Hydroxyl Protecting Groups

The book Protective Groups in Organic Synthesis which is listed in the general references, provides a thorough survey of protective groups and the conditions for introduction and removal. 

This protective group is introduced by an acid-catalyzed addition of the alcohol to the vinyl ether moiety in dihydropyran. / -Toluenesulfonic acid or its pyridinium salt is used most frequently as the catalyst, although other catalysts are advantageous in special cases. The THP group can be removed by dilute aqueous acid. The chemistry involved in both the introduction and deprotection stages is the reversible acid-catalyzed formation and hydrolysis of an acetal (see Part A, Section 8.1). 

The THP group, like other acetals and ketals, is inert to nucleophilic reagents and is unchanged under such conditions as hydride reduction, organometallic reactions, or base-catalyzed reactions in aqueous solution. It also protects the hydroxyl group against oxidation. 

Ethyl vinyl ether is also useful for hydroxyl-group protection. The resulting derivative (1-ethoxyethyl ether) is abbreviated as the EE group. As with the THP group, the EE group contains a stereogenic center. 

The methoxymethyl (MOM) and j -methoxyethoxymethyl (MEM) groups are used to protect alcohols and phenols as formaldehyde acetals. The groups are normally introduced by reaction of an alkali-metal salt of the alcohol with methoxymethyl chloride or P-methoxyethoxymethyl chloride.  

Below is a list of the most commonly used hydroxyl protecting groups including conditions for their introduction and removal. For a discussion of their regioselective introduction, see Section 3.3. A rough distinction between permanent and temporary protecting groups is also made. 

Standard conditions for the removal of ester protecting groups include a catalytic amount of sodium methoxide in methanol (Zemplen conditions), sometimes with a cosolvent. Additionally, other basic conditions such as ammonia in MeOH may be useful. 

Acetates and benzoates are excellent protecting groups. They can be introduced and removed in high yields in large numbers under mild conditions. Drawbacks as permanent protecting groups include their relatively limited base stability and their tendency to migrate. 

benzyl ethers are also excellent protecting groups. They are stable towards almost any conditions and are easily removed under essentially neutral conditions. The one drawback is the rather harsh conditions usually employed for their introduction. 

Acetal cleavage is achieved by acid hydrolysis standard conditions are acetic acid (70% aqueous) at elevated temperature or trifluoroacetic acid (TFA, 90% aqueous) at 0°C. 

2 Reviews Concerning Enzyme-Mediated Esterification and Hydrolysis of Esters 348 

3 Reviews Cortceming Organosilicon and Organotin Chemistry Relevant to Hydroxyl Protection 349 

An asterisk in the text indicates that a pertinent review can be found at ttie end of the chapter. 

The tetrahydropyranyl group, hke other acetals and ketals, is inert to nu- 

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 benzyl group can serve as an alcohol-protecting group when acidic conditions for ether cleavage cannot be tolerated. The benzyl C-O bond is cleaved by catalytic hydrogenolysis, or with sodium in liquid ammonia. Allyl ethers are an alternative to benzyl ethers as a protecting group. Allyl ethers may be isomerized quantitatively by potassium r-butoxide in dimethyl sulfoxide to propenyl ethers, which are quite labile to dilute acid.  

Silyl ethers have an important role as hydroxyl-protecting groups/ Alcohols can be easily converted to trimethylsilyl ethers by reaction with trimethylsilyl chloride in the presence of an amine or by heating with hexamethyldisilazane. Although these are useful compounds when the objective is preparation of a less polar derivative of 

Ethyl vinyl ether is also useful as a hydroxyl-protecting group although it, like dihydropyran, also gives rise to diastereomers when a chiral alcohol is used. 

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Selective removal of the hydroxyl protecting groups included in this review is generally difficult to achieve and of little practical importance. Selective hydrolysis of cyclic orthoesters to give monoesters merits attention for its practical interest. 

In a recent application of this strategy, nitrocyclohexane 143 (prepared from nitrosugar 142 by intramolecular Henry reaction) was subjected to a radical denitration by HSnBu3, after protection of the hydroxyl groups to avoid side reactions. Inositol 146 was selectively obtained in good yield, once the hydroxyl protecting groups were removed (Scheme 45).101... 

The benzyl group can serve as a hydroxyl-protecting group when acidic conditions for ether cleavage cannot be tolerated. The benzyl C—0 bond is cleaved by catalytic... 

These reaction conditions do not affect most of the other common hydroxyl-protecting groups, and methoxybenzyl groups are therefore useful in synthetic sequences that require selective deprotection of different hydroxyl groups. 4-Methoxybenzyl ethers can also be selectively cleaved by dimethylboron bromide.27... 

Methoxyphenyl (PMP) ethers find occasional use as hydroxyl-protecting groups. 

Table 13.1 gives the structures and common abbreviations of some of the most frequently used hydroxyl-protecting groups. 

Allyl carbonate esters are also useful hydroxyl-protecting groups. They are introduced using allyl chloroformate. A number of Pd-based catalysts for allylic deprotection have been developed.54 They are based on a catalytic cycle in which Pd(0) reacts by oxidative addition and activates the allylic bond to nucleophilic substitution. Various nucleophiles are effective, including dimedone,55 pentane-2,4-dione,56 and amines.57... 

To circumvent the low reactivity, low solubility and/or low yield problems associated with the previously mentioned hydroxyl functional initiators, we (15. 14) have built protective hydroxyl functionality into organolithium molecules. Specifically, alkyl" lithium initiators containing hydroxyl protecting groups have been prepared. These protected functional initiators contain acetals, i.e., tetrahydropyranyl... 

The subject of relative reactivities of hydroxyl groups in carbohydrates has been discussed previously in this Series.1,2 In these articles, emphasis was placed on the selective introduction of substituents into carbohydrates. A much less exploited approach for the preparation of partially substituted carbohydrates involves the selective removal of hydroxyl-protecting groups from carbohydrate derivatives. The purpose of the present article is to draw attention to this relatively neglected aspect of synthesis in the belief that the greater use of de-... 

As a result of investigations directed towards obtaining new, selective, hydroxyl-protecting groups having differing stabilities towards solvolytic conditions and yet favorable stability towards synthetic re-... 

In a recent re-examination of the thermolysis of benzocyclobutenes for the in situ generation of o-quinodimethanes, the resultant IMDA diastereoselectivity was highly dependent on the nature of the hydroxyl protective group.90 The intramolecular 4 + 2-cycloaddition of o-quinodimethanes (83), derived from ene-bis(sulfinylallenes) (82), with electron-deficient and electron-rich alkenes produced the corresponding polycyclic aromatic compounds (84) (Scheme 22).91 The enantioselective Diels-Alder... 

R)-Arbutamin was produced as follows 89.3 mg of (-)-l-di(t-butyldimethylsiloxy)phenyl)-2-aminoethanol, 50.0 mg of 4-(4-methoxymethoxyphenyl)butanoic acid, diethylphosphorylcyanide, and triethylamine were dissolved in N,N-dimethylformamide at 0°C, reacted at room temperature, so as to obtain 108.6 mg (in a yield of 82%) of amide compound. The amide compound obtained was reduced lithium aluminium hydride in an ether solvent at reflux temperature, so as to quantitative obtain amine. And 55.6 mg of (R)-arbutamin which is intended compound was obtained by deprotecting the hydroxyl-protecting group of amine in a methanol-THF solvent at room temperature using hydrochloric acid. 

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