Side reactions alkylation during deprotection

Peptide synthesis is quite regularly accompanied by undesired side reactions, for instance by the alkylation of side chains during deprotection. In addition to such general problems for which at least partial remedies have been found, also a special problem is encountered in solid phase syntheses the formation of deletion peptides and truncated sequences . Both incomplete acylation and incomplete deprotection result in peptide chains from which one or more amino acid residues are missing. A second kind of deletion, the loss of the C-terminal dipeptide sequence, is caused by diketopiperazine formation followed by acylation of the resulting hydroxymethyl polymer (Fig. 8). Premature chain termination (truncation) takes place if acetic acid or trifluoroacetic acid are not completely removed after deprotection and then co-activated in the following coupling step. 

The most important family of side reactions, namely potential loss of configuration at various stages of solid-phase anchoring and chain assembly, has been mentioned already (Sections 3.2.1 and 3.2.2). Other problems should be considered as well. Oxidation and alkylation of the thioether of S-protected Cys is always a possibility, but such processes appear to be less severe in the case of Cys than with Met. A number of side reactions are likely to be sequence dependent some of these involve modifications of other residues by species released during deprotection and/or oxidation. 

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