Tetrahydropyranyl enol ethers

Enol ethers (15) and mixed acetals (16) are readily obtained from secondary but not from tertiary alcohols, whereas tetrahydropyranyl ethers can be formed even from tertiary alcohols. This is a result of the greater steric requirements of the reagents (17) and (18) as compared to (19). 

The tertiary 17) -hydroxyl group does not form bulky enol ethers and mixed acetals. However, tetrahydropyranyl ethers are obtained from 17a-ethynyl-17]3-hydroxy compounds. Tetrahydropyranyl ethers have also been prepared from tertiary 17a-hydroxyl groups. ... 

A similar reaction occurs when enol ethers react with alcohols in acid solution and in the absence of water, but now we are starting in the middle of the acetal hydrolysis mechanism and going the other way, in the direction of the acetal A useful example is the formation of THP (= TetraHydroPyranyl) derivatives of alcohols from the enol ether dihydropyran. You will see THP derivatives of alcohols being used as protecting groups in Chapter 24. 

A /S-substituted enol ether bearing a typical protecting group, such as tetrahydropyranyl in compound 554, has been prepared by deprotonation with s-BuLi and trapped with Mel... 

Tetrahydropyranyl (THP) protection of the hydroxy group of 48 yields a useful reagent for the Horner-Wadsworth-Emmons synthesis of enol ethers from carbonyl compounds.103 104... 

This procedure consists of the synthesis of a precursor, methoxymethyl vinyl ether, an a-hydroxy enol ether, and the intramolecular hydrosilylatlon of the latter followed by oxidative cleavage of the silicon-carbon bonds. The first step, methoxymethylation of 2-bromoethanol, is based on Fujita s method.7 The second and third steps are modifications of results reported by McDougal and his co-workers. Dehydrobromination of 2-bromoethyl methoxymethyl ether to methoxymethyl vinyl ether was achieved most efficiently with potassium hydroxide pellets -9 rather than with potassium tert-butoxide as originally reported for dehydrobromination of the tetrahydropyranyl analog.10 Potassium tert-butoxide was effective for the dehydrobromination, but formed an adduct of tert-butyl alcohol with the vinyl ether as a by-product in substantial amounts. Methoxymethyl vinyl ether is lithiated efficiently with sec-butyllithium in THF and, somewhat less efficiently, with n-butyllithium in tetrahydrofuran. Since lithiation of simple vinyl ethers such as ethyl vinyl ether requires tert-butyllithium,11 metalation may be assisted by the methoxymethoxy group in the present case. 

Kluge has also prepared the related phosphonate 6 by tetrahydropyranylation of di-ft-butyl hydroxymethylphosphonate. This reagent has the advantage over 1 in that the enol ethers corresponding to 3 are very easily hydrolyzed by acid. 

Hydroxyl protection. Enol ether 1 has been developed. A tetrahydropyranyl sulfoxide 2 is available for the formation of mixed acetals upon activation with Cp2ZrCl2-AgC104. The fluorous bromosilane 3 form siloxanes with improved acid stabilityA method for selective tosylation of diol systems that is known to be catalyzed by organotin oxides is also modifiable in terms of fluorinated catalysts. ... 

A second major class of acyl anion equivalents are the enol ethers such as methyl 1-propenyl ether (359). When 359 was treated with tert-butyllithium (note the need for a stronger base with the less acidic vinyl hydrogen) and then condensed with benzaldehyde, the product was 260. Lithiation of vinyl derivatives was described in Section 8.5. Facile hydrolysis with aqueous acid liberated the corresponding ketone (361), completing the acyl anion equivalency. Schlosser co-workers found that a mixture of 5ec-butyllithium and potassium tert-butoxide could be used to generate the lithium anion of O-tetrahydropyranyl enol ethers.360 This modification generates a product that is more easily hydrolyzed to the ketone. 

The use of the tetrahydropyranyl qroup allows the enol ether to be cleaved to the aldehyde under milder conditions than the normal methyl derivative. 

Schaub ° introduced methyl groups at both the 16a- and 17a-positions by 1,4-addition of methylmagnesium iodide to the A -20-ketone (8) followed by methylation of the intermediate 16a-methyl-17-enolate anion (9) with methyl iodide. After hydrolysis of the tetrahydropyranyl ether group a 40% yield of the 16,17-dimethyl derivative (10) was obtained. With the corresponding 3j -acetoxy derivative, the yield of (10) is only 20%. 

Podophyllotoxin enolate tetrahydropyranyl ether Glinski, M. B. et al., J. Org. Chem., 1987, 53, 2749-2753 Attempted preparation of 2-fluoropodophyllotoxin by treatment of the tetrahydropyranyl ether with perchloryl fluoride led to a violent explosion. 

Treatment of the tetrahydropyranyl ether methyl ester 1 under standard conditions with LDA (THF, — 78 °C) gives the enolate 2, which is presumed to have predominantly the (Z) configuration. Attack of an electrophile on 2 yields the a-alkylated-a-hydroxy ester derivatives 3 and 4126. 

The analogue in which carbon replaces oxygen in the enol ring should of course avoid the stability problem. The synthesis of this compound initially follows a scheme similar to that pioneered by the Corey group. Thus, acylation of the ester (7-2) with the anion from trimethyl phosphonate yields the activated phosphonate (7-3). Reaction of the yhde from that intermediate with the lactone (7-4) leads to a compound (7-5) that incorporates the lower side chain of natural prostaglandins. This is then taken on to lactone (7-6) by sequential reduction by means of zinc borohydride, removal of the biphenyl ester by saponification, and protection of the hydroxyl groups as tetrahydropyranyl ethers. 

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