Acidic Phosphorus Esters,Synthesis and Structure-Reactivity Studies as Ligands

Abstract

Methods for the synthesis of five types of acidic phosphates, phosphonates as well as phosphinates have been described. The mechanism of extraction of various metals by these compounds is examined. A free energy relationship existed in plotting equilibrium constants against either pKa or ?σ values of the acidic organophosphorus compounds under investigation. Steric effects, which is closely related to the configuration of the coordination compounds play an important role in these extraction systems as expected. A trial on estimation of Es values in extraction reaction was proposed.     

Base-promoted O-deprotonation/alkylation reaction of P(O)–OH compounds with alkyl halides

A novel base-promoted O-deprotonation/alkylation reaction of P(O)–OH compounds with alkyl halides has been developed. The protocol is practical, representing a simple way to produce a broad spectrum of functionalized phosphinates, phosphonates, and phosphates from basic starting materials with good to excellent yields. A plausible mechanism was proposed for this reaction.     

CDI-promoted direct esterification of P(O)-OH compounds with phenols

A novel and efficient N,N′-carbonyl diimidazole-catalyzed protocol for the direct esterification of P(O)-OH compounds using phenols as efficient esterification reagents is illustrated. It is a simple way to synthesis a broad spectrum of functionalized O-aryl phosphinates, phosphonates, and phosphates from basic starting materials with moderate to excellent yields.     

Lipase-promoted kinetic resolution of racemic,P-chiral hydroxymethylphosphonates and phosphinates

Lipase-mediated acetylation of racemic P-chiral hydroxymethylphosphonates and phosphinates, and hydrolysis of their O-acetyl derivatives have been conducted under kinetic resolution conditions to give the enantiomerically enriched title products with up to 92% ee. Their absolute configuration has been determined by means of chemical correlation and CD measurements.     

Benzyl Mono-P-Fluorophosphonate and Benzyl Penta-P-Fluorophosphate Anions Are Physiologically Stable Phosphotyrosine Mimetics and Inhibitors of Protein Tyrosine Phosphatases

α,α-Difluoro-benzyl phosphonates are currently the most popular class of phosphotyrosine mimetics. Structurally derived from the natural substrate phosphotyrosine, they constitute classical bioisosteres and have enabled the development of potent inhibitors of protein tyrosine phosphatases (PTP) and phosphotyrosine recognition sites such as SH2 domains. Being dianions bearing two negative charges, phosphonates, however, do not permeate membranes and thus are often inactive in cells and have not been a successful starting point toward therapeutics, yet. In this work, benzyl phosphonates were modified by replacing phosphorus-bound oxygen atoms with phosphorus-bound fluorine atoms. Surprisingly, mono-P-fluorophosphonates were fully stable under physiological conditions, thus enabling the investigation of their mode of action toward PTP. Three alternative scenarios were tested and mono-P-fluorophosphonates were identified as stable reversible PTP1B inhibitors, despite of the loss of one negative charge and the replacement of one oxygen atom as an H-bond donor by fluorine. In extending this replacement strategy, α,α-difluorobenzyl penta-P-fluorophosphates were synthesized and found to be novel phosphotyrosine mimetics with improved affinity to the phosphotyrosine binding site of PTP1B.     

Enzyme-mediated synthesis of EEHP and EMHP,useful pharmaceutical intermediates of PPAR agonists

A new scaleable synthetic route to the title compounds has been developed. The reaction pathway is based on the α-chymotrypsin-catalysed hydrolysis of the racemic ethyl 2-ethoxy-3-(p-methoxyphenyl)propanoate or of the racemic ethyl 2-methoxy-3-(p-methoxyphenyl)propanoate to give the corresponding resolved (S)-esters with excellent ee. The acids were easily separated from the (S)-esters by a simple acid–base work-up. The overall yields of 1 and 2 were 16% and 17%, respectively.     

1‐hydroxy‐1,1‐bis(H‐phosphinates): Synthesis,stability, and sorption properties

A synthesis of 1‐hydroxy‐1,1‐bis(H‐phosphinates) from acylchlorides is described. Solid‐state structures of two bis(phosphinates) determined by X‐ray diffraction showed variations in the P C distances. The compounds show negligible sorption on hydroxyapatite and an intermediate chemical stability in aqueous solution. The hydrolysis occurs in acidic as well as alkaline media. Hydrolysis rates of four derivatives show the lowest stability for aromatic derivatives as a result of the electron‐withdrawing effect. Main products of hydrolysis are 1‐hydroxy‐(H‐phosphinates) and phosphorous acid. © 2012 Wiley Periodicals, Inc. Heteroatom Chem 23:195–201, 2012; View this article online at wileyonlinelibrary.com . DOI 10.1002/hc.21003     

The synthesis of 1-hydroxy phosphonates of high enantiomeric excess using sequential asymmetric reactions: titanium alkoxide-catalyzed PC bond formation and kinetic resolution

Titanium alkoxide-catalyzed asymmetric phosphonylation of aldehydes yields hydroxy phosphonates in moderate to good enantiomeric excess (e.e.s ∼70%). The hydroxy phosphonates were acetylated and the acetates were subjected to enzyme-catalyzed kinetic resolution. The non-racemic acetates 2 (predominantly (R)-enantiomer) were hydrolyzed with an (R)-enantiomer-selective lipase, resulting predominantly in the hydrolysis of the (R)-isomer (at 85% conversion) to give the alcohols 3 with high e.e. Alternatively, hydrolysis of the minor enantiomeric (S)-acetate to approximately 20% conversion left the enriched (R)-configured acetate with improved e.e. (>90%). The moderate enantioselectivities obtained in the catalytic PC bond formation are enhanced during the enzymatic hydrolysis. Furthermore, availability of the non-racemic phosphonates permits the use of less selective enzymes, resulting in higher yields in comparison with the standard resolution of racemic materials.     

A Synthetic Study of Chiral α‐Hydroxy‐H‐Phosphinates Based on Proline Catalysis

A highly enantioselective synthesis of α‐hydroxyphosphinates was achieved based on the L ‐proline‐catalyzed aldol reaction of α‐acylphosphinates and acetone. Due to the preexisting chirality at the phosphorus center, mixtures of two diastereomers of the α‐hydroxyphosphinates were obtained in moderate to good yields, with simultaneously high enantioselectivity for both diastereomers. The products could be converted into α‐hydroxy‐H‐phosphinates with satisfactory yields. Furthermore, an unprecedented oxidation–reduction reaction of the α‐hydroxyphosphinates or α‐hydroxy‐H‐phosphinates to form phosphonates was observed, and the mechanism involved in such a chemical transformation is discussed.     

Microwave-assisted neat synthesis of α-aminophosphonate/phosphinate derivatives of 2-(2-aminophenyl)benzothiazole as potent antimicrobial and antioxidant agents

A series of diethyl/ethylphenyl {2-(benzo[d]thiazol-2-yl)phenylamino}phosphonates and phosphinates were synthesized under microwave irradiation and neat conditions via Kabachnik-Fields reaction in high yields (80%–93%). The compounds were screened for antimicrobial and antioxidant properties. A few compounds showed effective antibacterial and antifungal activities at MIC value 12.5 μg/mL as compared with the standard at MIC value 6.25 μg/mL.     

Enzymatic Resolution of Ethyl α-Hydroxyphosphinates in a Modified Reaction Environment

The enzymatic resolutions of two racemic ethyl hydroxyalkane(P-phenyl)phosphinates were performed by both esterification and hydrolysis approaches. The first reaction was performed in anhydrous diisopropyl ether with triethylamine or pyridine as additives by using lipases from three different sources (Candida cylindracea, Aspergillus niger, and Mucor javanicus). The increase in enantioselectivity was observed when NEt₃ was applied. The second reaction—lipase-catalysed hydrolysis of ethyl butyryloxyalkane(P-phenyl)phosphinates—was carried out by Candida cylindracea lipase in diisopropyl ether saturated with water or in aqueous solutions containing MgCl₂, LiCl, or Triton X-100. The usefulness of biphasic systems consisting of diisopropyl ether and water or aqueous solution of MgCl₂, LiCl, or Triton X-100 also were tested. The use of biphasic system in the presence of Triton X-100 resulted in the higher conversion of the substrates.     

有机磷化合物的研究 VIII. 酸性有机磷化合物的气相色谱

Acidic organophosphorus compounds may be identified by GLC via their methyl esters, usually prepared from diazomethane. The wide applications of this mthod are, however, limited by the toxicity of diazomethane. Tetramethyl ammonium hydroxide in methanol solution reacted rapidly with acidic organophosphorus compounds at room temperature to form tetramethyl ammonium salts, which were then converted to the corresponding methyl esters by pyrolysis at 300-350 deg.C. A simple and convenient method for separation and identification of various types of acidic phosphates, phosphonates and phosphinates by GLC has been developed. The GLC behaviours of phosphoric acid dialkyl esters, mono-esters of phenyl-and cyclohexyl-phosphonic acids as well as dialkylphosphinic acids can be represented by corrected retention time (t'R) which correlates linearly with the number of carbon atoms of the alkyl groups in these organophosphorus compounds. The influence of number of carbon atoms and isomerization of alkyl group on t'R values and retention index (I) calculated by Kovats equation was discussed. As shown by our experiments the change in retention index (ΔI) in the homologous series of phosphoric acid dialkyl esters is nearly a constant on lengthening the alkyl group of the esters with methylene linkages.     

Radical Addition of Bis(Trimethylsilyl)Phosphonate to Vinyltrimethylsilane: Crystal Structure of (2-Trimethylsilylethyl)Phosphonic Acid

Abstract

The formation of phosphorus-carbon bond by free radical addition of phosphorus compounds containing P-H bond to olefins has been known since more than three decades ago. Alkyl or aryl phosphins, phosphinates, phosphonates and phosphorus or hypophosphorus acid have been used in these reactions, but a little attention have been paid to silyl phosphonates. As a part of ongoing study on the structure and reactivity of organosilicon-phosphonate compounds, we synthesized bis(trimethylsi1yl) (2-trimethylsilylethyl)phosphonate (I) by the reaction of bis(trimethylsily1) phosphonate with vinyltrimethylsilane in the presence of a peroxide. The product was characterized by its ¹H and ³¹P NMR and IR spectra. Hydrolysis of (I) led to the formation of corresponding phosphonic acid (n). The crystal structure of (11) has been determined by X-ray diffraction analysis.     

Dialkylaminoethylation of Trimethylsilyl Esters of Trivalent Phosphorus Acids

Abstract

Dialkylaminomethylation of trimethylsilyl esters of trivalent phosphorus acids using bis(dialkylamino)methanes was carried out for the first time. This reaction is a convenient method for preparation of quaternary coordinated phosphorus compounds, including dialkylaminomethyl and functional groups. Thus trimethylsilylphosphites and -phosphonites of various structures react with bis(dialklamino)-methanes according to Arbuzov reaction in the presence of zinc chloride as a catalyst, when heated to 120°C, resulting in formation of phosphonates and phosphinates (I)     

The influence of varying reaction conditions on the coordination behavior of the phosphonoformate anion

Abstract

In medical and pharmaceutical science phosphonic acids and phosphonates play an important role with regard to their wide application in various drugs as medicines against osteoporosis or antiviral agents. In the course of the investigations on the coordination chemistry of biologically active phosphonates different salts of the phosphonoformate anion were prepared via hydrolysis of corresponding esters under basic conditions. Depending on the reaction and crystallization conditions, different sodium salts with the phosphonoformate moiety were obtained and structurally characterized.     

Preparation of enantiomerically pure α-hydroxyl phosphinates via hydrophosphorylation of aldehydes with H-phosphinate

The hydrophosphorylation of aldehydes with a P-stereogenic H-phosphinate was realized by heating two compounds in a neat state or catalyzed by a base, to afford P-retention α-hydroxyl phosphinates. The (S_P,S_C) and other diastereomers were isolated, and their structures were confirmed by NMR spectroscopy and crystallography.     

Acidic hydrolysis of N-acyl-1-substituted 3-amino-1,2-dicarba-closo-dodecaboranes

Acidic hydrolysis of N-acyl 1-methyl- and 1-phenyl-3-amino-1,2-dicarba-closo-dodecaboranes has been studied. It has been shown that acidic hydrolysis of diastereomeric amides of 1-methyl-3-amino-1,2-dicarba-closo-dodecaborane results in the partial racemization of the target 3-amino-1-methylcarborane. Under the similar conditions, the hydrolysis of N-acyl-3-amino-1-phenyl-1,2-dicarba-closo-dodecaboranes resulted in amide bond cleavage accompanied by simultaneous deboronation with the removal of boron atom at position 6 of carborane cage and formation of 7,8-dicarba-nido-undecaborane derivative according to ¹¹B and ¹H NMR spectroscopy.     

The kinetics of the alkaline hydrolysis of aryl diphenylphosphinothioates; the significance for the mechanism of displacement at phosphorus.

The rate of hydrolysis of aryl phosphinothioates, the most reactive phosphinates yet studied, correlates with Hammett's σ values suggesting that formation of a pentaccordinate intermediate is the rate-determining step.     

Enantioconvergent Reductive C(sp)−C(sp3) Cross-Coupling to Access Chiral α-Alkynyl Phosphonates Under Dual Nickel/Photoredox Catalysis

Transition-metal-catalyzed asymmetric carbon−carbon bond formation to forge phosphonates with an α-chiral carbon center through C(sp³)−C(sp³) and C(sp²)−C(sp³) couplings has been successful. However, the enantioselective C(sp)−C(sp³) coupling has not yet been disclosed. Reported herein is an unprecedented enantioconvergent cross-coupling of alkynyl bromides and α-bromo phosphonates to deliver chiral α-alkynyl phosphonates.