The tea-bag protocol for comparison of Fmoc removal reagents in solid-phase peptide synthesis
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The tea‑bag protocol for comparison of Fmoc removal reagents in solid‑phase peptide synthesis Fanny Guzmán1 · Adriana Gauna2 · Omar Luna1 · Tanya Román2 · Claudio Álvarez3,4 · Fernando Albericio5,6,7 · Constanza Cárdenas1 Received: 25 June 2020 / Accepted: 18 August 2020 © Springer-Verlag GmbH Austria, part of Springer Nature 2020
Abstract Several factors have influenced the increasing presence of peptides as an important class of Active Pharmaceutical Ingredients. One is the continued development of synthetic methodologies for peptide synthesis. Herein, we investigated the Fmoc removal step, using the tea-bag strategy. In this regard, three different secondary amines: piperidine, 4-methylpiperidine, and piperazine, were evaluated. As a result of this study, 4-methyl piperidine showed to be an excellent alternative to the usually used piperidine in terms of purity and compliance with green chemistry principles as well. Keywords Piperidine · 4-Methylpiperidine · Piperazine · Parallel synthesis · Green chemistry · Tea-bag protocol · Simultaneous Fmoc synthesis
Introduction Nowadays, peptides are considered an important class of Active Pharmaceutical Ingredients (APIs) (de la Torre and Albericio 2019). There is not a doubt that this has been in part possible due to the incorporation of the solidphase peptide synthesis (SPPS) methodology to peptide research and peptide production processes (Merrifield 1963). Although several SPPS strategies are described, Handling Editor: J. D. Wade. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00726-020-02883-8) contains supplementary material, which is available to authorized users.
the so-called fluorenylmethoxycarbonyl (Fmoc)/tert-butyl (tBu) is the strategy of choice based on its performance and simplicity. Basically, the elongation of a peptide by SPPS involves two steps: coupling of the Fmoc-protected amino acid and removal of the Fmoc group after coupling. The widespread acceptance of the Fmoc/tBu/SPPS strategy for all peptide-based drug discovery stakeholders has been possible because of the great performance achieved in peptide synthesis through the continuous methodological work of several groups. In this regard, piperidine related amines were evaluated, selecting the best one for the removal of the Fmoc group. Classically, piperidine in N,N-dimethylformamide (DMF) has been used. However, piperidine is a controlled substance to be used as an intermediate for
* Fanny Guzmán [email protected]
4
Facultad de Ciencias del Mar, Universidad Católica del Norte, Coquimbo 1781421, Chile
* Constanza Cárdenas [email protected]
5
Department of Organic Chemistry and CIBER‑BBN, Networking Centre on Bioengineering, Biomaterials and Nanomedicine, University of Barcelona, 08028 Barcelona, Spain
6
Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Jordi Girona 18‑26, 08034 Barcelona, Spain
7
School of Chemistry, University of KwaZulu-Natal, Durban 4001, South Africa
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