Unwanted hydrolysis or alpha/beta-peptide bond formation: how long should the rate-limiting coupling step take?

Goldschmidt Gőz, Viktória and Nagy, Adrienn and Farkas, Viktor and Keszei, Ernő and Perczel, András (2019) Unwanted hydrolysis or alpha/beta-peptide bond formation: how long should the rate-limiting coupling step take? RSC ADVANCES (9). pp. 30720-30728. ISSN 2046-2069

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Official URL: https://doi.org/10.1039/c9ra06124j

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.

Item Type:	Article
Subjects:	Q Science / természettudomány > QD Chemistry / kémia
Depositing User:	Viktor Farkas
Date Deposited:	29 Sep 2020 09:09
Last Modified:	25 Jul 2025 08:19
URI:	https://real.mtak.hu/id/eprint/115337

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Unwanted hydrolysis or alpha/beta-peptide bond formation: how long should the rate-limiting coupling step take? (deposited 24 Sep 2019 18:07)
- Unwanted hydrolysis or alpha/beta-peptide bond formation: how long should the rate-limiting coupling step take? (deposited 29 Sep 2020 09:09) [Currently Displayed]

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