Improved Acylation of Pseudoproline: Masked Threonine in Flow Peptide Chemistry

Szaniszló, Szebasztian and Ferentzi, Kristóf and Perczel, András and Farkas, Viktor (2023) Improved Acylation of Pseudoproline: Masked Threonine in Flow Peptide Chemistry. ORGANIC PROCESS RESEARCH & DEVELOPMENT, 27. pp. 1053-1060. ISSN 1083-6160

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Abstract

Pseudoproline derivatives are incorporated into polypeptides as aggregation disrupters during synthesis, from which the unmodified side chains can be recovered during the final step (resin cleavage). However, direct coupling to pseudoproline is challenging and thus dipeptides of pseudoproline, Fmoc-Xaa-Yaa(ΨMe,Mepro)-OH, are traditionally introduced, which requires the entire library of Fmoc-Xaa-Thr(ΨMe,Mepro)-OH in stock, making this approach expensive. Here, we show how the in situ acylation of the incorporated H-Thr(ΨPro)– can be done successful in flow peptide chemistry, with almost all proteinogenic amino acids (Xaa or X). The Xaa-Thr(ΨPro) amide bond was established with a reagent excess of three to five equivalents, with better than 75% efficiency for most Xaa and 70% in the case of Met. Only for Asp was the efficiency too low (8%) to support the direct use of pseudoproline derivatives.

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