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.

     

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.     

Bifunctionalized allenes. Part XXIV. Competitive electrophilic cyclization of 5-(dimethoxyphosphoryl)-alka-3,4-dienoates leading to 2,5-dihydro-1, 2-oxaphospholes and 5,6-dihydro-2H-pyranes

Abstract

We report herein a study on the competitive electrophilic cyclization of 5-(dimethoxyphosphoryl)-alka-3,4-dienoates involving 5-endo-trig and 6-endo-trig mode cyclizations. Reaction with electrophiles produces mixtures of the 2-(2-oxo-2,5-dihydro-1,2-oxaphosphol-5-yl)-alkanoates and (6-oxo-5,6-dihydro-2H-pyran-2-yl)-phosphonates by competitive electrophilic cyclization due to the participation of the neighboring phosphonate and carboxylate groups.     

Mechanism on Iodine Induced Cyclization Reaction of Organophosphorus Compounds

Abstract

The iodine induced cyclization reaction of δ,?- or δ,γ- unsaturated phosphate, phosphonate or phosphoamidate were investigated by P-31 and C-13 NMR spectra. In each case, the diiodo-derivatives were observed and identified. For the δ,?-unsaturated phosphate and phosphonate the cyclized products formed predominately.     

Membrane‐permeable Triphosphate Prodrugs of Nucleoside Analogues

The metabolic conversion of nucleoside analogues into their triphosphates often proceeds insufficiently. Rate‐limitations can be at the mono‐, but also at the di‐ and triphosphorylation steps. We developed a nucleoside triphosphate (NTP) delivery system (TriPPPro‐approach). In this approach, NTPs are masked by two bioreversible units at the γ‐phosphate. Using a procedure involving H‐phosphonate chemistry, a series of derivatives bearing approved, as well as potentially antivirally active, nucleoside analogues was synthesized. The enzyme‐triggered delivery of NTPs was demonstrated by pig liver esterase, in human T‐lymphocyte cell extracts and by a polymerase chain reaction using a prodrug of thymidine triphosphate. The TriPPPro‐compounds of some HIV‐inactive nucleoside analogues showed marked anti‐HIV activity. For cellular uptake studies, a fluorescent TriPPPro‐compound was prepared that delivered the triphosphorylated metabolite to intact CEM cells.     

Bifunctionalized allenes. Part XXI. Electrophilic cyclization and addition reactions of 3-(α- or β-hydroxyalkyl)-allenylphosphonates and allenyl phosphine oxides

Abstract

The present paper discusses the electrophilic cyclization and addition reactions of 3-(α- or β-hydroxyalkyl)-allenylphosphonates and phosphine oxides. Treatment of 3-(α- or β-hydroxy-alkyl)-allenylphosphonates with electrophiles takes place with 5-endo-trig cyclization and gives 2-methoxy-2,5-dihydro-1,2-oxaphosphole 2-oxides as a result of the neighboring phosphonate group participation in the electrophilic cyclization. On the other hand, 3-(α- or β-hydroxyalkyl)-alk-(1E)-en-1-yl phosphine oxides were prepared by chemo-, regio-, and stereoselective electrophilic addition to the C²-C³-double bond in the 3-(α- or β-hydroxyalkyl)-alka-1,2-dienyl phosphine oxides and subsequent attack of the external nucleophile (halide anion). The paper proposes a possible mechanism that involves electrophilic cyclization and addition reactions of the phosphorylated (α- or β-hydroxyalkyl)allenes.     

Nano silver particles catalyzed synthesis,molecular docking and bioactivity of α-thiazolyl aminomethylene bisphosphonates

Abstract

A new series of α-thiazolyl aminomethylene bisphosphonates were synthesized by a three component reaction of 4-aryl substituted thiazol-2-amine with different dialkyl/aryl phosphites and triethyl orthoformate in the presence of Ag NPs (nano particles) as a catalyst under solvent free conditions. All the synthesized target compounds were characterized by ¹H, ¹³C, ³¹P, mass and elemental analysis. The target compounds were screened for their in vitro antioxidant, antibacterial and antifungal activity. Molecular docking studies were also performed. The results revealed that among the synthesized compounds tetramethyl(((4-(4-methoxyphenyl)thiazol-2-yl)amino) methylene)bis(phosphonate) (5d), tetramethyl(((4-(4-fluorophenyl)thiazol-2-yl)amino) methylene) bis(phosphonate) (5h), and tetramethyl(((4-(4-bromophenyl)thiazol-2-yl)amino)methylene) bis (phosphonate) (5j) showed remarkably higher antioxidant activity by DPPH and H₂O₂ than the standard ascorbic acid. Compounds tetramethyl(((4-phenyl thiazol-2-yl)amino) methylene) bis(phosphonate) (5a), 5d, 5h and tetraethyl(((4-(4-bromophenyl)thiazol-2-yl) amino)methylene)bis (phosphonate) (5k) showed good antibacterial activity. 5a, 5d, and 5h also showed rather higher antifungal activity than the standard flucanozole. Computational docking methods have been used to predict how several aminomethylene bisphosphonate derivatives compete against the inhibitor BPH-1330 at the crystal enzyme structure of the 4H3A protein active site and how R and R₁ influence their binding ability.     

Efficient Syntheses of 1H-Isochromen-1-Ylmethylphosphonates via Regioselective 6-Endo-Dig Addition to Carbon—Carbon Triple Bond Catalyzed by Pd(OAc)2

Abstract

An efficient, regioselective, palladium-catalyzed intramolecular cycloisomerization of dialkyl [(2-(2-ethynyl)phenyl)(2-hydroxyl)ethyl]phosphonate 6 is reported. The reactions proceed through a 6-endo-dig cyclization to afford 1H-isochromen-1-ylmethylphosphonates 7 in good to excellent yields using palladium(II) acetate as the catalyst in tetrahydrofuran at room temperature.

[Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements for the following free supplemental resource: General Comments. Figures S1–S33.]

GRAPHICAL ABSTRACT      

Glycosylphosphonates of 2-Amino-2-deoxy-aldoses. Synthesis of a Phosphonate Analogue of Lipid X

A preparation of glycosylphosphonates ( 27 , 28 , 36 , 38 , and 39 ) from 2-azido-2-deoxy-glycoses ( 26 , 35 , and 37 ) and the synthesis of the non-isosteric phosphonate analogue 3a of lipid X( 2 ) are described. The 2-azido group was introduced by azidonitration. Treatment of the 1-O-acetyl-2-azido-2-deoxy-β-D-galactopyranose 22 with 1.5-3 equiv. of P(OMe)₃ and 1.2-2.5 equiv. of TfOSiMe₃ gave mainly recovered starting material. In P(OMe)₃ as the solvent, the dimethyl phosphoramidate 24 was obtained by way of a Staudinger reaction, even in the presence of TfOSiMe₃. Treatment of the benzylated α-D-galacto-trichloroacetimidate 26 , however, with P(OMe)₃ and TfOSiMe₃ gave a 1:1 mixture of the α- and β-D-galacto-phosphonates 27 and 28 , while the acetylated α-D-gluco- imidate 35 led to the α-D-gluco-configurated phosphonate 36 . The stereoselectivity of the phosphonate formation is related to the relative ease of formation of oxonium-ion intermediates from 26 and 35 . Starting from the phosphonate 36 , deacetylation, benzylidenation, reduction of the azido group, acylation with (R)-3-(benzyloxy)tetradecanoic acid and deprotection yielded the desired compound 3a which was crystallized in the presence of 2 equiv. of (aminomethylidyne)trimethanol (Tris.). The structure of the phosphonates was deduced from their ¹H-, ¹³C-, and ³¹P-NMR spectra.     

Organophosphorus Chemistry,Part 37: Synthesis and Insecticidal Activities of Some Phosphonate Adducts Derived from 6-(Aryliminomethyl)-furobenzopyran-5-ones

Dialkyl phosphites attack 6-(Aryliminomethyl)furobenzopyran-5-ones at the imine-carbon atom to give new phosphonate 1:1 adducts. The obtained compounds regenerate the starting materials upon thermolysis under reduced pressure. Structures of the new products were attested by compatible analytical and spectroscopic measurements. Insecticidal activity tests assured that some new compounds show marked potency against adults of Aphis gossypii (Glover), which infests cotton crops.

Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.     

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 of tetradialdose phosphonate nucleosides as mimics of l-nucleotides

Structurally modified nucleoside analogues are a major source of therapeutic agents and building blocks for incorporation into synthetic oligonucleotides able to interfere with information transfer or other biological functions. This work describes the synthesis of non-natural l-nucleoside phosphonate mimics containing two anomeric centers. Such compounds feature either a di- or monohydroxy tetradialdose sugar as the glycone unit, while adenine is present as nucleobase. By judicious use of protecting groups at the 2- and 3-position of commercial 1-O-acetyl-2,3,5-tri-O-benzoyl-β-d-ribofuranose, both the phosphonate and nucleobase moieties were stereoselectively introduced to provide a dihydroxylated compound with cis-configured substituents as the sole reaction product. Subsequent selective deprotection and deoxygenation at the 3′-position occurred smoothly to afford the corresponding 4′-monohydroxy tetradialdose containing analogue.     

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 OF 2′-DEOXY-2′-FLUORO- 1-β-d-ARABINOFURANOSYL URACIL DERIVATIVES: A METHOD SUITABLE FOR PREPARATION OF [18F]-LABELED NUCLEOSIDES

ABSTRACT

N-glycosylation of 2,4-bis-O-(trimethylsilyl)-pyrimidine bases with 2-deoxy-2-fluoro-3,5-di-O-benzoyl-1-(Br, OBz)-α-d-arabinose derivatives are reported. 1-Bromo-arabinose provides high yield and a favorable anomeric ratio (β/α) of pyrimidine nucleoside in either MeCN or CH₂Cl?CH₂Cl. This method should be suitable for the synthesis of 2′-deoxy-2′-[¹⁸F]fluoro-1-β-d-arabinofuranosyluracil derivatives.     

Novel Synthesis and Structures of Amines and Triazole-Derived Glycoside and Nucleoside Derivatives of Phosphanyl Sugar Analogs

ABSTRACT

3-Methyl-1-phenyl-2-phospholene and 1-phenyl-2-phospholene 1-oxides were converted into 2-bromo-3-hydroxy-3-methyl-1-phenylphospholane and 2-bromo-3-hydroxy-1-phenylphospholane 1-oxide (1-bromo-1,3,4-trideoxy-1,4-C-[(R, S)-phenylphosphinylidene]-glycero-tetrofuranose) by the action of bromine in aqueous medium. The bromo substituent of the phospholane was substituted by treatment with amines or an azide anion to afford novel glycoside derivatives of phosphanyl sugar analogs such as 2-amino-3-hydroxy-1-phenylphospholane (3,4-dideoxy-1,4-C-[(R, S)-phenylphosphinylidene]-glycero-tetrofuranosylamine) and 2-azido-3-hydroxy-3-methyl-1-phenylphospholane 1-oxides with retention of the configuration. The 1,3-dipolar cycloaddition of the 2-azido derivative of the phospholane with alkynes gave 3-hydroxy-3-methyl-1-phenyl-2-(triazol-1′-y1)phospholane 1-oxides as a novel triazole-derived nucleoside of phosphanyl sugar analogs. The structure of the glycoside and nucleoside derivatives of the phosphanyl sugar analogs prepared was deterimined from IR, NMR, and X-ray crystallography analysis.     

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.     

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.     

Asymmetric Synthesis of Aziridinyl Phosphonates Using Darzens-Type Reaction of Chloromethyl Phosphonate to Chiral Sulfinimines

Darzens-type reaction of chloromethyl phosphonate with (S)-(+)-N-sulfinimines gave (Ss, 2S, 3R)-diethyl 3-aryl-2-N-(p-toluenesulfinyl)aziridinyl-phosphonate (3) in good yields.     

Studies on Bis(5′-Adenosyl)-P1, P4-Tetraphosphate,Appppa, and Some Synthetic Isosteric and Isopolar Phosphonate Analogues Using the Specific Appppaases from Artemia and Lupin

Abstract

We have recently reported the synthesis and separation of three diastereoisomers of diadenosine 5′, 5″-P¹,P⁴-(P¹, P⁴-dithiO-P², P³-methylene)-tetraphosphate, (Ap₅pCH₂pp₅A), and demonstrated their resistance to hydrolysis by and competitive inhibition of the asymmetrica1 NppppNase from Artemia (1), while Guranowski et al.(2) have studied the ability of four phosphonate analogues of AppppA to act as substrates and inhibitors of the lupin and E. coli NppppNases, lupin phosphodiesterase I, and the yeast AppppA phosphorylase.     

ETUDE STRUCTURALE DU(N,N-DIMETHYLAMINOCARBONYL-l-METHOXYCARBONYL-2-ETHENYL(Z))-2-OXO-2-TETRAMETHYL- 4,4,5,5-DIOXAPHOSPHOLANE-1,3,2. PHENOMENE DE PREFIGURATION A L'ETAT SOLIDE D'UN INTERMEDIAIRE REACTIONNEL PENTACOORDINE

Abstract

Phosphonate 2 is obtained by hydrolysis of the spirophosphorane 1. IR. ¹H and ³¹P NMR spectra confirm the phosphonate structure. However, one question remains about the relative position of the amide group and ester function relative to the phosphonate group. We resolved this difficulty through X-ray crystallography of 2.

Phosphonate 2 structure shows a slightly distorted figure of the spirophosphorane 1 of which it comes from. This observation is quite astonishing because of the many possible carbonyl positions of the new ester function. We can reasonably rationalize this phenomenon as the prefiguration of a pentacoordinated chemical intermediate which permits to explain easily the opposite reaction for the P_IV → P_v way. So, phosphonate 2 structure is in between two pentacoordinate structures.