The need for protection of certain side chain protecting groups is clear especially the e-amino function of Iysine, where branched peptides would result from acylation of an unprotected residue. It has been suggested that use of protecting groups for many of the other amino acids is unnecessary yet maintaining conditions under which side reactions are eliminated is a most difficult, if not impossible, task. It is therefore often best to maintain a cautious approach, protecting all but the least reactive functionalities.
The alcohol functions of serine and threonine, the phenol of tyrosine, the guanidine of arginine and the thiol of cysteine can all undergo acylation and alkylation. Protection of cysteine is also imperative to avoid uncontrolled formation of disulphide bridges. Histidine can also be alkylated and the indole nucleus is sufficiently basic to cause racemisation during activation and to catalyse O-acylation as well as N,O-acyl transfer. It is clear that the carboxyl groups in the side chains of aspartic and glutamic acids must be protected in order to achieve unambiguous activation. The primary amide functionalities of asparagine and glutamine are not involved in side reactions once the residues have been incorporated into a peptide yet their protection is often recommended to avoid dehydration to the nitrile during activation. The side chain protecting group table provides some commonly used protecting groups for the functional groups of the amino acid side chains.
The choice of protecting group depends on the methodology adopted for the protection of the a-amino group. If an acid labile amino protection is adopted, typically the tert -butyloxycarbonyl (BOC) group, then the side chain protection must be stable to moderately strong acids. Where Z is used, the side chain functions must be stable to hydrogenation or acidolysis with strong acids. If a base or nucleophile labile scheme is favoured then side chain protection groups may be acid labile, for example based on the tert-butyl or trityl groups.
Removal of protecting groups, particularly under acidic conditions, often results in the formation of cationic species which tend to alkylate the sensitive functionalities indicated above. For this reason scavengers are included in the deprotection media. Compounds such as water, anisole, thioanisole, ethylmethyl sulphide and ethane dithiol are included in excess in the deprotection medium since they readily react with any carbocation or other active species.