Ferrier carbocyclization

This process (also known as the Ferrier II Reaction ) has proved to be of considerable value for the effieient, one-step conversion of 5,6-unsaturated hexopyranose derivatives into funetionalized eyelohexanones useful for the preparation of sueh enantiomerically pure eompounds as inositols and flieir amino, deoxy, unsaturated and selectively O-substituted derivatives, notably phosphate esters. In addition, the products of the earboeyelization have been incorporated into many eomplex eompounds of interest in biologieal and medicinal chemistry.  

Complex bioactive compounds made following the application of the reaction  

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 95, Springer-Verlag Berlin Heidelberg 2009 

Perrier, R. J. J. Chem. Soc., Perkin Trans. 1 1979, 1455—1458. The discovery (1977) was made in the Pharmacology Department, University of Edinburgh, while R. J. Perrier was on leave from Victoria University of Wellington, New Zealand where he was Professor of Organic Chemistry. He is now a consultant with Industrial Research Ltd., Lower Hutt, New Zealand. 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 102, Springer International Publishing Switzerland 2014 

Sakuma, S. Nakamura, Y. Yoshimura, J. Hashimoto, H. Chem. Lett. 1991, 17. 

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Bayer-Villiger oxidation of the Ferrier carbocyclization products 69 and 70, derived from D-glucose, gave the isomeric 5-deoxyhexofuranosiduronic... 

The Baeyer-Villiger transformation of several protected derivatives having a free ketone group has been effected by m-chloroperoxybenzoic acid. Thus, 1,6-anhydro-3,4-0-isopropylidene-/f-D-/yxn-hexopyranos-2-ulose (28) was converted into the cyclic, orthoacid anhydride 29.67 As an additional example, the Baeyer-Villiger oxidation of Ferrier carbocyclization products derived from D-glucose afforded 5-deoxyhexofuranosiduronic acids, via the ring-expanded lactonic intermediates68 (Scheme 12). 

Ferrier carbocyclization can form only cyclohexanones. Nevertheless, chemical manipulations of the latter can provide us with seven-membered rings. This is illustrated by the synthesis of (—)-calystegine B2 by Boyer and Lallemand [305]. These natural polyhydroxylated nortropane compounds are growth stimulators of nitrogen fixing bacteria. 

For other examples of sluggish Ferrier carbocyclization, see Taillefumier, C, Chapleur, Y, Enantiomerically pure decalinic structures from carbohydrates using intramolecular Diels-Alder and Ferrier carbocyclization. Can. J. Chem., 78, 708-722, 2000. 

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. 

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 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... 

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... 

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