Phosphonothioic Acids Research Articles

Hydrolysis of Phosphonothioates with a Binaphthyl Group: P-Stereogenic O-Binaphthyl Phosphonothioic Acids and Their Use as Optically Active Ligands and Chiral Discriminating Agents.

The hydrolysis of phosphonothioates with a binaphthyl group afforded the first example of O-(2'-hydroxy)binaphthyl phosphonothioic acids in good to high yields and >95:5 diastereoselectivity. The reaction proceeds via an axis-to-center chirality-transfer reaction. The ability of these acids to act as chiral molecular auxiliaries was demonstrated by using them as optically active ligands for the asymmetric ethylation of benzaldehyde and as a chiral discriminating agent for chiral aliphatic amines.

Structural Analogues of Bioactive Phosphonic Acids: First Crystal Structure Characterization of Phosphonothioic and Boranophosphonic Acids

Phosphonothioic and boranophosphonic acids have been structurally characterized for the first time by single X-ray crystallography. These two functional groups, and the corresponding phosphonic acid, were all conveniently synthesized in high yields from trityl H-phosphinic acid (Ph3CPO2H2). The resulting trityl-substituted series: Ph3CP(O)(OH)2, Ph3CP(S)(OH)2, Ph3CP(O)(BH3 −)(OH)]LH+ (L = Lewis base) is fully characterized by spectroscopic methods, and the structural characteristics are compared. The results indicate that boranophosphonic acids should be investigated anytime a bioactive phosphonic acid has been identified. The solid state arrangements of the synthesized compounds are also discussed.

Nucleotides and nucleic acids: A source of inspiration for the development of new, phosphorus-centered functional groups

Synthetic methodologies aiming at the creation of new phosphorus-centered functional groups are reported, as well as applications to the field of nucleotide chemistry. Thus, difluorophosphonothioate-based, ionic reagents 3b and 3d are shown to allow the stereocontrolled and efficient synthesis of phosphonodifluoromethyl analogues of nucleoside-3'-phosphates. An alternate, radical approach describes the use of hypophosphorous acid to stereoselectively link two furanosyl units in positions 3 and 5, and to provide an access to alpha,alpha-difluoro-H-phosphinates. These intermediates are shown to be precursors to the corresponding fluorinated phosphonic acids, phosphonothioic acids and variously substituted phosphinates.

Determination of pentafluorobenzyl derivatives of phosphonic and phosphonothioic acids by gas chromatography–mass spectrometry

A method based on gas chromatography–mass spectrometry (GC/MS) has been evaluated and standardized for the analysis of pentafluorobenzyl (PFB) derivatives of alkylphosphonic, O-alkyl alkylphosphonic and phosphonothioic acids. The pentafluorobenzyl (PFB) derivatives are much more stable as compared to the conventionally used trimethylsilyl derivatives. The conditions for the derivatization and analysis have been optimized to achieve the best detection limits in negative chemical ionization (NCI) mode.

Analysis of Chemical Neutralization Products of Phosphonothiolates by Gas Chromatography Mass Spectrometry

A series of phosphonothiolates, including the highly toxic O-Ethyl-S-(2-diisopropylamino) ethyl methylphosphonothioate (VX), have been subjected to chemical neutralization reaction with metallic sodium. The phosphonothiolates decompose to their respective phosphonic and phosphonothioic acids and this results in the detoxification of VX. GC/MS technique in both EI and CI mode has been applied for reaction monitoring and final identification of the neutralization products formed in this reaction.

A Convenient Synthesis of Phosphonothioic Acids.

AbstractFor Abstract see ChemInform Abstract in Full Text.

A convenient synthesis of phosphonothioic acids

A method for the convenient synthesis of phosphonothioates, or phosphonothioic acids, is reported. A significant advantage of the method is the alleviation of the need for purification of intermediates, other than washing with water. No chromatography is needed and the only purification step is the crystallization of the final product. The method uses standard reagents and should be applicable to the synthesis of phosphonothioic acids bearing a range of functional groups.

A Facile Route to Substituted Dimethoxy Phosphonothionates Using Dimethyl Thiophosphite

Dimethyl thiophosphite reacts with aliphatic aldehydes and ketones, Michael acceptors, and N-benzyl imines to afford excellent yields of f -hydroxy phosphonothionates, g -substituted phosphonothionates and f -amino phosphonothionates, respectively. Dealkylation of f -amino phosphonothionates affords N-benzyl f -amino phosphonothioic acids. Dimethyl thiophosphite reacts with electrophiles at a significantly greater rate than dimethyl phosphite.

Synthesis of individual glutamate-containing phosphonamidothionate stereoisomers

The acquisition of the individual stereoisomers of chiral phosphonothioic acids is anticipated to reveal the significance of phosphorus stereochemistry upon the inhibition of metallocarboxypeptidases as well as their utility as chiral and stereoselective inhibitory probes. Two methods for preparing individual glutamate-containing phosphonamidothioic acid diastereomers have been identified. One method achieves the resolution through fractional crystallization of the intermediate 9-fluorenemethoxy phosphonamidates while the second does so through chromatographic resolution of intermediate β-(acylmercapto)ethyl phosphonamidothiolates.

Stereoselective inhibition of glutamate carboxypeptidase by chiral phosphonothioic acids

A series of phosphonothioic acid derivatives of (S)-2-hydroxyglutarate with various alkyl or aryl ligands to the central phosphorus atom was examined for stereoselective inhibition of the glutamate carboxypeptidase, carboxypeptidase G. The inhibitory potencies of these stereoisomers were compared to corresponding synthetic phosphonic acid analogues in order to reveal the significance of the sulfur ligand of the phosphonothioic acid motif upon the inhibition of this metallopeptidase. The acquisition of the individual phosphonothioic acid diastereomers was achieved through the resolution of the respective phosphonate ester precursors. In all cases, the (+)P-diastereomers of these phosphonothioic acid derivatives of (S)-2-hydroxyglutarate were found to be more potent inhibitors of glutamate carboxypeptidase than the corresponding (−)P antipodes with the most dramatic difference observed for the butyl isomers (13.6-fold). Based upon Ki values obtained, the most potent inhibitor of the series by nearly an order of magnitude was the (+)P-n-butylphosphonothioic acid derivative, revealing specific structural and stereochemical requirements by this glutamate carboxypeptidase. With the exception of the (+)P-n-butyl analogue, the isosteric replacement of oxygen with sulfur of the phosphonic acid moiety did not enhance inhibitory potency.

ChemInform Abstract: Easy and General Access to α,α‐Difluoromethylene Phosphonothioic Acids. A New Class of Compounds.

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Easy and general access to α,α-difluoromethylene phosphonothioic acids. A new class of compounds

The preparation of dibenzyl α,α-difluoromethylphosphonothioate 10 from the reaction between the corresponding phosphonate 9 and Lawesson's reagent is reported. Treatment of 10 with lithium di isopropylamide and a variety of electrophiles demonstrate the possibility of functionalizing it. Reductive debenzylation of the adducts affords the sodium salts of α,α-difluoromethylenephosphonothioates 22 which upon acidic treatment deliver the corresponding acids 4.

EVIDENCE FOR SELECTIVE S-ALKYLATION OF AN AMBIDENT ANION OF DICYCLOHEXYLAMMONIUM THIOPHOSPHONATE BY ALKYL HALIDES

Abstract Reaction of the DCHA salt of O-alkyl phenyl phosphonothioic acids 1a–c with alkyl halides 2a-d gave exclusively S-derivatives; 3e–h (85–93%) and 3b-d (40–43%). The cause for poor yields of the methyl analogues is its ability to participate in the methylation of salt 1a and give rise by-product O,S-dimethyl phenyl phosphonothiolate (3a). Awareness of the unusual pathway for the generation of the by-product has opened a new possibility to adopt this strategy for synthesis of enantiomerically pure thiolates.

Magnetic non-equivalence in organophosphorus esters

The 1H n.m.r. spectra of a number of esters of phosphoric, phosphonic, phosphorothioic, phosphonothioic, phosphorodithioic, and phosphonodithioic acids are reported. In certain cases the methylene protons of the ethoxygroups show non-equivalence and such spectra are analysed by full iterative calculations using the LAOCN 3 program. The effects of temperature and solvent changes on the non-equivalence are reported and the results are interpreted in terms of intrinsic non-equivalence (due to an asymmetric phosphorus atom) or unequal conformer populations or a combination of both factors.

Configuration of the optically active phosphorus thioacids—I : Chemical correlation of the configuration of O-alkyl alkyl-phosphonothioic acids

Chirality of the P atom in O-alkyl methylphosphonothioic acids, Me(RO)P(S)OH (RMe, Et, Pr n,Bu n), O-alkyl ethylphosphonothioic acids Et( acids Pr i(RO)P(S)OH (RMe,Et) was correlated with that of (+) R-O-isopropyl methylphosphonothioic acid, Me(Pr iO)P(S)OH. The chemical correlation was based on the synthesis of optically active O,O-dialkyl alkylphosphonothionates, R(RO)(R′O)P(S), from suitably substituted phosphonothioic acids via the corresponding O-alkyl alkylphosphonochloridothionates, R(RO)P(S)Cl. It has been shown that all the dextrorotatory O-alkyl alkylphosphonothioic acids have the R configuration. Additionally it has been demonstrated that alkaline hydrolysis occurs with inversion of configuration at the P atom connected with the isopropyl group.

The reaction of amidoesters of phosphonothioic and phosphorothious acids with carboxylic acid chlorides

The reaction of amidoesters of phosphonothioic and phosphorothious acids with carboxylic acid chlorides

Asymmetric reduction of sulphoxides with optically active phosphorus thioacids. Absolute configuration of O-ethyl ethylphosphonothioic acid

Partial reduction of racemic methyl alkyl sulphoxides with optically active phosphonothioic acids gives recovered sulphoxides that are optically active; the (R)-configuration is assigned to (–)-O-ethyl ethylphosphonothioic acid.