Use of Acetals as Protecting Groups

Acetals hydrolyze under acidic conditions, but they are stable to strong bases and nucleophiles. Acetals areeasily made from the corresponding ketones and aldehydes and easily converted back to the parent carbonyl compounds. This easy interconversion makes acetals attractive as protecting groups to prevent ketones and aldehydes from reacting with strong bases and nucleophiles. 

As an example, consider the following proposed synthesis. The necessary Grignaid reagent could not be made because the carbonyl group would react with the nucleophilic o-g nometallic group. 

If the aldehyde is protected as an acetal, however, it is unreactive toward a Grignard reagent. The masked aldehyde is converted to the Grignard reagent, which is allowed to react with cyclohexanone. Dilute aqueous acid both protonates the alkoxide to give the alcohol and hydrolyzes the acetal to give the deprotected aldehyde. 

Selective Acetal Formation Because aldehydes form acetals more readily than 

Show how you would accomplish the following syntheses. You may use whatever additional reagents you need. 

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Key Mechanism 18-6 Formation of Acetals 856 Problem-Solving Strategy Proposing Reaction Mechanisms 858 18-18 Use of Acetals as Protecting Groups 860 18-19 Oxidation of Aldehydes 861... 

Although the use of esters as protecting groups at the 4-position is clearly incompatible with the presence of the 4,6-0-benzylidene acetal, their electron-withdrawing nature should generally enhance p-selectivity for other donors. That such is the case is clear from this study of the 2-0-sulfonate protected rhamnopyranosyl donors, which alone gave only modest p-selectivity but which, when used in conjunction with a 4-0-benzoate group, showed considerably improved performance (Scheme 23) [50, 114]. 

Protection of an alcohol function by esterification sometimes offers advantages over use of acetal or ether groups. Generally, ester groups are stable under acidic conditions. Esters are especially useful in protection during oxidations. Acetates and benzoates are the most commonly used ester derivatives. They can be conveniently prepared by reaction of unhindered alcohols with acetic anhydride or benzoyl chloride, respectively, in the presence of pyridine or other tertiary amines. 4-Dimethylaminopyridine (DMAP) is often used as a catalyst. The use of A-acylimidazolides (see Section 3.4.1) allows the... 

Although there are numerous methods for the protection and deprotection of diacetyl acetals, these are rarely used in synthesis as protective groups, but have been used as starting materials for palladium-catalyzed alkylations. ... 

The use of acetals as carbonyl-protecting groups is illustrated by the synthesis of 5-hydroxy-5-phenylpentanal from benzaldehyde and 4-bromobutanal ... 

Many carbamates have been used as protective groups. They are arranged in this chapter in order of increasing complexity of stmcture. The most useful compounds do not necessarily have the simplest stmctures, but are /-butyl (BOC), readily cleaved by acidic hydrolysis benzyl (Cbz or Z), cleaved by catalytic hy-drogenolysis 2,4-dichlorobenzyl, stable to the acid-catalyzed hydrolysis of benzyl and /-butyl carbamates 2-(biphenylyl)isopropyl, cleaved more easily than /-butyl carbamate by dilute acetic acid 9-fluorenylmethyl, cleaved by /3-elimination with base isonicotinyl, cleaved by reduction with zinc in acetic acid 1-adamantyl, readily cleaved by trifluoroacetic acid and ally], readily cleaved by Pd-catalyzed isomerisation. 

Semicarbazones are used as protecting groups as a consequence of their stability to reducing agents such as potassium borohydride, sodium boro-hydride and lithium borohydride. Semicarbazones are cleaved by strong acids and by heating in acetic anhydride-pyridine. " ... 

Acetal (Section 19.10) A functional group consisting of two -OR groups bonded to the same carbon, R2C(OR )2-Acetals are often used as protecting groups for ketones and aldehydes. 

Dioxacycloalkanes are cyclic acetals that are used frequently as protective groups. Substituted derivatives have been synthesized to achieve easy removal. Simplest of all, the 4-phenyl-1,3-dioxolane has not been used commonly because cleavage needs electrolytic conditions. A mild hydrogenolysis method was developed in 1997 to make this protective group more popular (Scheme... 

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