Ethers, methyl alcohol-protecting groups

Like Still s reagent, tributyl[(methoxymethoxy)methyl)etannane incorporates an alcohol protective group that can be conveniently unmasked under mild acidic conditions. However, an advantageous feature of this MOM ether derivative is that, in contrast to Still s reagent, it is achiral. In many applications the introduction of an additional chiral center into synthetic intermediates is undesirable because of the complications associated with the manipulation, analysis, and purification of diastereomeric mixtures. 

In the first step the alcohol moiety of 32 is protected as tert-butyldi-methylsilyl ether (TBS). The TBSOTf / 2,6-lutidine system is one of the most powerful methods for the formation of TBS ethers. This silyl protecting group is quite stable to a variety of organic reaction conditions and is cleaved under strong acidic or strong basic conditions, under Lewis acid catalysis and in the presence of a fluorine source (e.g. TBAF). In the second step the methyl ester is hydrolyzed using standard saponification conditions to give 33. 

A.I. Ether and Acetal Protecting Groups. A simple way to protect the OH of an alcohol is as its methyl ether (-OMe). Reaction of an alcohol with a base [often sodium hydride (NaH) in THF or DMF] gives an alkoxide. Subsequent reaction with iodomethane gives the methyl ether via an Sn2 reaction (sec. 2.7.A.i). Formation of dialkyl ethers via reaction of an alkoxide with an alkyl halide is called the Williamson ether... 

A major disadvantage of the tetrahydropyranyl ether as a protecting group is that an asymmetric center is produced at C-2 of the tetrahydropyran ring on reaction with the alcohol. This asymmetry presents no difficulties if the alcohol is achiral, since a racemic mixture results. If the alcohol has an asymmetric center anywhere in the molecule, however, condensation with dihydropyran can afford a mixture of diastereomeric tetrahydropyranyl ethers, which may complicate purification and characterization. One way of surmounting this problem is to use methyl 2-propenyl ether, rather than dihydropyran. No asymmetric center is introduced, and the acetal offers the further advantage of being hydrolyzed under milder conditions than those required for tetrahydropyranyl ethers. Ethyl vinyl ether is also useful as a hydroxyl-... 

The methylthiomethyl (MTM) group is a related alcohol-protecting group. There are several methods for introducing the MTM group. Alkylation of an alcoholate by methylthiomethyl chloride is efficient if catalyzed by iodide ion. Alcohols are also converted to MTM ethers by reaction with dimethyl sulfoxide in the presence of acetic acid and acetic anhydride or with benzoyl peroxide and dimethyl sulfide. The latter two methods involve the generation of the methyl-thiomethylium ion by ionization of an acyloxysulfonium ion. 

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). 

Ethers are among the most used protective groups in organic synthesis. They vary from the simplest, most robust, methyl ether to the more elaborate, substituted, trityl ethers developed for use in nucleotide synthesis. They are formed and removed under a wide variety of conditions. Some of the ethers that have been used to protect alcohols are included in Reactivity Chart 1. ... 

Birch s procedure for tropone synthesis appears to be widely applicable to 2,3- or 2,5-dihydroanisole derivatives which are readily obtained by reduction of appropriate aromatic methyl ethers by alcoholic metal-ammonia solutions. " Additional functional groups reactive to dibromocarbene or sensitive to base such as double bonds, ketones and esters would need to be protected or introduced subsequent to the expansion steps. 

The oxirane ring in 175 is a valuable function because it provides a means for the introduction of the -disposed C-39 methoxy group of rapamycin. Indeed, addition of CSA (0.2 equivalents) to a solution of epoxy benzyl ether 175 in methanol brings about a completely regioselective and stereospecific solvolysis of the oxirane ring, furnishing the desired hydroxy methyl ether 200 in 90 % yield. After protection of the newly formed C-40 hydroxyl in the form of a tert-butyldimethylsilyl (TBS) ether, hydrogenolysis of the benzyl ether provides alcohol 201 in 89 % overall yield. 

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