OxymaPure®: the green coupling additive

OxymaPure® has been declared by the ACS Green Chemistry Initiative  Chemical Manufacturers Roundtable to be one of the greenest coupling additives (17).

OxymaPure® shows a better solubility than HOBt in almost all current solvents,  used in peptide synthesis.  This facilitates its use in combination with green solvents.

2-MeTHF (2-methyltetrahydrofuran) has been used for the solid-phase synthesis of Aib-enkephalin pentapeptide. Coupling conditions were DIC/Oxyma Pure in 2-MeTHF (10)

Polar Clean ® DIC/OxymaPure® is used in the synthesis of  A) H-Tyr-Gly–Gly-Phe-Leu-NH₂ (Leu enkephalinamide), (B) H-Ala-Lys-Asp-Gly-Tyr-Ile-NH₂ (fragment 1–6 of the toxin II from scorpion Androctonus australis Hector (27) and C) H-Lys-Thr-Thr-Lys-Ser-NH₂ (peptide-4 used as an anti-wrinkle agent in cosmetics) (11)

Binary Solvents. Synthesis of Bivalirudin (H-fPRPGGGGNGDFEEIPEEYL-OH) using SPPS approach and OxymaPure /DIC coupling strategy and various binary solvents revealed that using a combination of DMSO/2-Me-THF (2:8) and DMSO/EtOAc (1:9) with results comparable to those of DMF. (12)

γ-Valerolactone (GVL) Synthesis of H-Gly-Phe-Leu-NH₂ (H-GFL-NH₂) and H-Leu-Phe-Gly-NH₂ was performed manually using an OxymaPure®/DIC combination and Fmoc-Rink-Amide AM-PS resin (13). OxymaPure®/DIC, GVL, and microwave have also allowed the synthesis of large peptides, such as α-thymosin and ABRF-1992.

 Although the solid-phase peptide synthesis strategy involves many green features, using large amounts of solvent to remove traces of piperidine and/or of the incoming amino acid is an important drawback.  In this regard, it has been demonstrated that after the deprotection step, washing the resin with the corresponding solvent containing 1% of OxymaPure® can reduce the consumption of solvents up to a 50%.  This reduction can reach up to 75% with other manipulations (14).

🔴 – Major known issues
🟡 – Some known issues
🟢 – Few known issues