Phosphoramidous diesters

The reactions between a,j -unsaturated carboxylic acids and phosphoramidous diesters or phosphorodiamidous esters are, as might be expected, more complex than those with phosphorus(III) triesters. The products from propenoic acid and EtOP(NEt2)2 include the amides 449 and 450 (in 21% total yield), the phosphonic amide 451 (26%) and N,N-... 

Variations in the phosphorus reactant include the use of phosphonous diesters, RP(0R )2, which lead to the monoacylphosphinic esters (488) (R = alkyl or aryl, R = alkyl, alkenyl or aryl n = 0) and phosphoramidous diesters, Et2NP(OR)2 and (Et2N)2POR, which with R COCl yield the monoamides 488 (R = NEt2, R = alkyl or Ph = 0) and diamides, R C0P(0)(NEt2)2 Well characterized products have been obtained from 2-methoxy-4,4,5,5,-tetramethyl-l,3,2-dioxaphospholane in which the five-mem-beredringisretained ... 

Dimethyl [a-(hydroxyimino)benzyl]phosphonate is stable in mineral acid but decomposes in formic acid containing formate with the liberation of benzonitrile, but otherwise the behaviour is different from that in boiling acetic acid when an additional product, a phosphoramidate ester, is obtained by a Beckmann rearrangement. For the oximes of the (4-methoxybenzoyl)- or (4-chlorobenzoyl)-phosphonic esters, only the phosphoramidate diester 127 is obtained, but for all the substrates examined [additionally the unsubstituted benzoyl- as well as the (4-methylbenzoyl)phosphonic derivatives], the formation of the phosphoramidate ester demonstrates a high migratory aptitude of the phosphinoyl group (Scheme 22) ... 

Mulliez and Wolf (1986) have studied the aminolysis and alcoholysis of similar five-membered species [29] to those studied by Kluger et al. (1987). Initial exocyclic cleavage is observed in solvolysis of the phosphoramidate diester [29a], whereas the phosphonamidate [29b] undergoes alcoholysis and hydrolysis with endocyclic P—N bond cleavage. These reactivity patterns are most easily accommodated by a mechanistic scheme in which initial attack is apical to nitrogen. 

Compound (1) phosphorylates phosphate monoesters and alcohols, although with the latter a considerable excess of alcohol is necessary to obtain satisfactory yields. In the absence of mercuric ions the milder phosphorylating species (3) can be isolated which converts monoalkyl phosphates to pyrophosphate diesters in good yield but does not react appreciably with alcohols unless catalytic amounts of boron trifluoride are added. Amine salts of (3) are converted to phosphoramidates on heating. In the presence of silver ions, O-esters of thiophosphoric acid behave as phosphorylating agents and a very mild and convenient procedure suitable for preparing labile unsymmetrical pyrophosphate diesters, such as the... 

Diesters of phosphoramidic acid are converted to the corresponding isocyanates by phosgene but with A-substituted derivatives the phosphoramidic chlorides are formed. In a similar reaction oxalyl chloride... 

Carbodi-imides are used to mediate the formation of amide linkage betwen a carboxylate and an amine or phosphoramidate linkages between a phosphate and an amine [12]. The following is essentially the method of Rockwood [13] and is modified to give a phospho-diester link between the terminal monophosphate of the oligonucleotide and the hydroxyl group of 2-hydroxyethyl disulfide (HEDS) [14]. 

A more complex pathway of activation is seen in N-amino acid derivative of phosphoramidic acid diesters of antiviral nucleosides, as exemplified by prodrugs of stavudine (9.79, Fig. 9.14) [153 -155], The activation begins with a carboxylesterase-mediated hydrolysis of the terminal carboxylate. This is followed by a spontaneous nucleophilic cyclization-elimination, which forms a mixed-anhydride pentacycle (9.80, Fig. 9.14). The latter hydrolyzes spontaneously and rapidly to the corresponding phosphoramidic acid monoester (9.81, Fig. 9.14), which can then be processed by phosphodiesterase to the nucleoside 5 -monophosphate, and by possible further hydrolysis to the nucleoside. 

The beauty of this reaction lies in the fact that nearly all the facts needed to elucidate the mechanism are, in one way or another, in the products. Although the formation of II might seem somewhat tantalizing at first, a second glance will reveal that simply isomerization of I will suffice to account for it. A rather unusual isomerization, however, because activation of the a carbon of the ester as a nucleophile and introduction of foimaldehyde (from where ) at this carbon need justification. The first argument may be reformulated as the formation of an ester enolate, which is made possible by the advent of lithium amide superbases such as lithium diisopropyl amide (LDA) in aprotic tetrahydrofuran (THF)-hexamethyl-phosphoramide (HMPA) solvent mixtures. The participation of an ester enolate is emphasized by the formation of condensed diester IV. 

Symmetrical dinucleoside phosphoramidates and iV-substituted phosphora-midates (63) and (64) were obtained after oxidative coupling of the symmetrical //-phosphonate diester of AZT with the appropriate amine Biological evaluation on HIV-infected TK-deficient cell lines suggested that such dinucleoside phosphoramidates could not be regarded as pronucleotides, as they were unable to deliver the corresponding 5 -nucleotide inside the cells. 

Enol ethers from (2-oxoalkyl)phosphonic diesters are themselves highly reactive in hydrolysis and addition reactions. (2-Butoxyethenyl)phosphonic dichloride in CCI4 solution readily adds bromine in the cold, but attempts to distil the resultant (1,2-dibro-mo-2-butoxyethyl)phosphonic dichloride result in dehydrobromination the product 334 is unreactive to further attempted bromination, but suffers ready hydrolysis to (1-hydroxy-2-oxoethyl)phosphonic acid, and similarly, hydrolysis of the precursor dichloride yields (2-oxoethyl)phosphonic acid. Reactions between enol ethers and amides, carbamates or phosphoramidates, under acidic conditions, yield the enamides 335 [R = CO-alkyl, CO-aryl, COO-alkyl or P(0)(0Pr%f (2-Alkoxyethenyl)phosphonic diisocyanates act as precursors to phosphapyrimidines 336 and analogous phosphapurines ... 

The bis (o, rn and p-nitrophenyOphosphate triesters of AZT have been found to be potent and non-toxic inhibitors of HIV in TK+ strains, but display comparably poor activity in TK strains to that of AZT. Thus their mode of action differs from that of the phosphoramidates mentioned earlier in that they act as prodrugs of the free nucleoside rather than as nucleotide delivery forms. A study of several aryl phosphotriesters of AZT has revealed that the anti-HIV activity is inversely related to the pKa of the respective phenol and probably therefore related to its leaving group ability. It has been shown that the triester is hydroly.sed in human plasma to the corresponding diester which is probably dephosphorylated extracellularly and thus enters the cell as the free nucleoside by diffusion. 

In 2010, Rueping s group reported the first enantioselective approach toward the synthesis of 4-substituted-4,5-dihydro-l//-[l,5]benzodiazepin-2(3//)-ones, which resemble cyclic (3-amino acids [65]. Due to the basic nature of these benzodiaze-pinones, the reactions conducted with various chiral phosphoric acid diesters gave only very low conversion, while improved reactivity was obtained when the corresponding Wtriflyl phosphoramides were employed as catalysts, with 2-naphthyl derivative selected as the best-performing one. Microwave irradiation proved to be beneficial to further improve the yields, and the reduction, followed by subsequent... 

Methodology. Filippov has reported a one-pot procedure to prepare phosphate, phosphorothioate and phosphorofluoridate monoesters as well as pyrophosphate monoesters of nucleosides. This versatile approach made use of di(p-methoxybenzyl)-A, A -diisopropylphosphoramidite. While little information was provided on the preparation and stability of the phosphoramidite reagent, its use in the reaction with benzoate-protected thymidine in the presence of dicyanoimidazole as an activator yielded the di(p-methoxybenzyl)phosphite of thymidine [46]. This phosphite could subsequently be oxidised (Scheme 3) to the phenylthioate ester [47a], the phosphate monoesters [47b], the phosphoramidate [47c, d], the phosphorofluoridate [47e], the nitrophenolate diester [47f] and to the fully protected dinucleotide [47g]." ... 

With familiarity of the various protecting groups available for the hydroxyl and base amino functions, it is possible to prepare nucleoside intermediates with reactive groups available only for the formation of a 3, 5 -phospho-diester linkage. Unwanted reactions (3, 3 - or 5, 5 -phosphodiester formation, phosphoramidate formation, etc.) cannot possibly occur with the selection of appropriate intermediates. A representative example would be the condensation between adenosine and uridine ... 

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