Synthesis of di(adamantylalkyl) tosyloxymethylphosphonates and di(adamantyloxyalkyl) tosyloxymethylphosphonates

A simple method for the synthesis of esters of tosyloxymethylphosphonic acid based on the adamantane series of alcohols and diethyl tosyloxymethyl phosphonate was developed. The di(adamantylalkyl) and di(adamantyloxyalkyl) tosyloxymethylphosphonates are of interest as key compounds in the synthesis of antiviral drugs of the nucleoside phosphonate class.     

Ready Access to Fluorinated Phosphonate Mimics of Secondary Phosphates. Synthesis of the (alpha,alpha-Difluoroalkyl)phosphonate Analogues of L-Phosphoserine, L-Phosphoallothreonine, and L-Phosphothreonine

In addition to the previously recorded reactions of diethyl lithio(difluoromethyl)phosphonate (8) with primary triflates and aldehydes, we report here that 8 reacts with functionalized, but unactivated, methyl esters to give efficient acyl substitution. Thus, 8 reacts cleanly (-78 degrees C, THF) with the following methyl esters (product, yield): methyl (S)-isopropylideneglycerate (14, 99%), methyl (S)-3-O-(tert-butyldimethylsilyl)-2 -O-tetrahydropyranylglycerate (16, 85%), and the Garner ester derived from D-serine (15, 77%). Expeditious treatment of the resultant alpha,alpha-difluoro-beta-keto phosphonates with hydride or Grignard reagents followed by alcohol deoxygenation provides a general method for the synthesis of (alpha,alpha-difluoroalkyl)phosphonate analogues of secondary phosphates. For tertiary alcohols, Dolan-MacMillan deoxygenation conditions are employed. The requisite methyl oxalate esters are obtained by an improved procedure wherein the lithium alkoxide of the hindered tertiary alcohol is irreversibly generated at low temperature and then condensed with methyl oxalyl chloride. Relative stereochemistry is assigned via conversion of the Garner ester derived Boc-amino alcohols to the corresponding cyclic, six-membered phosphonate esters and examination of their (1)H NMR spectra. The relevant vicinal coupling constants are extracted from these spectra by performing double quantum-filtered phase-sensitive COSY experiments. This new (difluoromethylene)phosphonate anion-methyl ester condensation, Grignard (hydride) addition, deoxygenation sequence has been applied to the synthesis of (alpha,alpha-difluoroalkyl)phosphonate analogues of L-phosphoserine (>/=96% ee) and L-phosphoallothreonine (93% ee) from D-serine and of L-phosphothreonine (91% ee) from L-glycerate, respectively.     

Direct conversion of benzylic and allylic alcohols to phosphonates

Benzyl phosphonate esters often serve as reagents in Horner-Wadsworth-Emmons reactions. In most cases, they can be prepared from benzylic alcohols via formation of the corresponding halide followed by an Arbuzov reaction. To identify a more direct synthesis of phosphonate esters, we have developed a one-flask procedure for conversion of benzylic and allylic alcohols to the corresponding phosphonates through treatment with triethyl phosphite and ZnI(2).     

Triazole phosphohistidine analogues compatible with the Fmoc-strategy

Phosphorylation of histidine is essential for bacterial two-component signalling; its importance to modulation of eukaryotic protein function remains undefined. Until recently, no immunochemical probes of this post-translational modification existed, however triazole phosphonate analogues of this modified amino acid have now been applied to the generation of site-specific antibodies. The protecting group strategy used in the original report is incompatible with standard protocols for Fmoc-solid phase peptide synthesis. In this paper, we report the application of P(III) chemistry to generate the complementary dibenzyl and di-tert-butyl phosphonate esters. These forms of the triazole analogue are fully compatible with standard Fmoc-SPPS and are therefore ideal for wider application by the chemical and biochemical community.     

Bis(phosphonate)‐Building Blocks Modified with Fluorescent Dyes

Preparation of two benzylic bis(phosphonic acids) modified with primary amine or carboxylic acid groups on the benzene ring is described. These compounds were prepared and characterized in the form of both bis(phosphonate) tetraesters and corresponding free acids. The phosphonic acid esters are suitable for further derivation, mainly for conjugation through the amide bond. Mild conversion of the bis(phosphonate) esters to free acids using trimethylsilylbromide allowed to work with functional groups sensitive to conditions of acidic and/or alkaline hydrolysis. Three bis(phosphonate)‐containing fluorescent probes were prepared from the building blocks, utilizing amide and sulfamide bonds as spacers. Dyes containing the dansyl group, rhodamine B, and fluorescein were chosen due to their common availability and low cost. The prepared bis(phosphonate)‐building blocks and modified fluorescent probes were used for adsorption studies with hydroxyapatite, the commonly used model of bone tissue. Sorption ability of the prepared bis(phosphonate) compounds was similar to that of pamidronate.     

环状膦酸酯的合成及其质谱特征

本文研究了环状膦酸酯的合成方法，通过三种方法合成了十五个具有各种烷基结构的六元和七元环膦酸酯，并对这十五个化合物质谱作了分析和归纳，得出了一些有助于鉴定这类膦酸酯的质谱特征。     

Methods of synthesis and synthetic application of α-diazomethylphosphonates

Data on methods of synthesis and reactivity of α-diazomethylphosphonic acid esters are classified. Main approaches to obtain diazomethylphosphonate ester (the Seyferth—Gilbert reagent) as well as α-substituted diazomethylphosphonates are considered. The most important reactions of α-diazomethylphosphonates are discussed: [1+2] cycloaddition to alkenes, insertion into heteroatom—heteroatom bonds, reactions with aldehydes and ketones, being of interest as preparative methods to obtain cyclopropane phosphonates, α-substituted methylphosphonic esters and alkynes, correspondingly.     

Biomimetic synthesis of esters of natural amino acids

A method for the synthesis of Gly, Ala, Phe, and Thr esters is proposed and considered as being a stage of possible biomimetic synthesis of peptides. The methyl esters of the said amino acids are obtained via intervention of 2‐hydroxypropyl phosphonate. The resulting aminoacyl phosphonates reacts with methanol to produce the amino acid methyl esters, with the release of phosphoric acid. The reaction is carried out at room temperature in water. © 2008 Wiley Periodicals, Inc. Heteroatom Chem 19:252–255, 2008; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20427     

P and H NMR studies of the transesterification polymerization of polyphosphonate oligomers

Polymeric phosphonate esters are an interesting class of organophosphorus polymers because both the polymer backbone and phosphorus substituents can be modified. These polymers have been prepared by ring-opening polymerizations of cyclic phosphites, stoichiometric polycondensations of dimethyl phosphonate with diols in conjunction with diazomethane treatment and by transesterification of polyphosphonate oligomers. Our initial attempts to prepare high molecular weight polymeric phosphonate esters by the transesterification methods were unsuccessful. Results indicate that the reactions of dimethyl phosphonate with diols to form polyphosphonate oligomers with only methyl phosphonate end groups are plagued by a serious side reaction that forms phosphonic acid end groups. These end groups do not participate in the transesterification reaction and limit the molecular weights of the polymers that can be obtained. The phosphonic acid end groups can be converted into reactive methyl phosphonate end groups by treatment with diazomethane, however diazomethane is explosive and the polymerization is slow. An alternative route for the production of high molecular weight polymers is the transesterification of the 1,12-bis(methyl phosphonato)dodecane, formed by the reaction of excess dimethyl phosphonate and 1,12-dodecanediol, with a Na₂CO₃ promoter. This allows polymers with molecular weights of up to 4.5×10⁴ to be prepared, and no phosphonic acid end groups are observed in these polymers. Thermal analyses of the poly(1,12-dodecamethylene phosphonate) have shown that this polymer has reasonable thermal stability (onset of thermal decomposition at 273 °C). This polymer also undergoes a cold crystallization process at 15 °C similar to that which has been observed in some polyesters, polyamides and elastomers.     

Synthesis and herbicidal activities of methyl-1-(2,4-dichlorophenoxyacetoxy)alkylphosphonate monosalts

A series of 1-(2,4-dichlorophenoxyacetoxy)alkylphosphonic acid dimethyl esters 5 and its corresponding phosphonate monosalts 6 were synthesized as potential herbicide. The phosphonate monosalts can be prepared from 1-(2,4-dichlorophenoxyacetoxy)alkylphosphonic acid dimethyl esters 5, which were synthesized by the condensation of O,O-dimethyl-1-hydroxyalkylphosphonates with dichlorophenoxyacetic chloride. This method provides a simple and efficient procedure for the synthesis of phosphonate derivatives containing sensitive groups to acid, base or water such as carboxylate ester bond; and the herbicidal activity of title compounds was evaluated in a set of experiments in greenhouse. Most of the compounds exhibited notable herbicidal activity.     

Synthesis and photophysical properties of benzo[c]thiophene,p-phenylene-, triphenylamine-, and pyrene-based vinylenes

An efficient synthesis of benzo[c]thiophenyl/p-phenylenyl/pyrenyl phosphonate esters has been achieved using ZnBr₂-catalyzed Michaelis–Arbuzov reaction of corresponding benzyl alcohol/bromides at room temperature. Horner–Wadsworth–Emmons reaction of the phosphonate esters with aryl/heteroaryl aldehydes in the presence of t-BuOK furnished the vinylenes in good yields. The absorption and emission characteristics of the synthesized vinylenes were also reported.     

Supported liquid membrane separation of amine and amino acid derivatives with chiral esters of phosphoric acids as carriers

Studies on the possible use of phosphate and phosphonate esters bearing chiral menthol or nopol moieties as carriers for the transport of amines, amino acids, and amino acid esters through supported liquid membranes (SLM) are presented. Additionally, the enantioselectivity of the SLM transport of alkyl esters of aromatic amino acids and a non‐protein amino acid was also evaluated. It could be concluded that the extent of transport strongly depends on the hydrophobicity of the amino compound. Moreover, the carrier structure also influences the transport of those compounds through SLM: chiral phosphate and phosphonate esters appear to be poor or moderate carriers for enantioselective SLM transport of amino acids and their esters. The transport efficiency and selectivity is strongly dependent on the structure of both the transported compounds and the carrier. However, no meaningful relationship exists between these structural features and transportation or enantioselectivity.     

Efficient synthesis of β-lactam containing α-hydroxy phosphonates using tartaric acid and fumaric acid as mild catalysts

A short and efficient protocol for the synthesis of β-lactam containing α-hydroxy phosphonate esters using inexpensive catalysts such as tartaric acid and fumaric acid is described.     

Method for the rapid synthesis of highly functionalized 2-hydroxy-1-naphthoates. Syntheses of the naphthoic acid components of neocarzinostatin chromophore and N1999A2

We describe a four-step sequence for the synthesis of complex 2-hydroxy-1-naphthoic acids involving Z-selective olefination of benzaldehyde derivatives with a novel dioxolenone-containing phenyl phosphonate reagent, followed by dioxolenone cleavage with alkaline trifluoroethanol and oxidative cyclization (Mn(OAc)(3)) of the resultant trifluoroethyl beta-keto esters. [reaction: see text]     

Synthesis of 2,2′-Biindolyls; Potential Intermediates for Indolocarbazole Alkaloids

The synthesis of 2,2′-biindolyls oxygenated in the benzenoid ring is reported. Wittig-Horner reaction of the phosphonate esters of 1-benzenesulfonyl-2- bromomethyl-3-substituted indoles with o-nitrobenzaldehydes followed by deoxygenation with triethyl phosphite gave 2,2′-biindolyls.     

Triethylamine-Mediated Transformation of Phosphonates into Phosphonamidates

Organophosphorus compounds such as phosphonamidates are gaining attention across different fields of chemistry, with interesting applications as pharmaceuticals, or pesticides. However, practical application of phosphonamidates is complicated by their difficult syntheses which often involve expensive or unstraightforward reagents and harsh conditions. To remedy these issues, we present a flexible, room temperature synthesis for novel P-alkylphosphonamidates without the need for intermediary purification. Commonly available phosphonates are first chlorinated by use of oxalyl chloride and phosphonylaminium salts are used to mediate the harsh reactivity of phosphonochloridates, giving rise to the desired products. We demonstrate the compatibility of our protocol with primary and secondary amines, as well as with different phosphonate esters. The proposed pathway also enables the synthesis of primary phosphonamidates using ammonium acetate as a cheap and safe alternative for ammonia. In future research, this protocol will also enable the synthesis of bioactive targets that are incompatible with current protocols.     

Synthesis of (2-Ethoxy-2-oxoethylthio)methyl Derivatives of Furoic Acids and Attempts of Their Intramolecular Cyclizations under the Conditions of the Claisen Reaction

Based on reactions of phosphorylated derivatives of halomethylfuroic acid esters with thioglycolic acid ester in the presence of bases, a method for the synthesis of mono-and bisphosphosphorylated esters of (2-ethoxy-2-oxoethylthio)methyl derivatives of furoic acids, containing an ester group in the position adjacent to the sulfide moiety was developed. Obtained compounds are relatively easily metallized with potassium tert-butylate, but intramolecular cyclization proceeds smoothly only in the case of 5-(diethoxyphosphorylmethyl)-2-(ethoxycarbonylmethylthiomethyl)furan-3-carboxylic acid. The resulting 1,3-dicarbonyl derivative of 7H-thiopyrano[3,4-b]furan is hydrolytically unstable, but its enol O-methyl ether is stabile. Alkaline hydrolysis of the latter compound was studied, and it was shown that it proceeds at the ester as well as at the phosphonate group.     

P-heterocyclic building blocks: application to the stereoselective synthesis of P-sugars

A strategy relying on the utilization of stereoselective additions to allyldiphenylphosphonate esters and subsequent ring-closing metathesis (RCM) to access P-chiral P-heterocyclic building blocks for the synthesis of phosphono sugars is described. These building blocks possess several attractive components, including the following: (i) P(2) and C(6) stereogenic centers for directing stereoselective transformations; (ii) an activated C(3) methylene group that promotes base-mediated olefin transposition to generate vinyl phosphonates available for further stereoselective reactions; and (iii) a P(2)-stereogenic center containing an exchangeable phosphonate ester armed to attenuate the "stereochemical environment" at phosphorus. Taken collectively, these attributes contribute to a concise method for the stereoselective synthesis of an array of P-sugars.     

Synthetic and mechanistic aspects of halo-F-methylphosphonates

The synthesis of a variety of new halo-F-methylphosphonates has been achieved by a Michaelis-Arbuzov type reaction between a halo-F-methane and a trialkyl phosphite. This synthesis has proved to be of wide scope and utility for the high yield preparation of a number of heretofore unknown compounds. The ¹H, ¹⁹F, ¹³C and ³¹P NMR spectroscopic properties are reported in detail. The mechanism for the formation of bromodifluoromethylphosphonates has been shown to proceed through the intermediacy of difluorocarbene:CF₂. The phosphonate products have been shown to react with a wide variety of reagents. Fluoride and alkoxide ions react by attack at phosphorus with cleavage of the carbon-phosphorus bond and formation of [:CF₂] from the bromodifluoromethylphosphonates and the CFBr₂⁻ anion from the dibromofluoromethylphosphonates. Iodide ion and tertiary phosphines react by attack at the ester carbon to give stable phosphonate salts. Hydrolysis of the phosphonate esters with 50% aqueous HCl gives the expected phosphonic acids. Trimethylsilyl bromide attacks phosphoryl oxygen to afford the bis(trimethylsilyl) esters.     

Lipase active-site-directed anchoring of organometallics: metallopincer/protein hybrids

The work described herein presents a strategy for the regioselective introduction of organometallic complexes into the active site of the lipase cutinase. Nitrophenol phosphonate esters, well known for their lipase inhibitory activity, are used as anchor functionalities and were found to be ideal tools to develop a single-site-directed immobilization method. A small series of phosphonate esters, covalently attached to ECE "pincer"-type d8-metal complexes through a propyl tether (ECE=[C6H3(CH2E)(2)-2,6]-; E=NR2 or SR), were designed and synthesized. Cutinase was treated with these organometallic phosphonate esters and the new metal-complex/protein hybrids were identified as containing exactly one organometallic unit per protein. The organometallic proteins were purified by membrane dialysis and analyzed by ESI-mass spectrometry. The major advantages of this strategy are: 1) one transition metal can be introduced regioselectively and, hence, the metal environment can potentially be fine-tuned; 2) purification procedures are facile due to the use of pre-synthesized metal complexes; and, most importantly, 3) the covalent attachment of robust organometallic pincer complexes to an enzyme is achieved, which will prevent metal leaching from these hybrids. The approach presented herein can be regarded as a tool in the development of regio- and enantioselective catalyst as well as analytical probes for studying enzyme properties (e.g., structure) and, hence, is a "proof-of-principle design" study in enzyme chemistry.