1,1,3,3-Bis(tetramethylene)chlorouronium Hexafluorophosphate

[207915-96-6; 135540-11-3]  · C9H16ClF6N2P  · (332)

(peptide synthesis coupling reagent)

Alternate Name: PyClU,1 BTCFH.2

Physical Data: mp 151-153 °C,1 146-148 °C.3

Solubility: soluble in CH2Cl2, CHCl3, DMF, DMSO, NMP, acetone.

Form Supplied in: colorless crystals.

Analysis of Reagent Purity: 1H-NMR; elemental analysis.

Preparative Methods: addition of POCl31 or a 20% solution of phosgene in toluene3,4 to the corresponding urea and then addition of KPF6/H2O.

Purification: recrystallization (acetone/Et2O).

Handling, Storage, and Precautions: the toxicological properties of this reagent have not been investigated and no special instructions for storage and handling are mentioned in the literature.

Reagent for Peptide Synthesis

This reagent, which was designed for coupling N-methylated amino acids (eq 1), gives results comparable to those obtained with PyBroP.1 Compared with the hydroxybenzotriazol-based activator HBTU, which produces the moderately activated benzotriazolyl esters from carboxylic acids, PyClU gives high yields and low racemization.1,5 However, significant epimerization is observed during segment condensation.6

In addition, the homologous tetrafluoroborate salt TPyClU proved to be efficient for monoester formation from N-protected a-amino phosphonic acid (eq 2).7

Preparation of Coupling Reagents for Peptide Synthesis

Several related uronium coupling reagents have been prepared from PyClU:

  • Bis(tetramethylene)phenoxyformamidinium hexafluorophosphate derivatives PfPyU,4 HPyOPFp, HpyOTcp, and HpyONp8 (eq 3).

  • Benzotriazolyl-1,1,3,3-bis(tetramethylene)chlorouronium hexafluorophosphate (HBPyU1 or BBC3) and its 7-azabenzotriazole9 analog, reagents for peptide synthesis (eq 4).

  • Bis(tetramethylene)fluoroformamidinium hexafluorophosphate (BTFFH), reagent for in situ conversion of amino acids into amino acid fluorides in peptide synthesis (eq 5).2

  • Related Reagents.

    PyCloP (chlorotripyrrolidinophosphonium hexafluorophosphate); PyBroP (bromotripyrrolidinophosphonium hexafluorophosphate); HBPyU [O-(benzotriazol-1-yl)-1,1,3,3-bis(tetramethylene)uronium hexafluorophosphate]; HAPyU [O-(7-azabenzotriazol-1-yl)-1,1,3,3-bis(tetramethylene)uronium hexafluorophosphate]; TpyClU [1,1,3,3-bis(tetramethylene)chlorouronium tetrafluoroborate]; CIP (2-chloro-1,3-dimethylimidazolidium hexafluorophosphate); HPyOPFp [(pentafluorophenyl)oxy-1,1,3,3-bis(tetramethylene)uronium hexafluorophosphate]; HpyOTcp [(2,4,5-trichlorophenyl)oxy-1,1,3,3-bis(tetramethylene)uronium hexafluorophosphate]; HPyONp [(2-nitrophenyl)oxy-1,1,3,3-bis(tetramethylene)uronium hexafluorophosphate]; BTFFH [bis(tetramethylene)fluoroformamidium hexafluorophosphate]; TFFH (tetramethylfluoroformamidium hexafluorophosphate).

    1. Coste, J.; Frérot, E.; Jouin, P.; Castro, B., Tetrahedron Lett. 1991, 32, 1967.
    2. Carpino, L. A.; El-Faham, A., J. Am. Chem. Soc. 1995, 117, 5401.
    3. Chen, S.; Xu, J., Tetrahedron Lett. 1992, 33, 647.
    4. Habermann, J.; Kunz, H., J. Prakt. Chem. 1998, 340, 233.
    5. Humphrey, J. M.; Chamberlin, A. R., Chem. Rev. 1997, 97, 2243.
    6. Li, P.; Xu, J.-C.; Tetrahedron 2000, 56, 9949.
    7. Galéotti, N.; Coste, J.; Bedos, P.; Jouin, P., Tetrahedron Lett. 1996, 37, 3997.
    8. El-Faham, A., Lett. Peptide Sci. 2000, 7, 113.
    9. Carpino, L. A.; El-Faham, A., J. Org. Chem. 1994, 59, 695.

    Jacques Coste & Patrick Jouin

    CNRS-UPR9023, Montpellier, France

    Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.