Aryl phosphoramidates

Alkyl and glycosyl isocyanates and isothiocyanates are produced in good yield under phase-transfer catalytic conditions using either conventional soluble catalysts or polymer-supported catalysts [32, 33]. Acyl isothiocyanates are obtained under similar conditions [34]. A-Aryl phosphoramidates are converted via their reaction with carbon disulphide under basic conditions into the corresponding aryl isothiocyanates, when the reaction is catalysed by tetra-n-butylammonium bromide [35]. 

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-... 

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-... 

Acid-catalysed solvolysis of N-aryl phosphoramidates is characterised by the negative value of the reaction constant (p = -1.2).These inversed substituent effects illustrate two points discussed before. First, if the N-protonated form repre -sents the reactive intermediate in solvolysis of (2), much stronger dependence of the protonation preequilibrium on the effect of N-substitution is expected. Secondly, if the resonance effects are poorly transmitted to the P atom through the -NH- bridge, structural variation in the N-aryl substituent should have weak effect upon the ability of phosphorus to accept a nucleophile. 

Most recent work on aryl phosphoramidates has employed protected L-alanine esters for the amine moiety [126]. In several cases where the o-alanine analogues were prepared, they were found to display significantly lower activity [127-129]. One comparison of PMPA prodrugs reported that a phenyl phosphoramidate displayed a tenfold greater activity than the corresponding POC prodrug. 

While aryl phosphoramidates based on amino acids are by far the most common examples of this class, further variations in the ester and amine components certainly are known [142]. For example, in place of an aryl ester, a 3-acyloxymethoxypropyl group has been studied (e.g., 65), and hydrolysis of the ester was found to be 20 times faster than the corresponding phenyl phosphoramidate [131]. In this work, small differences in the reactivity of the Rp and Sp isomers were noted, but it was not possible to identify which was the more reactive (Fig. 14). 

A similar approach has been taken to prepare aryl phosphoramidates such as 99 [223], as prodmgs of SH2 domain analogs for Src/Lck inhibitors. The compounds exhibit low micromolar growth inhibition in Jurkat T cells, and undergo spontaneous hydrolysis with half-lives of approximately 30 min. The same masking groups have been applied in phosphonate 100 as a suspected SH2 domain blocker through inhibition of mitotic centromere-associated kinesin protein function in a panel of... 

Romanowska J, Sobkowski M, Szymanska-Michalak A, Kolodziej K, Dabrowska A, Lipniacki A, Piasek A, Pietrasiewicz ZM, Figltaowicz M, Gnranowski A et al (2011) Aryl H-phosphonates 17 (N-aryl)phosphoramidates of pyrimidine nucleoside analogues and their synthesis, selected properties, and anti-HIV activity. J Med Chem 54 6482-6491... 

Ruda GF, Wong PE, Alibu VP, Norval S, Read KD, Barrett MP, Gilbert IH (2010) Aryl phosphoramidates of 5-phospho erythronohydroxamic acid, a new class of potent trypanocidal compounds. J Med Chem 53 6071-6078... 

Kinetic studies of the acid hydrolysis of two A-aryl phosphoramidates XC6H4NHPO3H were reported, that of the A-(3-chloro-2-methylphenyl) compound at pH 0.00-7.46 and that of the A-(4-methyl-2-nitrophenyl) compound in 0.10-7.0M HCl. Kinetic studies in 30% dioxane-water at 338 K of the acid hydrolysis of bis[A-(4-methyl-2-nitrophenyl)] phosphoramidate at pH 0.00-7.46 were reported. ... 

SCHEME 3.72 Synthesis of N-aryl phosphoramidates through the phosphoramidation of C-H... 

Reaction of the (S)-amino alcohol 171 with A-(2-bromoethyl)phosphoramidic dichloride or aryl phosphonodichloridates 154 in the presence of triethylamine led to the formation of a single diastereomer in each case of 1,3,2 oxazaphospholidine-2-ones 172a-e (taking into consideration that in the 31P-NMR spectra only one singlet in the range 6.49-2.45 ppm was observed) (Scheme 48) [79],... 

Several approaches to the 1,2,3-triazole core have been published in 2000. Iodobenzene diacetate-mediated oxidation of hydrazones 152 led to fused 1,2,3-triazoloheterocycles 153 <00SC417>. Treatment of oxazolone 154 with iso-pentyl nitrite in the presence of acetic acid gave 1,2,3-triazole 155, a precursor to 3-(W-l,2,3-triazolyl)-substituted a,P-unsaturated a amino acid derivatives <00SC2863>. Aroyl-substituted ketene aminals 156 reacted with aryl azides to provide polysubstituted 1,23-triazoles 157 <00HC387>. 2-Aryl-2T/,4/f-imidazo[43-d][l,2,3]triazoles 159 were prepared from the reaction of triethyl AM-ethyl-2-methyl-4-nitro-l//-imidazol-5-yl phosphoramidate (158) with aryl isocyanates <00TL9889>. 

R = PhCHMe) have been prepared and distinguished by n.m.r. spectroscopy.31 Attempts to prepare 7V-aryl derivatives of cyclophosphamide by cyclization of the phosphoramides (36) proved unsuccessful.32 Although this type of reaction has proved to be of great value in the preparation of perhydro-l,3,2-oxazaphosphorines and 1,3,2-oxazaphospholidines when NaOEt, NaOH, or NaH are employed as reagent, in this instance the bis(chloroethyl)amide side-chain presents a further possible reaction site. However, steric effects, also considered as an explanation for instances of failure of the reaction (see Organophosphorus Chemistry , Vol. 7, p. Ill) may be operating adversely. 

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. 

In 2008, Yamamoto et al. disclosed an asymmetric 1,3-dipolar cycloaddition of diarylnitrones 156 with ethyl vinyl ether (157) (Scheme 66). Under the influence of the bulky chiral A-triflyl phosphoramide (5)-4s (5 mol%, R = 2,6- Prj-4-Ad-C Hj), the enrfo-products 158 were formed as the major diastereomers in good yields and enantioselectivities (66 to >99%, 7 1-32 1 endolexo, 70-93% ee(endo)) [86]. High asymmetric induction was achieved only with electron-deficient aryl groups on the nitrones. 

While the introduction of heteroatoms at non-bridging positions of the phosphodiester bond can be easily achieved, modifications involving bridging positions of the phosphorus centre often require elaborated chemical approaches. A novel P3 - N5 dinucleotide linkage (74) has now been described. Thymidine-3 -W-(thymidine-5 -yl)-/7-phosphonamidate (74a) was synthesised by reacting the appropriately protected 3 -aryl /7-phosphonate derivative of thymidine with the 3 -protected-5 -amino-thymidine in the presence of pivaloyl chloride. The phosphonamidate was subsequently oxidised to yield the dinucleoside phosphoramidate (74b) and dinucleoside phosphoramidothioate derivatives (74c). 

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