Carbocyclic enol ether

A very useful method to prepare carbocyclic enol ethers is the Birch reduction of aryl ethers. In the simplest example, metal ammonia reduction of methoxybenzene gives methoxycyclohexadiene (21). The reaction has been applied to numerous aryl ethers of complex structures. 

The use of oxygen-containing dienophiles such as enol ethers, silyl enol ethers, or ketene acetals has received considerable attention. Yoshikoshi and coworkers have developed the simple addition of silyl enol ethers to nitroalkenes. Many Lewis acids are effective in promoting the reaction, and the products are converted into 1,4-dicarbonyl compounds after hydrolysis of the adducts (see Section 4.1.3 Michael addition).156 The trimethylsilyl enol ether of cyclohexanone reacts with nitrostyrenes in the presence of titanium dichloride diisopropoxide [Ti(Oi-Pr)2Cl2], as shown in Eq. 8.99.157 Endo approach (with respect to the carbocyclic ring) is favored in the presence of Ti(Oi-Pr)2Cl2. Titanium tetrachloride affords the nitronates nonselectively. 

In contrast, the closely related palladium acetate-promoted intramolecular alkylation of alkenes by tri-methylsilyl enol ethers (Scheme 4)6,7 has been used to synthesize a large number of bridged carbocyclic systems (Table 1). In principle, this process should be capable of being made catalytic in palladium(II), since silyl enol ethers are stable to a range of oxidants used to carry the Pd° -> Pd11 redox chemistry required for catalysis. In practice, catalytically efficient conditions have not yet been developed, and the reaction is usually carried out using a full equivalent of palladium(II) acetate. This chemistry has been used in the synthesis of quadrone (equation 2).8 With the more electrophilic palladium(II) trifluoroace-tate, methyl enol ethers underwent this cyclization process (equation 3).9... 

For recent reviews on step-wise [3 + 3] formal cycloadditions leading to bridged carbocycles, pyridines or pyridones using enamines, enaminones, enol ethers, or (J-... 

Diaryliodonium fluorides can be used as efficient reagents for the arylation of silyl enol ethers [71, 72]. The reaction of silyl enol ethers 95 with o-nitro-phenyliodonium fluoride 96 results in a regiospecific arylation yielding arylke-tones 97 in good yields (Scheme 43) [72]. This arylation has been applied in a new, regiocontrolled synthesis of carbocycle-fused indoles [72]. 

Annelation-ring cleavage.1 A bifunctional reagent with an acetal and an allylsi-lane group can be used for annulation of silyl enol ethers to six- and seven-membered carbocycles (equation I).2 The reaction involves conjugate addition to give an adduct that undergoes intramolecular cyclization. 

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 preparation of 6-deoxy-hex-5-enopyranoses needs special attention since these sugar derivatives are important starting materials for the preparation of carbocyclic compounds (Scheme 3.7).32 6-Deoxy-hex-5-enopyranoses are enol ethers but, unlike glycals, the exocyclic double bond is located between C(5) and C(6). They can easily be prepared by... 

The intramolecular aldol reaction in the presence of a titanium Lewis acid is a viable means of preparation of cyclic compounds. The cyclization is most conveniently performed between an enol silyl ether and an acetal, because the former is a reactive enol derivative and is readily prepared by silylation of the corresponding ketone in the presence of the acetal moiety in the same molecule. Equation (12) exemplifies a substrate undergoing intramolecular ring closure mediated by TiCU [74]. The conversion of sugar derivatives to carbocycles (called the Perrier reaction [75,76]) has been reported to occur in the presence of a Lewis acid. This process involves the aldol reaction between the enol ether and acetal moieties in the same molecule promoted by a titanium salt, as illustrated in Eq. (13) [77]. The similar reaction of a different type of substrate was also reported [78]. 

A first hint comes from the fact that the carbonyl carbon of the acyl substituent in IV may be the a carbon of the enol ether moiety in I. In fact, the vinyl ether would be converted into a methyl ketone by breakage of the bond between the acetal carbon and the endocyclic oxygen. In that case, the resulting oxycarbenium ion would serve as a linking position for the carbocyclization that eventually affords the cyclohexyl ring of IV. 

It is also important to realize that the construction of the (3-keto ester function in VI, whose predictable role as a stabilized carbanion can be exploited to build the carbocycle, requires the consolidation of a C-C bond between C-6 of compound I and a methyl acetate unit from II. This task cannot be accomplished without a preliminary step, since the carbons involved are hardly active in the nucleophilic sense at the outset. This prior step consists of the coupling of I and II as the consequence of the nucleophilic character of the enol ether fragment of I and the strongly electrophilic nature of the triple bond of II. The result would be zwitterion V (see Scheme 38.1). 

Lewis acid catalyzed intramolecular alkylations of silyl enol ethers containing 5n1-reactive functionality provide useful routes to a variety of carbocyclic systems. - Smith et al have employed an intramolecular Mukaiyama reaction of the enol derivative (76) to produce the tetracyclic system (77) (equation 7). This transformation was a key step in their elegant synthesis of jatrophone. The synthesis... 

A similar rearrangement to a [4.4.0] carbocyclic skeleton was observed by Harmata upon treatment of 146 with bromine. The proposed mechanism involves formation of a bromonium ion which rearranges and loses a proton to form an enol ether, which reacts with a second mole of bromine to give, after hydrolysis, an excellent yield of the rearranged product (Scheme 9) [148]. 

The success of the strategy is further applied for the synthesis of carbo-and spiro-aimulated aromatic compounds [146,147] by the intramolecular cyclization of silyl enolethers to PET-generated arene radical cations. Two types of carbocyclic compounds (170 and 173), varying in ring sizes, may be synthesized [146] starting from the same ketone (i.e., 169), as two types of silyl enol ethers can be produced using either thermodynamic or kinetic enolisation procedures. The core spiro structure (177) of the anticancer antibiotic ffed-ericamycin is also prepared [147] by the PET cyclization of 176 (Scheme 36). 

Five-membered carbocycles Ethoxycyclopropane reacted with TCNE in various sob vents. In dioxane and acetonitrile 3-ethoxy-1,1,2,2-cyclopentane-tetracarbonitrile 375 was the only product. Performing the reaction in benzene also yields a ring-opened enol ether, which reacts further with TCNE . 

Certain alkane- and arenesulfonic acids are well known and widely used catalysts in organic transformations (27). Metanesulfonic acid, alone or in conjunction with P2O5, is applied in cyclocondensations to form carbocyclic or heterocyclic compounds (28a). p-Toluenesulfonic acid is a toxic compound applied usually as monohydrate (28b). It is most useful in the protection of ketones to form acetals and to transform ketones to enol ethers and acetates. Further uses include esterification, dehydration, rearrangement, and isomerization. 

Shibasaki and co-workers used a ring-closing metathesis approach to prepare a number of five-, six-, and seven-membered rings from electron-deficient olefins. Treatment of acyclic enol ether 18 with 7 mol % of 3 in refluxing benzene provided the corresponding cyclic enol ether 19 in 94% yield. Deprotection of the silyl ether 19 (not shown) resulted in the corresponding cyclic ketone, a valuable synthetic intermediate in natural products synthesis and a number of industrial processes. The authors reported additional examples of the synthesis of five-membered ring carbocycles as part of this study. 

Independently, Aggarawa and co-workers prepared five-, six-, and seven-membered carbocyclic methyl and silyl enol ethers bearing phenyl and... 

Aggarawa and co-workers applied their strategy for the synthesis of five- and six- membered ring carbocyclic silyl enol ethers to the the synthesis of seven-membered ring carbocyclic silyl enol ether bearing a phenyl substituent. Substrate 230 required upward of 20 mol % of 4 in refluxing benzene to achieve modest yields of the desired product 231. 

Arene oxidation leading to direct C—C bond formation allows rapid assembly of complex and ste-reochemically rich carbocyclic ring systems. Crucial to the success of this approach is the identification of carbon nucleophiles that are stable in the presence of oxidation agents typically used to effect arene dearomatization. Enolates and enol ethers are problematic as these species undergo rapid oxidation under mild conditions [62]. Stabilized enolates (such as those derived from activated methylenes) exhibit greater compatibility with oxidation conditions and have been used as nucleophilic participants in intramolecular oxidative dearomatizations initiated by [Fe(CN)g] and PIDA to afford spirocyclic cyclohexadienones [63, 64]. Detailed mechanisms for these reactions have not been defined so it is unclear whether bond formation occurs through ionic or radical intermediates. 

A. Carbocyclic - A few new methods are available to prepare the steroidal skeleton. For tne most part, these involve variations of the previously reported methods for the total synthesis of steroids. Racemic equilenin is prepared stereo-specifically starting with 2-bromo-6-methoxynaphthalene and the i "butyl enol ether of 2-methyl-l,3-cyclopentanedione. Estrone was prepared from the cheap natural product eugenol the key intermediate m-methoxyallylbenzene. Progress toward the total synthesis of terpenes, specifically the pentacyclic triterpene alnusenone, is reported. The synthesis of B-nor, B-nor-D-homo, or normal steroids by the use ot an electrophilic reagent on a bicyclic enamine is recorded. In addition, a bicyclic intermediate can be converted into a D-homo-8g-methyl-B-norestrane. ... 

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