed investigations will be required for a more conplete understanding of the mechanism of the Ferrier carbocyclization reaction. 

Chiral cyclohexanones obtained by the Ferrier carbocyclization reaction are useful precursors for the synthesis of cyclitols and aminocyclitols, some of which are found in clinically important aminoglycoside antibiotics. Additionally, highly substituted cyclohexenones, prepared by the Ferrier carbocyclization followed by (3-elimination, can undergo various further transformations, also making these compounds potential chiral building blocks for the preparation of structurally complex compounds having cyclohexane unit(s). This section provides an overview of the reported synthetic strategies toward various types of natural products based on utilization of the Ferrier carbocyclization reaction. 

The Ferrier carbocyclization reaction of an enol-acetate substrate gives an a,p-dihydroxy-cyclohexanol derivative (see Schemes 12.7 and 12.81. This transformation would be effective for the chiral synthesis of inositol derivatives. A retrosynthetic plan for the marine natural product tetrodotoxin 88 based on the enol-acetate version of Ferrier carbocyclization is shown in Scheme 12.22. Tetrodotoxin 88 was planned to be synthesized from lactone 89, the precursor of which would be highly functionalized cyclohexane 90. Cyclohexane 90 was envisioned to arise from cyclohexanone 91. For the preparation of 91, Ferrier carbocyclization of enol acetate 92 would be a suitable transformation. d-Glucose derivative 93 possessing an exo-methylene at C-3 would serve as a promising precursor of 92. 

METHODOLOGIES FOR ASSEMBLING THE FERRIER CARBOCYCLIZATION REACTION SUBSTRATES... 

The substrates for the Ferrier carbocyclization reaction are 6-deoxy-hex-5-enopyranoside derivatives. The chemistry of the inter conversions of carbohydrates has a long history hence, a number of reliable methods for the preparation of 5-enopyranosides have been established. A typical procedure for the preparation of 5-enopyranosides is (3-elimination of 6-deoxy-6-halo-aldohexopyranosides by the action of base. This section will provide an overview of some representative syntheses of 5-enopyranosides. 

APPLICATIONS OF THE FERRIER CARBOCYCLIZATION REACTION IN NATURAL PRODUCT SYNTHESIS... 

The phenanthridone alkaloid, lycoricidine 64 fScheme 12.32). is known to possess cytotoxic activity. Based on the retrosynthetic analysis as discussed in Section 12.3.2 f Scheme 12.18T the Chida group reported the total synthesis of lycoricidine starting from d-glucose in which the Ferrier carbocyclization reaction was enployed as the key reaction. For the preparation of the cyclohexene unit in lycoricidine, d-glucose was converted into 2-azido-d-altropyranoside derivative 122 via epoxide 121 fScheme 12.31T Protection of the diol moiety in 122 afforded 68, which was transformed into 5-enopyranoside 67 by the action of DBU. Ferrier carbocyclization of 67 with 1 mol% of Hg(OCOCF3)2, followed by p-elimination,... 

A synthesis of the carbocyclic analogue of uridine S -a-D-galactopyranosyl diphosphate (77) as an inhibitor of p-(l- 4)-galactosyltransferase has been achieved. The cyclitol ring was formed via a Ferrier carbocyclic reaction. ... 

This process (also known as the Ferrier II Reaction ) has proved to be of considerable value for the efficient, one-step conversion of 5,6-unsaturated hexopyranose derivatives into functionalized cyclohexanones useful for the preparation of such enantiomerically pure compounds as inositols and their amino, deoxy, unsaturated and selectively O-substituted derivatives, notably phosphate esters. In addition, the products of the carbocyclization have been incorporated into many complex compounds of interest in biological and medicinal chemistry. ... 

The Ferrier (II) reaction is quite efficient to form six membered carbocycles, but is unsuitable to prepare cyclopentitols. Five membered enollactone 14 was converted to the cyclopentanone derivative 16 as a single epimer upon treatment by LiAlH(OtBu)3 (Scheme 4) [41]. Spectroscopic studies established some mechanistic details. Accordingly, the hydride of the reducing agent rapidly added to the carbonyl and formed with the metal a stable alu-minate complex. The carbocydization occurred by protonation followed by fragmentation and aldol type cyclization process. 

Degradation Rearrangement Hydrolysis Double bond shift Ring transformation Ring-contraction Ring-expansion Ferrier carbocyclization Anomerization Aromatization Maillard reaction Amadori reaction... 

Laszio, P., Pelyvas, i. F., Sztaricskai, F., Szilagyi, L., Somogyi, A. Novel aspects of the Ferrier carbocyclic ring-transformation reaction. Carbohydr. Res. 1988,175, 227-239. 

This reaction was initiaiiy reported by Perrier in 1979. It is a mercury (II) salt -induced or promoted conversion of 5-enopyranosides into cyclohexanones with stereochemical control, by which substituents at positions 3 and 5 are predominantly in a trans relationship. To differentiate from another reaction also discovered by Perrier (called the Perrier Reaction), this reaction is known as the Ferrier-II rearrangement, " Ferrier-II carbocyclization, Perrier carbocyclization, or Ferrier-II reaction. Occasionally, it is also referred to as the Perrier Reaction. Therefore, it is called the Ferrier-II rearrangement in this book. It is useful in the conversion of carbohydrates into carbosugars, myo-inositols, and other natural products. ... 

The synthetic plan for an antitumor alkaloid, lycoricidine 64, based on the Ferrier carbocyclization is shown in Scheme 12.18. The tricyclic phenanthridone skeleton was envisioned to be constructed by C—C bond formation between C-lOa and C-lOb by a transition metal-catalyzed sp -sp carbon coupling reaction. The C-ring 65 possessing an... 

Combination of Ferrier Carbocyclization and Three-Component Coupling Reaction... 

To implement this strategy, tri-0-acetyl-d-glucal la was converted into fully protected derivative 155 by three reactions fScheme 12.421. Reductive opening of the benzylidene acetal and subsequent treatment with PhgP HBr and MeOH provided a methyl glycoside, which was transformed into primary iodide 156. Elimination of HI provided 20. Ferrier carbocyclization... 

Scheme 45. Aluminum-mediated carbocyclizations Ferrier-type reaction vs. Claisen rearrangement [77]...

Sugar enol-ethers, which inherently carry both the masked nucleophilic and electrophilic functions, were converted to carbocycles in different reactions. Among the carbocyclization methods the Ferrier (II) cyclization of hex-5-enopyranosides affording six membered carbocycles in the presence of Hg(II) salts is perhaps the most popular one (Scheme 3) [32], This remarkable reaction has provided a practical route to a large variety of bioactive substances such as aminocyclitols [33], pseudosugars [34], inositols [35], and other complex hexitols [36]. 

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