Protection of the Phenolic Group

Although the esterifiction of phenols and also their etherification (considered in the next chapter) can be regarded as protective methods for the phenolic hydroxyl group there have been few developments in this aspect of phenolic chemistry. The definitive text on this topic remains relevant (ref,59). 

It is interesting to note that 2-methyl and 2,6-dimethylphenol afford better protecting systems than 4-hydroxydiphenyl for phosphopeptide syntheses by solid phase techniques (ref.60). 

The 2-bromophenyl group in a phosphoryl compound was selectively removed over 2 hours by treatment in pyridine/water (9 1) with copper(ll) acetate without the nucleotide being affected (ref.61). 

---

The first asymmetric synthesis of (-l-)-abresoline was achieved from the chiral piperidine derivative 153, which upon treatment of its hydroxy side-chain substituent with carbon tetrabromide, triphenylphosphine, and triethyl-amine cyclized to the frarcr-quinazolidine 154. Deketalization and silyl protection of the phenolic group, followed by stereoselective reduction with lithium tri-t -butylborohydride (L-Selectride ), gave an alcohol, which after acylation and deprotection furnished (-l-)-abresoline 155 (Scheme 25) <2005TL2669>. 

The synthesis of the naphthoquinone 116 is shown in Scheme 3.24. Bromination of juglone (118) afforded the dibromojuglone derivative 134. Protection of the phenol group as its methoxymethyl ether formed the product 135 (50 % yield over two steps). Finally, the C-3 bromide substituent was regioselectively substituted with methoxide by heating 135 in methanol in the presence of sodium carbonate (96 %). The methoxy group was installed to impart electronic bias to the naphthoquinone in the TASF(Et) coupling (vide infra). 

Deprotection of O-methyltyrosine. O-Methylation of tyrosine (1) has represented an irreversible protection of the phenol group, since cleavage is accomplished only under drastic conditions. A new, mild method for deprotection involves treatment of 1 with thioanisole and trifluoromethanesulfonic acid in trifiuoroacetic acid. This method was used in the final step of a synthesis of a pentapeptide (43%... 

Methoxy-l-benzopyrans are prepared at or below room temperature from 2-bromophenols and 3-trimethylsilyloxyacroleins. Protection of the phenolic group and lithiation precede treatment with the acrolein when the protecting group is removed with cold mineral acid, cyclization occurs in good yield. Chalcone dibromides cyclize in a basic medium but yields of pyrans are often better under weakly basic conditions, as is demonstrated in this synthesis of a flavone in dilute alkali at room temperature. 

Since the alkyl group, usually the methyl, is used for the protection of the phenolic group, the reactions described in this section effectively extend the synthesis of phenols already described. Thus some of the syntheses from phenolic ethers in the last part of the preceding section would also appear to be equally an aspect of the reactions of phenolic ethers. The general reactions... 

Having successfully loaded all six aromatic substituents onto 90, all that remained to access 59 were some subtle modifications despite the straightforward nature of this statement, however, a rather lengthy sequence was required to complete these tasks. The first prerequisite step, selective and sequential protection of the phenolic groups in 92, was achieved without incident through initial protection of the more activated, non-hydrogen bonded phenol as... 

The phenolic hydroxyl group of tyrosine, the imidazole moiety of histidine, and the amide groups of asparagine and glutamine are often not protected in peptide synthesis, since it is usually unnecessary. The protection of the hydroxyl group in serine and threonine (O-acetylation or O-benzylation) is not needed in the azide condensation procedure but may become important when other activation methods are used. 

An isopropyl ether was developed as a phenol protective group that would be more stable to Lewis acids than would be an aryl benzyl ether. The isopropyl group has been tested for use in the protection of the phenolic oxygen of tyrosine during peptide synthesis."... 

The methyl group on a sulfoxide interestingly proves sufficiently acidic to substitute for phenolic hydroxyl. The preparation of this combined a- and 3-blocker, sulfinalol, begins by protection of the phenolic hydroxyl as its benzoate ester (34). Bromination (35) followed by... 

Properties. Vanillin is a colorless crystalline solid mp 82-83 °C) with a typical vanilla odor. Because it possesses aldehyde and hydroxyl substituents, it undergoes many reactions. Additional reactions are possible due to the reactivity of the aromatic nucleus. Vanillyl alcohol and 2-methoxy-4-methylphenol are obtained by catalytic hydrogenation vanillic acid derivatives are formed after oxidation and protection of the phenolic hydroxyl group. Since vanillin is a phenol aldehyde, it is stable to autoxidation and does not undergo the Cannizzarro reaction. Numerous derivatives can be prepared by etherification or esterification of the hydroxyl group and by aldol condensation at the aldehyde group. Several of these derivatives are intermediates, for example, in the synthesis of pharmaceuticals. 

Methods for the protection of the phenolic hydroxyl group are considered in Section 6.9.4, p. 988. 

SOME METHODS FOR THE PROTECTION OF THE PHENOLIC HYDROXYL GROUP... 

Partial N-methylation can also be accomplished with Mel. For example, tetrandrine (48) gave on treatment with 1 equiv Mel a 4 1 mixture of the monoquatemary salts 365 and 33. The pure minor isomer could be obtained by sequential quatemization of tetrandrine with 1 equiv benzyl bromide, then 1 equiv Mel, conversion of the bisquatemary salt to the dichloride form with anion-exchange resin, and cleavage of the benzyl group by catalytic reduction (H2/Pd-EtOH) (20). Partial O-methylation of alkaloids containing more than one OH can be accomplished with CH2N2 either by prior partial protection of the phenols as 0-acetates (148) or by use of less than a stoichiometric amount of CH2N2 (132) (see, e.g., Section II,C, 122). 

The dienone (210) has also been prepared (152, 153) by oxidation of the amide (211) with potassium ferricyanide, when 212 was obtained in 67% yield. After protection of the phenolic hydroxyl group, reduction with LAH... 

---