Alkyl enol ethers

In the prostaglandin synthesis shown, silyl enol ether 216, after transmetaJ-lation with Pd(II), undergoes tandem intramolecular and intermolecular alkene insertions to yield 217[205], It should be noted that a different mechanism (palladation of the alkene, rather than palladium enolate formation) has been proposed for this reaction, because the corresponding alkyl enol ethers, instead of the silyl ethers, undergo a similar cyclization[20I],... 

Acetals of benzaldehydes may undergo EGA-catalyzed aldol reactions also with alkyl enol ethers, (22) (R = alkyl), as nucleophiles [31] but in contrast to the reaction with enol silyl ethers the threo isomer is favored in this case. 

Scheme 9. Reaction with alkyl enol ethers is unsuccessful for acetals of aliphatic aldehydes [31].

An enantioselective intramolecular Pauson-Khand reaction based on chiral auxiliary-directed 7t-face discrimination in acetylenic 0-alkyl enol ether-dicobalt hexacarbonyl complexes, which proceeds with good yields and high facial diastereoselectivity, has recently been developed by M.A. Pericas, A. Moyano, A.E. Greene and their associates. The method has been applied to an enantioselective formal synthesis of hirsutene. Moreover, the process is stereodivergent and the chiral auxiliary -rran5-2-phenylcyclohexanol- is recovered in a yield as high as 92% [18]. 

Silyl enol ethers, enol esters and alkyl enol ethers of ketones and aldehydes can be C-alkylated with reactive alkylating agents in the presence of Lewis acids86-90. However, information regarding the use of these reactions for diastereoselcctive or asymmetric synthesis is still limited. 

Alkyl enol ethers and vinyl sulfides may also be oxidatively annulated onto electron-rich aromatic rings (Scheme 71)168. 

Simmons-Smith regioselective cyclopropanation of a-enone alkyl enol ethers also provided 1-alkoxyvinylcyclopropanes in high yields43 . 

Other known methods for preparing O-alkyl enol ethers include, most notably, alcohol elimination from acetals, double bond isomeri2ation in allylic ethers, reduction of alkoxy enol phosphates, and phosphorane-based condensation approaches.5 These methods, however, suffer from poor stereoselectivity, low yields, or lack of generality, if not a combination of these drawbacks. 

Photocyclization of A -alkylfuran-2-carboxyanilides conducted in inclusion crystals with optically active tartaric acid-derived hosts led to the formation of tricyclic /ra r-dihydrofuran compounds with up to 99% ee <1996JOC6490, 1999JOC2096>. 2-(/>-Alkoxystyryl)furans underwent photocyclization to give 5-(3-oxo-(/ )-butenyl)benzo[ ]furans as the predominant isomers in undehydrated dichloromethane as shown in Equation (59). The intermediate alkyl enol ether could be obtained by performing the reaction in anhydrous benzene <1999OL1039>. 

A furoannulation protocol via dichlorocarbene adducts of alkyl enol ethers has been applied to the synthesis of the furanosesquiterpene pallescensin A (Equation 39) <2006TL6817>. 

B. Alkyl Enol Ethers and Silyl Enol Ethers... 

Whereas alkyl enol ethers easily polymerize upon treatment with electrophilic reagents [202], silylated enol ethers are rapidly desilylated after the electrophilic attack, and regeneration of the carbonyl group prevents polymerization. Therefore, silyl enol ethers are frequently used reagents for synthesizing a-substituted carbonyl compounds (Scheme 45) [200,201,203-205]. 

Alkyl enol ethers polymerize under these conditions, and their reactivity, as that of other strong nucleophiles, has been determined with the LASER flash method (Table 7). Because this method of carbocation generation produces the nucleophilic counterions CL, eventual polymeriza-... 

Scheme 48, which compares silyl and alkyl enol ethers of analogous structure, shows that the two classes of compounds have similar reactivities. Although the rate constants for the bis(p-chlorophenyl)-carbenium... 

The comparable process for alkyl enol ethers involves participation of solvent,residual peiacid or water ° in cleaving the initially formed epoxide.Thus vinyl ether (74) produces the a-hydroxy derivative directly, while (75) provides the dimethoxy acetal. ... 

In the case of alkyl enol ethers the normal oie process competes with solvent incorporated and 1,2-di-oxetane products. Here however the ene process seems to be less inevitaUe when allylic protons are available and the product distribution may be effectively contndled by manipulation of solvent and temperature combinations. Best results are nonetheless achieved where the competitive processes are restricted. Thus enol ether (79) produces hydroxylated dimethoxy acetal (W) via direct incorporation of methanol or through reduction of the 1,2-dioxetane (81). 

Treatment of enol acetates with LTA in acetic acid affords a-acetoxy ketones. Fa example die tetracyclic substrate (82) is converted to the a-acetoxy doivative (83) in 95% yield and provides a stqi in the total synthesis of cycloneosamandione. Vinyl ethos react similarly, suggesting that alkyl enol ethers should follow suit... 

Since the report by Carboni and Lindsey in 1959 on the cycloaddition reaction of tetrazines to multiple bonded molecules as a route to pyridazines, such reactions have been extensively studied. In addition to acetylenes and ethylenes, enol ethers, ketene acetals, enol esters and enamines, and even aldehydes and ketones have been used as starting materials for pyridazines. A detailed investigation of various 1,2,4, 5-tetrazines in these syntheses revealed the following facts. In [4 + 2] cycloaddition reactions of 3,6-bis(methylthio)-l,2,4,5-tetrazine with dienophiles, which lead to pyridazines, the following order of reactivity was observed (in parenthesis the reaction temperature is given) ynamines (25°C) > enamines (25-60°C) > ketene acetals (45-100°C) > enamides (80-100°C) > trimethylsilyl or alkyl enol ethers (100-140°C) > enol... 

Very few pericyclic reactions of carbene complexes have been studied that are not in the cycloaddition class. The two examples that are known involve ene reactions and Claisen rearrangements. Both of these reactions have been recently studied and thus future developments in this area are anticipated. Ene reactions have been observed in the the reactions of alkynyl carbene complexes and enol ethers, where a competition can exist with [2 + 2] cycloadditions. Ene products are the major components firom the reaction of silyl enol ethers and [2 + 2] cycloadducts are normally the exclusive products with alkyl enol ethers (Section 9.2.2.1). As indicated in equation (7), methyl cyclohexenyl ether gives the [2 -t- 2] adduct (84a) as the major product along with a minor amount of the ene product (83a). The t-butyldimethylsilyl enol ether of cyclohexanone gives the ene product 9 1 over the [2 + 2] cycloadduct. The reason for this effect of silicon is not known at this time but if the reaction is stepwise, this result is one that would be expected on the basis of the silicon-stabilizing effect on the P-oxonium ion. 

Only a few cases of the reduction of alkyl enol ethers to the corresponding alkene have been reported. a-Ethoxystyrene and related derivatives are reduced to alkenes by treatment with Grignard reagents. In addition, enol ethers of cyclohexanone derivatives have been cleaved to the cyclohexene products using either DIBAL at elevated temperatures or diborane/boron trifluoride etherate. By analogy to the hy-droboration of silyl enol ethers, this latter method involves formation of an intermediate p-ethoxy or-ganoborane which undergoes acid-catalyzed elimination to afford the alkene. 

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