Isopropylidene acetals, deprotection

Scheme 24. Selective deprotection of sugar di-O-isopropylidene acetals using acid zeolites.

Selective removal of one isopropylidene group from a diacetal may be achieved by a variety of procedures, most of them involving protic or Lewis acids.100 Particularly common is the hydrolysis of the acetal engaging of the primary position of di-O-isopropylidene derivatives. Bhaskar et al,101 studied the selective deprotection of di-O-isopropylidene acetals derived from D-glucose, D-xylose, and D-mannose, using acid zeolites and montmorillonite K-10. When 102 was submitted to acid hydrolysis in aqueous methanol, the best yields (85—96%) for the monoacetal 105 were obtained when H-beta and HZSM-5 zeolites were employed as catalysts (Scheme 24, Table IV). HY zeolite proved to be ineffective, whereas the yield obtained for the montmorillonite K-10-catalyzed reaction was low (22%). The zeolites found most effective were then used for the hydrolysis of the diacetal 103 and 104, providing excellent yields for the desired corresponding monoacetals 106 and 107. 

A. Agarwal and Y. D. Vankar, Selective deprotection of terminal isopropylidene acetals and trityl ethers using HCIO4 supported on silica gel, Carbohydr. Res., 340 (2005) 1661-1667. 

Diastereoselective reduction of the aldol 221/ can be achieved using AIH3 in toluene at —78°C. The corresponding ra-diol is preferentially formed. The diol can be protected with isopropylidene acetal to provide tricyclic compound 222. This can be converted to conformationally rigid C-l ketone 223 by deprotection of the PMB group and successive oxidation with PDC (Scheme 7-73). 

The reaction was slow (15 h) but the yield of the diol product was 86%. The silica gel is not essential because iron(IIl) chloride hexahydrate in dichloromethane also deprotects isopropylidene acetals [Scheme 3-14],16... 

Oxidative debenzylatlon using dimethyldioxirane2 4 proceeds well with benzyl ethers of primary and secondary alcohols and the method is compatible with silyl ethers. Isopropylidene acetals are stable but benzylidene acetals are cleaved. The deprotection of p-bromo, p-cyano and 2-naphthylmethyl ethers can also be accomplished. 

Recently, an environmentally benign phosphomolybdic acid supported on silica gel has been used for the chemoselective deprotection of TBS ethers in carbohydrate derivatives (O Scheme 53). The mild conditions are compatible with the presence of other protecting groups such as isopropylidene acetal, OTBDPS, OTHP, OAllyl, OBn, OAc, OBz, N-BOc, N-CBz, and N-Fmoc which are stable under the reaction conditions. Another advantage of this procedure is that the catalyst can be readily recovered and recycled [327]. 

The simultaneous protection of the 3 and 5 hydroxy groups of nucleosides and the 4,6- or 3,4-hydroxyls of hexopyranoses is a common problem in organic synthesis In the case of hexopyranoses, we have already seen that benzylidene acetals and, in certain circumstances, isopropylidene acetals can be used to good effect. An alternative silicon-based group would offer a wider repertoire of conditions for mild deprotection and such a group was devised by Markiewicz the 1,1,3,3-tetraisopropyldisiloxanylidene group (abbreviated TIPDS). TIPDS groups are stable to water, 0.3 M p-toluenesulfonic acid in dioxane, 10% tri-fluoroacetic acid in chloroform, 5 M ammonium hydroxide in dioxane-H20 (4 1), and tertiary amines in pyridine. 

Once in place, both isopropylidene and benzylidene functionality survive many routine synthetic operations and, when no longer required, may be readily removed by hydrolysis. Two aspects of acetal deprotection are of interest here (1) partial hydrolysis of bis-acetals, particularly bis(isopropylidenes) and (2) protecting group interchange, particularly of benzylidenes. 

P. M. Bhaskar, M. Mathiselvam, and D. Loganathan, Zeolite-catalyzed selective deprotection of di- and tri-O-isopropylidene sugar acetals, Carbohydr. Res., 343 (2008) 1801-1807. 

Alkyl (or acyl) derivatives of the 6-amino-6-deoxy carbohydrates are examples of derivatives in which the hydrophilic and hydrophobic moieties are linked at other positions than C-1. Thus 6-amino-6-deoxy-D-galactose derivatives 34 were prepared from l,2 3,4-di-0-isopropylidene-6-0-tosyl-a-D-galacto-pyranose by the following reactions (1) substitution of the leaving group at C-6 by a phthaloyl function, (2) hydrazinolysis to afford a 6-amino-6-deoxy intermediate, (3) reaction of acyl or sulfonyl chlorides at the amino function, (4) deprotection of the acetal rings to afford the expected glycolipid 34 [56]. 

Mild conditions for the selective deprotection of the acyclic diethyl acetal in Scheme 2.48 without collateral destruction of the adjacent isopropylidene group entailed treating the substrate with excess chlorotrimethylsilane in the presence of silica.105... 

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... 

Trost first introduced the di-fe/7-butylsilylene derivative as a means for protecting 1,2- and 1,3-diols during a synthesis of PiUaromycinone derivatives.213 Di-ferf-butylsilylene derivatives are not as robust as isopropylidene or benzylidene acetals and their use is best reserved for systems requiring deprotection under very mild conditions. Di-isopropylsiiylene derivatives are occasionally used but they usually only survive in highly crowded environments.214 Di-feri-butylsily-lene derivatives survive hydroboration with 9-BBN, mild oxidation (e g the Dess-Martin, ozone), Lewis acids such as trifluoroborane e the rate and titanium tetrachloride, mild acids (pyridinium p-toluenesulfonate). camphorsulfonic acid, strong bases such as feri-butyllithium (THF, -50 °C), DDQ, and sodium meth-oxide in methanol at 0 C — conditions used to cleave acetate esters. 

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