Bis(2,2,2-trichloroethyl) Phosphorochloridate

[17172-53-6]  · C4H4Cl7O3P  · Bis(2,2,2-trichloroethyl) Phosphorochloridate  · (MW 379.22)

(phosphorylating reagent)

Physical Data: mp 45-47 °C.

Form Supplied in: colorless solid.

Handling, Storage, and Precautions: may decompose on exposure to air or water. Store in a dry, cool environment. Corrosive material and it should be handled in a well-ventilated fume hood.

Phosphorylating Reagent.

Phosphorochlorides have been widely used for the direct introduction of a phosphate group in hydroxy amino acids.1 The use of the 2,2,2-trichloroethyl group for the phosphate protection2 in phosphoserine derivatives3 constitutes an efficient method for effective phosphopeptide synthesis.4 Nucleotides are selectively protected as the 5-OH phosphate ester derivatives5,6 with bis(2,2,2-trichloroethyl) phosphorochloridate (eq 1).7

The isolated esters are stable in alkaline medium,8 and selective cleavage of the 2,2,2-trichloroethyl group to afford the phosphate nucleotides occurs upon treatment with Zinc metal9,10 (in DMF or acetic acid media) in presence of other protecting groups.11 Bis(2,2,2-trichloroethyl) phosphorochloridate has also been successfully used as a phosphorylating agent for carbohydrates (eq 2),12,13 and for the preparation of forskolin derivatives.14

Preparation of Mixed Trialkyl Phosphates.

In a general transesterification method designed to prepare mixed trialkyl phosphates,15 reactions of bis(2,2,2-trichloroethyl) phosphorochloridate with different alcohols, in pyridine solvent, and in presence of fluoride ion (Cesium Fluoride or Tetra-n-butylammonium Fluoride), afford the mixed trialkyl phosphates (eq 3).16 Reactions with diols give cyclic phosphates (eq 4).16 The 2,2,2-trichloroethyl group has been also conveniently used for the preparation of mixed triesters of nucleotides.17

1. Paquet, A.; Johns, M. 1990, 36, 97.
2. Paquet, A. TL 1990, 31, 5269.
3. Paquet, A.; Int. J. Peptide Protein Res. 1992, 39, 82.
4. (a) Perich, J. W.; Johns, R. B. AJC 1990, 43, 1633. (b) Perich, J. W. Peptides and Protein Phosphorylation; Kemp, B. E., Ed.; CRC Press: Boca Raton, FL, 1990; pp 289-314.
5. (a) Woodward, R. B. Science 1966, 153, 487. (b) Franke, A.; Scheit, K.-H.; Eckstein, F. CB 1968, 101, 2998.
6. Eckstein, F.; Scheit, K.-H. AG(E) 1967, 6, 362.
7. Preparation by analogy with bis(2,2,2-trifluoroethyl) phosphorochloridate: MOC 1964, Part 2, 276.
8. (a) Cherbuliez, E.; Gabbai, A.; Probst, H.; Yazgi, A.; Rabinowitz, J. HCA 1962, 45, 2282. (b) Lichtenthaler, F. W. CRV 1961, 61, 607.
9. (a) LeGoff, E. JOC 1964, 29, 2048. (b) Eckstein, F.; AG(E) 1966, 5, 671.
10. van Boom, J. H.; Burgers, P. M. J.; van Deursen, P. H. TL 1976, 869.
11. Eckstein, F. CB 1967, 100, 2228.
12. Auzanneau, F.-I.; Charon, D.; Szabó, L. JCS(P1) 1990, 2831.
13. Lammers, J. G.; van Boom, J. H. RTC 1979, 98, 243.
14. Lal, B.; Gangopadhyay, A. K. JCS(P1) 1992, 1993.
15. Ramirez, F.; Marecek, J. F.; Ugi, I. JACS 1975, 97, 3809.
16. Ogilvie, K. K.; Beaucage, S. L.; Theriault, N.; Entwistle, D. W. JACS 1977, 99, 1277.
17. Letsinger, R. L.; Lunsford, W. B. JACS 1976, 98, 3655.

Isabel Mathieu-Pelta & Slayton A. Evans, Jr.

University of North Carolina, Chapel Hill, NC, USA

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