Phosphinic Esters Research Articles

Synthesis of dipeptide mimics based on amino phosphinate backbones and cyclic derivatives

Dialkyl phosphinates are valuable peptide mimics fo r metallopeptidase targets. Despite their large pharmaceutical potential, the synthesis of many pho sphinates remains challenging. An additional drawback for many applications is the high polarity of the phosphinate group. Herein we describe the synthesis of stereoisomerically pure GPI ( 1), a phosphinate with high binding affinity for the cancer specific zinc peptidase PSMA (prostate speci fic membrane antigen). In addition, analogous cyclic phosphinate esters 13 , 16 and 23 are reported that might be useful as less polar li gands for metallo peptidase binding. The key step to these ne w 1,2-oxaphosphorinan-2-ones is an intramolecular cyclization of an intermediate H-phosphinate. The cyclizations work with modest diastereoselectivities of ~2:1 in favor of the trans arrangement of substituents at 2- and 4-position of the 1,2-oxaphosphorinan-2-one scaffolds.

Directed Ortho-Lithiation of Aminophosphazenes: An Efficient Route to the Stereoselective Synthesis of P-Chiral Compounds

Ortho-directed lithiation of P,P-diphenylaminophosphazenes followed by electrophilic quench is described as an efficient process for synthesizing P-chiral ortho-functionalized derivatives in high yields and diastereoselectivities. The method allows the tunable preparation of structurally diverse enantiopure P-chiral compounds including phosphinic and phosphinothioic amides, phosphinic esters, phosphine oxides, and o-aminophosphines.

Exploring the binding mechanism of phosphoramidate derivative with DNA: Spectroscopy, calorimetry and modeling

In this study, one of the amino phosphine ester derivatives α-(3-hydroxy-4-methoxyphenyl)-N-phenyl-α-aminophosphonate (HMPAP) was synthesized, and the molecular interaction of HMPAP with ct-DNA has been investigated by UV–Vis absorption spectra, fluorescence spectra, isothermal titration calorimetry (ITC) and molecular modeling. The binding constant (Kb) of HMPAP to ct-DNA at different temperatures were calculated from fluorescence spectra. According to the UV–Vis absorption spectra, ethidium bromide displacement studies and ITC experimental results, we can conclude that HMPAP is an intercalator. The molecular modeling results indicated that HMPAP can slide into the G–C rich region of ct-DNA. ITC data showed that ct-DNA/HMPAP binding is enthalpy controlled. Furthermore, the results obtained from molecular modeling corroborated the experimental results obtanied from spectroscopic and ITC investigations.

New organized systems based on amphiphilic oxyethylated calix[4]arene

The aggregation of amphiphilic oxyethylated calix[4]arene is studied in the absence and presence of polyethyleneimine. At low calixarene concentrations, large ensembles with a hydrodynamic diameter of about 100 nm are formed and coexist with small (smaller than 10 nm) aggregates, which are observed in the entire concentration range. It is established that calixarene-based systems catalyze the neutral hydrolysis of bis(chloromethyl)phosphinic acid p-nitrophenyl ester, with the catalytic effect being as high as two orders of magnitude in the presence of La(III) ions. The rate of hydrolysis of phosphonates depends on the composition of the supramolecular system. The maximum acceleration exceeds three orders of magnitude in comparison with alkaline hydrolysis of the substrates.

Preparation of new imidazol-2-yl-(amino)methylphosphonates, phosphinates and phosphine oxides and their unexpected cleavage under acidic conditions

The efficient synthesis of new imidazol-2-yl-(amino)methylphosphonic acids, phosphonates phosphinate esters and phosphine oxides is described. The synthetic methodology is based on nucleophilic addition of phosphorus species to imidazole-2 derived imines. Additionally, it was discovered that heating the imidazol-2-yl-(amino)methylphosphonates with aqueous HCl or H 2SO 4 leads to their decomposition resulting in a rupture of the C–P bond, elimination of the phosphorous-containing fragment and formation of the corresponding secondary imidazole-2 alkylamines. A mechanistic pathway for the cleavage is postulated.

Highly Convergent Synthesis of Chiral Bicyclophosphinates by Domino Hydrophosphinylation/Michael/Michael Reaction

Diastereoselective domino reactions of iminoalcohols and allenyl H-phosphinates produce chiral phosphorus bicycles in a regio- and stereoselective fashion. A predictive model for diastereoselection is used for these new chiral phosphinic esters.

Study on the interaction of amino phosphine ester derivatives with DNA by spectroscopy, modeling and calorimetry

The binding properties of amino phosphate ester derivatives, compound 1 and 2 with calf thymus DNA (CT-DNA) were investigated by UV spectra, fluorescence spectra, molecular modeling and isothermal titration calorimetry (ITC). The intrinsic binding constants K b of compound 1 and 2 with CT-DNA were determined by fluorescence spectroscopy and ITC, respectively. The results indicated that the two compounds bind to CT-DNA with different binding affinity, which is in the order of compound 1 > compound 2. At the same time, fluorescence spectra suggested that the mechanism of the binding of the two compounds to CT-DNA is a static enhancing type. According to the ethidium bromide displacement experiments, UV spectra, molecular modeling and ITC studies, it can be concluded that compound 1 and 2 are intercalators that can slide into the G–C rich region of CT-DNA. Furthermore, ITC data showed that compound/DNA binding is enthalpy controlled.

Synthesis and Characterization of Novel Alkyl-Substituted Aryl Diphenylphosphinate Esters

In this work, the reactions of diphenylphosphinic chloride, (C6H5)2P(O)Cl, 1, with the sodium salts of sterically hindered phenol derivatives (2a-2j) were investigated. Novel alkyl-substituted aryl diphenyl phosphinate esters (C6H5)2P(O)OAr (3-12) were obtained from these reactions. Satisfactory analytical and spectroscopic results were obtained for all the new compounds. GRAPHICAL ABSTRACT

Palladium-Catalyzed Cross-Coupling of H-Phosphinate Esters with Chloroarenes

The palladium-catalyzed cross-coupling reaction between H-phosphinate esters and chloroarenes or chloroheteroarenes is described. This reaction is the first general metal-catalyzed phosphorus-carbon bond-forming reaction between a phosphorus nucleophile and chloroarenes.

Photooxidation of Mixed Aryl and Biarylphosphines

Arylphosphines and dialkylbiarylphosphines react with singlet oxygen to form phosphine oxides and phosphinate esters. For mixed arylphosphines, the most electron-rich aryl group migrates to form the phosphinate, while for dialkylbiarylphosphines migration of the alkyl group occurs. Dialkylbiarylphosphines also yield arene epoxides, especially in electron-rich systems. Phosphinate ester formation is increased at high temperature, while protic solvents increase the yield of epoxide. The product distribution provides evidence for Buchwald's recent conformational model for the aerobic oxidation of dialkylbiarylphosphines.

Novel Synthesis of Phosphinates by the Microwave-Assisted Esterification of Phosphinic Acids

1-Hydroxy-3-phospholene oxides (1 and 3) and phenyl-H-phosphinic acid (6) are converted to the corresponding phosphinic esters (2, 4, and 7, respectively) by reaction with simple alcohols on microwave irradiation. Under traditional heating conditions, the esterification does not take place, as in the cases of 1 and 3, or is highly incomplete, as in the case of 6. Steric hindrance in diphenylphosphinic acid prevents efficient microwave-assisted esterification.

Stereospecific Nucleophilic Substitution of Optically Pure H-Phosphinates: A General Way for the Preparation of Chiral P-Stereogenic Phosphine Oxides

Contrary to the generally held view, it is found that the rapid epimerization of (-)-menthyl (RP)-phenylphosphinate under basic conditions is not due to the so far believed inherent stereolability of its corresponding anion but due to a reaction of the hydrogen phosphinate ester with a metal alkoxide. This finding successfully leads to a discovery that, by adding an H-phosphinate to organolithiums or Grignard reagents at a low temperature, the nucleophilic substitution of the alkoxy group of the H-phosphinate with organolithiums or Grignard reagents proceeds stereospecifically with inversion of configurations at phosphorus to give a wide range of P-stereogenic secondary phosphine oxides and tertiary phosphine oxides, by quenching the reaction mixture with water and alkyl halides, respectively. This finding establishes a general protocol for the preparation of optically active secondary phosphine oxides and tertiary phosphine oxides from the easily accessible optically pure H-phosphinates. Mechanistic studies show that the substitution reactions of H-phosphinates with organolithiums and Grignard reagents proceed via two competing reaction paths, that is, a two-step reaction path involving first a deprotonation of H-phosphinates followed by a substitution of the corresponding anion with inversion of configuration at phosphorus and a direct substitution of RM with H-phosphinates generating the SPO directly.

Mild Synthesis of Organophosphorus Compounds: Reaction of Phosphorus-Containing Carbenoids with Organoboranes

Organoboranes react with phosphorus-containing carbenoids to produce a variety of functionalized organophosphorus compounds under mild conditions. In some cases, selective migration of one group attached to boron can be observed. Phosphonite-borane complexes are introduced as novel synthons for the synthesis of phosphinic esters.

Alkylation of H-phosphinate esters under basic conditions.

An efficient and general procedure was developed for the direct alkylation of H-phosphinate esters with LHMDS at low temperature. The simplicity of the reaction allows the use of various H-phosphinate esters and takes place with a wide range of electrophiles. The approach can be employed to access some GABA analogues or precursors to GABA analogues. The isolated yields are moderate to good. This is the first report of an alkylation with a secondary iodide or a primary chloride.

Resolution of Chiral Phosphate, Phosphonate, and Phosphinate Esters by an Enantioselective Enzyme Library

An array of 16 enantiomeric pairs of chiral phosphate, phosphonate, and phosphinate esters was used to establish the breadth of the stereoselective discrimination inherent within the bacterial phosphotriesterase and 15 mutant enzymes. For each substrate, the leaving group was 4-hydroxyacetophenone while the other two groups attached to the phosphorus core consisted of an asymmetric mixture of methyl, methoxy, ethyl, ethoxy, isopropoxy, phenyl, phenoxy, cyclohexyl, and cyclohexoxy substituents. For the wild-type enzyme, the relative rates of hydrolysis for the two enantiomers ranged from 3 to 5.4 x 10(5). Various combinations of site-specific mutations within the active site were used to create modified enzymes with alterations in their enantioselective properties. For the single-site mutant enzyme, G60A, the stereoselectivity is enhanced relative to that of the wild-type enzyme by 1-3 orders of magnitude. Additional mutants were obtained where the stereoselectivity is inverted relative to the wild-type enzyme for 13 of the 16 pairs of enantiomers tested for this investigation. The most dramatic example was obtained for the hydrolysis of 4-acetylphenyl methyl phenyl phosphate. The G60A mutant preferentially hydrolyzes the SP-enantiomer by a factor of 3.7 x 10(5). The I106G/F132G/H257Y mutant preferentially hydrolyzes the RP-enantiomer by a factor of 9.7 x 10(2). This represents an enantioselective discrimination of 3.6 x 10(8) between these two mutants, with a total of only four amino acid changes. The rate differential between the two enantiomers for any given mutant enzyme is postulated to be governed by the degree of nonproductive binding within the enzyme active site and stabilization of the transition state. This hypothesis is supported by computational docking of the high-energy, pentavalent form of the substrates to modeled structures of the mutant enzyme; the energies of the docked transition-state analogues qualitatively capture the enantiomeric preferences of the various mutants for the different substrates. These results demonstrate that the catalytic properties of the wild-type phosphotriesterase can be exploited for the kinetic resolution of a wide range of phosphate, phosphonate, and phosphinate esters and that the active site of this enzyme is remarkably amenable to structural perturbations via amino acid substitution.

Oxygen insertion in a carbon–phosphorus bond of the phenylethynyl-di-(tert-butyl)-phosphine bridged dicobalt complex: exploring the nature of oxygen migration using DFT

In the process of isolation under aerobic conditions phenylethynyl-di-(tert-butyl)-phosphine bridged dicobalt complex [(micro-PPh(2)CH(2)PPh(2))Co2(CO)4(micro,eta-PhC[triple bond]CP(t-Bu)2)] 4a underwent a partial oxidation. The identity of the oxidized product, [(micro-PPh(2)CH(2)PPh(2))Co2(CO)4(micro,eta-PhC[triple bond]C-O-P([double bond]O)(t-Bu)2)] 5, was established by spectroscopic means as well as the single-crystal X-ray diffraction method. This is the first crystallographic evidence that unambiguously supports the formation of an organometallic version of a phosphinate ester. The mechanism for the formation of 5 from 4a was proposed, and its validity was examined by DFT means. For the purpose of comparison, a similar mechanism illustrating the transformation of PhC[triple bond]CP(t-Bu)2 1O into PhC[triple bond]C-O-P([double bond]O)(t-Bu)2 5O, the organic counterpart of 5, was examined by the same method. It was found that the metal fragment is indeed capable of assisting the oxidation process by lowering the activation energy, although the effect is small. The impact of the presence of an electron-withdrawing substituent such as a fluorine atom in the alkynylphosphine was also investigated. Results demonstrated that the conversion of fluorine-substituted phosphines to the corresponding phosphinate esters can be achieved more readily. In addition, the energy barrier for the reaction of a phosphine with dioxygen yielding the phosphine oxide was calculated to be much lower than that on the way to the phosphinate ester.

Synthesis of α1‐(Cbz‐Aminoalkyl)‐α2‐ (hydroxyalkyl)phosphinic Esters.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Physical Organic Perspectives on Phospho Group Transfer from Phosphates and Phosphinates

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis of α 1-(Cbz-aminoalkyl)-α 2-(hydroxyalkyl)phosphinic esters

A synthesis of α 1-(Cbz-aminoalkyl)-α 2-(hydroxyalkyl)phosphinic esters was achieved by the 1,2-addition of the appropriate aldehyde to Cbz-protected phosphinic analogues of amino acid esters in the presence of at least three equivalents of trimethylsilyl chloride and NEt 3. The complete deprotection of the product esters could be achieved in one step using 35% HBr in acetic acid.

Physical Organic Perspectives on Phospho Group Transfer From Phosphates and Phosphinates

As phosphoryl transfer reactions are ubiquitous in biological chemistry, organic chemists have been very interested in the mechanisms of phosphate and phosphinate esters. Physical organic chemistry methods, including stereochemical studies, linear free energy relationships, and, most recently, heavy-atom kinetic isotope effects, have been used in the quest for mechanistic information about the chemistry of these compounds. This review summarizes what has been learned about the uncatalyzed phosphoryl transfer reactions of phosphate and phosphinate esters. Keywords: dianions, hydrolysis, phosphorothioate analogs, isotope, solvolysis