Cyclic Phosphonate Research Articles

ChemInform Abstract: Synthesis of Cycloheptenyldiphenylphosphine Oxides from the Reactions of a Cyclic Phosphonium Salt with α,β-Unsaturated Carbonyl Compounds.

The reactions of the ylide from the five-membered cyclic phosphonium salt 1 with methyl vinyl ketone, chalcone, and benzylidene acetone afforded cycloheptenyldiphenylphosphine oxides via a Michael-type reaction followed by an intramolecular Wittig reaction.

Synthesis of Ester Prodrugs of 9-(S)-[3-Hydroxy-2-(phosphonomethoxy)propyl]-2,6-diaminopurine (HPMPDAP) as Anti-Poxvirus Agents

9-(S)-[3-Hydroxy-2-(phosphonomethoxy)propyl]-2,6-diaminopurine (HPMPDAP) and its cyclic form were selected for further evaluation as potential drug candidates against poxvirus infections. To increase bioavailability of these compounds, synthesis of their structurally diverse ester prodrugs was carried out: alkoxyalkyl (hexadecyloxypropyl, octadecyloxyethyl, hexadecyloxyethyl), pivaloyloxymethyl (POM), 2,2,2-trifluoroethyl, butylsalicylyl, and prodrugs based on peptidomimetics. Most HPMPDAP prodrugs were synthesized in the form of monoesters as well as the corresponding cyclic phosphonate esters. The activity was evaluated not only against vaccinia virus but also against different herpes viruses. The most potent and active prodrugs against vaccinia virus were the alkoxyalkyl ester derivatives of HPMPDAP, with 50% effective concentrations 400-600-fold lower than those of the parent compound. Prodrugs based on peptidomimetics, the 2,2,2-trifluoroethyl, the POM, and the butylsalicylyl derivatives, were able to inhibit vaccinia virus replication at 50% effective concentrations that were equivalent or ∼10-fold lower than those observed for the parent compounds.

ChemInform Abstract: Reaction of Epoxides with Metaphosphoric Acid Derivatives.

Ethyl metaphosphate (EtOPO 2 ), eliminated in the thermolysis of the bridged cyclic phosphonate endo-3-ethoxy-6-methyl-N-phenyl-2,3-oxaphosphabicyclo [2.2.2] oct-5-ene-8,9-dicarboximide 3-oxide, has been found to cause ring opening of epoxides, resulting in formation of 2 -ethoxy-4-substituted 1,3,2-dioxaphospholane 2-oxides as major products. N,N-Diethyl metaphosphoramidate (Et 2 NPO 2 ) reacted similarly. With ethyl metathiophosphate (EtOP(S)O), the 1,3,2-oxathiaphospholane 2-oxide ring was formed. Products of these reactions were characterized by 31 P NMR spectroscopy and by GC-MS

ChemInform Abstract: Kinetics and Mechanism of the Hydrolysis of a (5,6)-Spirophosphorane. Thermodynamics of the Hydrolysis of Cyclic Five-Membered and Six- Membered Phosphonium Ions.

The cyclic five-membered phosphonium ion 2b (2-(2′-hydroxyethoxy)-2-phenyl-1,3,2-dioxaphospholan-2-ylium) derived from ring-opening of the (5,5)-spirophosphorane 1b (5-phenyl-1,4,6,9-tetraoxa-5-pho...

ChemInform Abstract: Heats of Reaction of Cyclic and Acyclic Phosphate and Phosphonate Esters. “Strain Discrepancy” and Steric Retardation.

The millionfold enhancement of the rate of hydrolysis of five-membered cyclic phosphate esters compared to their acyclic analogues is purely enthalpic and arises at least partially from destabilization of the four-coordinate cyclic reactant compared to the acyclic analogue, assuming that both react with hydroxide through unstrained five-coordinate transition states. Calorimetric analysis of the hydrolysis of cyclic and acyclic phosphates and phosphonates is reported in which the absolute value of the difference in enthalpy of hydrolysis of the cyclic and acyclic species is considerably less than the difference in activation enthalpies (about 2 kcal/mol discrepancy)

ChemInform Abstract: Reaction of a Cyclic Phosphonium Ylide with α,β-Unsaturated Thioesters.

The tandem Michael−intramolecular Wittig reactions of a five-membered cyclic phosphonium ylide (2) with α,β-unsaturated thioesters afforded cycloheptene derivatives 4a−g in 29−58% yield. The reaction proceeded via a rigid phosphabicyclic intermediate and supplied the cycloheptene derivatives with high stereoselectivity. On the other hand, although the reaction using S-cyclohexyl cyclopentenethiocarboxylate 5a as a substrate gave a 1:1 mixture of cis and trans adducts of the corresponding hydroazulene derivatives, the reaction of S-tert-butyl cyclopentenethiocarboxylate 5b gave cis-adduct as a major product (cis:trans =17:3).

ChemInform Abstract: Palladium-Catalyzed Acetoxylation of Cyclic Allyl Phosphonates in the Presence of Isopentyl Nitrite and Using Molecular Oxygen as Final Oxidant.

Abstract The palladium-catalyzed acetoxylation of cyclic dialkyl allyl phosphonates is effected using palladium chloride as catalyst, in the presence of isopentyl nitrite in acetic acid under an oxygen atmosphere. The proposed mechanism for the reaction involves a palladium nitro–nitroso redox couple.

ChemInform Abstract: Synthesis of Glycophostones: Cyclic Phosphonate Analogues of Biologically Relevant Sugars.

Analogues of l-fucose, N-acetyl-d-glucosamine, N-acetyl-d-mannosamine, and N-acetyl neuraminic acid in which the anomeric carbon atom was replaced by a phosphonyl group (phostones or cyclic phosphonates) were synthesized by stereocontrolled methods relying on the Abramov reaction.

New cyclic phosphonium salts derived from the reaction of phosphine-aldehydes with acid

Various cyclic phosphonium structures are formed in high yield by the deprotection of unstable phosphine-aldehydes in acidic solution. When there is a methylene spacer between the phosphine and the aldehyde, a phosphonium ion [PHR 2CH 2CH(OEt) 2]Br 2, R=iPrOH, Et is obtained. Reaction of these phosphonium salts with water produces the dimers [–PR 2CH 2CH(OH)–] 2[Br] 2 R = iPr, Et. When there is an ethylene spacer as in PPh 2CH 2CH 2CH(OCH 2CH 2O), a remarkable tetramer with a 16-membered ring [–PPh 2CH 2CH 2CH (OH)–] 4[Cl] 4 forms as one diastereomer in hydrochloric acid solution. Reaction of HCl with the protected phosphine-aldehyde with a propylene spacer (PPh 2CH 2CH 2CH 2CH(OCH 2CH 2O)) results in the formation of the monomeric phosphonium salt [–PPh 2 CH 2CH 2CH 2CH(OH)–]Cl with a 5-membered ring. Solid state structures of different ring types were determined using X-ray diffraction experiment.

C-1 Antiviral activity of acyclic and cyclic nucleoside phosphonates

C-1 Antiviral activity of acyclic and cyclic nucleoside phosphonates

Phosphonate analogues of cyclopropavir phosphates and their E-isomers. Synthesis and antiviral activity

Z- and E-Phosphonate analogues 12 and 13 derived from cyclopropavir and the corresponding cyclic phosphonates 14 and 15 were synthesized and their antiviral activity was investigated. The 2,2-bis(hydroxymethylmethylenecyclopropane acetate ( 17) was transformed to tetrahydropyranyl acetate 18. Deacetylation gave intermediate 19 which was converted to bromide 20. Alkylation with diisopropyl methylphosphonate afforded after protecting group exchange ( 21 to 22) acetylated phosphonate intermediate 22. Addition of bromine gave the dibromo derivative 16 which was used in the alkylation–elimination procedure with 2-amino-6-chloropurine to give Z- and E-isomers 23 and 24. Hydrolytic dechlorination coupled with removal of all protecting groups gave the guanine phosphonates 12 and 13. Cyclization afforded the cyclic phosphonates 14 and 15. Z-Phosphonate 12 was a potent and non-cytotoxic inhibitor of human and murine cytomegalovirus (HCMV and MCMV) with EC 50 2.2–2.7 and 0.13 μM, respectively. It was also an effective agent against Epstein-Barr virus (EBV, EC 50 3.1 μM). The cyclic phosphonate 14 inhibited HCMV (EC 50 2.4–11.5 μM) and MCMV (EC 50 0.4 μM) but it was ineffective against EBV. Both phosphonates 12 and 14 were as active against two HCMV Towne strains with mutations in UL97 as they were against wild-type HCMV thereby circumventing resistance due to such mutations. Z-Phosphonate 12 was a moderate inhibitor of replication of herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) but it was a potent agent against varicella zoster virus (VZV, EC 50 2.9 μM). The cyclic phosphonate 14 lacked significant potency against these viruses. E-isomers 13 and 15 were devoid of antiviral activity.

Microsynthesis and mass spectral study of Chemical Weapons Convention related 2‐alkyl‐1,3,6,2‐dioxathiaphosphocane‐2‐oxides

AbstractChemical Weapons Convention (CWC)‐related compounds where the phosphorus atom is part of a ring have very limited representation in mass spectral libraries and the open literature. Here we report electron ionization (EI), chemical ionization (CI) and electrospray ionization tandem mass spectrometry (ESI‐MSn) spectra and retention indices for 2‐alkyl‐1,3,6,2‐dioxathiaphosphocane‐2‐oxides (alkyl C1 to C3) which are new cyclic chemicals covered under the CWC. The EI mass spectra show a pattern of ion fragmentation that is similar to that of other cyclic phosphonates in that loss of the alkylphosphonic acid as a neutral loss is more important than the presence of the protonated alkylphosphonic acid. In contrast to other cyclic phosphonates, the 2‐alkyl‐1,3,6,2‐dioxathiaphosphocane‐2‐oxides show almost no protonated alkylphosphonic acid and as a result the spectra do not carry the same distinctive signature of the phosphorus–carbon bond that is required for the chemical to be covered under the CWC. Copyright © 2008 John Wiley & Sons, Ltd.

Platinum(II) complexes of 2-alkoxy-dibenzo[c.e][1,2]oxaphosphorines

2-Alkoxy-dibenzo[c.e][1,2]oxaphosphorines were prepared by the reaction of chloro-dibenzooxaphosphorine with alcohols and were converted to the cyclic phosphonates by oxidation and to the corresponding phosphonous boranes by reaction with borane-dimethylsulfide. Interaction of the alkoxy-dibenzooxaphosphorines with dichlorodibenzonitrileplatinum led to bis(dibenzooxaphosphorino)dichloroplatinum complexes exhibiting the P-ligands in the cis disposition. Relative energetics for the prepared cis and the theoretically possible trans isomers of the complexes along with their stereostructures were investigated by quantum chemical calculations.

Synthesis and conformational study of P‐heterocyclic androst‐5‐ene derivatives

AbstractThe reactions of (20R)‐3β‐acetoxy‐21‐hydroxymethylpregn‐5‐en‐20‐ol (2) and (20R)‐3β‐acetoxypregn‐5‐ene‐20,21‐diol (11) with phenylphosphonic dichloride 3 and aryl dichlorophosphates 4–6 afforded novel types of P‐heterocyclic androst‐5‐ene derivatives 7–10 and 12 as epimeric pairs. The diastereomers were separated by column chromatography and were characterized by NMR spectroscopy. Estimation of the stereostructures of the corresponding epimers by B3LYP/631G(d) DFT ab initio calculations suggested that the six‐membered hetero ring in compounds 7b and 8a–10a adopts predominantly a chair conformation, with the P‐substituents in their preferred orientation. The cyclic phosphonate moiety in 7a or 8b–10b, however, seems to exist as an equilibrium mixture of chair–distorted‐boat or chair–chair forms. The theoretical calculations indicate that the conformational equilibrium is shifted toward the distorted‐boat conformer for 7a, with a pseudoequatorial P‐phenyl substituent, whereas for 8b–10b the chair conformer with an equatorial P‐phenoxy group predominates. © 2008 Wiley Periodicals, Inc. Heteroatom Chem 19:7–14, 2008; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20372

The Potential for Volatile Phosphorus-containing Flame Retardants in Textile Back-coatings

A number of volatile phosphorus-containing flame retardant species has been identified as possible replacements for bromine-containing formulations used in textile back-coatings because of the need for vapor-phase activity. The selected retardants include tributyl phosphate (TBP), a monomeric cyclic phosphonate Antiblaze CU (Rhodia Specialites) and the oligomeric phosphate-phosphonate Fyrol 51 (Akzo). When combined with an intumescent char-forming pentaerythritol derivative (NH1197, Chemtura) and applied as a back-coating on to cotton and polypropylene substrates, significant improvements in overall flame retardancy are observed. One sample applied to cotton and comprising both TBP and intumescent passed the simulated match-ignition test, BS5852:1979:Part1 after a water soak at 40°C for 30 min. Determination of residual phosphorus within chars shows that there is significant volatile activity present in these formulations. Addition of volatile nitrogen as melamine also demonstrated improved flame retardancy in similar formulations.

Ester Prodrugs of Cyclic 1-(S)- [3-Hydroxy-2-(phosphonomethoxy)propyl]-5-azacytosine: Synthesis and Antiviral Activity

Reaction of 1-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-azacytosine (1) with dicyclohexylcarbodiimide and N,N,-dicyclohexyl-4-morpholinocarboxamidine in dimethylformamide at elevated temperature afforded the corresponding cyclic phosphonate 2, that is, 1-{[(5S)-2-hydroxy-2-oxido-1,4,2-dioxaphosphinan-5-yl]methyl}-5-azacytosine. Compound 2 exerts strong in vitro activity against DNA viruses, comparable with activity of parent compound 1. Transformation of 2 to its tetrabutylammonium salt followed by reaction with alkyl or acyloxyalkyl halogenides enabled us to prepare a series of structurally diverse ester prodrugs: alkyl (octadecyl), alkenyl (erucyl), alkoxyalkyl (hexadecyloxyethyl), and acyloxyalkyl (pivaloyloxymethyl) (3-6). The introduction of an alkyl, alkoxyalkyl, or acyloxyalkyl ester group to the molecule resulted in an increase of antiviral activity; the most active compound was found to be the hexadecyloxyethyl ester 5. The relative configuration of the diastereoisomer trans-6 was determined using H,H-NOESY NMR.

Synthesis and Structure of O,O‐Diethyl N‐[(trans‐4‐Aryl‐5,5‐dimethyl‐2‐oxido‐2λ5‐1,3,2‐dioxaphosphorinan‐2‐yl)methyl]phosphoramidothioates

AbstractA study on the synthesis of the novel N‐(cyclic phosphonate)‐substituted phosphoramidothioates, i.e., O,O‐diethyl N‐[(trans‐4‐aryl‐5,5‐dimethyl‐2‐oxido‐2λ5‐1,3,2‐dioxaphosphorinan‐2‐yl)methyl]phosphoramidothioates 4a–l, from O,O‐diethyl phosphoramidothioate (1), a benzaldehyde or ketone 2, and a 1,3,2‐dioxaphosphorinane 2‐oxide 3 was carried out (Scheme 1 and Table 1). Some of their stereoisomers were isolated, and their structure was established. The presence of acetyl chloride was essential for this reaction and accelerated the process of intramolecular dehydration of intermediate 5 forming the corresponding Schiff base 7 (Scheme 2).

A Convenient Approach to λ5‐Phosphinines via Interaction of Phosphorylated 3‐Pyrrolidinocrotonitrile with 2‐Bromoacetophenones.

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Formation of Cyclic Phosphonium Salts in Trichlorosilane Reduction of Phosphine Oxides Bearing a Pendant Hydroxyl Group and Their Hydrolysis to Cyclic Phosphine Oxides

An unusual ring closure to cyclic phosphonium salts was observed during trichlorosilane reduction of phosphine oxides with a pendant hydroxylmethyl group. Alkaline hydrolysis of the cyclic phosphonium salts afforded a cyclic phosphine oxide and a ring-fission product.

A convenient approach to λ 5-phosphinines via interaction of phosphorylated 3-pyrrolidinocrotonitrile with 2-bromoacetophenones

The alkylation of 2-(diphenylphosphino)-3-pyrrolidin-1-ylbut-2-enenitrile with a set of bromoacetophenones has been studied. Cyclization of the phosphonium salts into 6-cyano-3-hydroxy-3-aryl-1,1-diphenyl-5-pyrrolidin-1-yl-1,2,3,4-tetrahydrophosphininium bromides under heating in the presence of catalytic amount of a base is discussed. Starting both from the acyclic and the cyclic phosphonium salts, new types of λ 5-phosphinines have been synthesized.