Hydrogenphosphonates synthesis

A. V. Nikolaev, I. A. Ivanova, V. N. Shibaev, and N. K. Kochetkov, Application of the hydrogenphosphonate approach in the synthesis of glycosyl phosphosugars linked through secondary hydroxyl groups, Carbohydr. Res., 204 (1990) 65-78. 

Hydroxyalkyt and Epoxyalky Acids. The reaction of aldehydes or ketones with dialkyl hydrogenphosphonate continues to be widely used for the synthesis of a-hydroxyalkylphosphonates ° and magnesium oxide has been reported to be an effective catalyst for the reaction. The reaction has been used in enantioselective synthesis. For example, in the preparation of chiral a, -dihydroxyphosphonic acids 171 and 172 (Scheme 14), with preferential formation of the jyn-isomer 171, and the statin analogue 2-amino-1-hydroxy-3-phenylpropylphosphonic acid (173) (Scheme 15). Catalytic asymmetric... 

Many communications have concentrated on specific amino phosphonic acids or derivative types. Thus, esters of phosphonoaminoacetic add were obtained by the reactions between trialkyl (ethyl) phosphite and (218) and which are thought to proceed via the phosphorane (219). A sequence has been presented for the preparation of the mono- and di-benzyl esters of N-chz protected (a-aminoben-zyl)phosphonic acid. A synthesis of (aminomethylene)bisphosphonic acid from dibenzylamine, dibenzyl hydrogenphosphonate and triethyl orthoformate has been noted and the asymmetric hydrogenation of (220) in the presence of chiral phosphine catalysts yields samples of (221) with e.e.s of 63-96%. The pyrrolidine-based compound (222) has been prepared from methyl S)-N-methoxycarbonyl-4-oxo-2-pyrrolidinecarboxylate and iV-coupled 4-amino-butanal diethyl acetals were the starting materials in syntheses of the pyrrolidine-2-phosphonic add derivatives (223) in which Z represents the iV-protected amino add or peptide moiety. ... 

Within this area, the most recent developments in the synthesis of esters of phosphonic acids have been the direct alkylation of hydrogenphosphonates using diazoalkanes in the presence of copper-containing catalysts in benzene as the solvent Of those catalysts examined, the most effective seem to be [Cu(acac)2] and [Cu(OTf)2], with Cu, Pd and Rh acetates and [Ni(acac)2] being less effective. The overall reaction is that represented in equation 18, in which R and R may be H, Ph or a simple alkyl group, but they may also consist of a functionalized alkyl group in reactions catalysed by trifluoromethanesul-phonic acid A similar procedure has been applied to the hydrogenphosphinate Ph(MeO)P(0)H ... 

F. Synthesis from Hydrocarbons and Hydrogenphosphonates or Related Compounds... 

Much attention has been devoted to the conversion of aldehydes into the trimethylsilyl ethers of (a-hydroxyalkyl)-phosphonic acids 210 or analogous -phosphinic acids, or of the corresponding (a-hydroxyalkyl)phosphonic diamides 211 by the use of dialkyl trimethylsilyl phosphite or Me3SiOP(NEt2)2 (or other phosphorodiamidite) It is a reaction which occurs very readily, even at room temperature, and the ready methanolytic or hydrolytic removal of the silyl protecting group makes the procedure an attractive alternative to the direct synthesis of the (a-hydroxyalkyl)phosphonic acids from dialkyl hydrogenphosphonates and carbonyl compounds. Silyl-protected hydroxy-phosphonic and -phosphinic acid derivatives are useful for further synthetic development. ... 

Latterly, attention has been turned to the alkylation of the hydrogenphosphonates themselves under essentially neutral conditions, thus obviating the several possible side reactions. The formation (in 38% yield) of triethyl phosphonoacetate from diethyl hydro-genphosphonate and ethyl diazoacetate has been known for some time, and the synthetically useful methyl (di-tcrt-butoxyphosphinoyl)acetate (in 40% yield) has been similarly and more recently obtained Steps have been to tiy to improve yields under photoinitiation in the presence of copper salts or complexes ", or through catalysis by trifluoromethanesulphonic acid Such procedures allow the ready synthesis of the esters 411 (R = alkyl or RO). 

X = Se ". These and other synthesis procedures will be considered in more detail later. Unfortunately, the acetals of (oxomethyl)phosphonic diesters do not liberate the free (oxomethyl)phosphonic esters under acidic conditions, but instead, tend to decompose with the formation of dialkyl hydrogenphosphonate. 

In Section VILA, the 1,2-addition of a hydrogenphosphonic diester or related compound to an a,j5-unsaturated aldehyde or analogous ketone " " was discussed in relation to the synthesis of (l-hydroxyalkyl)phosphonic diesters. The latter are formed under condition of kinetic control whereas 1,4-addition (the so-called Pudovik reaction), which leads to the (2-oxoalkyl)phosphonic diester occur under thermodynamic controP" ". In general, reactions which involve ethylenic aldehydes, or acetylenic aldehydes or ketones, tend to result in adduct formation across the carbonyl group, whilst ethylenic ketones tend to take part in 1,4-additions and afford 3-oxoalkyl phosphonic (or phosphinic) acid systems 550 34,946-949 consistent with Markovnikov predictions. Such statements are a broad oversimplification, however, at least with regard to the formation of the oxoalkyl phosphonates. In practice, the manner of addition depends on experimental circumstances, the nature and even amount of catalyst and other factors For instance, for the additions of dimethyl hydrogenphosphonate to the ketones 561 ( = 1 or 2) and 559 (R" = H, R = 2-furyl, R = Me), carried out by the addition of a trace of saturated MeONa-MeOH solution to a mixture of reactants in diethyl ether, yielded (within 5 min) the respective 1,2-adducts (1-hydroxyalkylphosphonates) in yields of64,69 and 52% ... 

A one-pot process has been devised for the synthesis of dialkyl [(a-phenylamino)ben-zyljphosphonates from dialkyl hydrogenphosphonate, benzaldehyde and aniline, presumably adaptable for other aromatic amines or aldehydes To avoid multiple reactions of the Mannich type when using a primary amine and a particularly reactive carbonyl component such as formaldehyde, initial silylation of the amine, or the use of diethyl trimethylsilyl phosphite, are valuable moderating variations The amine can be replaced by a carboxamide" or carbamate ester, conveniently the benzyl ester , and the product can then be selectively deacylated with HBr in acetic acid at room temperature or by hydrogenolysis. Alternatively, even a phosphoric amide may be used to afford an A-phos-phorylated product (221)" ... 

Mention might be made of a useful synthesis which is based on the Abramov-type reaction between a hydrogenphosphonate and a dialkyl (l-oxoalkyl)phosphonate, formed in situ, to produce tetramethyl (l-hydroxy-4-phthalimido)butane-l,l-bisphosphonate, readily deprotected to give the free amino phosphonic acid 364. ... 

An Abramov condensation between diisopropyl hydrogenphosphonate and propenal and subsequent O-methoxycarbonylation to give the intermediate (402), forms the first stage in a useful synthesis of an A-hydroxy system following a reaction with bocNHOboc (0,A-di-bochydroxylamine) and subsequent hydrogenolysis and acidolysis ... 

Marugg, J. E Tromp, M., Kuyl-Yeheskiely, E, van der Marel, G. A., and van Boom, J. H. (1986) A convenient and general approach to the synthesis of properly protected d-nucleoside3 -hydrogenphosphonates via phosphite intermediates Tetrahedron Lett 27,2661-2664. 

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