期刊
TETRAHEDRON
卷 99, 期 -, 页码 -出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.tet.2021.132452
关键词
Green chemistry; Solid-phase peptide synthesis; Anisole; Fmoc removal; Green bases
资金
- Grant Agency of the Czech Republic (GACR) [18-17978Y]
By utilizing green bases, solvents, and solvent mixtures, the Fmoc solid-phase peptide synthesis procedures were optimized and the impact on side products was evaluated. The new green protocols demonstrated good applicability in practical synthesis, effectively reducing the generation of harmful by-products.
As a step toward green Fmoc solid-phase peptide synthesis (SPPS), we explored the compatibility of the green bases morpholine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and NaOH with the green solvent anisole as a replacement for the traditionally used hazardous piperidine in N,N-dimethylformamide (DMF) for the Fmoc removal step. Green Fmoc cleavage protocols were optimized for the Fmoc-Ala-NHRink resin model and subsequently verified for other Fmoc-amino acids. Only Gly required a modified NaOH-based protocol with the addition of 5 % water. Furthermore, we evaluated the effects of basic treatment on the notorious aspartimide formation as an undesired side product of SPPS. We also introduced a new green solvent mixture, anisole/dimethyl sulfoxide (DMSO) (4:1) for acylation step, which did not cause racemization. The applicability of these new green protocols was shown during SPPS of the pentapeptides Leu-enkephalin and Aib-enkephalin using polystyrene (PS)-based resins. Additionally, we identified the new sequence-dependent side products that formed after treatment with NaOH in anisole/ethanol (EtOH) (1:1). (c) 2021 Elsevier Ltd. All rights reserved.
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