Benzyl ethers, protecting alcohols with

The enzymatically catalyzed kinetic resolution of amino alcohols has been established on the multi-ton scale by BASF [7] (Scheme 7.14). Initial studies gave poor selectivity for the unprotected alcohols, as the resolution of trows-2-aminocyclopen-tanol (racemic 28) gave the amine (S,S) 29 and the amide (R,R) 30 in 25% . When the hydroxy functionality was protected as an ether, then resolution of racemic benzyl ether 31 proceeds with high to the give the amine (S,S) 32 and the RR amide 33 with >99.5 and 93 % respectively [33, 34]. 

The benzyl ether is prepared in a similar manner to the methoxymethyl ether, that is, by reaction of the conjugate base of the alcohol with benzyl bromide in an SN2 reaction. An example of a sequence that employs a benzyl ether protecting group is illustrated in the following sequence ... 

Another hybrid protecting group is the p-[(trimethylsilyl)ethoxy]methoxy benzyl (p-SEM-benzyl) ether354 Phenolate anions generated by treatment of p-SEM-benzyl ethers with TBAF in DMF at 80 °C eliminate to give the deprotected alcohol as illustrated in Scheme 4.303 p-SEM-benzyl ethers are compatible with many of the standard manipulations in oligosaccharide synthesis and they arc orthogonal to benzyl and p-methoxybenzyl ethers. 

Protection of hydroxyl groups (11, 166).- 3.4-Dimethoxybcnzyl ethers are oxidized by DDQ more readily thanp-methoxybenzyl ethers. Moreover, the dimethoxybenzyl ethers of secondary alcohols can be selectively oxidized in the presence of the corresponding ethers of primary alcohols. Benzyl, p-methoxybenzyl, and 3,4-dimethoxybenzyl ethers all undergo hydrogenolysis catalyzed by Pt/C or Pd/C, but selective hydrogenolysis of benzyl ethers is possible with W-2 Raney Ni. 

Similar utilization for cleavage of benzyl alcohols, ethers and esters has made this method the preferred one where regioselectivity is required, but for allylic cleavage double bond isomerization becomes a problem. A number of benzylic ethers and alcohols (equation 13), and benzhydric ethers and acetals (equation 14) have been cleaved in relatively high yield using cyclohexene in the presence of AlCb. Mild conditions of cleavage are frequently required for debenzylation of carbohydrates and a number of protected carbohydrates have been cleaved with formic acid as donor (equation 15). ... 

Substituted benzyl ethers. Protection of alcohols in the form of substituted benzyl ethers is accomplished by alkylation of RONa in DMF. These ethers are cleaved with BU4NF. 

The reductive cleavage of benzylic ethers and alcohols makes the benzyl group a useful protecting group for alcohols. It is stable to many acidic and basic conditions, and it can be removed by reduction with Li in liquid NH3 (or by Pd-catalyzed hy-drogenolysis). The products of the reductive cleavage are the desired alcohol plus toluene or methylcyclohexadiene (either of which is easily removed by evaporation). 

Benzyl trichloracetimidate (48) is a new reagent for acid-catalysed benzylation of alcohols in the presence of trifluoromethanesulphonic acid, and benzyl p-toluenesulphonate-potassium carbonate has been recommended as abenzylat-ing system for phenols, especially in cases where benzyl chloride-potassium carbonate gives C-alkylated impurities.Facile removal of benzyl ether protecting groups has been achieved by catalytic transfer hydrogenation with Pd(OH)2 on carbon and cyclohexene as hydrogen-donor. A new procedure for O-tritylation by treatment of an alcohol trimethylsilyl ether with trityl trimethylsilyl ether is shown in equation (6). The synthesis and characterization has been completed of 4-dimethylamino-N-triphenylmethylpyridinium chloride (49)," a postulated intermediate in the formation of trityl ethers from alcohols... 

Six protective groups for alcohols, which may be removed successively and selectively, have been listed by E.J. Corey (1972B). A hypothetical hexahydroxy compound with hydroxy groups 1 to 6 protected as (1) acetate, (2) 2,2,2-trichloroethyl carbonate, (3) benzyl ether, (4) dimethyl-t-butylsilyl ether, (5) 2-tetrahydropyranyl ether, and (6) methyl ether may be unmasked in that order by the reagents (1) KjCO, or NH, in CHjOH, (2) Zn in CHjOH or AcOH, (3) over Pd, (4) F", (5) wet acetic acid, and (6) BBrj. The groups may also be exposed to the same reagents in the order A 5, 2, 1, 3, 6. The (4-methoxyphenyl)methyl group (=MPM = p-methoxybenzyl, PMB) can be oxidized to a benzaldehyde derivative and thereby be removed at room temperature under neutral conditions (Y- Oikawa, 1982 R. Johansson, 1984 T. Fukuyama, 1985). 

The benzyl group has been widely used for the protection of hydroxyl functions in carbohydrate and nucleotide chemistry (C.M. McCloskey, 1957 C.B. Reese, 1965 B.E. Griffin, 1966). A common benzylation procedure involves heating with neat benzyl chloride and strong bases. A milder procedure is the reaction in DMF solution at room temperatiue with the aid of silver oxide (E. Reinefeld, 1971). Benzyl ethers are not affected by hydroxides and are stable towards oxidants (e.g. periodate, lead tetraacetate), LiAIH, amd weak acids. They are, however, readily cleaved in neutral solution at room temperature by palladium-catalyzed bydrogenolysis (S. Tejima, 1963) or by sodium in liquid ammonia or alcohols (E.J. Rcist, 1964). 

Bu2BOTf, BH3-THF, CH2CI2, 0°, 70-91% yield. In a variety of pyrano-sides, cleavage occurs primarily to give the primary alcohol, with the secondary alcohol protected as the benzyl ether." ... 

The C2-symmetric epoxide 23 (Scheme 7) reacts smoothly with carbon nucleophiles. For example, treatment of 23 with lithium dimethylcuprate proceeds with inversion of configuration, resulting in the formation of alcohol 28. An important consequence of the C2 symmetry of 23 is that the attack of the organometallic reagent upon either one of the two epoxide carbons produces the same product. After simultaneous hydrogenolysis of the two benzyl ethers in 28, protection of the 1,2-diol as an acetonide ring can be easily achieved by the use of 2,2-dimethoxypropane and camphor-sulfonic acid (CSA). It is necessary to briefly expose the crude product from the latter reaction to methanol and CSA so that the mixed acyclic ketal can be cleaved (see 29—>30). Oxidation of alcohol 30 with pyridinium chlorochromate (PCC) provides alde-... 

The synthesis of the trisubstituted cyclohexane sector 160 commences with the preparation of optically active (/ )-2-cyclohexen-l-ol (199) (see Scheme 49). To accomplish this objective, the decision was made to utilize the powerful catalytic asymmetric reduction process developed by Corey and his colleagues at Harvard.83 Treatment of 2-bromocyclohexenone (196) with BH3 SMe2 in the presence of 5 mol % of oxazaborolidine 197 provides enantiomeri-cally enriched allylic alcohol 198 (99% yield, 96% ee). Reductive cleavage of the C-Br bond in 198 with lithium metal in terf-butyl alcohol and THF then provides optically active (/ )-2-cyclo-hexen-l-ol (199). When the latter substance is treated with wCPBA, a hydroxyl-directed Henbest epoxidation84 takes place to give an epoxy alcohol which can subsequently be protected in the form of a benzyl ether (see 175) under standard conditions. 

Noyori and coworkers found that tetrafluorosilane or trimethylsilyl tri-flate catalyzes the condensation of appropriately protected glycopyranosyl fluorides with trimethylsilyl ethers or alcohols. The strong affinity of silicon for fluorine was considered to be the driving force for this reaction. In the case of Sip4, attack of a nucleophile on the glycosyl cation-SiFj ion-pair intermediate was anticipated. Thus, condensation of 2,3,4,6-tetra-O-benzyl-a- and - -D-glucopyranosyl fluorides (47a and 47fi) with methyl... 

The use of trichloroimidates for the preparation of ethers is an effective method for O-alkylation of alcohols [27]. This method has found widespread use in the protection of alcohols as benzyl ethers since the corresponding trichlorobenzylimi-date is inexpensive and commercially available. The mechanism involves activation of the imidate with a catalytic amount of a strong acid (typically TfOH) which leads to ionization of the electrophile and the formation of carbocation which is rapidly trapped by an alcohol. For the preparation of sec-sec ethers, this protocol has been limited to glycosidation reactions, due to the SN1 nature of the reaction which often leads to diastereomeric mixtures of products [26],... 

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