Direct Carbodiimide-Mediated Conjugation of Carboxylates Using ­Pyridinium p-Toluenesulfonate and Tertiary Amines as Additives

Abstract

The use of carboxylates in the carbodiimide-mediated coupling to amines was investigated. The addition of pyridinium p-toluenesulfonate (PPTS) and a tertiary amine was found to significantly improve acylation yields by up to 70%.

Key words

amides - coupling - carbodiimides - carboxylates - solid-phase synthesis

References

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• 12a

  General Procedure for the Carbodiimide-Mediated Amidation: The carboxylic acid or carboxylate was diluted/suspended in DMF to yield a 0.1 M concentration. Under stirring HOBt (1 equiv), PPTS (specified amount), carbodiimide (1 equiv) and DIPEA (2 equiv when mentioned) was added. After 10 min 1 equiv of amine was added. The resulting mixture was stirred for 4 h and analyzed by RP-HPLC.

• 12b

  HPLC was performed on a Gilson 1105 HPLC-system (Nebula series) using a reversed phase Nucleodur C-18 Gravity 3 µm column (Macherey-Nagel, Düren) and a detection wavelength of 254 nm. Eluents: A: 98.9% H₂O, 1% MeCN (HPLC-grade, Biosolve BV, Valkenswaard, NL) 0.1% TFA (Peptide Synthesis Grade, Biosolve BV); B: 98.9% MeCN, 1% H₂O, 0.1% TFA. Gradient: 3-80% B in 20 min followed by 5 min 80% B (Phloxine B, Erythrosin B: Gradient: 3-100% B in 20 min followed by 5 min 80% B).

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14

HPLC was performed on a Gilson 1105 HPLC-system (Nebula series) using a reverse-phase Nucleodur C-18 Gravity 3 µm column (Macherey-Nagel, Düren) and detection wavelengths of 260 nm and 450 nm. Eluents: A: 98.9% H₂O, 1% MeCN (HPLC-grade, Biosolve BV, Valkenswaard, NL) 0.1% TFA (Peptide Synthesis Grade, Biosolve BV); B: 98.9% MeCN, 1% H₂O, 0.1% TFA. Gradient: 3-30% B in 30 min.