Intramolecular cleavage, prevention

Studies in which the effect of inserting variable-length linkers between the 5 end of the substrate and the 3 end of the ribozyme showed that coaxial stacking of helices 2 and 3 prevented intramolecular cleavage activity, and strongly suggested that a sharp bend must occur between these helices to form the active configuration (12-13). 

Caprolactams can be prepared by intramolecular nucleophilic cleavage of support-bound 6-aminohexanoates (Entry 9, Table 15.35). The yields of such reactions are usually not high, even if reactive esters are used for attachment to the support. High loading should be avoided to prevent the formation of oligomers by intermolecular nucleophilic cleavage. 

Diazepanones have been prepared on insoluble supports by intramolecular nucleophilic cleavage, by intramolecular Mitsunobu reaction of sulfonamides with alcohols, and by intramolecular acylations (Table 15.36). As in the case of azepines, these reactions do not always proceed smoothly, and care must be taken to prevent potential side reactions from occurring. For instance, intramolecular acylations in peptides containing aspartic acid (Entry 2, Table 15.36) will generally lead to the formation of suc-cinimides (see Table 13.20) unless A-alkylamino acids are used. 

SP synthetic strategy to 3.83 The designed synthesis included as a final step the formation of an urea on 3.89 with simultaneous intramolecular cyclization on the carboxylic ester (Fig. 3.34) the use of an ester function to support the 3.89-like intermediate would have allowed the cyclative cleavage of the desired hexahydro-2,3a,7-triazacyclopenta[c]pentalene-l,3-dione. The use of classical PS resins was not prevented by any of the transformations needed to give 3.83. 

Cycloalkyl esters for the side-chain protection of aspartic acid in SPPS have been developed to increase resistance to aspartimide formation. Based on mechanistic studies of this side reaction, these protection groups should fulfill the following criteria provide steric hindrance to intramolecular aminolytic attack of the ester by the amide nitrogen in acidic and basic media, provide increased stability toward repetitive TFA treatments but quantitative cleavage by HE, as well as stabilization of the carbenium ion produced by cleavage of the protecting group to prevent recapture by the peptide. The secondary cycloalkyl esters are more acid stable and more sterically hindered if compared to the primary benzyl esters. In Scheme 7, different cycloalkyl esters are shown. 

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