Oxoalkylphosphonates

Natural Products.—The use of 2-oxoalkylphosphonates still appears to be the method of choice for the preparation of the C8-side-chain of prostaglandins. Examples reported this year were in the preparation of azaprostaglandins,119 aryl analogues,120 and the analogue (131),121 among others. Royal jelly acid has been... 

Oxoalkylarsonic acids lose arsenite by elimination, presumably after enolization, as described earlier (Section IV,B,2,c, and Fig. 9). In contrast, 3-oxoalkylphosphonic acids are stable e.g., the phosphono-methyl analogue of glycerone phosphate is a substrate for aldolase (118). The elimination of arsenite from 3-oxoalkylarsonic acids, but not of phosphite from 3-oxoalkylphosphonic acids, may reflect the fact that arsenite is relatively stable compared with arsenate, whereas phosphite is unstable compared with phosphate. 

Oxoalkylphosphonic acids can be hydrolyzed in this way (119), as in the enzyme-catalyzed hydrolysis of phosphonoacetaldehyde (73, 69-71), but with much more difficulty. The lability of 2-oxoalkylarsonic acids presumably reflects the ease with which water can more easily enter the coordination shell of arsenic than that of phosphorus, because of the larger size of the atom, i.e., the same feature expressed in the lability of esters and anhydrides of arsenate. 

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). 

Phosphonopyruvate systems were the first candidates submitted to reductive amination. Because of the presence of the ester group, the a-ketoester carbonyl is less reactive than traditional oxoalkylphosphonates, and yields of isolated amino-esters never exceeded 55 %. The reaction is run at pH 7 in ethanol and it is general for ammonia and primary amines. Steric hindrance represents the second limiting factor since a-substituted or thiono-phosphonopyruvates react sluggishly thus secondary amines cannot be introduced. When the reductive amination process is effected the exclusive by-product is the a-hydroxyester which arises by reduction of the carbonyl group (7j-8). 

Oxoacids. It has been shown that Cobalt(O) or magnesium-mediated reactions of a-halomethylphosphonates (294) with esters constitute a novel approach to 2-oxoalkylphosphonates (295) (Scheme 74). ... 

Reactions of Dialkyl 1-Oxoalkylphosphonates with Conservation of the P-C Bond... 

The effectiveness of dialkyl 1-aIkynylphosphonates as acelonyl equivalents for the preparation of dialkyl 2-oxoalkylphosphonates has long been established. Because 2-oxoaIkylphosphonates themselves are versatile synthetic intermediates, especially as the reagents of choice for promoting a number of Homer-Wadsworth-Emmons cyclization reactions, procedures that effect the direct conversion of dialkyl 1-alkynylphosphonates into dialkyl 2-oxoalkylphosphonates are of special importance. The procedure for the hydration of dialkyl 1-alkynylphosphonates has remained unchanged since the first report in 1966 (Scheme 1.21). Thus, treatment of diethyl 1-alkynylphosphonates with aqueous H2SO4 in MeOH in the presence of HgSO4 gives, after reflux for 15 h - ... 

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... 

Balczewski. P.. Novel 1-phosphonyl radicals derived from I-mono and l.l-diheterosubslilulcd 2-oxoalkylphosphonates as useful phosplioroorganic intermediates in organic synthesis, Tetrahedmn, 53, 2199, 1997. 

Diethyl 2,3-epoxy-4-oxoalkylphosphonates can be converted on reaction with thioureas and thioamides into diethyl 2-hydroxy-2-(5-thiazolyl)ethylphosphonates or into 2-(5-thiaz-olyl)vinylphosphonates (Scheme 4.49)."" Cleavage of both systems into phosphorus-free thiazoles can be readily achieved with CsF in DMF. Reaction of diethyl 2,3-epoxy-4-oxoalkylphosphonates with 2-mercaptobenzimidazole yields oc-substituted enones arising from regioselective oxirane opening and subsequent dehydration (Scheme 4.49). °° These derivatives exist, mainly or exclusively, as cyclic tautomers. The cyclization step depends on the reaction conditions. °°... 

Diethyl 2-oxoalkylphosphonates are synthetically useful compounds that are known to give stable 1,3-dianions at ambient temperature. After generation using NaH and LDA (2 eq) at low temperature, 1,3-dianions react smoothly with HCO2Et to provide stabilized water-soluble bis-enolates. Acidification with 4 M HCl produces diethyl 3-formyl-2-oxoalkyIphosphonates in high yields (81-89%).This sequential one-pot procedure offers a short and efficient route to a variety of functionalised diethyl 3-formylphosphonates from readily available starting materials (Scheme 5.34).An alternative preparation of diethyl 3-formyl-2-oxopropylphosphonate from diethyl 2-oxopropyIphosphonate involves a multistep route. " ... 

Good general synthetic rontes to dialkyl 1-oxoalkylphosphonates have been available for many years. Although good general methods now exist, dialkyl 2-oxoalkylphosphonates were traditionally less accessible, and many relatively specihc protocols have been developed. These ketophosphonates are important reagents for synthesis and useful intermediates for the preparation of elaborate phosphonates. This chapter describes their synthesis and applications. 

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