Phosphonate monoesters

Another instructive example is provided by a series of a-phenyl-a,P-dibromo-phosphonates 170, 171, 172. While the phosphonate dianion 170 fragments instantaneously at room temperature with formation of the POf ion (see also Sect. 4.1.3), the analogous reaction of the phosphonic monoester anion 171 leading to methyl metaphosphate 151 requires more drastic conditions and is at least 1000 times slower the diester 172 is essentially stable under the reaction conditions described for 171 addition of triethylamine leads to slow demethylation H0). The behavior of 171 contrasts with that of simple (3-haloalkylphosphonic monoesters which merely eliminate HHal on treatment with bases94. Thus it is the possibility of formation of a phenyl-conjugated double bond which supports the fragmentation of 171 to olefin + 151. 

If monomeric 151 is generated from the phosphonic monoester 171 (OH in place of Oe) in the presence of 2,2,6,6-tetramethylpyridine as base, then it also adds to carbonyl compounds U9,120). Thus acetophenone is smoothly phosphorylated to the corresponding enol phosphate in 90% yield. 

A most intriguing cycloaddition reaction of phosphoryl isocyanates with poly-a-haloaldehydes provides a heterocyclic phosphonate monoester/monoamide as an isolable but reactive species (Equation 3.20).353... 

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... 

Phosphate diester Phosphorothioate diester Phosphonate monoester Phosphonamidate... 

N. Li, J. Rahil, M. E. Wright, R. F. Pratt, Structure-Activity Studies of the Inhibition of Serine beta-Lactamases by Phosphonate Monoesters , Bioorg. Med. Chem. 1997, 5, 1783-1788. 

Phosphonamidates are usually prepared by coupling an activated phosphonate monoester with the amine of interest. Since most phosphonate amino add analogues are prepared as their diesters, this procedure first requires selective cleavage to the monoester. Activation from the phosphonic acid oxidation level typically involves preparation of the phosphono-chloridate, but it can also be accomplished by chlorination of an H-phosphinic acid analogue. 

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. 

After conversion of the phosphonate monoester into a phosphonochloridate, or subsequently to a phosphonamidate, a new chiral center at phosphorus is created. Thus, after coupling to a chiral amine, even optically pure aminoalkylphosphonate monoesters produce a mixture of two diastereomers (racemic aminoalkylphosphonates result in four diastereo-mers). It is often possible to separate these diastereomers chromatographically. Of course, this is not necessary if the phosphorus ester will eventually be hydrolyzed. 

Scheme 31 Synthesis of Phosphonate Monoesters by Esterification and Oxidation of H-Phosphinic Acids 63-1231...

An important advantage of the //-phosphonatc method is that at no stage of the synthetic route, is a labile phosphotriester prepared.1036 1041 1 8 The reaction of salicylchlorophosphite (Scheme 3.19) with a glucosamine derivative furnished a phosphite triester which was subsequently hydrolysed to the //-phosphonate monoester. The latter compound was coupled... 

The incorporation of fluorine into biologically active compounds can greatly enhance their potency fluoroalkyl phosphonates are isosteres of the natural phosphonate monoesters. The alkylation chemistry of a-fluoro- and a,a-difluoro-alkyl phosphonates has been reported. Burton and Sprague have described the alkylation of (diethoxyphosphoryl)difluoromethylzinc bromide with allylic halides the reaction is catalyzed by copper(I) bromide. The alkylation of (diethoxyphosphoryl)dichloromethyllithium was reported by Normant and coworkers. The products can be transmetallated and further alkylated. 

The synthesis of the cyclic 2 -deoxyribodinucleotides 82 by a solution-phase H-phosphonate method has been described in which a 5 -protected nucleoside-3 -H-phosphonate (83) is first coupled to a nucleoside 3 -H-phosphonate diester (84). Removal of the cyanoethyl group from the 3 -phosphonate group reveals an H-phosphonate monoester function which remains intact during oxidation of the internucleoside H-phosphonate diester linkage. After further deprotection, this 3 -H-phosphonate is reacted to produce the cyclic derivative 82 in 15% overall yield. 

Concerning the oxygen-containing bidentate ligands [R E02+ ] and MC, discrete dimeric, tetrameric and hexameric ring assemblies have been reported for organotin carboxylate, phosphinate, phosphonate monoester, phosphate diester, " sulfonate, and tungstate derivatives. 

The Class II DMBPs are able to ion exchange with one ligand and coordinate with a different ligand. The phosphonate monoester/diester polymer (Figure 1) is a representative example and will be discussed in more detail below (14). The phosphonic acid/dimethylamine polymer is another example of this class. 

A detailed NMR study of the mechanism of ribozymomimetic phos-phonylation with phosphorus acid and two oxiranes revealed consecutive formation of p-hydroxy-if-phosphonate monoesters (38a,b), di-(P-hydroxyalkyl)-H-phosphonates (39a,b), alkylene-H-phosphonates (40a,b), p-hydroxyalkylalky-lene phosphites (41a,b) and the corresponding stereoelectronically-stabilized H-tetraoxaspirophosphoranes (42a,b). The equilbrium between (41 a,b) and (42a,b) shifts towards (41a,b) at higher temperature. " ... 

Transformations of nucleoside H-phosphonate monoesters into their corresponding if-phosphonothioate and H-phosphonodithioate derivatives and the nature of the side-reactions that may accompany these processes have been... 

The only exception was an attempt at the 5 -to-3 solid-phase oligonucleotide synthesis using nucleoside 3 -H-phosphonate monoesters, polymer-bound through a trityl-type linker, and oxidative coupling conditions (HgCl2) [123], The H-phosphonates were produced by phosphitylation of the polymer-bound N-unpro-tected nucleoside with phosphorus trichloride followed by hydrolysis by aqueous pyridine [61c]. However, despite some advanced features [124] the stepwise yields were comparable with those in the contemporary phosphodiester method-that is they were too low for the method to be truly competitive. 

An additional reason for the inferior performance of the H-phosphonate method compared to the phosphoramidite lies in its mechanism, which makes the synthesis very sensitive to pre-activation of the H-phosphonate monoesters with the conventional coupling agents, which must be avoided [138], However, the main appeal of the H-phosphonate approach lies in the ease it offers for the synthesis of backbone analogues modified at the phosphorus atom phosphorothioates [139], phos-photriesters [126] and especially phosphoramidates [126, 140, 141]. Now it is rarely used for routine oligonucleotide synthesis but very often for the preparation of variously modified analogues. Further developments in the H-phosphonate method have been made in the last decade by Polish [142] and Japanese researchers [143]. 

The methodology has been resurrected very recently in the H-phosphonate variant. An attempt by Adamo et al. [326] to use a chlorosulfonated polystyrene resin for activation of the nucleoside H-phosphonate monoesters was not particularly impressive, but the corresponding chlorocarbonylated polystyrene performed well, permitting the synthesis of up to a hexanucleotide. Similar results were reported by Mohe et al. [327] for the dinucleoside H-phosphonate synthesis promoted by a phosphorochloridate supported on polystyrene. 

Addition of hypophosphorous acid, PH(OH)2 to Schiff bases, yielding (l-aminoalkyl)phosphorous acids, can also be effected by mixing the three reactants.129 Further, Schiff bases have also been added to dialkyl thiophos-phites,130 phosphonous monoesters,130 secondary phosphine oxides,117 and metal derivatives of secondary phosphines 131 these phosphides, however, give well-defined products only after hydrolytic working up to phosphine oxides. 

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