n-Propylphosphonic Anhydride

[68957-94-8]  · C9H21O6P3  · n-Propylphosphonic Anhydride  · (MW 318.21)

(peptide coupling reagent1)

Alternate Name: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide.

Physical Data: colorless, water-clear syrup, bp 200 °C/0.3 mmHg. The structure is considered to be a trimer.

Solubility: sol dichloromethane, dioxane, THF, DMF, N-methyl-2-pyrrolidinone.

Form Supplied in: not commercially available.

Preparative Method: prepared in high yield by hydrolysis of propylphosphonic dichloride to propylphosphonic acid, followed by heating and distillation under reduced pressure (eq 1).2

Purification: can be purified by vacuum distillation.

Handling, Storage, and Precautions: as a 50% w/v solution in dichloromethane, the anhydride can be stored in a brown bottle for several months.1 It is reported to be relatively nontoxic.1

Peptide Synthesis.

Alkylphosphonic anhydrides have been explored as condensing agents for the synthesis of peptides and this reagent (1) was identified as the most useful of this class.1,2 It shows good shelf stability and good solubility and leads to little racemization of the protected amino acid substrates. In addition, unlike reagents such as the carbodiimides, the byproduct formed from the condensing agent (an alkylphosphonic acid derivative) is soluble in water and easily removed from the peptide product by extraction with aqueous alkaline buffers (eq 2).

The use of (1) on a technical scale has been explored and its toxicity has been investigated.1 It appears to be relatively nontoxic (no intoxication at 2000 mg kg-1 in mice, orally administered). In addition to the synthesis of dipeptides, (1) has been used for the synthesis of larger peptides such as a dodecapeptide from the C-terminal region of adenovirus 82 K-protein, a dodecapeptide related to ACTH, and other ACTH and LHRH derivatives.1,3,4 The level of racemization observed using (1) has been shown to be as low as with the best other peptide condensing agents and it has been shown to couple sterically hindered peptides with little problem.1,3 A recent patent has appeared covering the use of (1) in a quick and technically simple synthesis of tripeptides.5 A brief reference has been made to the use of (1) in the esterification of N-protected amino acids with alcohols.3

Cyclic Peptides.

(1) has also been used in the synthesis of the linear undecapeptide precursor of the cyclic undecapeptide cyclosporin.6 In addition, the use of (1) in excess along with 4-Dimethylaminopyridine at 10-3 M leads to cyclization of the unprotected linear undecapeptide to give cyclosporin in 65% yield (eq 3).6


Propylphosphonic anhydride (1) in 1-Methyl-2-pyrrolidinone (NMP) has been used for the direct synthesis of polyamides from dicarboxylic acids and diamines.7 Thus reaction of isophthalic acid and 4,4-oxydianiline with an excess of (1) in NMP at 100 °C for 2 h gives a virtually quantitative yield of the polyamide (eq 4).7 The same authors also describe the use of (1) in the synthesis of a number of simple amides from carboxylic acids and amines.7

1. Wissmann, H. PS 1987, 30, 645.
2. Wissmann, H.; Kleiner, H-J. AG(E) 1980, 19, 133.
3. Wissmann, H.; Koenig, W.; Teetz, V.; Geiger, R. Pept., Proc. Eur. Pept. Symp. 1980, 16th, 174 (CA 1983, 98, 54439s).
4. Wissmann, H.; Koenig, W.; Geiger, R. in Pept.: Struct. Funct., Proc. 8th Am. Pept. Symp.; Hruby, V. J.; Rich, D. H., Eds.; 1983; p 111 (CA 1984, 101, 55 513d).
5. Flemming, H. W.; Rukwied, M.; Schmidt, M. Ger. Offen. 3 839 379, 1990 (CA 1990, 113, 212 687f).
6. Wenger, R. M. HCA 1984, 67, 502.
7. Ueda, M.; Honma, T. Polym. J. (Tokyo) 1988, 20, 477 (CA 1988, 109, 110 976z).

Christopher Millbanks

King's College London, UK

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