Protecting Groups Cleaved by Acid

Figure 1. Schematic of the deprotection reaction showing the protected polymer, PBOCSt, and deprotected analog, PHOSt, Shown encircled is the protecting group cleaved by the photogenerated acid.

The cleavage proceeds by initial reduction of the nitro groups followed by acid-catalyzed cleavage. The DNB group can be cleaved in the presence of allyl, benzyl, tetrahydropyranyl, methoxy ethoxy methyl, methoxymethyl, silyl, trityl, and ketal protective groups. 

The dibenzosuberyl ether is prepared from an alcohol and the suberyl chloride in the presence of triethylamine (CH2CI2, 20°, 3 h, 75% yield). It is cleaved by acidic hydrolysis (1 N HCl/dioxane, 20°, 6 h, 80% yield). This group has also been used to protect amines, thiols, and carboxylic acids. The alcohol derivative can be cleaved in the presence of a dibenzosuberylamine. ... 

The pixyl ether is prepared from the xanthenyl chloride in 68-87% yield. This group has been used extensively in the protection of the 5 -OH of nucleosides it is readily cleaved by acidic hydrolysis (80% AcOH, 20°, 8-15 min, 100% yield, or 3% trichloroacetic acid). It can be cleaved under neutral conditions with ZnBrj, thus reducing the extent of the often troublesome depurination of A -6-benzyloxy-adenine residues during deprotection. Conditions which remove the pixyl group also partially cleave the THP group (t,/2 for THP at 2 -OH of ribonucleoside = 560 s in 3% Cl2CHC02H/CH2Cl2). ... 

In general, imines are too reactive to be used to protect carbonyl groups. In a synthesis of juncusol, however, a bromo- and an iodocyclohexylimine of two identical aromatic aldehydes were coupled by an Ullman coupling reaction modi-fied by Ziegler. The imines were cleaved by acidic hydrolysis (aq. oxalic acid, THF, 20°, 1 h, 95% yield). Imines of aromatic aldehydes have also been prepared... 

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. 

An isobutyl carbonate was prepared by reaction with isobutyl chloroformate (Pyr, 20°, 3 days, 73% yield), to protect the 5 -OH group in thymidine. It was cleaved by acidic hydrolysis (80% AcOH, reflux, 15 min, 88% yield). ... 

The THP derivative of the imidazole nitrogen in purines has been prepared by treatment with dihydropyran (TsOH, 55°, 1.5 h, 50-85% yield). It is cleaved by acid hydrolysis. The THP group is useful for the protection of 1,2,4-triazoles. ... 

This group was used as a protective group and chiral directing group for the asymmetric synthesis of o -aminophosphonic acids. It is cleaved by acid hydrol-... 

A -Sulfenylarnines are prepared from sulfenyl chlorides ArSCl, and can be cleaved by acids, phosphines, or various nucleophiles [230,321], The 2-nitrobenzenesulfenyl protective group (2-(02N)C6H4-S-NH-R), developed as amino group protection for cx-amino acids [321,322], has been completely superseded by the Fmoc group. 

When l,l,2-triphenylethane-l,2-diol-derived esters are submitted to a monodeprotonation and subsequently treated with Chlorotrimethylsilane, the formation of 2-trimethylsilyloxy-l,3-dioxolanes results. The orthoester moiety thus obtained serves as a protecting group for carboxylic acids (eq 3) it is stable towards alkyllithium reagents and can be cleaved under nonacidic conditions by alkaline hydrolysis. ... 

Heterocyclic intermediates are being used more and more in synthesis as protecting groups, readily generated and, when their job is done, readily removed. We have seen two examples of this the temporary incorporation of the carboxyl group into a 2-oxazoline ring (Sec. 26.6), and the temporary formation of tetrahydropyranyl (THP) esters, resistant toward alkali but extremely easily cleaved by acid (Problem 16, p. 692). 

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