Electron-impact-induced rearrangements in the mass spectra of phosphinyl stabilized triphenylphosphonium ylides

Examination of the mass spectra of some methyl and phenyl phosphonate stabilized triphenylphosphonium ylides revealed that these compounds are quite stable to electron-impact and provided valuable structural information. They exhibit strong molecular and [M - H]⁺ ions, and fragment ions which are characteristic for the phosphonium or the phosphonate portion of the molecules. Numerous rearrangement ions were detected, however, the most prominent of which involves the migration of a phosphonate phenyl to the ylide carbon, leading to the base peak (m/e 352) in the spectrum of diphenyl triphenylphosphoranylidenemethylphosphonate. The mechanism of these fragmentations has been studied with the aid of high resolution analysis and deuterium labeled analogs whose preparation is reported.     

Synthesis of (sulfonyl)methylphosphonate analogs of prenyl diphosphates

Syntheses of several (sulfonyl)methylphosphonate analogs of geranyl, neryl, and farnesyl diphosphates are described. Key steps include utilization of an (E)-selective Horner-Wadsworth-Emmons olefination which couples an aldehyde to the sulfone phosphonate moiety, and a selective reduction of the resulting dienyl sulfone phosphonate substrates.     

Synthesis and photophysical properties of benzo[c]thiophene,p-phenylene-, triphenylamine-, and pyrene-based vinylenes

An efficient synthesis of benzo[c]thiophenyl/p-phenylenyl/pyrenyl phosphonate esters has been achieved using ZnBr₂-catalyzed Michaelis–Arbuzov reaction of corresponding benzyl alcohol/bromides at room temperature. Horner–Wadsworth–Emmons reaction of the phosphonate esters with aryl/heteroaryl aldehydes in the presence of t-BuOK furnished the vinylenes in good yields. The absorption and emission characteristics of the synthesized vinylenes were also reported.     

Synthetic Studies Toward the Preparation of Phosphonate Analogs of Sphingomyelins and Ceramide 1 -Phosphate Using Pentacovalent Organophosphorus Methodology

Abstract

Non-isosteric phosphonate analogs of sphingomyelin and ceramide 1-phosphate are being synthesized from the condensation product of a pentacovalent oxaphospholene and azodicarboxylates. Model studies are initially described.     

Modification of cellulose phosphonate with N,N-dimethylacrylamide and 4-vinylpyridine,and flame-retardant properties of the products

Cellulose phosphonate was added to N,N-dimethylacrylamide (A) and 4-vinylpyridine (B) in the presence of sodium ethoxide to yield cellulose 2-(N,N-dimethyl)carbamoylethylphosphonate and cellulose 2-pyridinylethylphosphonate, respectively. The extent of the addition was 50% for (A) and 10% for (B), based on P—H bonds in cellulose phosphonate. The modification of cellulose with (A) resulted in an increase in the threshold temperature for weight loss, a decrease in the amount of residual products, and retardation of deammoniation of ammonium salts of the products. Modification of (B) resulted in a lower threshold temperature and amount of residue and an acceleration of the oxidation of cellulose chains. Cellulose phosphonate fabrics modified with (A) had powerful flame-retardant properties. It was deduced that the combination of phosphoryl and amide groups was an effectual flame retardant.     

Properties of polyethylene modified with phosphonate side groups. II. Dynamic mechanical behavior

The viscoelastic behavior of phosphonate derivatives of phosphonylated low-density polyethylene (LDPE) was studied by dynamic mechanical techniques. The polymers investigated contained from 0.2 to 9.1 phosphonate groups per 100 carbon atoms and included the dimethyl phosphonate derivative and two derivatives for which the phosphonate ester group was an oligomer of poly(ethylene oxide) (PEO). The temperature dependences of the storage and loss moduli of the dimethyl phosphonate derivatives were qualitatively similar to those of LDPE. At low phosphonate concentrations, the α, β, and γ dispersion regions characteristic of PE were observed, while at concentrations greater than 0.5 pendent groups per 100 carbons atoms, only the β and α relaxations could be discerned. At low degrees of substitution, the temperature of the β relaxation T_β decreased from that of PE, but above a degree of substitution of 0.1, T_β increased. This behavior was attributed to the competing influences of steric effects which tend to decrease T_β and dipolar interactions between the phosphonate groups which increase T_β. For the phosphonate containing PEO, a new dispersion region designated as the β′ relaxation was observed as a low-temperature shoulder of the β relaxation. The temperature of the β′ loss was consistent with T_g(U) of the PEO oligomers as determined by differential scanning calorimetry, and it is suggested that the β′-loss process results from the relaxation of PEO domains which constitute a discrete phase within the PE matrix.     

Regioselective synthesis of pyridines and dihydropyridines derived from β-amino acids and aminophosphonates by reaction of N-vinylic phosphazenes with α,β-unsaturated ketones

Reaction of N-vinylic phosphazenes with α,β-unsaturated ketones leads to the formation of pyridines derived from β-amino acids in a regioselective fashion. The use of functionalized enones derived from α-acylstyryl-carboxylates or -phosphonates affords biologically active asymmetrical and symmetrical dihydropyridines substituted with carboxylate or phosphonate groups including nitrendipine, felodipine, MRS 1097, and efonidipine analogs.     

Homonucleoside phosphonic acid-I: Ageneral synthesis of isosteric phosphonate analogs of nucleoside 3'-phosphates

A general synthetic route to 3'-deoxy-3'-dihydroxyphosphinylmethyl ribonucleosides 3 the isosteric phosphonate analogs of nucleoside 3'-phosphates, is described. This involved alkylation of 1,2;5,6-di-O-isopropylidene-α-D-ribo-hexofuranose-3-ulose 7) with tetraethyl methylenediphosphonate 6, followed by stereoselective catalytic reduction and cleavage of C₆ to generate 3-deoxy-3-diethoxyphosphinylmethyl-1,2-O-isopropylidene-α-D 12a. Benzoylation followed by acetolysis then generated the key crystalline intermediate 1,2-di-O-acetyl-5-O-benzoyl-3-deoxy-3-diethoxyphosphinylmethyl-β-D-ribofuranose 13, This compound, or the related glycosyl chloride, was condensed with several purine and pyrimidine bases and all protecting groups were removed by mild alkaline treatment via a series of intramolecular cyclizations and hydrolysis. In this manner the phosphonate analogs of nucleoside 3'-phosphates derived from adenine, 6-dimethylaminopurine, uracil, thymine, and cytosine were prepared.     

Synthesis and Transformations of 5-Substituted 2-Furoyl Phosphonates

5-Chloromethyl-2-furoyl chloride when treated with triethyl phosphite has given 5-chloromethyl-2-furoyl phosphonate. This compound has reacted with sodium azide in the presence of potassium iodide to give 5-azidomethyl-2-furoyl phosphonate. Treatment of 5-chloromethyl-2-furoyl phosphonate with secondary amines even under mild conditions has caused cleavage of P–C bond with liberation of diethyl hydrogen phosphite and formation of 5-chloromethyl-2-furancarboxamide. Butanthiol in the presence of potassium carbonate in acetonitrile has converted the chloromethyl group into the butylthiomethyl one and simultaneously split the P–C bond with the formation of the corresponding thioester. Under the action of S-methylthiuronium iodide and triethylamine, 5-chloromethyl-2-furoyl phosphonate has been unexpectedly reduced into the 5-methyl derivative. 5-Butylthiomethyl- and 4-(N-morpholinomethyl)-2-furoul chlorides have been phosphorylated with triethyl phosphite into the corresponding 5-functionalized 2-furoyl phosphonates. The prepared furoyl phosphonates have reacted with resonance-stabilized phosphoranes to give phosphorylated derivatives of 3-(furyl)acrylates and 4-(furyl)but-3-en-2-one with trans-location of phosphoryl and carbonyl groups with respect to the double bond.

     

Transesterification of oligomeric dialkyl phosphonates,leading to the high‐molecular‐weight poly‐H‐phosphonates

Polycondensation of 1,10‐decanediol with dimethyl‐H‐phosphonate taken in excess leads to oligomers with methyl‐H‐phosphonate end groups. The polytransesterification of the resulting oligomer as well as the related model reactions were studied. The synthesis of poly(decamethylene‐H‐phosphonate) was analyzed and the final product had M̄_n = 1.4–1.9 10⁴ (from end groups, vpo, and M̄_n of the derived polymers). The exchange of the ester groups between two homoesters (dimethyl and diethyl phosphonates) used as models, conducted at r.t. and catalyzed by metal alkoxide provides mixed (hetero) ester in a few minutes. If the concentration of the catalyst is not high enough, then the reaction does not go to equilibrium, because the alcoholate anions are converted into the anions of monoesters of the H‐phosphonic acid, catalytically inactive at this temperature. However, these monoesters become catalytically active at higher temperature, i.e., at the conditions used for preparing higher molecular‐weight products by transesterification. The apparent rate constants (k̄) of the ester exchange catalyzed by monoester salt (modeling the propagation step in polytransesterification) were determined by two independent methods; at 130°C k̄ ∼ 1.0 · 10⁻² mol⁻¹ · L · s⁻¹. The detailed study of the model polytransesterification, and particularly of the polymer end groups appearance and disappearance (studied by ¹H‐, ¹³C‐, and ³¹P‐NMR) allowed postulation of the reaction mechanism and confirmed our previous work, describing formation at these conditions of polymers with M̄_n > 10⁴. © 1999 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 37: 1365–1381, 1999     

Phosphonylation Controls the Protein Corona of Multifunctional Polyglycerol‐Modified Nanocarriers

Nanocarriers are a platform for modern drug delivery. In contact with blood, proteins adsorb to nanocarriers, altering their behavior in vivo. To reduce unspecific protein adsorption and unspecific cellular uptake, nanocarriers are modified with hydrophilic polymers like poly(ethylene glycol) (PEG). However, with PEG the attachment of further functional structures such as targeting units is limited. A method to introduce multifunctionality via polyglycerol (PG) while maintaining the hydrophilicity of PEG is introduced. Different amounts of negatively charged phosphonate groups (up to 29 mol%) are attached to the multifunctional PGs (M_n 2–4 kg mol^?1, Ð < 1.36) by post‐modification. PGs are used in the miniemulsion/solvent evaporation procedure to prepare model nanocarriers. Their behavior in human blood plasma is investigated to determine the influence of the negative charges on the protein adsorption. The protein corona of PGylated nanocarriers is similar to PEGylated analogs (on same nanocarriers), but the protein pattern could be gradually altered by the integration of phosphonates. This is the first report on the gradual increase of negative charges on nanocarriers and intriguingly up to a certain amount of phosphonate groups per nanocarrier the protein pattern remains relatively unchanged, which is important for the future design of nanocarriers.     

Three hydrates of the bisphosphonate risedronate,consisting of one molecular and two ionic structures

Three different hydrates of risedronate were obtained by varying the pH of a solution containing the compound. At the pH values used, the N atom of the pyridine group is protonated and the compounds are zwitterionic. Crystals obtained directly from the synthesis resulted in risedronate monohydrate, or [1‐hydroxy‐1‐phosphono‐2‐(pyridinium‐3‐yl)­ethyl]phosphonate monohydrate, C₇H₁₁NO₇P₂·H₂O, (I), in which just one phosphonate group is negatively charged. Recrystallizations at pH values of 2 and 4 yielded risedronate dihydrate, or sodium [1‐hydroxy‐2‐(pyridinium‐3‐yl)­ethane‐1,2‐diyl]­bis­(phosphonate) dihydrate, Na⁺·C₇H₁₀NO₇P₂⁻·2H₂O, (II). Finally, recrystallizations at pH values of 7 and 8 produced risedronate 2.5‐­hydrate, or sodium [1‐hydroxy‐2‐(pyridinium‐3‐yl)­ethane‐1,2‐diyl]­bis­(phosphonate) 2.5‐hydrate, Na⁺·C₇H₁₀NO₇P₂⁻·­2.5H₂O, (III). At these four pH values, both phosphonate groups in (II) and (III) are negatively charged and coordinated to an Na⁺ ion. Crystals of (II), i.e. those grown at pH values of 2 and 4, have isomorphous polymeric ion aggregate structures with geminal phosphonate and alcohol groups coordinated to the same Na⁺ ion. On the other hand, crystals of (III), i.e. those grown at pH values of 7 and 8, have isomorphism polymeric ion aggregate structures with geminal phosphonate and alcohol groups coordinated to different Na⁺ ions.     

Reaction of cellulose phosphonate with N-vinyl-2-pyrrolidone and flame-retardant properties of the product

The reaction of cellulose phosphonate and N-vinyl-2-pyrrolidone in ethanol in the presence of sodium ethoxide was investigated and thermal stabilities and flame-retardant properties for cellulose phosphonate modified with N-vinyl-2-pyrrolidone were discussed. The results in this study point out the following important aspects of flame retardation of cellulose fabrics: (1) The reaction of cellulose phosphonate and N-vinyl-2-pyrrolidone in the presence of sodium ethoxide results in graft polymerization of N-vinyl-2-pyrrolidone at P? H sites in cellulose phosphonate; an average chain length of the graft polymer is about five units of vinylpyrrolidone. (2) The graft polymerization of N-vinyl-2-pyrrolidone can improve both stabilities, especially the flame-retardant properties of cellulose fabrics. (3) Amides, whether noncyclic or cyclic, are suitable for nitrogen compounds that can effectively operate as synergists.     

Deoxy-nitrosugars 12th communication Synthesis of isosteric mono-phosphonate analogues of β-and α-D-fructose 2,6-bisphosphate

A synthesis of the isosteric mono-phosphonate analogues 2a and 19 of the β-and α-D -fructose 2,6-bisphosphate, respectively, is described. Chain elongation of the 1-deoxy-1-nitro-D -arabinose 3 (Scheme 1) by a Henry reaction with paraformaldehyde followed by protection of the resulting alcohol (methoxymethyl ether) and a radical-chain substitution by nitromethane anion gave the key intermediates, the gluco-anhydroalditol 6 and the manno-anhydroalditol 7 . These products equilibrated under basic conditions. Conversion of 7 to the aldehyde 9 , Abramov reaction of 9 with diphenyl phosphite followed by deoxygenation according to Barton gave the phosphonate 11 (Scheme 2). Selective hydrogenolysis of 11 , phosphorylation and deprotection gave 2 which was converted to the tetrasodium salt 2a . Similarly, 6 was transformed into the isosteric phosphonate analogue 19 of the α-D -fructose 2,6-bisphosphate (Scheme 3).     

Enantiopurity analysis of new types of acyclic nucleoside phosphonates by capillary electrophoresis with cyclodextrins as chiral selectors

CE methods have been developed for the chiral analysis of new types of six acyclic nucleoside phosphonates, nucleotide analogs bearing [(3‐hydroxypropan‐2‐yl)‐1H‐1,2,3‐triazol‐4‐yl]phosphonic acid, 2‐[(diisopropoxyphosphonyl)methoxy]propanoic acid, or 2?(phosphonomethoxy)propanoic acid moieties attached to adenine, guanine, 2,6‐diaminopurine, uracil, and 5‐bromouracil nucleobases, using neutral and cationic cyclodextrins as chiral selectors. With the exception of the 5‐bromouracil‐derived acyclic nucleoside phosphonate with a 2‐(phosphonomethoxy)propanoic acid side chain, the R and S enantiomers of the other five acyclic nucleoside phosphonates were successfully separated with sufficient resolutions, 1.51–2.94, within a reasonable time, 13–28 min, by CE in alkaline BGEs (50 mM sodium tetraborate adjusted with NaOH to pH 9.60, 9.85, and 10.30, respectively) containing 20 mg/mL β‐cyclodextrin as the chiral selector. A baseline separation of the R and S enantiomers of the 5‐bromouracil‐derived acyclic nucleoside phosphonate with 2‐(phosphonomethoxy)propanoic acid side chain was achieved within a short time of 7 min by CE in an acidic BGE (20:40 mM Tris/phosphate, pH 2.20) using 60 mg/mL quaternary ammonium β‐cyclodextrin chiral selector. The developed methods were applied for the assessment of the enantiomeric purity of the above acyclic nucleoside phosphonates. The preparations of all these compounds were found to be synthesized in pure enantiomeric forms. Using UV absorption detection at 206 nm, their concentration detection limits were in the low micromolar range.     

Cyclisierungsreaktionen von Diazoalkenyl-phosphonsäureestern Synthese von Pyrazolyl- und 2,3-Benzodiazepinylphosphonsäureestern

Tosylhydrazones3 and4 of dialkyl 3-oxo-1-alkenylphosphonates1 and 1-oxo-2-alkenylphosphonates2, respectively, react with aqueous sodium carbonate to give the pyrazoles7 in excellent yields. Under analogous conditions the tosylhydrazone9 of diethylo-vinylbenzoyl phosphonate (8) affords diethyl 2-hydroxy-1-indanyl phosphonate (10). Upon thermolysis of the sodium salt12 generated from9 in anhydrousD M E, one obtains, depending on the reaction conditions, either the 1-H-benzodiazepinyl derivative14 or its 5H-isomer15. At room temperature the diazo compound13 cyclizes slowly to give14, which can be isomerized to15 by action of base.

     

A new preparative method for the synthesis of diethyl 1-diazo-2,2,2-trifluoroethylphosphonate <Emphasis Type="Italic">via</Emphasis> an imino phosphonate

A preparative method for the synthesis of diethyl 1-diazo-2,2,2-trifluoroethylphosphonate from trifluoroacetic anhydride and benzyl carbamate via diethyl 1-benzyloxycarbonylimino-2,2,2-trifluoroethylphosphonate is developed. Optimum conditions for the chlorination of benzyl N-trifluoroacetylcarbamate with SOCl₂—Py to afford the imidoyl chloride, phosphorylation of the latter under the conditions of the Arbuzov reaction, as well as diazotization of amino phosphonate with isopropyl nitrite are found.     

Studies on the Regioselectivity of Horner-Wadsworth-Emmons (Hwe) Reactions on 3,4-Enuloses. Further Evidence of Phosphonate-Phosphate Rearrangements Through Five Membered Cyclic Intermediates.

ABSTRACT

The Horner-Wadsworth-Emmons (HWE) reaction was performed on methyl 3,6-di-O-benzoyl-2-deoxy-α-D-glycero-hex-2-enopyranosid-4-ulose (1) with the potassium enolates of dimethyl [(methoxycarbonyl)methyl]phosphonate (2) or diethyl [(ethoxycarbonyl) methyl]phosphonate (3) under different conditions (metallic cation and solvent) in order to study regio- and stereochemical aspects of the reaction. In the presence of lithium ions, no reaction took place. When sodium enolates were employed, 1,2-addition was the main reaction in chelating solvents, whereas the 1,4-adduct is favoured in the less polar, non chelating toluene. Only 1,2-addition was observed with potassium enolates. Evidence of phosphonate-phosphate rearrangements through five membered cyclic intermediates is described.     

Synthesis and Characterization of Copper(II)–Phosphonate Coordination Chain Array of Metallocages

Reaction of CuCl₂ ·2H₂O and 2,4,6‐tris(phosphorylmethyl)mesitylene (H₆tpmm) in H₂O?DMF solution at room temperature afforded green crystals of [Cu₆(H₂tpmm)₃(H₂O)₉]·3H₂O ( 1 ), which were characterized by Fourier transform infrared (FT‐IR), thermogravimetric (TG) analysis, and powder X‐ray diffraction (PXRD). The solid‐state structure of 1 reveals a one‐dimensional chain array of M₄L₂ ‐metallocages constituted by the connection of two kinds of metallocage units, namely MC‐A (phosphonate/water‐bridged) and MC‐B (phosphonate‐bridged only), via μ₂‐O(phosphonate)? Cu bonds in ABAABA order. The tris‐phosphonate ligand H₆tpmm is partially deprotonated to form H₂tpmm^4?, which displays a cis,cis,cis conformation to bridge six Cu(II) centers via two monodentate phosphonate groups in a η ⁰:η ⁰:η ¹‐bonding mode and one tridentate phosphonate group in a μ₄, η ¹:η ¹:η ²‐bondingng mode.     

Synthesis of adamantyl-containing cidofovir analogs as potential antiviral prodrugs with high bioavailability parameters

We report on preparation of potential nucleoside phosphonate prodrugs: 1-{3-hydroxy-2-[O-(adamantylalkyl)phosphorylmethoxy]propyl}cytosines containing two structural fragments providing antiviral activity, nucleoside phosphonate and adamantyl sites.