Methyl 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. 

A new carboxy protecting group that takes advantage of the facile solvolysis of cyclopropyl methyl substrates was proposed by Carpino et al.f The dicyclopropylmethyl (Dicyc-propme) ester can be used for carboxylic acid protection where selective removal is required in the presence of tBu or Trt side-chain protection. The ester is stable toward conditions of... 

Table 3 Substituted Methyl Esters, R—COO—R, as Carboxy-protecting Groups...

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. 

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. 

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