Hydrolysis of phosphoramidates

Mechanistically, the compounds (162 X = O or S) and (163) represent two extremes in the base hydrolysis of phosphoramidates and phosphoramidothioates the former hydrolyse in an elimination-addition (EA) process whereas for the latter the sequence is one of addition followed by elimination AE). Further exploration of... 

An obvious difficulty arises with this rather elaborate rationale when phosphoramidate and aryl phosphoramidate monoanions are compared for example, the dissimilarity of the dioxan effect yet the identity of product distribution observed in methanol-water competition experiments. Preliminary studies in the author s laboratory have revealed striking differences in the hydrolytic behavior between a series of phosphoramidafes derived from primary aliphatic amines and the above aryl systems. No linear structure-reactivity relationship between the logarithmic rate of hydrolysis of the monoanion species and the pKa of the amine is observed19. Moreover, the rate of hydrolysis of phosphoramidate monoanions derived from aliphatic amines is at least 104 times slower than those formed from aryl amines. In contrast, only a thirtyfold decrease in rate is observed for the corresponding ApKa in the O-phos-phate monoester series. The suspicion that mechanism (1), even with the above proposed modification, is not an accurate description of phosphoramidate monoanion hydrolysis derives some further support from the observation that the monoanion is subject to nucleophilic attack by substituted pyridines al-... 

Hydrolysis of phosphoramidic acid (NH2-P03H2) has been studied " in the acidity range pH 2-8, in aqueous solution and in some mixed solvents. Reaction appears to occur through the mono-anion, the neutral molecule and through a protonated species (rate equation (1) and Table 13). 

Another example of reagent-induced asymmetric synthesis is the enantioselective preparation of phosphoramides 6 by addition of dialkylzine reagents to A-diphenylphosphinoylimincs 4 in the presence of the enantiomerically pure 1,2-amino alcohols 5a or 5 b (diethylzinc does not add to A-silyl- or A-phenylimines)12. Phosphoramides 6 (crystalline solids) are obtained in moderate to good yield and good enantioselectivity. The latter can be enhanced by recrystallization. Acidic hydrolysis with dilute 3 M hydrochloric acid/tetrahydrofuran provides the corresponding amines 7 without any racemization. 

Phosphoramidates continue to attract much attention, not only with regard to their interest in organophosphorus chemistry but also in the context of general organic synthesis. Acid hydrolysis of the phosphoramidates (123) and (124) with... 

Relatively low molecular weight polymers include R1R2P(0)(N=PR1Ra) n-PRxR2OH (R1, R2 included alkyl, aryl, and alkoxy)175 and phosphoramidic acids from the hydrolysis of (NPC12)W,178 the latter of which form hydrophobic materials. 

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. 

A few organophosphorus insecticides are also phosphoramidates, hydrolysis of the P-N bond being considered a route of detoxification. This is exemplified by the metabolism of acephate (9.82, Fig. 9.15), whose mechanisms of activation and detoxification have recently been re-examined in mice to better understand the relative innocuity of the compound in mammals and its selective toxicity in insects [156],... 

The study of the monoanions of a third class of phosphorus-containing monoesters, the phosphoramidates, has been restricted for the present to p- and o-substituted aryl phosphoramidates, and phosphoramidate and its O-methyl derivatives13-16. Two striking differences from the behavior of O- and S-phos-phate monoester monoanions are noted in the experimental criteria compiled in order to postulate mechanism (a) solvolysis in mixed organic solvents, particularly 50% v/v dioxan-water, results in a 50% decrease in the rate of hydrolysis of o- and p-substituted aryl phosphoramidate monoanions and all ionic forms of phosphoramidate and its O-methyl derivatives excepting the parent monoanion, and (b) partitioning of the aryl phosphoramidates and phos-... 

Tabic 7.7 Product ratios in the hydrolysis of phosphate esters and phosphoramidates by alkaline phosphatase"... 

The basic hydrolysis of acyclic phosphoramidates occurs with a mixture of C-0 and P-0 bond cleavage (l, 2) however similar treatment of l,3>2-oxazaphospholidines can result in substantial P-N cleavage ( 1, 3). 1,3,2-Oxazaphospholidines derived from (-)-ephedrine react with solutions of alkoxides in alcohol to give only the products of P-N cleavage and with inversion of configuration at phosphorus. Scheme I ( +, 5). ... 

A related reaction is the addition of isonitriles 75 to aldehydes 1 (the Passerini reaction). Denmark has demonstrated that SiCU, upon activation by a chiral Lewis base, which increased the Lewis acidity of the silicon (vide supra Scheme 7.14), can mediate this reaction to produce a-hydroxy amides 77 after aqueous work-up (Scheme 7.16). Phosphoramide 60 was employed as the chiral Lewis-basic catalyst [74]. Modification of the procedure for hydrolysis of 76 gives rise to the corresponding methyl ester (rather than the amide 77) [74]. (For experimental details see Chapter 14.5.5). 

The kinetics of the alkaline hydrolysis of iV-alkyl OO-diphenyl phosphoramidates have been studied, as well as those of the acid hydrolysis of OO-dialkyl phos-phoramidates. ... 

O -Ethyl-iV,iV-dimethylamido phosphoric acid Ethyl-iV,iV-dimethyl phosphoramidate (EDPA) Ethyl hydrogen dimethylphosphoramidate c4h12no3p 2632-86-2 Hydrolysis of GA, identified in soiF... 

Dimethylphosphoramidate N,N-Dimethylphosphoramidate Dimethyl phosphoramidic acid c2h8no3p 33876-51-6 Hydrolysis of GA... 

This ease of synthesis of cyclic acetals makes them appropriate for the preparation of certain well-defined, mono-substituted esters of different origin. 2,3 4,5-Di-0-isopropylidene-/8-D-fructopyranose has been used for the synthesis of certain phosphoramidate compounds. The acetal is dissolved in 20 ml of toluene and refluxed for 6 to 8 hours in the presence of phosphoramidic chloride. The sirupy l-[iV,W-bis-(2-chloroethyl)phos-phoramidic chloride] (5) is then used for the preparation of other derivatives, such as the phosphoramidate itself. Hydrolysis with ethanolic hydrogen chloride removes the isopropylidene groups and results in the formation of ethyl /3-D-fructopyranoside l-[iV,JV-bis-(2-chloroethyl)phosphoramidate]. 

---