Methylphosphonate derivatives

Several uimatural nucleoside phosphate modifications (Fig. 2e) have been generated, which include phosphorothioate, phosphoroamidate, phosphorothiolate, and methylphosphonate derivatives. The syntheses of these modifications have been reviewed by Verma and Eckstein (19). A modification of those procedures can be used for the generation of phosphoroselenoate RNAs (20). 

A straightforward synthesis of methyl 4-toluenesulfonyloxymethylpho-sphonate (447) which served as a novel alkylating reagent for introduction of the phosphonate moiety into nucleosides, via tosylation of (445) and hydrolysis of the resulting (446), has been described by Rosenberg and coworkers (Scheme 110). The effciency of the alkylation was demonstrated by preparation of several 2 -deoxyribonucleoside-0-methylphosphonate derivatives as well as synthesis of a Hepsera precursor (a potent antiviral acyclic nucleoside phosphonic acids). 

Alkylphosphonates are a neutral modification in which a non-bridging oxygen is substituted for an alkyl group, the most widely studied in the past being methylphos-phonates. However, methylphosphonate derivatives are infrequently used because they have solubility problems, but have been used in mechanistic studies of the junctionresolving enzyme T7 endonuclease A number of other nucleoside phosphonate derivatives have been described. An improved microwave-assisted Michaelis-Arbuzov method for synthesis of substituted-phosphonates is reported, " and the reaction of dialkyl phosphate derivatives with the 5 -aldehyde-derivative of nucleosides leads to high yields of 5 -C-phosphonates. The reactivity of 5 -C-phosphonates towards periodate oxidation has been reported. Various nucleoside phosphonates have been... 

The methylphosphonates differ from the phosphodiesters and phosphorothiolates in that the methyl derivatives are uncharged and are thus less water soluble. Moreover, compared to the naturally occurring phosphodiesters, the methylphosphonates form slightly less stable duplexes with complementary DNA and RNA sequences. This effect has been ascribed to the iaevitable chiraUty problem that is, if one isomer biads less well, the overall binding is decreased. Methylphosphonates can enter cell membranes by a passive mechanism and are completely resistant to nucleases. 

Derivatives substituted on phosphorus are named by standard procedures [13, 14] e.g, / -methyl derivatives are named as methylphosphonates. 

Estimates of exposure levels posing minimal risk to humans (Minimal Risk Levels or MRLs) have been made for diisopropyl methylphosphonate. An MRL is defined as an estimate of daily human exposure to a substance that is likely to be without an appreciable risk of adverse effects (noncarcinogenic) over a specified duration of exposure. MRLs are derived when reliable and sufficient data exist to identify the target organ(s) of effect or the most sensitive health effect(s) for a specific duration within a given route of exposure. MRLs are based on noncancer health effects only and do not reflect a consideration of carcinogenic effects. MRLs can be derived for acute, intermediate, and chronic duration exposures for inhalation and oral routes. Appropriate methodology does not exist to develop MRLs for dermal exposure. 

Minimal risk level (MRL) values were not derived for acute, intermediate, or chronic inhalation exposures to diisopropyl methylphosphonate because no toxicity data were identified concerning the inhalation of the compound. 

Purdon JG, Pagotto JG, Miller RK. 1989. Preparation, stability, and quantitative analysis by gas chromatography and gas chromatography-electron impact mass spectrometry of tert-butyldimethylsilyl derivatives of some alkylphosphonic and alkyl methylphosphonic acids. J Chromatogr 475 261-272. 

Reactions and Properties of Phosphonic and Phosphinic Acids and their Derivatives.-A free radical mechanism has been proposed to account for the cleavage of the phosphorus-carbon bond in the alkylphosphonic acids (155) by E coli to give a mixture of alkane (methane only, from methylphosphonic acid) and terminal alkene. 

The rate of appearance of p-nitrophenolate ion from p-nitrophenyl methylphosphonate (7), an anionic substrate, is moderately accelerated in the presence of cycloheptaamylose (Brass and Bender, 1972). The kinetics and pH dependence of the reaction are consistent with nucleophilic displacement of p-nitrophenolate ion by an alkoxide ion derived from a cycloheptaamylose hydroxyl group to form, presumably, a phosphonylated cycloheptaamylose. At 60.9° and pH 10, the cycloheptaamylose-induced rate acceleration is approximately five. Interestingly, the rate of hydrolysis of m-nitrophenyl methylphosphonate is not affected by cycloheptaamylose. Hence, in contrast to carboxylate esters, the specificity of cycloheptaamylose toward these phosphonate esters is reversed. As noted by Brass and Bender (1972), the low reactivity of the meta-isomer may, in this case, be determined by a disadvantageous location of the center of negative charge of this substrate near the potentially anionic cycloheptaamylose secondary hydroxyl groups. 

The reaction of cycloheptaamylose with diaryl carbonates and with diaryl methylphosphonates provides a system in which a carboxylic acid derivative can be directly compared with a structurally analogous organo-phosphorus compound (Brass and Bender, 1972). The alkaline hydrolysis of these materials proceeds in twro steps, each of which is associated with the appearance of one mole of phenol (Scheme Y). The relative rates of the two steps, however, are reversed. Whereas the alkaline hydrolysis of carbonate diesters proceeds with the release of two moles of phenol in a first-order process (kh > fca), the hydrolysis of methylphosphonate diesters proceeds with the release of only one mole of phenol to produce a relatively stable aryl methylphosphonate intermediate (fca > kb), In contrast, kinetically identical pathways are observed for the reaction of cycloheptaamylose with these different substrates—in both cases, two moles of phenol are released in a first-order process.3 Maximal catalytic rate constants for the appearance of phenol are presented in Table XI. Unlike the reaction of cycloheptaamylose with m- and with p-nitrophenyl methylphosphonate discussed earlier, the reaction of cycloheptaamylose with diaryl methylphosphonates... 

Elkaim, J.C., Casabianca, F., and Riess, J.G., The direct synthesis of dibromo-methylphosphonic dibromide and some of its derivatives, Synth. React. Inorg. Met.-Org. Chem., 9, 479, 1979. 

The reaction of the carbanion derived from diethyl methylphosphonate with perhalogenated aromatics may result in substitution of halide to yield perhaloaryl(hetaryl)methylphosphonates, which can be converted into tris- or bis-(perhaloaryl)methanes. Displacement of fluoride ion has been reported in the reaction of dimethoxycarbene with l-fluoro-2,4-dinitrobenzene and with hexafluorobenzene. The hydrodehalogenation of halogenated aryl ketones may be facilitated using hydrogen over a Pt/C catalyst. " ... 

Dialkyl methyl phosphonate derivatives 37a-c of mannopyranosides may be prepared from cyclic sulfate 36 by reaction with the appropriate lithiated methylphosphonate, prepared by titration of the corresponding methyl-phosphonate with butyllithium in the presence of 1,1-diphenylethylene as indicator (Equation 4) <2002TL4017>. 

A related approach directed toward cyclohexane derivatives affords products without carbon substituents on the rings. Ozonolysis of the 6-deoxyhex-5-enopyranoside derivative 14, followed by silylation, gives the unusual pseudolactone 15 in high yield, and this reacts with lithio dimethyl methylphosphonate to yield the cyclohexenone 18 (Scheme 3),... 

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