Phosphonous diesters

If alkyl groups are attached to the ylide carbon atom, cis-olefins are formed at low temperatures with stereoselectivity up to 98Vo. Sodium bis(trimethylsilyl)amide is a recommended base for this purpose. Electron withdrawing groups at the ylide carbon atom give rise to trans-stereoselectivity. If the carbon atom is connected with a polyene, mixtures of cis- and rrans-alkenes are formed. The trans-olefin is also stereoseiectively produced when phosphonate diester a-carbanions are used, because the elimination of a phosphate ester anion is slow (W.S. Wadsworth, 1977). 

Alkoxy titanium acylate derivatives coordinated with a phosphite diester (phosphonate diester) can be prepared by reaction of a tetraalkyl titanate and an equal molar amount of a carboxyUc acid, such as methacrylic acid or isostearic acid, and a phosphite or phosphonate diester, such as dibutyl hydrogen phosphite (103). These materials reduce the viscosity of a composite system, improve... 

Phosphonate diesters of the general formula RPCOXOR1) where R = Ci2H25 or C14H29 and R1 = CH3 or C2H5, are effective bacteriostats [161,273]. 

Glycine and its esters also readily form isolable trimeric HHT derivatives. These interme ates have also been successfully utilized in constructing the glyphosate backbone when they have sufficient thermal stability to tolerate the reaction conditions. For example, good overall yields of GLYH3 were obtained under similar conditions with the stable HHT of sodium glycinate 24 via the phosphonate diester 14b (30). 

An interesting variation of this reaction that made use of a three-component, one-pot solventless procedure with the corresponding trialkyl phosphites gave dramatically improved yields of many heterosubstituted glyphosate phosphonate diesters (37). When exactly one equivalent of water, 25, and tris-p-chloroethyl phosphite were mixed and heated under neat conditions for a few hours, nearly quantitative yields of displaced p-chloroethanol and the desired triester product 27 were obtained. If desired, the displaced alcohol was first removed by vacuum distillation, or the mixture could be hydrolyzed directly to GLYH3. Various oxygen, sulfur, nitrogen, cyano, and carboxylate functionalities were similarly accommodated in the trialkyl phosphite. 

Like similarly activated carboxylate esters, these aromatic phosphonate diesters 30 were readily hydrolyzed to GLYH3 in good yield and purity under typical strongly acidic or basic conditions, or in a stepwise fashion under extremely mild conditions via the zwitterionic monoaryl esters 32 (44). Products such as 32 or 33 readily precipitated after a few hours at room temperature from aqueous acetone. 

The benzyl phosphonate triesters 100 reacted with isocyanates under similar conditions to give the corresponding cyclic urea phosphonate diesters 101 (2). 

The synthesis of 5-phosphono-l,2,4-triazolin-3-one 137 began with the low-temperature metalation and phosphorylation (77) of the f-butyldimethylsilyl (TBDMS)-protectedlV-benzyl-tiiazolinone 134. The phosphonate diester 135 was obtained ter the silyl protecting group... 

Several benzothiazinone analogs have been synthesized in an attempt to introduce hetero substituents at the a-carbon center in these heterocyclic compounds. The required a-halo-benzothiazinone intermediate 148 was prepared by chlorination with sulfiiryl chloride. This material was used successfully in an Arbuzov reaction to prepare the phosphonate diester 149,... 

Preparation of a phosphonochloridate by reaction of a phosphonate diester with phosgene... 

Two reports are available on the rearrangement of mixed vinyl phosphite esters to produce phosphonate diesters in moderate yield.94 95 In both instances, the vinyl phosphite esters were prepared by reaction of the dialkyl phosphorous chloride with highly enolized carbonyl compounds. The mixed ester products undergo thermal rearrangement to the phosphonate diesters (Figure 6.25). 

To complement the above information, a highly enantioselective synthesis of a-amino phosphonate diesters should be mentioned.164 Addition of lithium diethyl phosphite to a variety of chiral imines gives a-amino phosphonate with good to excellent diastereoselectivity (de ranges from 76% to over 98%). The stereoselective addition of the nucleophile can be governed by the preexisting chirality of the chiral auxiliaries (Scheme 2-63). 

The H-phosphonate approach entails phosphitylation of a hydroxylic component with an activated unprotected derivative of phosphonic acid to furnish H-phosphonate (a stable tetra-coordinate form of the unprotected monophosphite) followed by oxidation on phosphorus. The H-phosphonate approach is not generally used for the synthesis of monophosphates due to the difficulty of oxidation of the H-phosphonate monoesters and the necessity either to render the phosphorus atom of H-phosphonate into the three-coordinate form by silylation (to form disilylphosphite) or to introduce a protecting group (to form H-phosphonate diester) prior to oxidation. Nevertheless, in rare cases, the H-phosphonate procedure turns out to be a method of choice if, for instance, the simultaneous oxidation of functional groups other than H-phosphonate is required.51... 

Figure 17 Generation, by the reactive immunization strategy, of antibody SP049H that catalyzes the hydrolysis of phosphonate diester 24 and that of ester 25.

Pharmacology Tenofovir disoproxil, an acyclic nucleoside phosphonate diester analog of adenosine monophosphate, inhibits the activity of HIV reverse transcriptase. 

Decomposition of the species with loss of the apical phenolate presumably would be more rapid than pseudorotation since any such process brings a negatively charged oxygen atom into an apical position. The stereospecific nature of the hydrolysis may also be viewed as arising from the linear steric requirements of nucleophilic displacements on phosphorus and may not involve the actual intermediacy of a pentacovalent species. A large rate enhancement (107) also has been discovered in the oxime-catalyzed hydrolysis of structurally similar phosphonate diester (57) 37. 

In a detailed study on phosphonate diester and phosphonamidate synthesis, Hirschmann, Smith, and co-workers reported that pyrophosphonate anhydrides may be produced as side products during conversion of phosphonate monoesters into phosphonochloridates. 72 They recommended adding the phosphonate monoester to a solution of the chlorinating agent (thionyl chloride or oxalyl chloride) to minimize formation of the less reactive anhydrides. They also found that addition of tertiary amines (e.g., TEA) to the phosphonochloridates, prior to addition of the alcohol or amine component, results in formation of a phospho-nyltrialkylammonium salt that is more reactive than the corresponding phosphonochloridate and leads to better yields of the phosphonate esters and amides. 

A soln of a (—)-4-nitrobenzyl [cyclohexyl(Fmoc-amino)methyl]phosphonic add (57 40.0 mg, 0.073 mmol) in CH2C12 (2mL) was cooled to 0°C, and dry DMF (6pL, 0.01 mmol) and oxalyl chloride (13 pL, 0.147 mmol) were added. The mixture was stirred for 0.5 h at 0°C, diluted with benzene (5mL), and concentrated. The phosphonochloridate was redissolved in benzene (2mL), and treated with TEA (20 pL, 0.147 mmol) followed by AgCN (29 mg, 0.217 mmol). After 5 min at rt, D-2-hydroxy-3-(l//-indol-3-yl)propanamide (22.4mg, 0.011 mmol) was introduced, and the mixture was heated at reflux for 2h, cooled to rt, filtered, and concentrated. The phosphonate diester was purified via flash chromatography (2% MeOH/CH2Cl2) to give a mixture of diastereomers (19.8mg, 37%), which were separated by RP-HPLC. For the minor diastereomer (4.5 mg, amorphous solid) [a]D +15 (c 0.47, EtOH). 

Scheme 27 Cleavage of Phosphonate Diesters with Bromotrimethylsilane 119"121 ...

This step is required for dimethylation of the phosphonate diester. 

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