Enol etherification

Cross-conjugated dienones are quite inert to nucleophilic reactions at C-3, and the susceptibility of these systems to dienone-phenol rearrangement precludes the use of strong acid conditions. In spite of previous statements, A " -3-ketones do not form ketals, thioketals or enamines, and therefore no convenient protecting groups are available for this chromophore. Enol ethers are not formed by the orthoformate procedure, but preparation of A -trienol ethers from A -3-ketones has been claimed. Another route to A -trien-3-ol ethers involves conjugate addition of alcohol, enol etherification and then alcohol removal from la-alkoxy compounds. 

However, 17a,21-acetonides (103), as well as acetals of other ketones or aldehydes, can be easily prepared by acid-catalyzed exchange reaction with dimethoxypropane or other alkyl acetals in dimethylformamide or benzene. Enol etherification of the A -S-ketone also occurs with the former procedure. 

A Dieckmann reaction of 7 and enol etherification provided trans-octalone 6 in 90% yield. An additional 10% of the transposed /3-ethoxy -enone 24 was also isolated. Compound 24 could easily be removed chromatographically (the first chromatography of the synthesis) and could be isomerized back to the 9 1 mixture in favor of 6 by resubjection to the etherification conditions. Compound 7 had three different CC Et groups, yet only the one adjacent to the CN group was attacked by the nascent ketone enolate. This selectivity, attributed to the effect of the powerfully electron-withdrawing CN group, was expected, as it was observed previously in the preparation of 3c.3 The selectivity of the enol ether formation was also expected from previous work. 

Enol etherification. 3-Ethoxy-A -cyclohexenone, the enol ether of dihydroresorcinol, was obtained similarly by refluxing followed by azeotropic distillation in 6-8 hrs. ... 

Enol etherification 2,2-Dimethoxypropane. p-Toluenesulfonic add. Triethyl orthoformate. Enzymes, titration N-rrans-Cinnamoylimidazole. 

Alkoxycarbonylmethyl enol ethers. A convenient preparation of these enol ethers from carbonyl compounds is by a Rh2(OCOCF3)4-catalyzed reaction of a diazoacetic ester. The enol etherification is applicable to a-pyridone. 

Symmetrical labile ethers such as cycloalkenyl ethers (15) or mixed acetals (16) can also be prepared from the 3-hydroxyl group by acid-catalyzed exchange etherification or by acid-catalyzed addition to cyclohexanone methyl enol ether. 

A survey of Wacker-type etherification reactions reveals many reports on the formation of five- and six-membered oxacycles using various internal oxygen nucleophiles. For example, phenols401,402 and aliphatic alcohols401,403-406 have been shown to be competent nucleophiles in Pd-catalyzed 6- TZ /fl-cyclization reactions that afford chromenes (Equation (109)) and dihydropyranones (Equation (110)). Also effective is the carbonyl oxygen or enol of a 1,3-diketone (Equation (111)).407 In this case, the initially formed exo-alkene is isomerized to a furan product. A similar 5-m -cyclization has been reported using an Ru(n) catalyst derived in situ from the oxidative addition of Ru3(CO)i2... 

A broad range of compounds can be O-alkylated with carbene complexes, including primary, secondary, and tertiary alcohols, phenols, enols, hemiaminals, hydroxylamines, carboxylic acids, dialkyl phosphates, etc. When either strongly acidic substrates [1214] and/or sensitive carbene precursors are used (e.g. aliphatic diazoalkanes [1215] or diazoketones) etherification can occur spontaneously without the need for any catalyst, or upon catalysis by Lewis acids [1216]. 

The fluoro-lactonization of alk-4-enoic acids and the fluoro-etherification of alk-4-enols with pentachloro-l-fluoropyridinium triflate (lo) proceed smoothly in a regioselective manner when the substrates contain an aryl substituent on the double bond.63 Some stereospecificity is observed in the case of 5-exo ring closure, possibly due to participation of the oxygen atom in the aryl-stabilized cationic intermediate. 

Enol-phosphates and thioketal-mediated etherification for the construction of the EFGH ring skeleton ofbrevetoxin A... 

The cyclizations of 85 to 86 and of 87 to 88 represent the simple cases in which the internal nucleophile is the OH group of an alcohol [64,65]. An in situ generated hydroxy group, as in the addition of alcohols to carbonyl compounds, can also participate in phenylseleno-etherification reactions. This is examplified by the conversion of 89 into 90 in the presence of benzyl alcohol [66]. Another type of OH, which gives rise to these reactions is the enolic OH of /1-dicarbonyl compounds. Thus, Ley reported that compounds like 91 and 93 can be transformed into the cyclic derivatives 92 and 94 by treatment with N-PSP 11 in the presence of zinc iodide [67]. The cyclization of 95 to 96 represents a simple example of the selenolactonization process [68, 69]. It is interesting to note that the various cyclization reactions indicated in Scheme 14, which require different electrophilic selenenylating agents, can all be effected with phenyselenyl sulfate [70]. 

In a series of elegant studies, Paquette and coworkers demonstrated the potential of the Claisen rearrangement for the stereocontrolled total synthesis of natural products. Dehydrative coupling of (2)-3-(trimethylsilyl)-2-propen-l-ol with cyclohexanone (51) under Kuwajima s conditions, followed by rearrangement of enol ether (52) in decalin, led in excellent stereoselectivity (>99 1) to aldehyde (53 Scheme 8). Concise construction of the eight-membered core of acetoxycrenulidine was achieved by intramolecular phenylseleno etherification of lactone (54), introduction of the exocyclic vinyl ether double bond by selenoxide elimination and subsequent Claisen rearrangement (Scheme 9, 66% from 54). ... 

Alkylation of heterofunctionalities. Etherification of alcohols can be conducted in the absence of solvent using a polyether." The O-alkylation of 1-perfluoro-alkyl-2-fluoroethanols is accompanied by dehydrofluorination thus the products are enol ethers. Selective (9-alkylation of o-aminophenols is observed, and an efficient method for the synthesis of triaryl phosphates from sodium phenolates and... 

On heating methylbutenol (9.21) with 2-methoxypropene (9.27) (which is the methyl enol ether of acetone), a /ra .v-etherification occurs with the elimination of methanol and the formation of the allyl vinyl ether (9.28). This ether is perfectly set up for a Claisen rearrangement, which it undergoes, to produce methylheptenone (9.5). 

An interesting contrast is provided by the reported behaviour of l,l-bis(inethoxy-carbonyl)-3,3,-bis(trifluoromethyl)propadiene (144) with watcr,i which apparently leads to a stable enol not accompanied by StsT type products. The enol (153) was converted by diazomethane etherification into the product of methanol addition (154) (see Scheme 43). 

For example, the enolate 77 is obtained by reacting 68 with hydrogen peroxide in an alkaline medium. Hydrogenation and ketal formation then yield the astaxanthin precursor 71. Reduction of 77 with zinc in formic acid followed by etherification produce the canthaxanthin synthon 72 [83]. 6-Oxoisophorone 68 can be reduced enantioselectively with baker s yeast to give the diketone 78. Raney nickel hydrogenation of this gives the zeaxanthin precursor 73 [84] (Scheme 23). 

Homoallyl bromide 314, prepared from readily available non-racemic ester 313, was converted to the Grignard reagent, which reacted with non-racemic epoxide, derived from D-maUc acid, to afford the alcohol 305. Ozonolysis of the alkene gave a ketone, which was converted into enol tri-flate 316. Ni-catalyzed cross coupling with trimethylsilylmethyl magnesium chloride afforded the allyl silane, which was converted into the allyl stan-nane 317. The asymmetric allylation of 313 with 317 provided 304 with a ration of 8.5 1. Methyl etherification and oxidative cleavage of exo-methylene... 

The 1,5-anti-aldol reaction was performed with chiral boron enolate of 325 and aldehyde 327, prepared by Evans asymmetric alkylation, cross metathesis, and Wittig homologation (Scheme 72), to afford 324 with a 96 4 diastereoselectivity. Stereoselective reduction of C9-ketone provided the 5y -l,3-diol, which was exposed to catalytic f-BuOK to give 2,6-cis-tetrahyderopyran 333 via an intramolecular Michael reaction. Finally, methyl etherification, deprotection, hydrolysis of ester, and Yamaguchi macrolac-tonization yielded the leucascandrolide macrolide 201 (Scheme 73). 

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