Bromotripyrrolidinophosphonium Hexafluorophosphate1

[132705-51-2]  · C12H24BrF6N3P2  · (466)

(reagent for carboxylic acid activation, particularly used for peptide synthesis; reagent for formamidine synthesis)

Alternate Name: PyBroP.

Physical Data: mp 138-139 °C.

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 Br2 to tripyrrolidinophosphine2 or addition of tripyrrolidinophosphine oxide to an acetonitrile solution of phosphoryl tribromide,1,2 then addition to a KPF6 solution in water.

Purification: recrystallization from CH2Cl2/Et2O; CH2Cl2/hexane; acetone/Et2O; EtOAc.

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 bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP) in the presence of base produces the unstable acylphosphonium intermediate. Such species directly react with a nucleophile or decompose into a different activated form (e.g. carboxylic anhydride).1 The reagent was first designed for coupling in peptide synthesis but is also widely used for the synthesis of amides or esters, and for macrocyclization. This reagent gives results that are comparable to those obtained with BroP [bromotris(dimethylamino)phosphonium hexafluorophosphate]3 with the advantage of not producing the carcinogen HMPA as a side product of the coupling reaction.4 By-products have been observed from slowly reacting activated carboxylates: (i) the formation of pyrrolidide derivatives due to the presence of small amounts of pyrrolidine in the commercial phosphonium salt (avoided by recrystallization of the reagent),5 and (ii) a side reaction in DMF but favorable for the preparation of formamidines.6

Reagent for Peptide Synthesis

PyBroP was efficiently used in both liquid and solid phase peptide synthesis, but it can lead to epimerization when used for segment condensation.7 Compared with hydroxybenzotriazol-based activators like BOP, PyBOP, HBTU or DCC/HOBT, which produce the moderately activated benzotriazolyl esters from carboxylic acids, PyBroP is highly recommended for coupling N-methylated amino acids,1,8-14 as illustrated by the difficult coupling of NMeVal (eq 1),1,8 and other N-alkylated amino acids15-17 as well as a-disubstituted amino acids (e.g. a-MeSer,18 Aib19 or a-MeCys (eq 2).20 Coupling of N-alkylated amino acids can be improved by addition of HOAt.21 The addition of a catalytic amount of DMAP or 4-pyrrolidinopyridine is recommended to improve both the rate and the yield of the coupling reaction for non-epimerizable substrates.10,13,18-20 PyBroP activation of Boc-amino acids can, however, give moderate yields due to the formation of the N-carboxyanhydride (NCA).1,22

Synthesis of Amides

PyBroP has been employed in the synthesis of unsubstituted amides,23 N-monosubstituted amides (eq 3),24 and disubstituted amides, even from conformationally constrained derivatives (eq 4)25 and anilines.19,26,27 It has also been used for activation of conjugated carboxylic acids (eq 5).28

PyBroP also gives good results for the synthesis of macrocyclic lactams (eq 6),29 including cyclic peptides at high dilution13 with addition of HOAt30 or on solid phase.31

Synthesis of Carboxylic Esters

Ester linkage from carboxylic acid activation with PyBroP was reported for primary and secondary alcohols. This reagent gives impressive results for depsipeptide synthesis (eq 7).32 PyBroP has been used to attach nucleosides to a hydroxylated solid support.33

In addition, this activation was selected over carbodiimide-derived reagents for the preparation of polymer-bound activated esters derived from 1-hydroxybenzotriazole (eq 8)34,35 and for the preparation of the storable p-nitrophenyl esters in solution.36

PyBroP gives improved yields for the cyclization step in the synthesis of the macrocyclic dynemicin A, when compared with the Yamaguchi macrolactonization protocol (eq 9).37

Synthesis of Amidines

Formamidinium formation has been reported as a side reaction of PyBroP with DMF in solid-phase peptide synthesis. This reaction proved to be suitable for the synthesis of formamidines from aliphatic or aromatic amines and DMF (eq 10).6

Preparation of Coupling Reagents for Peptide Synthesis

Several phosphonium-related coupling reagents for peptide synthesis have been prepared from PyBroP (eq 11): PyBOP,2 PyAOP,38 and CF3PyBOP.39

Related Reagents.

BroP, bromotris(dimethylamino)phosphonium hexafluorophosphate; PyCloP, chlorotripyrrolidinophosphonium hexafluorophosphate; BOP, 1H-benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate; PyBOP, 1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate; AOP, 7-azabenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate; PyAOP, 7-azabenzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate; HBTU, O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate; HATU, O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium 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; BOP-Cl, bis(2-oxo-3-oxazolidinyl)phosphinic chloride; 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; TFFH, tetramethylfluoroformamidium hexafluorophosphate; BTFFH, bis(tetramethylene)fluoroformamidium hexafluorophosphate.


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Jacques Coste & Patrick Jouin

CNRS-UPR9023, Montpellier, France



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