Guanidino formation, side reaction

Uronium salts have been used for cyclization of linear peptides in both solution and solid-phase modes. Since this reaction is sequence dependent, there are no general conditions. Thus cyclization in solution with uronium salt methods give, for some peptides, better results than the classical rt gtniDiphenylPhosphorazidate (DPPA), " but for another case the converse is true. Furthermore, dehydration of C-terminal aspartylamide peptides during cyclization with HBTU has been described. This side-reaction can be prevented by the addition of one equivalent of HOBt. Although good results have been obtained in the solid-phase, guanidino formation side-reactions have also been reported. ... 

In order to examine the extent of this side reaction, the relatively slow coupling of Fmoc-Deg-OH with H-Phe-OFm (51) in the presence of 2 equivalents of DIPEA and HBTU or HATU was analyzed. After 75 minutes, the desired dipeptide was formed in 85 and 94% yield, respectively, with <0.5% formation of the guanidino side products in either case.P ... 

The formation of guanidino side products is not critical for the stepwise solid-phase synthesis of standard peptides, in which a preactivation of reactive amino acids is conducted. However, if activation in situ is carried out or activation of hindered amino acids, protected peptides, or a carboxylic moiety before a cycli-zation step is performed, the use of phosphonium salts may be more efficient. For slow activation reactions, the addition of more coupling reagent (e.g., PyAOP) during the course of the reaction is advisable because the coupling derivative is hydrolyzed after a few minutes. 

---