Oxoalkylphosphonic acids synthesis

As seen in Scheme 1 a route similar to the biological pathway has now been explored by the independent synthesis of each precursors by chemical means. Work presented in this communication describes the production of synthetic 2-aminoethylphosphonic acids by the controlled reductive amination of 2-oxoalkylphosphonate diesters... 

Briefly we review the chemical improvements which we achieved in the oxoalkylphosphonates field which represent the key compounds. Phosphonic aldehydes are obtained in adapting the Arbuzov procedure to 6 or V haloketals (4). A modification of the phospho-nylation conditions (t°, stoichiometry) followed by removal of the protecting group in dilute acid and then continuous extraction allows synthesis of suitably branched compounds on a large scale (5). 

The synthesis of diethyl l,l-difluoro-2-oxoalkylphosphonates has been reported by a cerium-mediated reaction between diethyl 1-lithio-1,1-difluoromethylphosphonate and ethyl esters at low temperature in THF. After acidic quench at low temperature, diethyl I, I -difluoro-2-oxoalkyIphosphonates are isolated in good yield.- Addition of diethyl 1-lithio-1,1-difluoromethylphosphonate to di-ferf-butyl oxalate at low temperature in THF affords exclusively the addition product, an unusually stable ferf-butyl hemiketal. When a solution of this material is heated at reflux in ( ,1 f, or chromatographed on silica gel, only a few percent is converted to the hydrate. This conversion is best effected by dissolving the hemiketal in MeCN followed by reaction with aqueous Nal ICO . Subsequent azeotropic dehydration with CgHg affords diethyl l,l-difluoro-2-oxo-2-(fert-butoxycar-bonyl)ethylphosphonate. 5... 

Readily available dialkyl l-bromo-l,l-difluoromethylphosphonates can also participate in the synthesis of 2-oxoalkylphosphonates. Thus, dialkyl 1-bromo-1,1-difluoromethylphosphonates, on reaction with activated Zn metal, are converted into difluoromethylphosphonylzinc bromides, which are coupled with carboxylic acid chlorides at room temperature to give dialkyl l,l-difluoro-2-oxoalkylphosphonates in good yields.- " Dimethyl 1-lithiomethylphosphonate undergoes trans-metallation with MnCl2 in THF to give dimethyl 2-oxobutylphosphonate in 80% yield on reaction with propionyl anhydride. " ... 

The process has been extended to the synthesis of diethyl l-fluoro-2-oxoalkylphosphonates. Thus, low-temperature acylation of diethyl l-(hydroxycarbonyl)-l-fluoromethylphosphonate with carboxylic acid chlorides in the presence of -BuLi in THF followed by decarboxylation provides an expeditious route for the synthesis of diethyl l-fluoro-2-oxoalkyIphosphonates in good yields (66-78%, Scheme 7.27). ° ... 

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