Methylenebisphosphonate

Phosphonates and related compounds, which can subsequently be used in the Wittig-Homer reaction (see Section 6.5), are readily alkylated in good yield (Table 6.8) [67-71], Mono-alkylation is observed with mildly basic conditions at 45°C [67] and dialkylation under stronger basic conditions at 60°C [70], Reaction of a,to-dihaloalkanes with phosphonocarboxylates leads to cycloalkylphosphonates [72], The methylenebisphosphonate reacts in a similar manner. 

Thymidine dimers in which the natural phosphodiester linkage has been replaced by a 2,5-disubstituted tetrazole ring have been synthesized and have been incorporated into oligodeoxynucleotides <02HCA2847>. The synthesis of mono- and bis-3-substituted thymidine derivatives with a polycyclic tetrazole linker (l,5-bis(tetrazol-5-yl)-3-oxapentane) has been reported <02TL1901>. a-Methylene tetrazole-based peptidomimetics were synthesized for inhibition studies of HIV protease <02JCS(P1)172>. A catalytic amount of tetrazole was found to be useful in the syntheses of symmetrical P,P -dialkyl partial esters of methylenebisphosphonic acid from the corresponding acid chloride via a facile two-step, one-... 

Stir the solution of pyrophosphoric acid (obtained in step 1) in an ice bath and add a 10% solution of tetra-/7-butylammonium hydroxide dropwise until pH 7.3 is reached (note use a pH meter). This will be around 50 mL (for methylenebisphosphonic acid and difluoromethylenebisphosphonic acid, the solutions should be titrated to pH 10 and 7.3, respectively). 

Blackburn, G. W., England, D. E. and Kolmann, F. (1981) Monofluoro- and difluoro-methylenebisphosphonic acids isopolar analogues of pyrophosphoric acid. J. Chem. Soc., Chem. Commun., 930-932. 

The esters also react readily with aryl hydrazines to give aryl hydrazone derivatives. Examples of the latter were first synthesized (prior to the availability of tetraalkyl carbonylphosphonates) from tetraalkyl methylenebisphosphonates and aryl diazonium salts, analogously to the phosphonoglyoxylate hydrazone synthesis described in a previous section. First made as possible precursors in a ketone synthesis, several of these compounds, converted to free acid salts by treatment with BTMS followed by dicyclohexylamine in methanol, proved to have unexpected inhibitory activity vs the pyrophosphate-dependent phospho-fructokinase of the parasite T. gondii, which causes a potentially lethal opportunistic infection in immunocompromised persons such as AIDS patients [94]. In fact, the 2,4-dinitrophenylhydrazone of carbonylbisphosphonic acid (as the tetrasodium salt) dramatically abated toxoplasmosis lesions in infected human foreskin fibroblasts [94]. Animal toxicity in this compound, probably arising from in vivo hydrolysis to the highly toxic hydrazine, precluded its future development, but the result remains an interesting lead. 

Addition of alkyl and aryl amines to carbonylbisphosphonates, which could afford a new route to a-amino methylenebisphosphonates if the imine reduction proceeds normally and competing fragmentation chemistry does not pose severe problems, is currently under investigation in our laboratory. 

The first examples of supercharged nucleotide analogues (85-87) have been described, in which methylenebisphosphonic acid containing an additional ioni-sable acidic function has been incorporated into p,y-bridged derivatives of adenosine triphosphate. The compounds and their protected precursors were obtained following acid-catalysed reaction of the respective precursors (88-90) with adenosine 5 -phosphoromorpholidate in pyridine in yields of 80,75 and 25%. 

A carbocyclic NAD(+) analogue (91) incorporating a methylenebisphospho-nate linkage in place of the natural pyrophosphate has been prepared as an inhibitor of ADP-ribosyl cyclase which is resistant to non-specific phosphatase degradation.The analogue 91 was obtained in 25% yield following a Poulter coupling of the precursor 92 with adenosine 5 -methylenebisphosphonate. 

Nucleoside Polyphosphates. - The preparation of the phosphonate analogues of IpJ and IpsI (130) and (131) has been described. Various methods for the efficient synthesis of these compounds have been examined. The most convenient method employed tris(imidazolido)phosphate and inosine 5 -methyl-enediphosphonate, which had been prepared from 2, 3 -isopropyledeneinosine and methylenebisphosphonic dichloride. ... 

X=0 or S) have been prepared from methylenebisphosphon(othio)-... 

Following this strategy, a straightforward approach was developed to d-arabinose-derived methylenebisphosphonate 76 in which one phosphorus atom belongs to the 1,2-phospholane moiety (Scheme 43) [95], This compound was designed as a possible transition state inhibitor of mycobacterial arabinosyltransferases, known to play a crucial role in the biosynthesis of arabinan part of the mycobacterial cell wall. 

A particularly important example of a gem-diphosphonic acid is, in fact, the simplest, namely methylenebisphosphonic acid (39) n- 1). The interaction of diiodomethane with excess triisopropyl phosphite at 150-160 °C has provided 50-60% of tetraisopropyl meth-ylenebisphosphonate , but marginally better yields are reported to be obtainable if dibro-momethane is employed Lower yields of the tetraethyl ester are obtainable using triethyl phosphite, and it should also be noted that a difference in the ratio of reactants is liable to provide dialkyl (halomethyl)phosphonates (Chapter 3, Section II. A). A similar procedure has provided the tetraethyl esters of a,co-alkanebisphosphonic acids (39) n - l-10) In a like manner, Dahl and Block " have obtained methylenebisphenylbisphosphinic acid (40) via its diisopropyl ester (not isolated) from diiodomethane and diisopropyl phenylphos-phonite. 

As in all Michaelis-Arbuzov and Michaelis-Becker reactions, the usual order of decreasing reactivity at the carbon-halogen bond, I > Br > Cl > F, applies with carbon-fluorine bonds tending to be unreactive, other than in exceptional circumstances. Even for diiodomethane, the most reactive dihalomethane, reactions with trialkyl phosphites can be made to yield esters of (iodomethyl)phosphonic acid (11 R = O-alkyl, R = alkyl, n=, X = I or in the presence of more phosphite ester, the methylenebisphosphonic ester 12... 

In a typical Wittig process, the lithium salt of tetramethyl methylenebisphosphonate acts upon the cyclic ketone 305 to give 306 further steps which consist essentially in reduction (Pt02, H2), de-esterification at phosphorus (Mc3SiBr) and further deprotection (aq. F3CCOOH), give racemic w> o-inositolmethylphosphonic acid (307 R also obtain-... 

In this procedure, the C-phosphorylated active methylene compound is first converted into its anion, through its reaction with KOBu BuLi, PhLi, NaH or even Et3N, and the anion is then acted upon by a sulphonyl azide the latter has been / -toluenesulphonyl azide in most recorded examples of the reaction. The first example of the adoption of this procedure to the synthesis of a phosphonic acid derivative appears to have been the conversion of triethyl phosphonoacetate into the diazo derivative (2). Since then, the procedure has been used to obtain A-substituted derivatives of the phosphonoacetamide corresponding to structure 2, but the primary amide itself undergoes further reaction to afford the C-phosphorylated 1,2,3-triazole (3)". Tetraethyl methylenebisphosphonate yields tetraethyl... 

Phosphorus-carbon bond fission by the action of metals or of organometallic reagents is exemplified by that in tetraalkyl methylenebisphosphonates during lithiation (to afford... 

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