Protected peptides side reactions

Incorporation of the Third Protected Amino Acid to Circumvent the Diketopiperazine Side Reaction That Occurs during Syntheses of Cyclic Peptides (R1 = C02Allyl) (Note 15)... 

M Bodanszky, J Martinez. Side reactions in peptide synthesis. 8. On the phenacyl group in the protection of the p-carboxyl function of aspartyl peptides. J Org Chem 43, 3071, 1978. 

The major side reaction associated with the use of mixed anhydrides is aminolysis at the carbonyl of the carbonate moiety (Figure 7.4, path B). The product is a urethane that resembles the desired protected peptide in properties, except that the amino-terminal substituent is not cleaved by the usual deprotecting reagents. Hence, its removal from the target product is not straightforward. The problem is serious when the residues activated are hindered (Val, lie, MeXaa), where the amounts can be as high as 10%. Other residues generate much less, but the reaction cannot be avoided completely, with the possible exception of activated proline (see Section 7.22). This is one reason why mixed anhydrides are not employed for solid-phase synthesis. 

The advantage of this synthetic approach over the total synthesis of selenocysteine peptides is the reduced number of synthetic steps to which the Se-protected selenocysteine is exposed, thus, largely preventing deselenation as an undesired side reaction. It also allows access to larger peptides and even proteins containing selenocysteine to exploit the Se atom for X-ray crystallography, 13 or as 77Se nucleus for NMR spectroscopy. 60 ... 

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