Deprotection by Acid-Catalyzed Hydrolysis

L Benoiton. Conversion of P-chloro-L-alanine to Vre-carbobenzoxy-DL-diaminopropi-onic acid. Can J Chem 46, 1549, 1968. 

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The carbonyl group can be deprotected by acid-catalyzed hydrolysis by the general mechanism for acetal hydrolysis (see Part A, Section 7.1). A number of Lewis acids have also been used to remove acetal protective groups. Hydrolysis is promoted by LiBF4 in acetonitrile.249 Bismuth triflate promotes hydrolysis of dimethoxy, diethoxy, and dioxolane acetals.250 The dimethyl and diethyl acetals are cleaved by 0.1-1.0 mol % of catalyst in aqueous THF at room temperature, whereas dioxolanes require reflux. Bismuth nitrate also catalyzes acetal hydrolysis.251... 

FIGURE 3.8 Deprotection of carboxyl groups by acid-catalyzed hydrolysis (A) of amides and (B) of esters. Protonation generates a relatively stable carbenium ion that usually requires heat to fragment it. 

Scheme 10.8 outlines the application of rhodium-catalyzed allyhc amination to the preparation of (il)-homophenylalanine (J )-38, a component of numerous biologically active agents [36]. The enantiospecific rhodium-catalyzed allylic amination of (l )-35 with the lithium anion of N-benzyl-2-nitrobenzenesulfonamide furmshed aUylamine (R)-36 in 87% yield (2° 1° = 55 1 >99% cee) [37]. The N-2-nitrobenzenesulfonamide was employed to facilitate its removal under mild reaction conditions. Hence, oxidative cleavage of the alkene (R)-36 followed by deprotection furnished the amino ester R)-37 [37, 38]. Hydrogenation of the hydrochloride salt of (l )-37 followed by acid-catalyzed hydrolysis of the ester afforded (i )-homophenylalanine (R)-3S in 97% overall yield. 

Oxazolines (75) may be formed from carboxylic acids by condensation with either 2-amino alcohols or aziridines (Scheme 74). They are stable to Grignard reagents and to L1A1H4 and are cleaved either by acid-catalyzed hydrolysis or dcoholysis. A disadvantage of the oxazolines is that they retain reactivity towards alkylating reagents. On the other hand, this forms the basis for an alternative deprotection in the presence of acid sensitive structures. After methylation the oxazolines can be hydrolyzed to the free acids with 2 M NaOH (94% yield). ... 

Deprotection of secondary (7) (eq 5) and tertiary Dios-amides (8) (eq 6) is achieved by acid-catalyzed hydrolysis of the acetal moiety to aldehyde in a hot aqueous solution of TEA followed by spontaneous retro-Michael reactiorr, giving the corresponding primary and secondary amines in excellent yields. Secondary Dios-amide (7) can be cleaved more easily than tertiary Dios-amide (8). A plausible reaction pathway is shown in eq 7. Acrolein generated as a co-product is not troublesome under these aqueous conditions. 

Another advantage over other Lewis acids is the thiophilic nature of copper this has led to its utility in the hydrolysis of thioacetals. Copper(II) chloride in conjunction with copper(II) oxide was introduced by Mukaiyama [16] for the deprotection of 1,3-dithianes and this method has found utility in a variety of synthetic protocols (Sch. 6) [17]. This combination, in which copper oxide plays the role of a buffer to prevent the medium from becoming too acidic, has also found application in the hydrolysis of a-heteroatom substituted and vinyl sulfides [18]. Acetals, which are prone to epimerization under acid-catalyzed hydrolysis conditions (21), can be con-... 

Proteases such as a-chymotrypsin, papain, and subtilisin are also useful biocatalysts for regio-selective or stereoselective hydrolytic biotransformations. For example, dibenzyl esters of aspartic and glutamic acid can be selectively deprotected at the 1-position by subtilisin-catalyzed hydrolysis (Fig. 6). In addition, a-chymotrypsin is used in the kinetic resolution of a-nitro-a-methyl carboxylates, which results in l-configured enantiomers of the unhydrolyzed esters with high optical purity (>95% e.e.). ... 

In 1979, Frechet and Willson put forward a very productive idea of a chemical amplification that was used in the development of a new generation of photoresists.They decided to use a photoresist comprising of a photochemical acid generator (PAG) and a polymer that was able to switch from hydrophobic to hydrophilic in the course of acid catalyzed hydrolysis. The PAG reacts with light to produce an acid catalyst. During a subsequent postexposure bake, the catalyst diffuses and reacts with the polymer component, causing many reaction events in the polymer and recovers the acid catalyst. The acid molecules catalyze the deprotection reaction and provide a prerequisite for chemical amplification. The number of the reaction events initiated by single quantum absorption has been estimated to be of order of 100. ... 

DMAP-Initiated Protecting Group Strategies. DMAP has also been utilized as a key component in several protecting group strategies. The formation of cyclic acetals from 1,2-diols and alkyl propynoates in the presence of DMAP has been demonstrated. These acetals are stable to acid-catalyzed hydrolysis, unlike other acetals, and methanolysis. These acetals can be deprotected by heating in neat pyrrolidine. 

Aryl and alkyl trimethylsilyl ethers can often be cleaved by refluxing in aqueous methanol, an advantage for acid- or base-sensitive substrates. The ethers are stable to Grignard and Wittig reactions and to reduction with lithium aluminum hydride at —15°. Aryl -butyldimethylsilyl ethers and other sterically more demanding silyl ethers require acid- or fluoride ion-catalyzed hydrolysis for removal. Increased steric bulk also improves their stability to a much harsher set of conditions. An excellent review of the selective deprotection of alkyl silyl ethers and aryl silyl ethers has been published. ... 

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 7.1). 

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,3 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). 

Before all these acetal-based protecting groups were introduced, the tetrahydropyranyl (THP) ether had found extensive use in organic synthesis. It can easily be synthesized from a variety of hydroxy-containing compounds like carbohydrates, amino acids, steroids and nucleotides by the acid-catalyzed reaction with dihydropyran. It is stable to bases, but the protection is removed through acidic hydrolysis with hydrochloric acid, toluenesulfonic acid or acidic ion-exchange resin (Scheme 27). In the case of acid sensitive substrates, e.g. containing an epoxide or a further acetal, pyridinium p-toluenesulfonate should be applied for particularly mild deprotection conditions. ... 

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