Acetal, 4-methoxybenzylidene

The p-methoxybenzylidene acetal is a versatile protective group for diols tl undergoes acid hydrolysis 10 times faster than the benzylidene group. ... 

The p-methoxybenzylidene ketal can be prepared by DDQ oxidation of a p-methoxybenzyl group that has a neighboring hydroxyl. This methodology has been used to advantage in a number of syntheses. " In one case, to prevent an unwanted acid-catalyzed acetal isomerization, it was necessary to recrystallize the DDQ and use molecular sieves. The following examples serve to illustrate the reaction " ... 

Acetonide Derivative 11. Benzylidene Acetal 13. p-Methoxybenzylidene Acetal 18. Methoxymethylene Acetal 20. Dimethoxymethylenedioxy Derivative... 

The IAD concept via p-methoxybenzylidene acetals was also shown to be suitable for polymer-supported syntheses of disaccharides (Scheme 5.107) [292], A suitable p-allyloxybenzyl group at position 2 of a 1-thio-mannosyl donor is first converted into a PEG-modified benzyl group that allows for the convenient isolation of the intermediate tethered glycosides. 

The synthesis of (3-D-fructofuranosides is yet another useful application of this concept [293-295]. The latter 1,2-cis-glycosidic linkage is as difficult to establish as in the case of (3-mannosides. In an elegant synthesis of a-D-fucofuranose-containing disaccharides, Plusquellec and coworkers used the IAD concept via p-methoxybenzylidene acetals in combination with a glycosylation protocol via pentenyl glycosides. Here, the intermediate NIS-adduct could be isolated (Scheme 5.108) [295]. 

The anodic oxidation of a number of 1-arylmethylenesemicarbazides (60) has been studied in CH3CN-AcOH containing sulfuric acid.118 This method provides a convenient preparative route to either oxadiazole (61) or triazoli-none (62) derivatives. The reactions were very sensitive to the concentration of water and under ordinary conditions the oxadiazole (61) is formed in 85% yield by oxidation of l-(p-methoxybenzylidene)semicarbazide. By addition of acetic anhydride, in order to reduce the water content, the triazolinone derivative 62 was formed in 45% yield [Eq. (50)]. 

The use of a Lewis acid (e.g., friethylfluoroborate, zinc chloride, stannous chloride, titanium chloride, iron(m)chloride) and other reagents (e.g., iodine, trimethylsilane, trifluoiomethane-sulfonylsilane) have also been recommended. Exhaustive lists of catalysts and conditions can be found in reviews devoted to carbohydrates [5-7], or to general organic chemistry [27,28], However, one can add the new catalyst, which has been introduced for the smooth formation of p-methoxybenzylidene acetals and p-methaxy-phenylmethyl methyl ether [29], namely 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), and has been applied very recently [30] to the synthesis of isopropylidene mixed acetals. 

Y. Oikawa, T. Yoshioka, and O. Yonemitsu, Protection of hydroxy groups by intramolecular oxidative formation of methoxybenzylidene acetals with DDQ, Tetrahedron Lett. 889 (1982) Y. Oikawa, T. Nishi, and 0. Yonemitsu, Kinetic acetalatioa for 1,2- and 1,3-diol protection by the reaction of p-methoxyphenylmethyl methyl ether with DDQ, Tetrahedron Lett 4037... 

Reductive cleavage, using the NaCNBHj-HCl-THF system to produce 2 -pro-penylidene acetals, produced the same regioselectivity as that found in benzylidene acetals [27] (Scheme 11), and also for the p-methoxybenzylidene acetals (Scheme 12) [27]. These observations open the way to further strategies for protecting group manipulations. 

Due to the neutral and very mild conditions used in TPAP oxidations, virtually all protecting groups remain unaffected, including the very oxidant-sensitive PMB ethers77 and p-methoxybenzylidene acetals 78 and the very acid-sensitive TMS ethers.76... 

Compound 41 thus formed was elaborated into the common nonenolide core of ascidiatrienolide A and the didemnilactones by reductive opening of the p-methoxybenzylidene acetal with NaBH3CN in the presence of ethereal HCl, followed by a virtually quantitative Mitsunobu reaction of the resulting alcohol... 

Acid-catalysed hydrolysis offers a cheap and obvious method for the cleavage of arylmethylene acetals but oftentimes the conditions required (or pH 1) can be quite harsh, e.g. dilute sulfuric acid at elevated temperature. The lability of arylmethylene acetals can be enhanced both electronically or sterically. For example, p-methoxybenzylidene acetals hydrolyse about 10 times faster than benzylidene acetals79 owing to participation of the p-methoxy substituent in resonance stabilisation of the oxonium intermediate as illustrated by the hydrolysis shown in Scheme 3.48.80 p-Methoxybenzylidene acetals can be hydrolysed in 80% aqueous acetic acid at room temperature. 

A prospective difference in the rates of hydrolysis of a mesitylmethylene acetal and a p-methoxybenzylidene acetal in substrate 5L1 (Scheme 3.52] was a critical design feature in a synthesis of Erythromycin by Martin and co-workers.83 The plan was to liberate the C3 and C5 hydroxyls protected as a p-methoxybenzylidene acetal to make way for the attachment of two monosaccharides whilst... 

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... 

Owing to the higher acid and hydrolytic lability of p-methoxybenzylidene acetals, they are usually made by acetal exchange processes using anisaldehyde di-methylacetal and pyridinium p-toluenesulfonate or camphorsuifonic add [Scheme 3.80].149 Alternatively, the Noyori protocol can be implemented under very mild conditions [Scheme 3.81].150... 

Another demanding oxidative cyclisation to a p-methoxybenzylidene acetal taken from a synthesis of Swinholide A by Paterson and co-workers1 2 is shown in Scheme 3.83. Note the preservation of the labile di-fer/-butylsilylene group (see section 3,4). Other applications of the reaction to complex natural product synthesis include Oleandolide,88 Discodermolide153 and the Denticulatins.154... 

In cases where an isopropytidene acetal resists hydrolysis, the more labile p-methoxybenzylidene acetal can be used. The final steps of Mukaiyama s synthesis of Taxo 346 were impeded by difficulties associated with the esterification reaction by which the N-benzoylphenylisoserine side chain was attached to the Baccatin III core [Scheme 8.159]. Side chains protected as cyclic N 0-acetals were more reactive because of lower steric hindrance even so, the isopropyli-dene derivative of N-benzoylphenylisoserine (159.1) gave incomplete conversion (64%). Moreover, the isopropylidene group was resistant to hydrolysis. However, the corresponding p-methoxybenzylidene derivative (159.2) esterified the Baccatin III core (1593) in 95% yield and 93% conversion and it hydrolysed with aqueous trifluoroacetic acid at 0 cC to give Taxol in 93% yield. 

Methylazoxymethyl acetate Tris[l-(2-methyl)aziridinyl]phosphine Tris[l-(2-methyl)aziridinyl]phosphine sulfide Methacrylamidopropyltrimethylammonium chloride Methylaluminium sesquichloride W,W -Methylenebisacrylamide A-(p-Methoxybenzylidene)-p-butylaniline 1 - Methyl-1 -benzyloxy ethyl... 

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