Chlorotripyrrolidinophosphonium Hexafluorophosphate

[133894-48-1]  · C12H24ClF6N3P2  · (421)

(reagent for carboxylic acid activation, coupling agent in peptide synthesis)

Alternate Name: PyCloP.

Physical Data: mp 150-151 °C.1

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

Form Supplied in: colorless crystals.

Analysis of Reagent Purity: 31P NMR, HPLC.

Preparative Methods: addition of chlorine to a diethyl ether solution of tripyrrolidinophosphine, then addition of KPF6 in water.2 Addition of tripyrrolidinophosphine oxide to a DCM solution of phosphoryl trichloride, then addition of KPF6 in water.1-3

Purification: recrystallization (CH2Cl2/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.

Introduction

Treatment of a carboxylic acid with PyCloP in the presence of base produces the unstable acylphosphonium intermediate. This species directly reacts with a nucleophile or decomposes into a different activated form (e.g. carboxylic anhydride). This reagent gives results that are comparable to those obtained with PyBroP (bromotripyrrolidinophosphonium hexafluorophosphate).1

Reagent for Peptide Synthesis

Compared with hydroxybenzotriazol-based activators like BOP, PyBOP, HBTU, or DCC/HOBT, which produce moderately activated benzotriazolyl esters from carboxylic acids, PyCloP is highly recommended for coupling N-methylated amino acids, as illustrated by the difficult coupling of NMeVal (eq 1),1,4 and used in the total synthesis of natural peptoids.5-7 PyCloP activation of Boc-amino acids can, however, give moderate yields due to the formation of N-carboxyanhydride (NCA).1,8

Activation of a Monothiocarboxylic Acid

Using different phosphorus reagents for activation of a monothiocarboxylic acid, the observed oxygen/sulfur selectivities correlate with the hardness/softness of the reaction center. Compared with the soft leaving bromine atom in PyBroP (S selective) or the hard oxygen atom in PyBOP (O selective), the PyCloP is borderline in O/S (25:47) selectivity (eq 2).3

Preparation of Coupling Reagents for Peptide Synthesis

PyBOP, a related phosphonium coupling reagent for peptide synthesis, has been prepared from PyCloP,2 and several analogs of PyBOP have also been prepared as reagents for thioacylation of monothiocarboxylic acid 3 (eq 3).

Related Reagents.

PyBroP, bromotripyrrolidinophosphonium hexafluorophosphate; PyBOP, (1H-benzotriazol-1-yl)oxytripyrrolidinophosphonium hexafluorophosphate; PyClU, 1,1,3,3-bis(tetramethylene)chlorouronium hexafluorophosphate; TpyClU, 1,1,3,3-bis(tetramethylene)chlorouronium tetrafluoroborate; CIP, 2-chloro-1,3-dimethylimidazolidium hexafluorophosphate; PyAOP, (7-azabenzotriazol-1-yl)oxytripyrrolidinophosphonium hexafluorophosphate; PyPOP, (pentafluorophenyl)oxytripyrrolidinophosphonium hexafluorophosphate; PyNOP, (6-nitrobenzotriazol-1-yl)oxytripyrrolidinophosphonium hexafluorophosphate; PyFOP, [(6-trifluoromethyl)benzotriazol-1-yl]oxytripyrrolidinophosphonium hexafluorophosphate; PyDOP, (3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)oxytripyrrolidinophosphonium hexafluorophosphate.


1. Coste, J.; Frérot, E.; Jouin, P., J. Org. Chem. 1994, 59, 2437.
2. Castro, B.; Coste, J., I Patent WO 90/10009, 1990.
3. Hoeg-Jensen, T.; Olsen, C. E.; Holm, A., J. Org. Chem. 1994, 59, 1257.
4. Coste, J.; Frérot, E.; Jouin, P.; Castro, B., Tetrahedron Lett. 1991, 32, 1967.
5. Calmes, M.; Cavelier-Frontin, F.; Jacquier, R.; Mercadier, J.-L.; Sabil, S.; Verducci, J.; Quiot, J.-M.; Vey, A., Int. J. Peptide Protein Res. 1993, 41, 528.
6. Patino, N.; Frérot, E.; Galéotti, N.; Poncet, J.; Coste, J.; Dufour, M.-N.; Jouin, P., Tetrahedron 1992, 48, 4115.
7. Poncet, J.; Busquet, M.; Roux, F.; Pierré, A.; Atassi, G.; Jouin, P., J. Med. Chem. 1998, 41, 1524.
8. Frérot, E.; Coste, J.; Poncet, J.; Jouin, P.; Castro, B., Tetrahedron Lett. 1992, 33, 2815.

Jacques Coste & Patrick Jouin

CNRS-UPR9023, Montpellier, France



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