H-phosphonate Diesters Research Articles

Solid-Phase Synthesis of Boranophosphate/Phosphorothioate/Phosphate Chimeric Oligonucleotides and Their Potential as Antisense Oligonucleotides.

In this study, we successfully synthesized boranophosphate (PB), phosphorothioate (PS), and phosphate (PO) chimeric oligonucleotides (ODNs) as a candidate for the antisense oligonucleotides (ASOs). The PB/PS/PO-ODNs were synthesized utilizing H-boranophosphonate, H-phosphonothioate, and H-phosphonate monomers. Each monomer was condensed with a hydroxy group to create H-boranophosphonate, H-phosphonothioate, and H-phosphonate diester linkages, which were oxidized into PB, PS, and PO linkages in the final stage of the synthesis, respectively. As for condensation of an H-phosphonothioate monomer, regulating chemoselectivity was necessary since the monomer has two nucleophilic centers: S and O atoms. To deal with this problem, we used phosphonium-type condensing reagents, which could control the chemoselectivity. In this strategy, we could synthesize PB/PS/PO oligomers, including a 2′-OMe gapmer-type dodecamer. The physiological and biological properties of the synthesized chimeric ODNs were also evaluated. Insights from the evaluation of physiological and biological properties suggested that the introduction of suitable P-modification and sugar modification at proper sites of ODNs would control the duplex stability, nuclease resistance, RNase H-inducing ability, and one base mismatch discrimination ability, which are critical properties as potent ASOs.

The Synthesis and Mechanistic Considerations of a Series of Ammonium Monosubstituted H-Phosphonate Salts.

A series of ammonium monosubstituted H-phosphonate salts were synthesized by combining H-phosphonate diesters with amines in the absence of solvent at 80 °C. Variation of the ester substituent and amine produced a range of ionic liquids with low melting points. The products and by-products were analyzed by spectroscopic and spectrometric techniques in order to get a better mechanistic picture of the dealkylation and formal dearylation observed. For dialkyl H-phosphonate diesters, (RO)2 P(O)H (R=alkyl), the reaction proceeds via direct dealkylation with the reactivity increasing in the order R=iPr<Et<Me corresponding to DFT calculated activation enthalpies of 22.6, 20.8, and 17.9 kcal mol-1 . For the diphenyl H-phosphonate diesters, (PhO)2 P(O)H, the dearylation was found to proceed via phenol-assisted formation of a 5-coordinate intermediate, (PhO)3 PH(OH), from which P(OPh)3 and water were eliminated. The presence of an equivalent of water then facilitated the formation of P(OH)2 OPh and the amine, R'NH2 , subsequently abstracted a proton from it to yield [(PhO)PH(O)O]- [R'NH3 ]+ .

Zinc-Catalyzed Phosphonylation of Alcohols with Alkyl Phosphites.

In the presence of a catalytic amount of either Zn(acac)2 or bis(2,2,6,6-tetramethyl-3,5-heptanedionato)zinc(II) (Zn(TMHD)2), primary, secondary, and tertiary alcohol substituents on a wide range of substrates, including acyclic and cyclic structures, carbohydrates, steroids, and amino acids, reacted with dimethyl phosphite to afford the corresponding H-phosphonate diesters in high to excellent yields.

Magnetic nanoparticle-supported eosin Y ammonium salt: An efficient heterogeneous catalyst for visible light oxidative C–C and C–P bond formation

A highly efficient visible light mediated C–C and C–P coupling reactions of sp3 C–H bonds adjacent to the nitrogen atom in tetrahydroisoquinoline derivatives with pronucleophiles such as nitroalkanes, malononitrile, dimethyl malonate and H-phosphonate diesters were achieved by using a magnetic nanoparticle-supported eosin Y bis-benzyltriethylammonium salt (MNPs-Eosin Y) as catalyst and air as the sole oxidant, affording the corresponding products in good to excellent yields under mild reaction conditions. Notably, the supported eosin Y catalyst can easily be separated from the reaction mixture by an external permanent magnet and can be recycled at least eight times without a significant loss of activity.

Synthesis of Chimeric Oligonucleotides Having Modified Internucleotide Linkages via an Automated H-Phosphonate/Phosphoramidite Approach.

This article describes an automated solid-phase approach for the synthesis of chimeric oligonucleotides containing phosphoramidate-modified internucleotide linkages. An optimized H-phosphonate synthetic cycle is combined with the commonly used phosphoramidite approach to obtain oligonucleotides comprising blocks having various types of internucleotide linkages. This article is specific to the synthesis of oligonucleotides having phosphoramidate modifications, but is adaptable to permit the incorporation of other modified linkages accessible through H-phosphonate diester intermediates. © 2018 by John Wiley & Sons, Inc.

Reaction of Boranephosphonate Diesters with Amines in the Presence of Iodine: The Case for the Intermediacy of H-Phosphonate Derivatives.

Mechanistic and stereochemical aspects of the reaction of boranephosphonate diesters with amines promoted by iodine were investigated. This is a complex, multistep reaction that ultimately produces the corresponding phosphoramidate diesters via a formal replacement of the borane group by an amine moiety. We found by a stereochemical correlation analysis that, contrary to a literature report, the whole transformation proceeded with total inversion of the configuration at the phosphorus center. Our study also showed that instead of the postulated nucleophilic substitution by iodide at the phosphorus center of the initially formed intermediate, the corresponding iodoboranephosphonate, the crucial step of the reaction involved intermediacy of H-phosphonate derivatives that reacted with iodine to afford ultimately phosphoramidate diesters. The reaction of the iodoboranephosphonate with the amine to produce an aminoboranephosphonate diester that rapidly dissociated into the corresponding H-phosphonate and the borane parts was apparently instrumental to the formation of an H-phosphonate diester intermediate.

Sulfurization of H-Phosphonate Diesters by Elemental Sulfur under Aqueous Conditions.

To assess the plausibility of prebiotic nucleic acid polymerization by a sequential phosphitylation–sulfurization mechanism, the rates of hydrolysis and sulfurization of bis(2′,3′-O-methyleneadenosin-5′-yl)-H-phosphonate, a dinucleoside H-phosphonate diester, have been determined over a wide pH range (0.52–7.25) and in the presence of varying amounts (0–30 mg) of elemental sulfur. The pH-rate profile of hydrolysis resembled the one previously reported for the H-phosphonate analogue of thymidylyl-3′,5′-thymidine, with a relatively wide pH-independent region flanked by acid- and base-catalyzed regions. Sulfurization to the respective phosphorothioate diester, in turn, was found to be base-catalyzed over the entire pH range studied. Despite the facile hydrolysis of H-phosphonate diesters and the extremely low solubility of elemental sulfur in water, sulfurization and hydrolysis proceeded at comparable rates under neutral and mildly acidic conditions.

Pd-catalyzed C–P coupling of heteroaryl boronic acid with H-phosphonate diester

We report herein a novel protocol to construct C–P bond from heteroaryl boronic acid with H-phosphonate diester under Pd–Ag catalyzed system without addition of base. This method, directly using commercial available heteroaryl boronic acid as the starting material, provides a new way to synthesize a variety of useful heteroaryl phosphonates.

Manganese-mediated intermolecular arylation of H-phosphinates and related compounds.

The intermolecular radical functionalization of arenes with aryl and alkyl H-phosphinate esters, as well as diphenylphosphine oxide and H-phosphonate diesters, is described. The novel catalytic Mn(II) /excess Mn(IV) system is a convenient and inexpensive solution to directly convert Csp2 H into CP bonds. The reaction can be employed to functionalize P-stereogenic H-phosphinates since it is stereospecific. With monosubstituted aromatics, the selectivity for para-substitution increases in the order (RO)2 P(O)H<R(1) P(O)(OR)H<Ph2 P(O)H, a trend that may be explained by steric effects.

Efficient Synthesis of O-glycosyl-5′-H-Phosphonate Diesters of d4T

A novel and one-pot route for the synthesis ofO-glycosyl-5′-H-phosphonate diesters of d4T has been developed. This analogs were synthesized by controlling tandem substitution reaction on PCl3with 2,6-lutidine as suitable base.

Oxidation of H-Phosphonates with Iodine by Intramolecular Support of a 2-Pyridyl Thermolabile Protecting Group

Acceleration of H-phosphonate diester oxidation with iodine accompanied by a thermolabile protecting group (TPG) is presented. It is shown that the intermediate product of this reaction is an oxazaphospholidine oxide which forms a phosphate diester only when a 2-pyridyl TPG is applied. The intermediate product is formed with exocyclic nitrogen. The absolute configurations of phosphorothioate diesters, H-phosphonate diesters, and oxazaphospholidine oxides were determined. (31)P NMR spectroscopy was used to evaluate the relationship between chemical shift and absolute configuration at the phosphorus center of H-phosphonate diesters and oxazaphospholidine oxides.

DBU-promoted alkylation of alkyl phosphinates and H-phosphonates

The alkylation of alkyl phosphinates and some H-phosphonate diesters is promoted by the base DBU. Only more reactive alkyl halides react in preparatively useful yields. However, the method provides easy access to important H-phosphinate building blocks, without the need for a protecting group strategy or metal catalysts. The reaction is conveniently conducted at, or below, room temperature. The preparation of methyl-H-phosphinate esters is particularly interesting as it avoids the heretofore more common use of methyldichlorophosphine MePCl2.

Reactive intermediates in the H-phosphonate synthesis of oligonucleotides

The formation of H-phosphonate diesters is an important step in the synthesis of oligonucleotides. Using diphenylchlorophosphate as the activator for the coupling step is often accompanied by side reactions as a result of self 'capping' and other reactions of the reactive intermediate. In the absence of base, the activation of ethyl H-phosphonate with diphenylchlorophosphate probably occurs through the intermediate formation of bis diethyl pyro-di-H-phosphonate rather than the expected diphenyl ethyl pyro-H-phosphonate. Pyridine acts as a nucleophilic catalyst converting diphenylchlorophosphate to its pyridinium adduct. Several side and unwanted reactions are quantified so that conditions to minimise these can be identified.

Cd(ClO4)2∙xH2O as a novel catalyst for the synthesis of α-aminophosphonates under solvent-free conditions

Abstract In this paper, we report cadmium perchlorate hydrate to be an novel, expeditious catalyst for the three-component one-pot reaction of an amine, an aldehyde and a H-phosphonate diesters in open air without any solvent, leads to α-aminophosphonates in excellent yields. To the best of our knowledge this finding is the first example of a cadmium perchlorate hydrate catalyzed Kabachnik-Fields reaction.

Synthesis of Oligo(α-d-glycosyl phosphate) Derivatives by a Phosphoramidite Method via Boranophosphate Intermediates

An efficient method for the synthesis of short oligo(α-D-glycosyl boranophosphate) derivatives by using an α-D-glycosyl phosphoramidite as a monomer unit was developed. The synthesis of oligomers was carried out by repeating a cycle consisting of the condensation of the monomer unit with a terminal hydroxy group of carbohydrates, boronation of the resultant phosphite intermediates, and terminal deprotection. The phosphoramidite monomer unit was synthesized from the corresponding glycosyl iodide and methyl N,N-diisopropylphosphonamidate in a highly α-selective manner. Di- and tri(α-D-glycosyl boranophosphate) derivatives obtained by the synthetic cycle were converted into the corresponding H-phosphonate diester derivatives, which were then used to synthesize di- and tri(α-D-glycosyl phosphate) derivatives including a fragment of Leishmania glycocalyx lipophosphoglycans.

Copper-Catalyzed C−P Bond Construction via Direct Coupling of Phenylboronic Acids with H-Phosphonate Diesters

A mild and efficient method was developed for the copper-catalyzed additions of H-phosphonate diesters to boronic acids under the copper catalyst system Cu(2)O/1,10-phenanthroline. To the best of our knowledge this finding is the first example of a copper-catalyzed synthesis of aryl phosphonates from arylboronic acids and H-phosphonate dialkyl esters.

Pd触媒下の超原子価有機Sb(V)化合物を利用したヒドロホスホナート類のP―アリール化反応

Pd触媒下の超原子価有機Sb(V)化合物を利用したヒドロホスホナート類のP―アリール化反応

5′-Bis-conjugation of Oligonucleotides by Amidative Oxidation and Click Chemistry

A pent-4-ynyl tert-butyl N,N-diisopropyl phosphoramidite was coupled at the 5'-end of oligonucleotides to give a phosphite triester linkage, which forms an H-phosphonate diester linkage during treatment with dichloroacetic acid. Then an amidative oxidation with CCl(4) in the presence of an amine and a 1,3-dipolar cycloaddition with an azide under copper(I) catalysis afforded the bis-conjugated oligonucleotides with high efficiency. The introduction of a bromoalkyl group as a precursor of azidoalkyl by amidative oxidation allowed the performance of two selective 1,3-dipolar cycloadditions.

ChemInform Abstract: A Convenient Approach Towards the Conversion of H-Phosphonate and H-Phosphonothioate Diesters into Phosphoro(di)thioate Derivatives.

ChemInform Abstract: A Convenient Approach Towards the Conversion of H-Phosphonate and H-Phosphonothioate Diesters into Phosphoro(di)thioate Derivatives.

ChemInform Abstract: Nucleoside H-Phosphonates. Part 14. Synthesis of Nucleoside Phosphoroselenoates and Phosphorothioselenoates via Stereospecific Selenization of the Corresponding H-Phosphonate and H-Phosphonothioate Diesters with the Aid of New Seleniu

ChemInform Abstract: Nucleoside H-Phosphonates. Part 14. Synthesis of Nucleoside Phosphoroselenoates and Phosphorothioselenoates via Stereospecific Selenization of the Corresponding H-Phosphonate and H-Phosphonothioate Diesters with the Aid of New Seleniu