Bis(4,5-dimethyl-2-oxo-1,3,2-dioxaphospholenyl) Oxide1

[55894-94-5]  · C8H12O7P2  · Bis(4,5-dimethyl-2-oxo-1,3,2-dioxaphospholenyl) Oxide  · (MW 282.13)

(phosphorylating agent; selective for primary alcohols over secondary alcohols, especially in the presence of triethylamine; used for the preparation of various unsymmetrical phosphodiesters; precursor of the more reactive phosphorylating agents 4,5-dimethyl-2-chloro-2-oxo-1,3,2-dioxaphosphole and 4,5-dimethyl-2-(1-imidazolyl)-2-oxo-1,3,2-dioxaphosphole)

Alternate Names: bis(1,2-dimethylethylene)pyrophosphate; acetoin enediol cyclopyrophosphate.

Physical Data: mp 84-86 °C.

Solubility: widely sol organic solvents.

Preparative Methods: prepared from 4,5-dimethyl-2-methoxy-2-oxo-1,3,2-dioxaphosphole (1) by treatment with pyridine in benzene to form the salt (2), followed by reaction with phosgene in benzene (eq 1). The solid (3) is recrystallized from CH2Cl2/hexanes.2

Handling, Storage, and Precautions: the reagent is hydrolyzed by water.

Phosphorylative Coupling of Two Different Alcohols.

The pyrophosphate (3) is used for the preparation of unsymmetrical phosphodiesters in a one-pot operation with no additional activation required. The primary alcohol of a diol can be phosphorylated selectively in the presence of an unprotected secondary alcohol.3 This selectivity is catalyzed by Triethylamine. Thus the reaction of the monoester (4) (derived from the reaction of (3) with cyclopentanol) with trans-2-hydroxymethylcyclopentanol produces the diesters (6) and (7) in a 98:2 ratio in the presence of triethylamine (eq 2). With no added base, this ratio is 90:10, while in the presence of imidazole the ratio drops to 80:20.4 The preparation of unsymmetrical phosphodiesters works best if the first alcohol used is the more hindered of the two alcohols to be utilized. As expected, the triethylamine-induced rate enhancement of phosphorylation of a primary alcohol decreases with increasing steric requirements of the alkyl group in the phosphomonoester (4). The byproduct salts (5) can be reconverted into the pyrophosphate (3) by treatment with phosgene.3

Aminoethanol derivatives can be effectively phosphorylated and coupled with other alcohols (eq 3).5 The two phosphotriesters (8) and (9) were formed in a ratio of 5:1, and could be separated via chromatography.

Phospholipid Derivatives.

Phosphatidyl-6-D-glucose analogs (13) can be prepared from the pyrophosphate (3) via initial reaction with diacylglycerol (10) to form the phosphomonoester (11). Subsequent treatment of (11) with a suitably protected glucose derivative (12) gave (13) in 30-50% overall yield (eq 4).6 Better yields (55-60%) of the final product were obtained with the triprotected glucose (12a). Reaction of the initial adduct (11) with 0.5 equiv of 2-(t-butyldimethyl-siloxy)glycerol forms the basis of the synthesis of diphosphatidylglycerols (cardiolipins).7


This phosphorylative method has been applied to the syntheses of di- and tetradeoxynucleotides,8 as well as phospholiponucleotides (14) (eq 5).9

Preparation of Other Phosphorylating Agents Derived from (3).

Two more reactive (and less selective) phosphorylating agents can be easily derived from the pyrophosphate (3). The phosphochloridate (15) is formed from the reaction of (3) with phosgene (eq 6).2 This highly reactive phosphorylating reagent reacts well with poorly nucleophilic or sensitive alcohols in high yields in the presence of triethylamine or pyridine.10 The second derivative (16) is formed from the reaction of either the pyrophosphate (3) or the phosphorchloridate (13) with imidazole.2 This reagent, while more reactive than (3), exhibits less selectivity than (3) in the reactions of primary vs. secondary alcohols. Imidazole has also been found to catalyze the reaction between alcohols (including secondary) and phosphomonoesters such as (4).4

1. For a recent short review of this and other similar phosphorylating reagents, see: Lemmen, P.; Richter, W.; Werner, B.; Karl, R.; Stumpf, R.; Ugi, I. S 1993, 1.
2. Ramirez, F.; Okazaki, H.; Marecek, J. F.; Tsuboi, H. S 1976, 819.
3. Ramirez, F.; Marecek, J. F.; Ugi, I. JACS 1975, 97, 3809.
4. Ramirez, F.; Marecek, J. F.; Okazaki, H. JACS 1976, 98, 5310.
5. Triagalo, F.; Szabo, L. JCS(P1) 1982, 1733.
6. Ramirez, F.; Mandal, S. B.; Marecek, J. F. JOC 1983, 48, 2008.
7. Ramirez, F.; Iannou, P. V.; Marecek, J. F.; Dodd, G. H. S 1976, 769.
8. Ramirez, F.; Gavin, T. E.; Mandal, S. B.; Kelkar, S. V.; Marecek, J. F. T 1983, 39, 2157. Ramirez, F.; Evangelidou-Tsolis, E.; Jankowski, A.; Marecek, J. F. S 1977, 451.
9. Ramirez, F.; Mandal, S. B.; Marecek, J. F. S 1982, 402. Ramirez, F.; Mandal, S. B.; Marecek, J. F. JACS 1982, 104, 5483.
10. Ramirez, F; Okazaki, H.; Marecek, J. F. S 1975, 637.

Cynthia K. McClure & Pranab Mishra

Montana State University, Bozeman, MT, USA

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