Epoxyphosphonates

Certain optical isomers of epoxyphosphonic acids also have antibacterial activity [274,275]. Phosphates and polyphosphates with bactericidal properties are described in Refs. 276 and 277. 

Addition of triethyl phosphite to a-halosubstituted ketones has been reported to provide the a,P-epoxyphosphonate (as the diester) in reasonable yield (51%).346 Similar results were obtained using diethyl phosphite under basic conditions.346 347... 

Improved yields of epoxyphosphonates of type (48) are reported for a development of existing synthetic methods, involving mixing of stoicheiometric amounts of hydrogen phosphonate, a-halogeno-ketone, and alkoxide.42... 

Zbiral and co-workers reported on the reaction of mercaptotriazole with epoxyphosphonates 153 in acidic ethanol (88CB977). 

The a-chlorophosphonates are valuable intermediates that have applications in the synthesis of alkynes, chloroolefins, and 1,2-epoxyphosphonates. Tetrachloromethane seems to be the most widely used reagent in the electrophilic monochlorination of phosphonates, presumably because it gives very clean chlorine transfer and produces an easily removed byproduct (chloroform) (Scheme 3.27). Only leq of base (n-BuLi) is needed to achieve the two successive deprotonations. A large number of chloroalkenes, some of them showing interesting insecticidal properties, have been obtained in 27-87% yields by this method (Scheme 3.27). ... 

When diethyl 1-lithio-l-chloromethylphosphonate is treated with carbonyl compounds (aliphatic and aromatic aldehydes or ketones) in THF at low temperature, the intennediate chlorohydrin can eliminate upon warming to room temperature to give diethyl 1,2-epoxyphosphonates in good yields (51-90%) 2 or, in the case of aldehydes, can be treated at low temperature with LDA to give, after acidic work-up, diethyl 2-oxoalkylphosphonates in 65-92% yields (Scheme 3.63). 29. o... 

The reaction between diethyl phosphite and a-chloroketones can also be accomplished by fluoride ion-mediated deprotonation reaction in DMF (dry KF or KFTHjO as fluoride ion source), which constitutes anonbasic route to diethyl 1,2-epoxyalky Iphosphonates. Unfortunately, the application of this technique provides a mixture of 1,2-epoxyalkyIphosphonate (about 50%) and vinyl phosphate (about 30%) whatever the a-chloroketones. The reaction between 3-(co-bro-moacetyOcoumarin and diethyl or di- -butyl phosphite has been performed with 50% NaOH in CgHg under phase-transfer catalysis conditions with TEBA as catalyst. The only products of the reaction are the epoxyphosphonates isolated in 70% and 34% yields, respectively. In the presence of EtjN, diethyl phosphite reacts with 2-chloroacetoacetate to give diethyl 2-(ethoxycarbonyl)-l-methyl-l,2-epoxyethylphosphonate in 72% yield as a mixture of cis and trans isomers. ... 

Another variation of the classic Darzens reaction is a one-pot synthesis of dietliyl 1-perfluoro-alkyl-1,2-epoxyalkylphosphonates using the nucleophilic attack of lithium diethyl phosphite on the carbonyl carbon of perfluorinated P-oxophosphonium salts (Scheme 4.8). The resulting intermediate can eliminate in two directions. When the oxygen anion in the least sterically hindered position (R = R = Me) attacks the neighboring carbon atom, diethyl 1-perfluoroalkyl-1,2-epoxyalkylphosphonates aie obtained in moderate yields (42-51%) after elimination of PhjP (anti fashion). The formation of a-(perfluoroalkyl)vinylphosphonates by attack at phosphorus (syn fashion) can be a competing reaction. The results indicate that the selectivity can be controlled to produce exclusively either epoxyphosphonates or vinylphosphonates. ... 

One ingenious procedure for the construction of a nucleoside epoxyphosphonate from a 1,2-dihydroxyalkylphosphonate exploits the interesting properties of triflates, which serve as good... 

H) are readily separable, and each one converted to the corresponding 1,2-epoxyphosphonate (Scheme 4.13). Moreover, the use of these unsaturated intermediates allows the acid-catalyzed hydrolysis of the ester functions before epoxidation. 

Epoxidation of allylic phosphonates is achieved wilh success at room temperature witli MeCOjH in Et O, CF3CO3H in CHCI3, MCPBA in ( HT I- or MOO5/HMPA complex in CH2CI2 to give the corresponding 2,3-epoxyalkylphosphonates as a mixture of diastereomers. s- Allylic phosphonates may also be converted into 2,3-epoxyphosphonates via the 1,1,1-trifluorodimethyl-dioxirane-mediated oxidation. Dimethyldioxirane (DMD) in acetone at room temperature or methyl(trifluoromethyl)dioxirane (TED) in CHjClj at low temperature can be used instead of MCPBA. Because the reaction is quantitative, evaporation of acetone and excess of DMD allow the direct isolation of the pure product. 2,i55... 

Epoxidation of diethyl 3-(ethoxycarbonyl)-2-vinyl-l,l-difluoropropylphosphonate is very slow under MCPBA or MTO conditions, but TED prepared in situ proved to be more effective, and the desired 3,4-epoxyphosphonate is obtained in 91% yield as a mixture of diastereomers. 

Diethyl 4,5- and 5,6-epoxyalkyIphosphonates are prepared by treatment of the corresponding 4,5-and 5,6-unsaturated phosphonates with MCPBA in CH2CI2 at 4O C - or aqueous solution of monoperoxyphthalate in z-PrOH at room temperature.The epoxidation of the double bond of a 6-oxo-7,8-unsaturated phosphonate involves the use of H2O2 in NaOH-MeOH solution to provide the corresponding 7,8-epoxyphosphonate in 90% yield. 

The key step of a recent synthesis of fosfomycin is the Sharpless asymmetric di hydroxylation (AD) reaction.Dibenzyl ( )-l-propenylphosphonate is prepared in 94% yield from ( )-propenyl bromide and dibenzyl phosphite in THF at 60°C in the presence of I il.,N and catalytic amount of PdfPPh,). A modified AD-mix-a is used to speed up the dihydroxylation reaction. The resulting 5y/r-a,3-dihydroxyphosphonate is isolated in 65% yield after recrystallization and then submitted to regioselective oc-sulfonylation followed by cyclization by treatment with K CO, in acetone at room temperature to produce di benzyl (17 ,25)-l,2-epoxypropylphosphonate in 67% yield (Scheme 4.31). = Fosfomycin can be obtained by hydrogenolysis of this epoxyphosphonate. i... 

Whereas oc-halohydrinphosphonates are converted into 1,2-epoxyphosphonates by treatment with strong bases, the corresponding P-halohydrins rearrange instantaneously in the presence of aqueous NaHCOj and slowly in water alone to give 1-formylethylphosphonic acid (Scheme 4.35). ... 

Springs, B., and Haake, P., A one-step synthesis of epoxyphosphonates, J. Org. Chem., 1,1165, 1976. Kossev, K., Troev, K., and Roundhill, D.M., Synthesis of dialkyl 1,2-epoxyphosphonates under phase-transfer catalyst conditions, Phosphorus, Sulfur Silicon Relat. Elem., 83, 1, 1993. 

Agawa, T., Kubo, T., and Ohshiro, Y, Synthesis of dialkyl epoxyphosphonates. Synthesis, 27, 1971. Sturtz, G., and Pondaven-Raphalen, A., Cyclization of 1,2-halohydrins of diethyl ethylphosphonate for the synthesis of diethyl 1,2-epoxyethylphosphonate, Phosphorus Sulfur, 20, 35, 1984. 

Coutrot, P., Grison, C., Lecouvey, M., Kribii, A., and El Gadi, A., Highly functionalized new small molecules. Preparation of a-chlorinated epoxyphosphonates. Study of their transformation to P-halo-genated a-ketophosphonates. Phosphorus, Sulfur Silicon Relat. Elem., 133, 167, 1998. 

Ohler, E., Kang, H.-S., and Zbiral, E., Regioselective cyclisation reactions of acyl-substituted epoxyphosphonates with 2-mercaptoazoles. Syntheses of thiazolo[3,2-fii]benzimidazole, imidazo[2,l-fc]thi-azole, and thiazolo[3,2-fc]-[l,2,4]triazole derivatives, Chem. Ber, 121, 977, 1988. 

Phillips. A.M.M.M., Mphahlele. M.J.. Modro, A.M., Modro, T.A., and Zwierzak, A., Phosphonic systems. Part 7. Reactions of 2.3-epoxyphosphonates with nucleophiles. Preparation of 2,3-disubstituted alkylphos-phonic esters and related systems. Phosphorus, Sulfur Silicon Relat. Elem., 71, 165, 1992. 

Christensen, B.G., and Cama, L.D., Antibacterial opticaUy-active epoxyphosphonic acid and its derivatives, Merck, German Patent Appl. DE 2002415, 1970 Chem. Abstr, 75, 77031s, 1971. 

The methodology for the conversion of epoxyphosphonates into allylic alcohols has been used in the preparation of diethyl 2-formylvinylphosphonate by basic ring opening of diethyl 2,3-epoxypropylphosphonate. When the latter is allowed to react with MeONa in MeOH at 0°C and then treated with an ion-exchange resin (Dowex SOW), diethyl ( )-3-hydroxy-l-propenylphosphonate is isolated in quantitative yield. " It is converted by room temperature oxidation with PCC in CIFCF into pure diethyl ( )-2-formylvinylphosphonate in 52% yield (Scheme 5.27). 

The reaction of sodium dialkyl phosphite with a-halogenokctoncs leads to a mixture of products consisting of P-ketophosphonates, 1,2-epoxyphosphonates, and vinyl phosphates (Scheme The subject has been covered in the Section 4.1.1.2. 

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