P-Methoxybenzyl ether

NBS, CH3CN, H2O, 62-90% yield.The POM group has been selectively removed in the presence of an ethoxy ethyl ether, TBDMS ether, benzyl ether, p-methoxybenzyl ether, an acetate, and an allyl ether. Because the hydrolysis of a pentenyl 2-acetoxyglycoside was so much slower than a pentenyl 2-benzyloxyglycoside, the 2-benzyl derivative could be cleaved selectively in the presence of the 2-acetoxy derivative. The POM group is stable to 75% AcOH, but is cleaved by 5% HCl. 

Protection of alcohols. Even somewhat hindered secondary alcohols or tertiary alcohols are converted into (p-methoxybenzyloxy)methyl (PMBM) ethers by reaction with 1 and diisopropylethylamine in CH2C12 for 3-30 hours. Deprotection can be effected by oxidation with DDQ (65-95% yield), a method previously recommended for deprotection of p-methoxybenzyl ethers (11, 166-167). 

Two closely related methods for the direct transformation of THP ethers into TBDMS ethers, using TBDMSOTf and a tertiary amine base, have been disclosed72,73. This reagent system has been reported74 to perform the same transformation on t-butyl and t-amyl ethers. In a similar vein75, p-methoxybenzyl ethers are converted directly into the corresponding silyl ethers using TMSOTf and triethylamine. 

Mercury(II) pivalate, 319 Mercury(II) trifluoroacetate, 320 Mesembranol, 169 a-Methallyl alcohol, 258 Methanesulfinyl chloride, 248 Methanesulfonic acid, 321 Methanesulfonyl chloride, 322 Methanol-sodium tetraborate, 322 Methoxyamine, 322-323 et Methoxy-a-arylacctic acid esters, 411 p-Methoxybenzyl ethers, 166, 167 Mcthoxycarbonylketene, 340, 341 4(R)-Methoxycarbonyl-l,3-thiazolidine-2-thione, 323-324... 

Since 1,4 addition of a variety of appropriate aryl caibanions to 36 failed, an intramolecular version of the Heck reaction was examined. With this end in view, the ketone 36 was reduced stereospecifically to the corresponding allyl alcohol which was then protected as its p-methoxybenzyl ether 37. The amine, obtained on reduction of the azide 37, was condensed with 6-bromopiperonylic acid to furnish the amide 38. 

An intermediate in the synthesis of laulimalide by Davidson8 illustrates the differential protection of alcohols. The starting materials 56 and 57 already have an alcohol protected as a TBDMS silyl ether and a diol protected as an acetal. The alcohol in 58 is protected as a p-methoxybenzyl ether and the acetal hydrolysed by acetal exchange to give the free diol 60. Selective protection of the primary alcohol by a bulky acyl group (pivaloyl, i-BuCO ) 61 allows silylation of the secondary alcohol with a TIPS group 62. Finally the pivaloyl group is selectively removed by DIBAL reduction to release just one free alcohol 63. 

Later on, all the protecting groups will be removed the silyl groups with fluoride and the p-methoxybenzyl ether by oxidation with Ce(IV). In Ley s recently completed synthesis9 of azadirachtin 64 after 22 years of hard labour the key intermediate was 65. You will notice benzyl ethers, acetals and a silyl ether. This is a more modem, one might almost say minimalist, use of protection. In an ideal world no protecting groups would be necessary but in a real synthesis they will almost certainly be required as we shall see in the rest of the book. But our aim should be to keep them to a minimum. 

Lewis acids can also be exploited for the cleavage of isopropylidene derivatives. One of the mildest examples comes from a synthesis of Lankacidin in which cleavage of an isopropylidene acetal without harm to a p-methoxybenzyl ether was effected with copper(Il) chloride dihydrate in methanol at reflux [Scheme 3.11].13 Alternatively, zinc(II) nitrate hexahydrate in acetonitrile at 50 DC can be used in which case even a primary tert-butyldimethylsilyl ether survives [Scheme 3.12].14 During a synthesis of Quinocarin, Katoh and co-workerscleaved an isopropylidene group using iron(IIT) chloride adsorbed onto silica gel [Scheme 3.13]. 

DDQ. a reagent typically used to deprotect p-methoxybenzyl ethers (see section 4.3 4), has been used for the deprotection of acetals19 and thioacetals.20 The use of 0.1 -0.4 equivalents of DDQ in acetonitrile-H20 (9 1) cleaves isopropylidene groups at room temperature to 80 C without affecting p-toluenesulfonyl, benzoyl, benzyl, or acetate groups. Monosubstituted dioxolanes [Scheme 3.17]21 are more readily hydrolysed than bicyclic, spirocyclic, and disubstituted systems and 1,3-dioxanes are more labile than 1,3-dioxolanes. Removal of dithioacetals requires 2 equivalents of DDQ at 80 °C... 

The relative ease of acid-catalysed hydrolysis (0.53 M sulfuric acid in 2 1 aqueous 2-propanol at room temperature) follows the order cyclopentylidene > isopropylidene > cyclohexylidene. For example, the half life for the hydrolysis of 1,2-0-alkylidene-cx-D-glucopyranoses followed the order cyclopentylidene (8h), isopropylidene (20 h), cyclohexylidene (124 h).57 The higher acid lability of cyclopentylidene acetals has been frequently exploited in synthesis. Thus, aqueous or ethanolic acetic acid at room temperature is able to liberate a 1,2-diol in the presence of an isopropylidene group [Scheme 3.37],5R an 0-trityl group [Scheme 3.38]59 and a p-methoxybenzyl ether but not a tetrahydropyra-nyl group [Scheme 3.39],60... 

The regiochemistry of reductive cleavage of p-methoxybenzylidene acetals depends on the substrate and the reaction conditions. By suitable choice of solvent and electrophile, the distribution of regioisomers can be controlled in some cases. For example, sodium cyanoborohydride cleaved glucose derivative 66.1 [Scheme 3.66] selectively to the 6-0-p-methoxybenzyl ether 663 using trifluoro-acetic add as electrophile and DMF as solvent whereas the 4-Op-methoxy-benzyl ether 663 predominated when chlorotrimethylsilane was used as electrophile in acetonitrile as solvent.115 Note, however, that application of the latter conditions to the p-methoxybenzylidene acetal 67,1 [Scheme 3.67] gave the p-methoxybenzyl ether of the less hindered primary hydroxyl as well as rearrangement of the isopropylidene acetal,116... 

Oxidative cyclisation of p-methoxybenzyl ethers can be used to accomplish de-svmmetrisation of 1,3,5-triols with good to excellent regioselectivity [Scheme... 

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