Hydroxyl groups, reaction with benzyl

Benzyl 4, 6 -0-benzylidene-P-lactoside with five free hydroxyl groups was converted to the dibutylstannylene intermediate by azeotropic removal of water from its mixture with 2.5 molar equiv. dibutyltin oxide in benzene, the reaction with benzyl bromide in the presence of tetrabutylammonium bromide then gave the 2,3 -di-0-benzyl derivative in 52% yield [139]. When the 3, 4 -0-isopropylidene analog was treated with 1.2 molar equiv. only, the 2-O-benzyl derivative was the main product [150]. 

For GC analysis, the salts of the lowest molecular weight acids present in ozonation products subjected to base-promoted hydrolysis have been converted to their benzyl esters by reaction with benzyl bromide (Bonnet et al. 1989). The salts of all acids produced have commonly been converted to the free acids, usually with the aid of a cation exchange resin. The acids have then been converted to methyl esters by reaction with diazomethane (Bonnet et al. 1989) or, more often, have been converted to trimethylsilyl (TMS) esters (Matsumoto et al. 1986, Taneda et al. 1989, Habu et al. 1990). Trimethylsilylation has the major advantage that alcoholic and phenolic hydroxyl groups are simultaneously converted to TMS ethers, thus greatly facilitating GC analysis. 

The relative reactivity toward sodium of the hydroxyl groups at the various carbon atoms of a sugar has been exploited in order to prepare selected derivatives. By the addition of one molar equivalent of sodium to 4,5-0-isopropylidene-D-fucose dimethyl acetal in ethyl ether, followed by benzyl chloride, Schmidt and Wernicke were able to isolate a 42 % yield of 2-0-benzyl-4,5-0-isopropylidene-D-fucose dimethyl acetal. Freudenberg and Noe reacted molar equivalents of 1,2-0-isopropylidene-a-D-glucofuranose and sodium in boiUng dioxane. Subsequent reaction with benzyl chloride, and acetylation, gave a 29 % yield of crystalline 5,6-di-0-acetyl-3-0-benzyl-1,2-0-isopropylidene-a-D-glucose. 

The sequence starts out with the protection the hydroxyl group at C17 as its benzyl ether by reaction with benzyl chloride in the presence of base such as sodium carbonate (27-2). Treatment of a solution of the benzyl ether in acetic acid with / -toluenesulfonic acid causes the styrenoid bond to shift from the B-C ring fusion to the more transoid, and presumably more stable, 9,11-position. This now provides a means for activating Cn. Hydroboration with diborane... 

In order to suppress competing reactions, one often has to protect the other hydroxyl groups. 6-0-Benzyl-2,3, 4,5-di-O-isopropylidene-aldehydo-L-talose, for example, is converted by base into a mixture containing 95% of the protected L-galacto diastereomer. This isomer is formed because the 2,3-acetal ring with trans substituents is thermodynamically more stable than the original ring with cis substituents (Scheme 4.3.5). 

Benzyl ethers of carbohydrates are formed with both primary and secondary hydroxyl groups by reaction with benzyl chloride or bromide in a strong alkaline solution of the carbohydrate. The carbohydrate is dissolved directly in the benzyl halide, containing 4.5 M potassium hydroxide, and heated to 90-100 C for several hours [13] (reaction 4.17). Sometimes the carbohydrate is dissolved in dioxane or dimethylformamide (DMF), containing 4.5 M potassium hydroxide and benzyl halide, and heated for several hours. Difficult benzylations are accomplished by dissolving the carbohydrate in DMF that was treated with sodium hydride, similar to the Hakomori reagent, followed by the addition of benzyl halide [14]. 

In many cases, substituents linked to a pyrrole, furan or thiophene ring show similar reactivity to those linked to a benzenoid nucleus. This generalization is not true for amino or hydroxyl groups. Hydroxy compounds exist largely, or entirely, in an alternative nonaromatic tautomeric form. Derivatives of this type show little resemblance in their reactions to anilines or phenols. Thienyl- and especially pyrryl- and furyl-methyl halides show enhanced reactivity compared with benzyl halides because the halogen is made more labile by electron release of the type shown below. Hydroxymethyl and aminomethyl groups on heteroaromatic nuclei are activated to nucleophilic attack by a similar effect. 

The stereoselective reactions in Scheme 2.10 include one example that is completely stereoselective (entry 3), one that is highly stereoselective (entry 6), and others in which the stereoselectivity is modest to low (entries 1,2,4, 5, and 7). The addition of formic acid to norbomene (entry 3) produces only the exo ester. Reduction of 4-r-butylcyclohexanone (entry 6) is typical of the reduction of unhindered cyclohexanones in that the major diastereomer produced has an equatorial hydroxyl group. Certain other reducing agents, particularly sterically bulky ones, exhibit the opposite stereoselectivity and favor the formation of the diastereomer having an axial hydroxyl groi. The alkylation of 4-t-butylpiperidine with benzyl chloride (entry 7) provides only a slight excess of one diastereomer over the other. 

The importance of the o-hydroxyl moiety of the 4-benzyl-shielding group of R,R-BOX/o-HOBn-Cu(OTf)2 complex was indicated when enantioselectivities were compared between the following two reactions. Thus, the enantioselectivity observed in the reaction of O-benzylhydroxylamine with l-crotonoyl-3-phenyl-2-imi-dazolidinone catalyzed by this catalyst was 85% ee, while that observed in a similar reaction catalyzed by J ,J -BOX/Bn.Cu(OTf)2 having no hydroxyl moiety was much lower (71% ee). In these reactions, the same mode of chirality was induced (Scheme 7.46). We believe the free hydroxyl groups can weakly coordinate to the copper(II) ion to hinder the free rotation of the benzyl-shielding substituent across the C(4)-CH2 bond. This conformational lock would either make the coordination of acceptor molecules to the metallic center of catalyst easy or increase the efficiency of chiral shielding of the coordinated acceptor molecules. 

With ring G in place, the construction of key intermediate 105 requires only a few functional group manipulations. To this end, benzylation of the free secondary hydroxyl group in 136, followed sequentially by hydroboration/oxidation and benzylation reactions, affords compound 137 in 75% overall yield. Acid-induced solvolysis of the benzylidene acetal in 137 in methanol furnishes a diol (138) the hydroxy groups of which can be easily differentiated. Although the action of 2.5 equivalents of tert-butyldimethylsilyl chloride on compound 138 produces a bis(silyl ether), it was found that the primary TBS ether can be cleaved selectively on treatment with a catalytic amount of CSA in MeOH at 0 °C. Finally, oxidation of the resulting primary alcohol using the Swem procedure furnishes key intermediate 105 (81 % yield from 138). 

Quebrachitol was converted into iL-c/j/roinositol (105). Exhaustive O-isopropylidenation of 105 with 2,2-dimethoxypropane, selective removal of the 3,4-0-protective group, and preferential 3-0-benzylation gave compound 106. Oxidation of 106 with dimethyl sulfoxide-oxalyl chloride provided the inosose 107. Wittig reaction of 107 with methyl(triphenyl)phos-phonium bromide and butyllithium, and subsequent hydroboration and oxidation furnished compound 108. A series of reactions, namely, protection of the primary hydroxyl group, 0-debenzylation, formation of A-methyl dithiocarbonate, deoxygenation with tributyltin hydride, and removal of the protective groups, converted 108 into 7. 

The oxidation by strains of Pseudomonas putida of the methyl group in arenes containing a hydroxyl group in the para position is, however, carried out by a different mechanism. The initial step is dehydrogenation to a quinone methide followed by hydration (hydroxylation) to the benzyl alcohol (Hopper 1976) (Figure 3.7). The reaction with 4-ethylphenol is partially stereospecific (Mclntire et al. 1984), and the enzymes that catalyze the first two steps are flavocytochromes (Mclntire et al. 1985). The role of formal hydroxylation in the degradation of azaarenes is discussed in the section on oxidoreductases (hydroxylases). 

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