An efficient synthesis,spectral characterization,antimicrobial, and antioxidant activities of novel α-hydroxyphosphonates and α-hydroxyphosphinates

A simple, novel, and an efficient synthesis of α-hydroxy phosphonates (3a–d) and phosphinates (5a–f) has been accomplished from febuxostat aldehyde (1) with various dialkylphosphites (2) and dialkylphosphinates (4) in the presence of 1, 4-dimethylpiperazine as a strong base with good to excellent yields (78%–95%) is reported. The structures of the title compounds were established by elemental analysis and spectral data (IR, ¹H, ¹³C and ³¹P NMR, and LC-MS). All the title compounds (3a–d) and (5a–f) were tested for their antimicrobial and antioxidant activities. Bioassay results reveal that a few of the title compounds exhibited promising antimicrobial and antioxidant activities.     

Synthesis of phosphinic acids on the basis of hypophosphites: VI. General methods for synthesis of pseudo-γ-glutamylpeptides

A general method for synthesis of 2-substituted pseudo-γ-glutamylpeptides, namely, [2-(hydroxycarbonyl)ethyl][3-amino-3-(hydroxycarbonyl)propyl]phosphinic acids I which are phosphinic acid analogs of γ-glutamylpeptides. Bis(trimethylsilyl) hypophosphite (IV) formed from ammonium hypophosphite (II) in situ was added to the respective α-substituted acrylate to form bis(trimethylsilyl) [2-R-2-(alkoxycarbonyl)ethyl]-phosphonites V. Treatment of compounds V in situ with excess dibromoethane followed by alcoholysis gave [2-R-2-(alkoxycarbonyl)ethyl](2-bromoethyl)phosphinic acids VI which without isolation were treated with excess triethyl orthoformate. The simultanious esterification and dehydrobromination led to [2-R-2-(alkoxy-carbonyl)ethyl](vinyl)phosphinates III which were isolated and characterized. The Michael addition of diethyl acetamidomalonate to vinylphosphinates III followed by acid hydrolysis of phosphinates VII without their isolation resulted in formation of target [2-R-2-(hydroxycarbonyl)ethyl][3-amino-3-(hydroxycarbonyl)]proly]phosphinic acids-pseudo-γ-glutamylpeptides I. Original Russian Text V.V. Ragulin, 2007, published in Zhurnal Obshchei Khimii, 2007, Vol. 77, No. 5, pp. 763–768. For communication V, see [1].     

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.     

Effects of Chemical Reactivity on the Toxicity of Phosphorus Fluoridates

Abstract

Semiempirical quantum calculations were performed on a series of organophosphorus fluoridates to determine the relative reactivity for hydrolysis. This value was determined by subtracting the energy of the metastable intermediate from the energy of the stable molecule. Plotting this relative reactivity for each compound vs. its toxicity resulted in a parabolic curve with nerve agents and other similarly toxic compounds in the center. The more reactive phosphinates and less reactive phosphates were at the edges of the graph in the region of lower toxicity. The results indicate that for compounds meeting minimal structural requirements, chemical reactivity is the principal determinant of cholinesterase inhibition.     

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)     

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.     

Preparation,Reactions, and Stereochemistry of 4-Tert-Butyl-1-Chlorophosphorinane 1-Sulfide and Derivatives

Abstract

Nucleophilic substitution at tetracoordinated phosphorus centers has been extensively investigated.¹ Transesterification of acyclic phosphinates proceeds with inversion of configuration,² whereas four-membered phosphinates react with retention.³ In previous work⁴ we suggested that transesterification in six-membered phosphinates occurs via an S_N2 mechanism. The title compound was synthesized as a model structure to study the stereochemical and mechanistic aspects of nucleophlic substitution at phosphorus in a six-membered ring. A mixture of diastereomers was produced and separated by column chromatography. Both the mixture and separate isomers were used for an investigation of substitution with methanol, methoxide ions, and phenoxide ions; the reactions proceeded with inversion. Transesterification reactions of the resulting thiophosphinates were studied and found to proceed with inversion. Reactions of these with phenyllithium, benzyllithium, lithium phenylacetylide, and the corresponding organomagnesium halides were also carried out. The stereochemical assignments for the title compound (cis and trans) and two derivatives have been firmly anchored by X-ray studies;⁵ assignments for others are tentative and based on spectroscopic measurements, including ¹H, ¹³C, and ³¹P NMR data.     

Asymmetric P−C Bond Formation: Diastereoselective Synthesis of Adjacent P,C‐Stereogenic Allylic Phosphorus Compounds

A novel catalytic asymmetric P?C bond formation between phosphinates/phosphine oxide and allylic carbonates was developed. This methodology could not only afford a variety of functionalized adjacent P,C‐stereogenic phosphorus compounds in high yields with high regio‐ and diastereoselectivities but also provide an alternative strategy to access enantiomerically enriched (S_P)‐phosphinates through kinetic resolution.     

Isolation and identification of two new compounds from the Penicillium sp. SYPF7381

Abstract

Two new compounds, (7R, 2E, 5E)-3,5,7-trimethyl-2,5-octadienedioic-8-methyl ester (1) and neovasipyridone G (3), together with a new natural product compound (7R,2E,5E)-3,5,7-trimethyl-2,5-octadienedioic acid (2), and six known compounds (4–9) were isolated from Penicillium sp. SYPF7381. Their structures were elucidated on the basis of extensive spectroscopic analysis, and the absolute configurations of compounds 1 and 2 were determined by optical rotation. The absolute configuration of compound 3 was determined by means of electronic circular dichroism (ECD) calculation. In addition, the in vitro anti-inflammatory activities of all compounds were assayed in RAW 264.7 cells by assessing LPS-induced NO production. Furthermore, the structure-antiinflammation activity relationships for these isolated compounds were summarized based on the experimental as well as the docking results.     

Synthesis of H‐Phosphinates by the UV Light–Mediated Fragmentation‐Related Phosphorylation Using Simple P‐Heterocycles

Photolysis of aryl‐substituted 2,5‐dihydrophosphole oxides (5a–e and 8) in the presence of methanol afforded methyl aryl‐H‐phosphinates (2a–e) in good yields. In the case of 1‐ethyl‐, cyclohexyl‐, or ethoxy‐2,5‐dihydrophosphole oxides, the reaction was much slower (5f and 5h) or did not take place at all (5g). In such instances, the presence of an additional skeletal methyl group (7) or the use of the more strained 7‐phosphanorbornene derivatives (6) promoted the fragmentation‐related phosphorylations. Furthermore, the effect of the ring saturation in 8 and the possible extensions to 2‐phosphabicyclo[3.1.0]hexanes (10a and 10f), a 1,2‐dihydrophosphinine oxide (11), and a 1,2,3,4,5,6‐hexahydrophosphinine oxide (12) were also investigated. Model compounds with P‐phenyl substituent that are of sufficient ring strain (8, 10a, and 11) could be utilized well.     

Enzymatic resolution of α-hydroxyphosphinates with two stereogenic centres and determination of absolute configuration of stereoisomers obtained

The use of quinine as a chiral solvating agent allows us to determine a tentative absolute configuration at the phosphorus atom of hydroxyphosphinates with two stereogenic centres (at the phosphorus and α-carbon atoms). Two ethyl butyryloxyalkane(P-phenyl)phosphinates were hydrolysed using various lipases. In all cases isomers possessing α-carbon atom with an (S)-configuration were hydrolysed preferentially. The absolute configuration of both chiral centres of obtained α-hydroxyphosphinates was determined by using (S)-(+)-MTPA-Cl and quinine. The mode of chiral discrimination of α-hydroxyphosphinates by quinine was studied by means of computational chemistry, which confirmed the experimental findings that the signals in ³¹P NMR spectra of compounds with an (R_P)-configuration are situated upfield when compared with the respective (S_P) isomers.     

Two new labdane diterpenoids from aerial parts of Leonurus japonicus and their anti-inflammatory activity

Two new labdane diterpenoids, Leojaponin E (1) and F (2), together with three known compounds were isolated from the dried herb of Leonurus japonicus Houtt., Lamiaceae. Their structures were determined based on extensive spectroscopic analyses. The absolute configurations of 1 and 2 were elucidated on the basis of experimental and calculated electronic circular dichroism spectra. In addition, compounds 1 and 2 exerted inhibition of LPS-induced PGE₂ production in a dose-dependent manner at concentrations ranging from 5 to 20 μM.     

Two neolignans from Penthorum Chinense and their antiproliferative activities

Abstract

Chemical investigation of Penthorum chinense resulted in the isolation of two neolignans (1 and 2) together with two known compounds (3 and 4). The structures of compounds 1 and 2 were determined by interpretation of spectroscopic data, and absolute configurations were made based on electronic circular dichroism (ECD). All compounds were evaluated for their antiproliferative activity on hepatic stellate T6 cells (HSC-T6 cells), and 1 and 2 showed moderate activity with IC₅₀ values of 15.3 and 10.1?μM, respectively.     

Two new secondary metabolites from a mangrove-derived fungus Cladosporium sp. JJM22

Two new compounds (1 and 2), together with six known compounds (3–8), were obtained from the Cladosporium sp. JJM22, an endophytic fungus isolated from the stem bark of the mangrove plant Ceriops tagal collected in South China Sea. Their structures were elucidated on the basis of detailed spectroscopic analysis. The absolute configurations of 1 and 2 were confirmed by the comparison of optical rotation and the CD data with those of known compounds. The inhibitory activities of the isolated compounds against six terrestrial pathogenic bacteria and human cervical carcinoma Hela cell line were evaluated. Compound 3 exhibited a broad spectrum of antibacterial activities.     

Two new sesquiterpenes derivatives from marine fungus Leptosphaerulina Chartarum sp. 3608

Two new sesquiterpenes, leptoterpenes A (1) and B (2) were isolated from the fungus Leptosphaerulina Chartarum sp. 3608, derived from a crinoid. It was the first chemical study on this species. The structures of these compounds were elucidated by spectroscopic methods including NMR and MS spectrometry. The absolute configurations of the new compounds were determined on the basis of the single-crystal X-ray diffraction and electronic circular dichroism data analysis. All compounds were tested for their anti-inflammatory activity and the inhibitory effects on Tyrosyl DNA phosphodiesterase II (TDP2).     

Phytochemical constituents of the pericarps of Illicium difengpi and their anti-inflammatory activity

Abstract

Phytochemical investigation on the pericarps of Illicium difengpi lead to the isolation and structure elucidation of a new sesquiterpene, sesquicaranoic acid C (1), a new neolignan, difengpiol C (2), and 10 known compounds. The structures and absolute configurations of two new compounds were determined by a combination of NMR and CD spectroscopic analyses. All isolates were evaluated for their inhibitory effects on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW264.7 cells.     

Xylaropyrones B and C,new γ-pyrones from the endophytic fungus Xylaria sp. SC1440

Two new γ-pyrones, xylaropyrones B (1) and C (2), together with three known compounds, xylaropyrone (3), annularin A (4) and annularin C (5), were isolated from solid cultures of the endophytic fungus Xylaria sp. SC1440. The structures of these compounds were determined mainly by analysis of their NMR spectroscopic data. The relative configurations of 1 and 2 were assigned on the basis of J-based configurational analysis, and the absolute configurations were established by experimental and TDDFT calculated ECD spectra. The isolated compounds were evaluated for cytotoxic and tyrosinase inhibitory activity.     

A new azaphilone from the entomopathogenic fungus Hypocrella sp.

This report describes the isolation of a new azaphilone, designated hypocrellone A (2), together with five known compounds (1, 3–6) from a submerged culture of the entomopathogenic fungus Hypocrella sp. (isolate WYTY-21). The absolute stereostructures of the two compounds (1 and 2) were elucidated based on 1D and 2D NMR spectroscopic and mass spectrometric data combined with the data from various chemical transformations. Hypocrellone A (2) and three (3–6) of the five known compounds were cytotoxic to hepatoma cells (cell line BEL-7404); IC₅₀ values ranged from 6.2 to 17.4 μM. At 200 μM, none of the six compounds was toxic to normal human liver cells (cell line HL-7702) or to normal human kidney epithelial cells (cell line HEK-293T).     

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.