Mitsunobu phosphonic acids

Condensation of partially protected sucroses with the phosphonic acid under Mitsunobu conditions was the key step in the preparation of sucrose phospho-nates. A monoclonal antibody having good binding properties showed a regio-selective esterase activity towards the 6-heptylphosphonate as compared with 6 -octanoylsucrose (Scheme 25).102... 

The mechanism of the Mitsunobu reaction of alcohols with phosphonic acids has been recently studied [ 109]. A typical Mitsunobu coupling reaction proceeds via Path A and it is generally recognized that the rate-determining step is the re-... 

The syntheses of carbocyclic analogs of phosphononucleosides (29) and (30a-c) have been reported. Phosphonic acid (29) was obtained by introduction of the benzoylated thymine on the 2(4-hydroxycyclopent-2-enyl)ethyl phosphonic acid diisopropyl ester under Mitsunobu conditions while (30a-c) were prepared by building-up the base around a phosphono-cyclopentylamine moi-ety. The vinylphosphonate derivatives of uridine, cytidine and cytosine ara-binoside (31a-c) have been prepared by Wittig condensation of [(diethoxyphos-phinyl)methylidene]triphenylphosphorane with the appropriately protected 5-aldehydic nucleoside derivatives. Dihydroxylation of the novel vinyl phosphon-ates offered the dihydroxylated phosphonate derivatives (32a-c). Each of these novel compounds was evaluated as substrates for the enzyme nucleotide monophosphate kinase, and their toxicity to K562 cells. All analogues were found to be poorly phosphorylated by the kinase and exhibited poor in vivo toxicity. ... 

Further esterification of monobenzyl benzylphosphonate may be carried through the Mitsunobu procedure, the best yields being achieved using the potassium salt of the substrate. Monoesters of iV-protected (1-aminoalkyl)phosphonic acids are further esterified by alcohols in the presence of BOP-type reagents [(l-aminoalkyl)alkylj- and [(l-aminoalkyl)aryl]-phosphinic acids, again as their potassium salts, have been converted into esters by reactive alkyl halides in the presence of 18-crown-6 ether (see also reference The... 

Amino-l-hydroxyethyl)phosphonic acid occurs in the plasma membrane of Acanthamoeba castellani and the 2R isomer is formed, in that organism, by the hydroxy-lation of (2-aminoethvl)phosphonic acid This biosynthesis step in vitro has been studied by Hammerschmidt" who synthesized various chiral deuterium-labelled derivatives of both compounds using the isotopically labelled 2-benzyloxyethanal in Abramov reactions to obtain, initially, the dimethyl (2-benzyloxy-l-hydroxyethyl)phosphonate (362). This ester was resolved through the diastereoisomeric carbamates 363 the separated carbamates were sequentially de-l-O-protected, silylated at the a-HO group, debenzylat-ed and, by means of the Mitsunobu reaction, converted into dimethyl [2-eizido- -(tert-butyldimethylsilyloxy)ethyl]phosphonates. Subsequently, standard reactions were used to transform the latter into the diastereoisomeric, isotopically labelled (2-amino-1-hydroxy-ethyl)phosphonic acid. 

Although this group of compounds is, as yet, very poorly represented, at least three routes for their synthesis already exist. The reactions between acethydroximic acids and (haloalkyl)phosphonic diesters yield the O-derivatives 372, from which selective work-up steps (Scheme 53) lead to the esters 373 or to the free [(aminooxy)alkyl]phosphonic acids 37 580 conventional approach consists in the reaction between a (1-hydroxyalky 1)-phosphonic or -phosphinic diester with A-hydroxyphthalimide in the presence of diethyl azodicarboxylate and PhjP under Mitsunobu conditions the resultant [l-(phthal-imidooxy)alkyl] acicl diesters lose the phthalimido group on hydrazinolysis, and a final aci-dolysis provides the [l-(aminooxy)alkyl]-phosphonic or -phosphinic acids. 

In an interesting study on antibody-catalysed prodrug activation, the phosphonate 205 was prepared by Mitsunobu condensation of the phosphonic acid with the 3 -t2-Tbdms derivative of FdU. This hapten was linked to keyhole limpet hemocyanin and bovine serum albumin via the carboxylate group. The monoclonal antibodies specific for 205 were found to catalyse the hydrolysis of 5 -C -(/V-acetyl-D-valyl)-FdU, an FdU prodrug that was not hydrolysed by endogenous esterases, and a combination of 205 and antibody was as effective as FdU itself in preventing the growth of E.coli in vitro. ... 

Phosphonate esters can be readily prepared from alcohols and phosphonic acid derivatives. The selective phosphorylation of the 5 -hydroxy groups of thymidine and uridine was originally reported Mitsunobu s group in 1969. More recent examples include the modified derivative of the antitumor C-nucleoside tiazofurin (240) and an AZT triphosphate analog (241) shown... 

Synthesis of the modified triphosphate subunit was accomplished starting from ethyl bis(bromomethyl)phosphinate 253 (Scheme 51). An Arbusov reaction with triethyl phosphite and trimethyl phosphite, respectively, produced bis (phosphonomethyl)phosphjnate 255 in 40% overall yield. A selective monodemethylation by cyanide and acidificaticHi led to monophosphonic acid 256. Bismethylene triphosphate (BMT) 258 analogues of nucleosides were obtained by coupling of the 5 -free OH nucleosides 257 with phosphonate 256 under Mitsunobu conditions [181,182]. TMSBr mediated deprotection followed by treatment with aqueous anmumia and cation exchange afforded bismethylene analogues 259 of nucleoside triphosphate in yields up to 62%. 

Lewis acid-catalysed reaction of diisopropyl (hydroxymethyl)phosphonate [( Pr0)2p(O)CH2OH] with di-O-acetyl-D-xylal, followed by reaction with metha-nolic ammonia, affords 14 as the major isomer a brief description of the diastereoselectivity of this reaction is also given. Compoimd 14 on reaction with 2-amino-6-chloropurine under Mitsunobu conditions affords access to dihydro-pyranyl nucleoside phosphonate analogues, which on reduction of the double bond lead to the corresponding tetrahydropyranyl derivatives. EH-O-acetyl-L-arabinal was also used as a starting material. ... 

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