To replace dimethylformamide (DMF) in fluorenylmethoxycarbonyl (Fmoc) solid-phase peptide synthesis, we explored the application of mixtures of green solvents (green solvents mixtures for solid-phase peptide synthesis (GM-SPPS)) as combinations of Cyrene (dihydrolevoglucosenone), sulfolane, or anisole with dimethyl carbonate or diethyl carbonate, in different proportions. Their ability to swell differently functionalized polystyrene and polyethylene glycol resins was explored, and solubility of amino acids and coupling reagents was studied. Moreover, the synthesis of the model peptide Aib-enkephalin was performed in the new green mixtures, confirming the possibility to fully replace DMF all over SPPS. The two established best green protocols were then successfully applied to the synthesis of a longer peptide (Aib-ACP). Finally, the green solvent-based procedure was applied to the synthesis of the reduced form of the active pharmaceutical ingredient (API) Octreotide. After oxidative cyclization and a single high-pressure column chromatography, the pharmaceutical-grade compound was isolated in comparable high yield to that obtained with the standard procedures.

Green Solvent Mixtures for Solid-Phase Peptide Synthesis: A Dimethylformamide-Free Highly Efficient Synthesis of Pharmaceutical-Grade Peptides

Ferrazzano, L
Investigation
;
Corbisiero, D
Investigation
;
Martelli, G
Investigation
;
Tolomelli, A
Conceptualization
;
Cabri, W
Conceptualization
2019

Abstract

To replace dimethylformamide (DMF) in fluorenylmethoxycarbonyl (Fmoc) solid-phase peptide synthesis, we explored the application of mixtures of green solvents (green solvents mixtures for solid-phase peptide synthesis (GM-SPPS)) as combinations of Cyrene (dihydrolevoglucosenone), sulfolane, or anisole with dimethyl carbonate or diethyl carbonate, in different proportions. Their ability to swell differently functionalized polystyrene and polyethylene glycol resins was explored, and solubility of amino acids and coupling reagents was studied. Moreover, the synthesis of the model peptide Aib-enkephalin was performed in the new green mixtures, confirming the possibility to fully replace DMF all over SPPS. The two established best green protocols were then successfully applied to the synthesis of a longer peptide (Aib-ACP). Finally, the green solvent-based procedure was applied to the synthesis of the reduced form of the active pharmaceutical ingredient (API) Octreotide. After oxidative cyclization and a single high-pressure column chromatography, the pharmaceutical-grade compound was isolated in comparable high yield to that obtained with the standard procedures.
2019
Ferrazzano, L ; Corbisiero, D ; Martelli, G; Tolomelli, A ; Viola, A ; Ricci, A; Cabri, W
File in questo prodotto:
File Dimensione Formato  
ACS sus 2019.pdf

Open Access dal 21/06/2020

Tipo: Preprint
Licenza: Licenza per Accesso Aperto. Altra tipologia di licenza compatibile con Open Access
Dimensione 6.35 MB
Formato Adobe PDF
6.35 MB Adobe PDF Visualizza/Apri
suppinfo ACS.pdf

Open Access dal 21/06/2020

Tipo: File Supplementare
Licenza: Licenza per Accesso Aperto. Altra tipologia di licenza compatibile con Open Access
Dimensione 3.48 MB
Formato Adobe PDF
3.48 MB Adobe PDF Visualizza/Apri
Green Solvents Mixtures.pdf

Open Access dal 21/06/2020

Tipo: Postprint
Licenza: Licenza per Accesso Aperto. Altra tipologia di licenza compatibile con Open Access
Dimensione 2.41 MB
Formato Adobe PDF
2.41 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/723147
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 64
  • ???jsp.display-item.citation.isi??? 63
social impact