Ethers as protecting groups

The formation of mixed ethers directly from two alcohols usually gives a mixture of three products. However, it is possible to form mixed ethers in which one alkyl group is tertiary and the other is primary or secondary (Section 16.4). We carry out this acid-catalyzed reaction, converting the tertiary alcohol to a tertiary carbocation, which then reacts with the other alcohol. For example, we can protect the hydroxyl group of cyclohexanol with a tcrr-butyl group. 

Other alternatives to protecting hydroxyl groups are available that avoid the acidic conditions that could interfere with other functional groups in a molecule. Hydroxyl groups react with trialkylchlo-rosilanes to give silyl ethers in a reaction analogous to the Williamson ether synthesis. The reaction is carried out with one equivalent of pyridine, which reacts with the HCl by-product to give pyri-dinium hydrochloride. 

The Si—Cl bond is so reactive that chloride ion is displaced by the alcohol directly. That is, in contrast to the Williamson synthesis, the alcohol need not be converted to an alkoxide. 

The silyl ether forms by an Sj 2 reaction at a tertiary center. This reaction can occur at a tertiary silicon center because the C —Si bond length is 195 pm, compared to the 154 pm of a C—C bond length. The alkyl groups bonded to the tertiary sihcon atom are farther away from each other than alkyl groups bonded to a tertiary carbon atom. Therefore, they do not present as much steric interference to the approach of a nucleophile as the alkyl groups in the analogous carbon compound, r rr-butyl chloride. 

Silyl ethers are less reactive than ethers to both acid and base, and therefore they are stable under most reaction conditions. In practice, ferr-butyldimethylsilyl (TBDMS) ethers are prepared rather than trimethylsilyl (TMS) ethers because they are more stable. However, either trialkylsilyl group is easily removed by reaction with fluoride ion, provided in the form of the salt tetrabutylam-monium fluoride. This cleavage reaction is highly r ioselective because the fluoride ion has no effect on most other functional groups. 

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Silyl Ethers as Protective Groups for Alcohols. Oxidative Deprotection and Stability Under Alcohol Oxidation Conditions, Muzart. J. Synthesis. 1993, 11... 

R Gigg. The allyl ether as protecting group in carbohydrate chemistry. Part II. The 3-methyIbut-2-enyl ( Prenyl") group, J. Chem. Soc. Perkin TYans. 7 738 (1980) and references therein. 

The synthetic potential of silyl ethers as protecting groups for hydroxyls is based on the fact that they can be easily introduced and cleaved under mild conditions and their relative stability can be tuned by varying the substituents on silicon. In carbohydrate chemistry, the tert-butyl-dimethylsilyl (TBDMS), terl-butyldiphenylsilyl (TBDPS) and triethyl-silyl (TES) ethers are the most often applied silicon-based protecting groups (Scheme 2.9).23... 

TBS- vs. TIPS- ethers as protecting groups in the anomeric iithiation of giycais... 

General problems, as compared to the formation of 0-glycosides, are the incompatibility between catalytic hydrogenolysis and sulfur functions, which complicates the use of benzyl ethers as protecting groups, although Birch reduction might be an alternative, and the easy formation of disulfides from thiols, irrespective of if they are used as donors or acceptors. 

The hrst synthesis of pelargonidin chloride used methyl ethers as protecting groups for the phenolic hydroxyls during the Grignard addition step."" ... 

The suitability of tritylone ethers as protecting groups for alcohols has been explored, with cholesterol among model alcohols.The ether (134) was formed from tritylone alcohol and cholesterol under acidic conditions with azeotropic... 

Silyl Ethers.—Examples of the usefulness of t-butyldimethylsilyl ethers as protecting groups are nicely illustrated in Schemes 17 and 19. Methyl a-D-gluco-pyranoside reacted with a molar equivalent of t-butyldimethylsilyl chloride in pyridine to give the 6-0-(t-butyldimethylsilyl) derivative in virtually quantitative yield, and sucrose reacted with 3.5 molar equivalents of the silylating reagent to give almost exclusively r,6,6 -tri-0-(t-butyldimethylsilyl)sucrose and traces of mono- and di-substituted products. In the presence of an excess of sucrose, a mixture of 6 -, 6,6 -di-, and r,6,6 -tri-0-(t-butyldimethylsilyl)sucroses was obtained. 

This isomerization is a basis of using allyl ethers as protecting groups for alcohols [Eq. (139) (Corey and Suggs, 1973)]. 

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