Benzyl esters carboxy-protecting groups

In a formal sense, alkyl ester type carboxy protecting groups, e.g. benzyl, allyl, 4-picolyl, and (9,10-dioxo-2-anthryl)methyl esters, can be viewed at as modified methyl esters. However, because of their specific properties and cleavage conditions these esters will be discussed separately. In this section a series of acetal, phthalimidomethyl, various phenacyl, acetonyl, 9-anthryhnethyl, and cyclopropyhnethyl esters will be presented. 

Table 5 Substituted Benzyl Esters, RCO2R, as Carboxy-protecting Groups...

Benzyl ester, a reversible carboxy-protecting group for peptide synthesis cleaved by saponification, HBr/AcOH, HF, and by catalytic hydrogenolysis. 

FIGURE 8.7 Synthesis of a protected tripeptide containing a 2-hydroxy-4-methoxybenzyl-protected peptide bond.38 (A) Acylation of the carboxy-terminal residue, (B) removal of both protecting groups, (C) O-acylation of the benzyl-protector by the symmetrical anhydride of the amino-terminal residue, and (D) migration of the protected amino-terminal residue from the oxygen atom to the amino group of the dipeptide ester. 

The carboxy group is usually protected as a methyl or benzyl ester by reaction with an alcohol and an acid. 

To avoid any loss of benzyl ester protection during acidolytic removal of the benzyloxy-carbonyl and ferf-butoxycarbonyl groups, electron-withdrawing substituents were used to destabilize the intermediate benzyl cation and thus to increase the acid stability. In addition to the very useful 4-nitrobenzyl esters (vide infra), the picolyl ester (see Section 2.2.1.2.2.3) as well as halo-P l or cyano-P°°l substituted benzyl esters have been reported, the latter being rarely used for a-carboxy protection. Conversely, an increase in sensitivity toward acids can be achieved by introduction of electron-releasing substituents, such as methoxy or methyl groups. Addition of scavengers to quench intermediate carbocations and to prevent electrophilic substitutions at sensitive amino acid side chains is beneficial in the deprotection of such esters. 

The cyclopentyl (cPe) ester group was introduced by Blake for the protection of carboxy groups. The ester bond is stable against TFA and readily cleaved with HF at 0 °C. This ester is 14 times more stable than the corresponding benzyl ester when exposed to 55% TFA in dichloromethane. However, there is little difference in the extent of HF-catalyzed succini-mide formation between peptidyl-resins containing benzyl- or cyclopentyl-protected aspartyl residues, although the latter protection reduces base-catalyzed succinimide formation. 

In order to prepare Asp- or Glu-containing peptide fragments, in which side-chain carboxy groups are unblocked, one method is to introduce aspartic or glutamic acid into the peptide through its A-carboxyanhydride. Another method is to introduce aspartic or glutamic acid with the side chain protected as the benzyl ester and then to remove the benzyl ester by YiJ Pd and finally convert the C-terminal methyl ester into the corresponding hydrazide. 

One simple procedure allows the synthesis of phosphatidylserine by condensation of phosphatidic acid with an amino- and carboxy-protected serine. iV-Carbobenzoxyl-DL-serine benzyl ester was condensed with the phosphatidic acid in the presence of tri-isopropylbenzenesulphonyl chloride. The protecting groups were then removed by hydrogenation which limits the method to saturated phosphatidylserines. However, the use of different protecting groups should allow this method to be used for unsaturated compounds. An alternative procedure involves the introduction of the phosphate and serine functions via a complex silver salt to glycerol iodohydrin diesters (de Haas etal, 1964). 

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