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

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 investigate...

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Bibliographic Details
Published in:RSC advances 2019-09, Vol.9 (53), p.372-3728
Main Authors: Goldschmidt G z, Viktória, Nagy, Adrienn, Farkas, Viktor, Keszei, Ern, Perczel, András
Format: Article
Language:English
Subjects:
Amino acids
Bonding
Chain branching
Chemistry
Continuous flow
Coupling
Esters
Hydrolysis
Limiting factors
NMR
Nuclear magnetic resonance
Organic chemistry
Peptides
Reaction kinetics
Reagents
Solid phases
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Summary: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 1 H 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. Parallel to the amide bond formation, the hydrolysis of the active esters of α/β-amino acids, as an unwanted side reaction limiting coupling efficacy, is studied.
ISSN:2046-2069
2046-2069
DOI:10.1039/c9ra06124j