Unwanted hydrolysis or α/β-peptide bond formation: How long should the rate-limiting coupling step take?

Viktória Goldschmidt Gőz, Adrienn Nagy, Viktor Farkas, Ernő Keszei, András Perczel

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Nowadays, in Solid Phase Peptide Synthesis (SPPS), being either manual, automated, continuous flow or microwave-assisted, the reaction with various coupling reagents takes place via in situ active ester formation. In this study, the formation and stability of these key active esters were investigated with time-resolved 1H NMR by using the common PyBOP/DIEA and HOBt/DIC coupling reagents for both α- and β-amino acids. Parallel to the amide bond formation, the hydrolysis of the α/β-active esters, a side reaction that is a considerable efficacy limiting factor, was studied. Based on the chemical nature/constitution of the active esters, three amino acid categories were determined: (i) the rapidly hydrolyzing ones (t < 6 h) with smaller (Ala) or even longer side chains (Arg) holding a large protecting group; (ii) branched amino acids (Ile, Thr) with slowly hydrolyzing (6 < t < 24 h) propensities, and (iii) non-hydrolyzing ones, such as the hard-to-couple β-amino acids or β-sugar amino acid derivatives, stable for longer times (t > 24 h) in solution. The current insight into the kinetics of this key hydrolysis side reaction serves as a guide to optimize the coupling conditions of α- and β-amino acids, thereby saving time and minimizing the amounts of reagents and amino acids to be used-all key factors of more environmentally friendly chemistry.

Original languageEnglish
Pages (from-to)30720-30728
Number of pages9
JournalRSC Advances
Volume9
Issue number53
DOIs
Publication statusPublished - Jan 1 2019

ASJC Scopus subject areas

  • Chemistry(all)
  • Chemical Engineering(all)

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