Dibenzyl N,N-Diethylphosphoramidite

[67746-43-4]  · C18H24NO2P  · Dibenzyl N,N-Diethylphosphoramidite  · (MW 317.40)

(phosphorylation of simple alcohols,1 serine,2 threonine,3 and tyrosine;4 synthesis of glycosyl phosphites and phosphates5)

Physical Data: bp 131-132 °C/10-4 mmHg,6 150-152 °C/0.01 mmHg,7 154-156 °C/0.3 mmHg.8

Preparative Methods: by the reaction of dichloro N,N-diethylphosphoramidous acid with 2 equiv of benzyl alcohol.3,7 An alternative synthesis, described on a 1 mol scale, combines phosphorus trichloride, diethylamine, and 2 equiv of benzyl alcohol in a one-pot reaction.8 An earlier route to this reagent involved heating phosphorus hexaethyltriamide with 2 equiv of benzyl alcohol.6

Purification: by distillation at reduced pressure.

Handling, Storage, and Precautions: reported to be stable at rt and has been kept for at least 6 months.5

Preparation of Organic Phosphite and Phosphate Esters.

While dibenzyl N,N-diethylphosphoramidite will form phosphite triesters upon heating with 1,2-diacylglycerols in an uncatalyzed reaction (eq 1),6 phosphitylation of alcohols has more recently been accomplished at ambient temperature in nearly quantitative yield in the presence of added 5-methyl-1H-tetrazole, 1H-tetrazole, or 1,2,4-triazole.1,3,8 The phosphate triester has commonly been obtained by in situ oxidation of the phosphite ester intermediate using m-Chloroperbenzoic Acid,1 t-Butyl Hydroperoxide,3 or aqueous 30% Hydrogen Peroxide.8 t-Butyl dibenzyl phosphate has been obtained in excellent yield (eq 2).1

Protected serine and threonine derivatives have been phosphorylated for subsequent incorporation into peptides as the phosphate triesters (eq 3).2,3,9,10 Similarly, dibenzyl N,N-diethylphosphoramidite has been used to prepare both Boc and Fmoc tyrosine derivatives for use in peptide synthesis.4,11-14 Use of dibenzyl N,N-diethylphosphoramidite in phosphorylation of the side chain hydroxyls of serine- and threonine-containing peptides has been demonstrated.2,7,15-18

Dibenzyl N,N-diethylphosphoramidite has been used in phosphorylation sequences yielding dihydroxyacetone phosphate, D-myo-inositol 1,3,4,5-tetrakisphosphate (eq 4), and an inositol monophosphatase inhibitor.8,19,20 Phosphitylation of the anomeric hydroxy groups of a series of sugars has been examined. The resulting glycosyl dibenzyl phosphites are effective as glycosylating reagents (eq 5), or they may be oxidized to the phosphates and used in the synthesis of sugar nucleotides.5,21

Related Reagents.

Dibenzyl N,N-Diisopropylphosphoramidite.

1. Perich, J. W.; Johns, R. B. TL 1987, 28, 101.
2. Perich, J. W.; Johns, R. B. TL 1988, 29, 2369.
3. De Bont, H. B. A.; Veeneman, G. H.; Van Boom, J. H.; Liskamp, R. M. J. RTC 1987, 106, 641.
4. Perich, J. W.; Reynolds, E. C. SL 1991, 577.
5. Sim, M. M.; Kondo, H.; Wong, C. H. JACS 1993, 115, 2260.
6. Smirnova, L. I.; Malenkovskaya, M. A.; Predvoditelev, D. A.; Nifantev, E. E. ZOR 1980, 16, 1170.
7. Perich, J. W.; Johns, R. B. AJC 1990, 43, 1623.
8. Pederson, R. L.; Esker, J.; Wong, C. H. T 1991, 47, 2643.
9. Perich, J. W.; Alewood, P. F.; Johns, R. B. AJC 1991, 44, 253.
10. Perich, J. W.; Alewood, P. F.; Johns, R. B. AJC 1991, 44, 377.
11. Perich, J. W.; Johns, R. B. S 1989, 701.
12. Perich, J. W.; Johns, R. B. JOC 1989, 54, 1750.
13. Kitas, E. A.; Wade, J. D.; Johns, R. B.; Perich, J. W.; Tregear, G. W. CC 1991, 338.
14. Kitas, E. A.; Knorr, R.; Trzeciak, A.; Bannwarth, W. HCA 1991, 74, 1314.
15. De Bont, H. B. A.; Liskamp, R. M. J.; O'Brian, C. A.; Erkelens, C.; Veeneman, G. H.; Van Boom, J. H. Int. J. Pept. Protein Res. 1989, 33, 115.
16. Perich, J. W.; Johns, R. B. AJC 1990, 43, 1633.
17. Perich, J. W.; Alewood, P. F.; Johns, R. B. AJC 1991, 44, 233.
18. Perich, J. W.; Johns, R. B. AJC 1991, 44, 503.
19. Dreef, C. E.; Tuinman, R. J.; Elie, C. J. J.; Van der Marel, G. A.; Van Boom, J. H. RTC 1988, 107, 395.
20. Baker, R.; Carrick, C.; Leeson, P. D.; Lennon, I.; Liverton, N. J. CC 1991, 298.
21. Ichikawa, Y.; Sim, M. M.; Wong, C. H. JOC 1992, 57, 2943.

Charles G. Caldwell

Merck Research Laboratories, Rahway, NJ, USA

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