Heating and microwave assisted SPPS of C-terminal acid peptides on trityl resin: the truth behind the yield

Amino Acids, 2013, Volume: 45, Issue: 6, Pages: 1395-1403, DOI: 10.1007/s00726-013-1604-z

C. Echalier, S. Al-Halifa, A. Kreiter, C. Enjalbal, P. Sanchez, L. Ronga, K. Puget, P. Verdie, M. Amblard, J. Martinez, G. Subra


Despite correct purity of crude peptides prepd. on trityl resin by Fmoc/tBu microwave assisted solid phase peptide synthesis (Fmoc = 9-fluorenyl-methoxycarbonyl), surprisingly, lower yields than those expected were obtained while prepg. C-terminal acid peptides.  This could be explained by cyclization/cleavage through diketopiperazine formation during the second amino acid deprotection and third amino acid coupling.  However, we provide here evidence that this is not the case and that this yield loss was due to high temp. promoted hydrolysis of the 2-chloro-trityl ester, yielding premature cleavage of the C-terminal acid peptides.