Ferrier cyclization

In one additional example, illustrating the applicability of the Ferrier cyclization to amine-based substrates, the same strategy allowed the synthesis of carba-glucosamine (Scheme 8.33). Starting from Cbz protected methyl a-D-glucosaminide 123, 4,6-benzylidene formation, di-benzylation, cleavage of the acetal, regioselective iodination and simultaneous elimination... 

Treatment of the deuterated alcohol 38 sequentially with A -(2-nitrophenylseleno)phthalimide. then tqrdrogen peroxide gave the exo-glycal 39 which was used to study the stereochemistry at C-6 during the Ferrier cyclization to a deoxyinosose derivative. ... 

Glycals can be transformed into 1,6-anhydro sugar derivatives by intramolecular cyclization in the presence of Lewis and Brpnsted acids, a reaction that has been termed the intramolecular Ferrier glycosylation.168 Sharma el al.169 showed that a montmorillonite clay-supported silver reagent can be an efficient catalyst for this transformation. The 1,6-anhydro-2,3-dehydro sugars obtained were then selectively dihydroxylated to furnish 1,6-anhydro saccharides. 

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]. 

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. 

Friestad, G K, Branchaud, B P, A new approach to the pancratistatin C-ring from D-glucose Ferrier rearrangement, pseudoinversion and Pd-catalyzed cyclizations. Tetrahedron Lett, 38, 5933-5936, 1997. 

The aluminum-mediated Petasis-Ferrier rearrangement is a stepwise [1,3]-sigmatropic process. The first step is the coordination of the Lewis-acid to the 0-atom of the enol. Coordination to the ether O-atom is reversible and nonproductive. Cleavage of the adjacent C-O-bond, assisted by the antiperiplanar lone pair of the etheral O-atom, stereospecifically gives rise to an oxocarbenium enolate species, which cyclizes to the desired oxacycle. The rate difference in the rearrangement for the five- versus six-membered series can be explained by the more facile 6-(enolendo)-endo-trig cyclization. The last step is the intramolecular equatorial hydride delivery. 

Finally a unique approach starting at ring A was presented by the introduction of the C25 substituent of avermectin B via carbon-Ferrier technology [33]. Thus reaction of D-glucal derivative 12 with Z-triphenylcrotylsilane displaced a pivalate group and sets up another pivalate displacement via 13 by dimethylcuprate to introduce the C24 methyl group and positioned the double bond exactly where required for avermectin B. The other unique feature of this route is the oxidative cyclization of a hydroxyl function onto a dihydropyran to effect spiroketalization. 

Cyclization of 5,6-dideoxv-6-nitro-D-xylo-hexofuranose led to a mixture of myo- and epi-isomers (43) which were separated and converted to the corresponding amino compounds.Examples of the use of the Ferrier reaction for preparing cyclitols and amino-cyclitols from D-glucose and D-glucosamine have been published, e.g., (44)- (45).52... 

Scheme 12.1.3 Proposed mechanism nf the Ferrier carhocyclization reactinn. Scheme 12.14 Possible transition structures of the cyclization.

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. 

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. 

A gold catalysis-initiated cascade process toward the synthesis of electron-rich arene-fused hexahydroquinolizinones 131 was developed by Zhang and Liu in 2012 (Scheme 12.57) [62]. In this cascade reaction, a gold-catalyzed amide cyclization to a tethered C-C triple bond initiates a subsequent Frie del-Crafts type cyclization, followed by a Ferrier rearrangement. Synthetic utility of this... 

Fig. 8.72 Ferrier rearrangements leading to cyclizations catalyzed by InCb.

Ferrier-rearrangement-based ring-opening reactions of cyclopropylated sugar derivatives also find attractiveness, especially in the case of functionalized oxepane formation. With the emergence of the methods described in Section 13.2.8, in addition to cyclization, methodologies of linear precursors offer now a reasonable number of synthetic methods to prepare oxepanes and septanoses. 

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