Synthesis Of Phosphonates Research Articles

Synthesis and preliminary cytotoxicity evaluation of water soluble pentacyclic triterpenoid phosphonates.

Synthesis, solubility and cytotoxicity evaluation of anionic phosphonates derived from betulin, betulinic acid, oleanolic acid and ursolic acid is reported. Phosphonate moieties were successfully installed at terpenoid C28 by carboxylic acid deprotonation/alkylation sequence using (dimethoxyphosphoryl)methyl trifluoromethanesulfonate as alkylation reagent. Also, betulin-derived and ether-linked bis-phosphonate is obtained and characterized. After demethylation in the presence of TMSI the resulting phosphonic acids were transformed into their disodium salts. All target compounds display excellent water solubility, which was determined by qNMR in D2O. Cytotoxicity tests were performed in different concentrations of each compound (10-50 µM) against human osteosarcoma cell line MG-63 and osteoblast precursor cell line MC3T3-E1. Improved aqueous solubility and low cytotoxicity profile of the newly designed triterpenoid phosphonates reveal high potential for various medicinal chemistry and pharmacological applications in the future.

Palladium-Catalyzed Decarbonylative Michaelis-Arbuzov Reaction of Carboxylic Acids and Triaryl Phosphites.

A Pd-catalyzed decarbonylative Michaelis-Arbuzov reaction of carboxylic acids and triaryl phosphites for preparing aryl phosphonates under anhydride-free conditions has been reported. In this context, triaryl phosphites serve as both reagents for activating the carboxylic acids and substrates for the reaction. There have been no reports to date of efficient and direct methods for the in situ activation of carboxylic acids using triaryl phosphites. In comparison to known methods, this reaction avoids the use of organohalides and has an excellent functional group tolerance for the synthesis of various aryl phosphonates from triaryl phosphites and carboxylic acids. This reaction is scalable and applicable to the synthesis of aryl phosphonates featuring bioactive fragments.

Dual isotopic (33P and 18O) tracing and solution 31P NMR spectroscopy to reveal organic phosphorus synthesis in organic soil horizons

Soil microorganisms can do both, mineralize and synthesize organic and condensed phosphate (P) species. Whereas P mineralization has been extensively studied, few studies have assessed the biological synthesis of organic P species, which can potentially accumulate in soil. The goal of this study was to investigate biotic and abiotic P transformations, particularly the synthesis of organic P species, upon water-soluble P addition in the organic (O) horizons of two beech forest sites with contrasting P availability.The two O horizons (low-P and high-P) were subjected to four different nutrient addition treatments (Control without addition, CN, P, and CNP additions) in an incubation experiment of up to 104 days. We combined isotopic tracing (33P-labelled P addition and 18O-enriched soil water) into sequentially extracted P pools with the characterization of organic P species (solution 31P nuclear magnetic resonance (NMR) spectroscopy) and soil respiration measurements.The P availability of the two O horizons shaped the microbial response to the nutrient additions. In the low-P O horizon, P addition stimulated microbial activity together with the increase of organic (phosphodiesters and phosphonates) and condensed (polyphosphates) P species, most likely from microbial origin. In the high-P O horizon, microbes were unaffected by the added P and abiotic processes controlled its fate. CN addition had no effect on P fate in the high-P O horizon but reduced the transformation of added P into organic P and increased soil-derived P in the resin P pool in the low-P O horizon. The 18O isotopic values in phosphate of the resin P pool suggest that the released P was biologically cycled.Our study confirms with a unique multi-analytical approach the microbial synthesis of phosphodiesters, phosphonates, and polyphosphates upon inorganic P addition under low P availability.

Organo‐Soluble Colloidal MoS2 Quantum Dots (QDs) as an Efficient Photocatalyst for α‐Amino Phosphonate Synthesis

Abstractα‐Amino phosphonates are bio‐isosteres of amino acids and have numerous biochemical activities. While they are generally prepared via carbon–phosphorus bond formation using a plethora of methods but using recyclable photo‐catalysts and readily accessible amine and phosphites are not commonly used in synthesis. Herein, we used organo‐soluble MoS2 Quantum Dots (QDs) as an exceptionally efficient nano‐photocatalyst for the synthesis of α‐amino phosphonates. Our approach emphasizes on photocatalysis within organic media, providing a facile and effective method for conducting these intricate organic conversions under mild conditions. This straightforward process harnesses the power of molecular oxygen (O2) as an oxidizing agent. To elaborate, our method is intricately guided by the inherent capability of MoS2 QDs to enter an excited state upon absorption of blue light. This excited state bears appropriate potential energy to initiate the formation of reactive iminium ion species from N‐phenyl benzylamine, thus driving the desired product formation. Mechanistic analysis has also unveiled the pivotal role of MoS2 QDs in generating reactive superoxide radicals from O2 through single electron transfer (SET), underscoring their significance in the process. Remarkably, this photocatalytic transformation furnishes a diverse array of functionalized products, expanding its applicability and potential implications in various contexts.

Synthetic Methods for Azaheterocyclic Phosphonates and Their Biological Activity: An Update 2004-2024.

The increasing importance of azaheterocyclic phosphonates in the agrochemical, synthetic, and medicinal field has provoked an intense search in the development of synthetic routes for obtaining novel members of this family of compounds. This updated review covers methodologies established since 2004, focusing on the synthesis of azaheterocyclic phosphonates, of which the phosphonate moiety is directly substituted onto to the azaheterocyclic structure. Emphasizing recent advances, this review classifies newly developed synthetic approaches according to the ring size and providing information on biological activities whenever available. Furthermore, this review summarizes information on various methods for the formation of C-P bonds, examining sustainable approaches such as the Michaelis-Arbuzov reaction, the Michaelis-Becker reaction, the Pudovik reaction, the Hirao coupling, and the Kabachnik-Fields reaction. After analyzing the biological activities and applications of azaheterocyclic phosphonates investigated in recent years, a predominant focus on the evaluation of these compounds as anticancer agents is evident. Furthermore, emerging applications underline the versatility and potential of these compounds, highlighting the need for continued research on synthetic methods to expand this interesting family.

Zn-Catalyzed Dehydroxylative Phosphorylation of Allylic Alcohols with P(III)-Nucleophiles.

A novel and efficient protocol for the synthesis of diarylallyl-functionalized phosphonates, phosphinates, and phosphine oxides through the zinc-catalyzed dehydroxylative phosphorylation of allylic alcohols with P(III)-nucleophiles via a Michaelis-Arbuzov-type rearrangement is reported. A broad range of allylic alcohols and P(III)-nucleophiles (P(OR)3, ArP(OR)2, and Ar2P(OR)) are well tolerated in this reaction, and the expected dehydroxylative phosphorylation products could be synthesized with good to excellent yields under the optimal reaction conditions. The reaction can be easily scaled up at a gram-synthesis level. Furthermore, through the step-by-step control experiments, kinetic study experiments, and 31P NMR tracking experiments, we acquired insights into the reaction and proposed the possible mechanism for this transformation.

Catalytic enantioselective synthesis of cyclopropyl α-amino carboxylates and phosphonates

Herein, the catalytic asymmetric synthesis of tetra-substituted cyclopropyl α-amino carboxylates and cyclopropyl α-amino phosphonates is reported.

CAMDOL-enabled diastereoselective synthesis of α-substituted phosphonates.

Enantiopure α-substituted phosphonic acids are widely utilized as drugs, pesticides, and ligands. Despite numerous synthetic approaches having been investigated, precise construction of P-adjacent chiral tertiary carbon centres by the employment of recoverable chiral auxiliaries is traditional and still one of the most reliable and practical synthetic methodologies so far. Herein, we present a highly diastereoselective synthesis of α-substituted phosphonates via the unique CAMDOL-derived P-substrates by an efficient sequential deprotonation with LiHMDS and alkylation/arylation with RI. A wide range of 30 structurally diverse α-substituted phosphonate products, including the well-known P-analogues of naproxen and ibuprofen, were thus afforded conveniently in up to 92% yields and 99 : 1 diastereomeric ratios. The related chiral phosphonic acid could be easily obtained by simple acidic hydrolysis with fully recovered auxiliary. This CAMDOL-enabled asymmetric synthetic protocol exhibits comparative advantages over known chiral-induction methods with easy accessibility and compatibility of furnishing a variety of C-stereogenic centres in the proximity of the phosphorus atom, including some rare examples.

Photocatalyst-free visible-light-promoted C(sp2)-P coupling: efficient synthesis of aryl phosphonates.

A novel and efficient method for the synthesis of aryl phosphonates from aryl halides and trialkylphosphites via EDA complex-based photochemistry has been developed. It is demonstrated that aryl radicals, generated from the photoexcitation of the EDA complex formed by aryl halide and potassium thioacetate, could be intercepted with trialkylphosphite to produce the corresponding aryl phosphonates in moderate to good yields. It should be noted that the reaction is performed at room temperature in the absence of any transition metal catalyst, oxidant and photocatalyst, exhibiting high efficiency, high selectivity, and operational simplicity.

Divergent Synthesis of (Benzo[b][1,4]diazepin‐2‐yl)phosphonates and (Quinoxalin‐2‐yl)methylphosphonates from Phosphoryl‐Substituted Conjugated Ynones

AbstractIt is shown that the reaction of conjugated ynones containing a phosphoryl group with o‐phenylenediamines can, depending on the conditions, lead to the selective formation of phosphorylated 1,5‐benzodiazepines and quinoxalines. Phosphorylated quinoxalines can be used for synthesis of substituted vinyl quinoxalines.

Non-hydrolytic sol-gel synthesis of zirconium phosphonates with controlled mesoporosity

We disclose the preparation of high-surface-area mesoporous zirconium phosphonates by the non-hydrolytic sol-gel reactions (NHSG) of Zr(NEt2)4 with trimethylsilylated phosphonates RP(O)(OSiMe3)2 (R = Me, tBu, Ph, OSiMe3), and bis-phosphonates (Me3SiO)2(O)P–X–P(O)(OSiMe3)2 (X = CH2, C6H4, CH2(C6H4)CH2, and CH2(C6H4)2CH2) in dry toluene under ambient pressure. Zirconium phosphonate xerogels are prepared by condensation reaction with the elimination of silylamine Me3SiNEt2. This irreversible reaction provides the amorphous xerogels and drives the formation of the porous structure. The influence of organic moieties bonded to phosphorus atoms on porosity was examined in this study. The final surface area of dried xerogels reached 720 m2 g−1 without any extra templating agent. Xerogels were characterized by 13C, 29Si, and 31P solid-state NMR to define atomic homogeneity and evidence the presence of organic phosphonate substituents and residual amido and trimethylsilyl groups. The amount of residual reactive groups was determined by gravimetric measurements and the thermal analysis (TG-DSC) method. These groups may be applied in post-synthetic surface modification, such as controlling the hydrophobic/hydrophilic properties.The catalytic properties of NHSG-prepared xerogels were tested on a model reaction of aminolysis of styrene oxide in a batch mode employing relatively bulky molecules. Products were identified and quantified by the 1H NMR spectroscopy. Catalyst performance parameters, such as selectivity, conversion, turnover frequency, and others, were exceeded compared to benchmark microporous layered zirconium phosphonate catalysts.

Design and synthesis of phosphonate functionalized naphthalenediimide: Application to induce mitochondria mediated apoptosis in the human skin melanoma cells (SKMEL2)

New phosphonate functionalized naphthalenediimides (NDI-1 and NDI-2) have been synthesized and evaluated as potential drug candidates to treat the skin malignancy. The aforementioned candidates have resulted in an induced apoptosis pathway of cytotoxicity, at concentrations lower than 4 µM, in human skin melanoma cells, and elicited a stronger apoptotic response in cells. Regulation of the Bcl2, Caspases, Bak1, Bax protein in NDI-induced apoptosis in cells has been analyzed by real time PCR, and the cell viability and apoptosis determined by flow cytometry. The obtained results indicate that NDI-induced apoptosis by regulation of Bcl2 and Bak1 occurs in human skin melanoma cells (SKMEL-2).

Recent Advances in the Asymmetric Catalytic Synthesis of Phosphonates with an α-Chiral Center

AbstractPhosphonates and derivatives with an α-chiral center are of great importance and they are widely distributed in many natural products, pharmaceuticals, and agrochemicals with various bioactive features. Great effort has been made toward the development of efficient methods for their synthesis. In this short review, recent advances in the asymmetric catalytic synthesis of phosphonates with an α-chiral center are summarized, including asymmetric hydrogenation of α,β-unsaturated phosphonates, asymmetric addition of phosphonates to unsaturated electrophiles, and asymmetric addition of nucleophiles to α,β-unsaturated phosphonates. In addition, continuous development of enantioselective catalytic synthetic methods and the application of phosphonates and derivatives with α-chiral center are future prospects.1 Introduction2 Asymmetric Hydrogenation of α,β-Unsaturated Phosphonates3 Asymmetric Addition of Phosphonates to Unsaturated Electrophiles4 Asymmetric Addition of Nucleophiles to α,β-Unsaturated Phosphonates5 Conclusion

Constructive On-DNA Abramov Reaction and Pudovik Reaction for DEL Synthesis.

Organophosphonic compounds are distinctive among natural products in terms of stability and mimicry. Numerous synthetic organophosphonic compounds, including pamidronic acid, fosmidromycin, and zoledronic acid, are approved drugs. DNA encoded library technology (DELT) is a well-established platform for identifying small molecule recognition to target protein of interest (POI). Therefore, it is imperative to create an efficient procedure for the on-DNA synthesis of α-hydroxy phosphonates for DEL builds.

3,3]-Rearrangements of N-Oxyindoles

AbstractThe concerted Ag-catalyzed rearrangement of N-indolyl carbonates and esters to afford 3-oxyindole derivatives with broad functional-group compatibility is presented. In addition, this concerted [3,3]-rearrangement approach was expanded to the synthesis of phosphonate and sulfonamide derivatives without the use of an Ag catalyst. Control experiments suggested that no radical pathway is involved at any stage of the rearrangement process.

In situ synthesis of titanium phosphonate by a non-hydrolytic sol-gel route within a viscous polymer medium

In situ synthesis of titanium phosphonate by a non-hydrolytic sol-gel route within a viscous polymer medium

Synthesis of Phosphonates with Identical and Different Alkyl Groups by the Microwave-Assisted Alkylation of Phosphonic Ester-Acid Derivatives.

Monoalkyl phosphonic derivatives obtained by the microwave (MW)- and ionic liquid-promoted direct esterification of alkylphosphonic acids were converted to the corresponding dialkyl alkylphosphonates on reaction with alkyl halides in the presence of triethylamine, under solvent-free MW-assisted conditions. Derivatives with different alkoxy groups were also synthesized. A minor "disproportionation" side reaction was identified during the preparation of dialkyl alkylphosphonates with different alkoxy groups. All together 12 alkylphosphonates were prepared by the efficient method developed.

Two-Step Transesterification of Phosphates, Phosphorothioates, and Phosphonates with a Binaphthyl Group for the Synthesis of P-Chirogenic Phosphates and Phosphonates

AbstractTwo-step transesterification of four-coordinate pentavalent organophosphorus compounds with a binaphthyl group has been studied in detail. The first step involves transfer of the axial chirality of a ­hydroxybinaphthyl group to the central chirality of the phosphorus atom. The second step is the substitution reaction of P-chirogenic compounds with a hydroxybinaphthyl group with lithium alkoxides, leading to the formation of P-chirogenic phosphates and phosphonates with primary and secondary alkoxy groups.

Catalytic Asymmetric Synthesis of C-Chiral Phosphonates

The current review is devoted to the achievements in the development of methods for the catalytic asymmetric synthesis of phosphonates containing a chiral center in the side chain. C-chiral phosphonates are widely represented among natural compounds with various biological activities as insecticides, herbicides, antibiotics, and bioregulators. Synthetic representatives of this class have found practical application as biologically active compounds. The review summarizes methods of asymmetric metal complex catalysis and organocatalysis as applied to such reactions as phospha-aldol reaction, two-component and three-component phospha-Mannich reaction, phospha-Michael reaction, as well as hydrogenation of unsaturated phosphonates and phosphine oxides, ketophosphonates, and iminophosphonates. Methods for the asymmetric hydride reduction of C=X phosphonates (X=O, S, NR) are also discussed in detail. The review presents updated literature reports, as well as original research by the author.

Synthesis and anti-trypanosomal evaluation of novel N-branched acyclic nucleoside phosphonates bearing 7-aryl-7-deazapurine nucleobase

A series of novel 7-aryl-7-deazaadenine-based N-branched acyclic nucleoside phosphonates (aza-ANPs) has been prepared using the optimized Suzuki cross-coupling reaction as the key synthetic step. The final free phosphonates 15a-h were inactive, due to their inefficient transport across cell membranes, but they inhibited Trypanosoma brucei adenine phosphoribosyltransferase (TbrAPRT1) with Ki values of 1.7–14.1 μM. The corresponding phosphonodiamidate prodrugs 14a-h exhibited anti-trypanosomal activity in the Trypanosoma brucei brucei cell-based assay with EC50 values in the range of 0.58–6.8 μM. 7-(4-Methoxy)phenyl-7-deazapurine derivative 14h, containing two phosphonate moieties, was the most potent anti-trypanosomal agent from the series, with EC50 = 0.58 μM and SI = 16. Finally, phosphonodiamidate prodrugs 14a-h exerted low micromolar cytotoxicity against leukemia and/or cancer cell lines tested.