Imide Formation from Substituted Dicarboxylic Acid Residues

13 IMIDE FORMATION FROM SUBSTITUTED DICARBOXYLIC ACID RESIDUES 

FIGURE 6.15 Imide formation from a dipeptide sequence containing an aspartyl residue with side-chain functional group in various states followed by generation of two peptide chains resulting from cleavage at the bonds indicated by the dashed arrows. The reaction is catalyzed by base52 or acid. [Merrifield, 1967]. The table shows the effect of the nature of the substituent on the extent of this side reaction. Dmpn = 2,4-dimethylpent-3-yl. 

Efficient, though not total, suppression of the reaction is achieved in a synthesis using Fmoc chemistry by including an acid such as 1-hydroxybenzotriazole or 

4-dinitrophenol at 0.1 M concentration in the deprotecting solution (piperidine-dimethylformamide, 1 4). Use of piperazine (1,4-diazacyclohexane see Section 8.12) instead of piperidine also suppresses the reaction. The 3-methylpent-3-yl ester may be the best for minimizing piperidine-induced imide formation. The only way to eliminate the reaction is to temporarily replace the hydrogen atom of the peptide bond by 2-Fmoc-oxy-4-methoxybenzyl (see Section 8.5).52-62 

E Sondheimer, RW Holley. Imides from asparagine and glutamine, (effect of alkali 

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