Abstract
2-MeTHF and CPME were evaluated as greener alternatives for the most employed solvents in peptide synthesis. The ability of these solvents to dissolve amino acid derivatives and a range of coupling reagents were evaluated as well as the swelling of polystyrene and polyethylene glycol resins. In addition, racemization and coupling efficiencies were also determined. We concluded that the use of 2-MeTHF with combination of DIC/OxymaPure gave the lowest racemization level during stepwise synthesis of Z-Phg-Pro-NH2 and the highest purity during SPPS of Aib-enkephalin pentapeptide (H-Tyr-Aib-Aib-Phe-Leu-NH2).
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Abbreviations
- ACN:
-
Acetonitrile
- ACS GCIPR:
-
American Chemical Society Green Chemistry Institute Pharmaceutical Roundtable
- COMU:
-
1-[(1-(cyano-2-ethoxy-2-oxoethylideneaminooxy)-dimethylamino-morpholinomethylene)]methanaminium hexafluorophosphate
- CPME:
-
Cyclopentyl methyl ether
- DCM:
-
Dichloromethane
- DIC:
-
N,N′-diisopropylcarbodiimide
- DIEA:
-
N,N-diisopropylethylamine
- DMF:
-
N,N-dimethylformamide
- HATU:
-
N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]-pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide
- HBTU:
-
N-[(1H-benzotriazol-1-yl)(dimethylamino)-methylene]-N-methylmethanaminium hexafluorophosphate N-oxide
- HOAt:
-
1-Hydroxy-7-azabenzotriazole
- HOBt:
-
1-Hydroxybenzotriazole
- 2-MeTHF:
-
2-Methyltetrahydrofuran
- NMP:
-
N-methyl-2-pyrrolidone
- Oxyma-B:
-
5-(Hydroxyimino)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione
- OxymaPure:
-
Ethyl 2-cyano-2-(hydroxyimino)acetate
- PS:
-
Polystyrene
- THF:
-
Tetrahydrofuran
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Acknowledgments
This work was funded in part by the following: the National Research Foundation (NRF) and the University of KwaZulu-Natal (South Africa); the CICYT (CTQ2012-30930), the Generalitat de Catalunya (2014 SGR 137), and the Institute for Research in Biomedicine Barcelona (IRB Barcelona) (Spain). In addition, the authors thank the Deanship of Scientific Research at King Saud University for partially funding this work through research group No. RGP-234 (Saudi Arabia). Finally, we thank Dr Karine Salim (Pcas) for the generous gift of ChemMatrix resin and Yoav Luxembourg (Luxembourg Bio Technologies Ltd) for his continuous support of this study.
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Handling Editor: J. Bode.
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Jad, Y.E., Acosta, G.A., Khattab, S.N. et al. 2-Methyltetrahydrofuran and cyclopentyl methyl ether for green solid-phase peptide synthesis. Amino Acids 48, 419–426 (2016). https://doi.org/10.1007/s00726-015-2095-x
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DOI: https://doi.org/10.1007/s00726-015-2095-x
Keywords
- Green solvents
- Solid-phase peptide synthesis
- Peptide synthesis
- 2-methyltetrahydrofuran
- Cyclopentyl methyl ether