Phosphorus triesters

A new method for the preparation of 5 -amino-5 -deox)mucleotides has been described, based on the reaction between phosphorus triesters and phenyl azide. Treatment of protected 5 -azido-5 -deoxynucleosides with trimethyl or triphenyl phosphite leads, after removal of the nucleoside protecting groups and one of the esterifying groups from the phosphoryl residue, to the phosphoramidates (9). Snake venom phosphodiesterase hydrolyses (9) to 5 -aminonucleosides. 

The formation of compounds 495 from phosphorus triesters and orthoalkanoic esters has already been referred to, and the same compounds are also obtainable when mixtures of hydrogenphosphonate or phosphonous acids [RP(0)(0H)H] and orthoalkanoic esters are heated in sealed tubes ... 

Hydrolytic rate data in the range Ho = —2 to pH 12 have been reported for a series of phosphorus triesters, the asymmetric dialkyl esters of 5 -0-pivaloyl-3 -uridylic acid (245 R = Et, CH2CH20Me, CH2CHF2). This provided scope for comparison with similar data for a series of symmetrical dialkyl esters of 5 -0-pivaloyl-3 -uridylic acid (246 R = Me, Et, IV, CH2CH20Me) reported previously by the same group and... 

On the other hand, phosphorous acid monoesters of lower alcohols easily undergo transesterification [75]. A preferred starting material is the triester of ethylene chlorohydrin, obtained by reaction of phosphorus trichloride with ethylene oxide, according to Eq. (28). 

The monoesters of phosphorous acid are therefore monobasic. The diesters are neutral and moderately resistant to oxidation. While the coordination number of phosphorus in triesters is three, the coordination number in mono- and diesters is four. 

The outlined scheme can also be used to calculate the amount of phosphoric acid triesters. In that case the difference must be formed of the total phosphorus content minus that of free phosphoric acid, phosphoric acid monoester, and phosphoric acid diester. The resulting value is then multiplied with the calculated molecular mass of the triester. 

Phosphotriesterase from P. diminuta (PTE) was found to exhibit high hydrolytic activity towards various types of tetracoordinated phosphorus acid esters. Apart from the phosphonothionate 92, phosphoric acid triesters 94 (Equation 45), °" benzenephosphonic acid diester 95 (Equation 46) ° and methyl-phenylphosphinic acid ester 96 (Equation 47) were also stereoselectively hydrolysed under kinetic resolution conditions. Of course, in the case of the latter three kinds of substrates, half of the reacting ester was irreversibly lost due to the formation of achiral phosphorus acids. 

The mechanism of phosphate ester hydrolysis by hydroxide is shown in Figure 1 for a phosphodiester substrate. A SN2 mechanism with a trigonal-bipyramidal transition state is generally accepted for the uncatalyzed cleavage of phosphodiesters and phosphotriesters by nucleophilic attack at phosphorus. In uncatalyzed phosphate monoester hydrolysis, a SN1 mechanism with formation of a (POj) intermediate competes with the SN2 mechanism. For alkyl phosphates, nucleophilic attack at the carbon atom is also relevant. In contrast, all enzymatic cleavage reactions of mono-, di-, and triesters seem to follow an SN2... 

The reaction depended upon the marked difference in reactivity between the chlorine atoms and the fluorine atom in phosphorus oxydichlorofluoride. In general, the reaction with alcohols waa clear-cut, and most of the phosphorofluoridic esters were obtained in excellent yield and uncontaminated with the phosphoric triester. For example, when ethyl alcohol and phosphorus oxydichlorofluoride were allowed to react in the odd, diethyl phosphorofluoridate (VII, R = Et) was obtained in 93 per cent yield. No tertiary base was necessary to remove the hydrogen chloride produced in the reaction. The general process was patented during the war.1... 

From phosphorus trichloride, benzyl alcohol and 2 mol. of a tertiary base, dibenzyl hydrogen phosphite (XIV), is obtained which on treatment with chlorine or a chlorinating agent (e.g. sulphuryl chloride)4 gives the phosphorochloridate (XV). Although not isolated, (XV) is almost certainly obtained by treatment of (XIV) with a polyhalogen hydrocarbon because reaction in the presence of an alcohol or of a primary or secondary amine gives a triester (XVI) or a phosphoramidate. 

Ah initio calculations to map out the gas-phase activation free energy profiles of the reactions of trimethyl phosphate (TMP) (246) with three nucleophiles, HO, MeO and F have been carried out. The calculations revealed, inter alia, a novel activation free-energy pathway for HO attack on TMP in the gas phase in which initial addition at phosphorus is followed by pseudorotation and subsequent elimination with simultaneous intramolecular proton transfer. Ah initio calculations and continuum dielectric methods have been employed to map out the lowest activation free-energy profiles for the alkaline hydrolysis of a five-membered cyclic phosphate, methyl ethylene phosphate (247), its acyclic analogue, trimethyl phosphate (246), and its six-membered ring counterpart, methyl propylene phosphate (248). The rate-limiting step for the three reactions was found to be hydroxyl ion attack at the phosphorus atom of the triester. ... 

Our aim was to synthesize phosphoric acid triesters XXV and XXVI by the reaction of chloromethyl methylnitrosamine with the corresponding silver salts. Workup allowed the isolation of crystalline substances which were shown to be triesters XXVII and XXVIII. By variation of the N-alkyl group in the nitrosamine from methyl to ethyl, the corresponding phosphoric ethyl ester were obtained. Thus it seems clear that the N-alkyl group was transferred to the oxygen of phosphorus... 

Chemical modification may also simply be achieved by complex formation with an optically active agent191. For example, the correlation of the configuration of chiral non-racemic phosphate triesters, such as 11 (see p 417)11, with the relative (when compared with ent- ) change in H chemical shift of the methoxy doublet induced by the addition of Eu(hfc)3192 has been used for the assignment of absolute configuration of optically active phosphate triesters (chiral at phosphorus), which were obtained by asymmetric synthesis as indicated. 

No triester of levoglucosan was found92 that polymerized at temperatures much below 0°. At —78°, the triacetate complexed with phosphorus pentafluoride, and, at high concentration, precipitated from solution.91 The tris(monofluoroacetate) failed to polymerize under a variety of conditions.91 The trinitrate polymerized at 0°, but the product was not fully characterized.92 Polymerization of the triacetate proceeded to reasonable conversions with a number of catalysts at 0°, but the viscosity and the stereoregularity of these polymers were low.92 In a simple, copolymerization experiment, it was demonstrated that the low polymerizability of levoglucosan triacetate was due not only to a failure to initiate but also to sluggish propagation.92... 

Other kinetically allowed mechanistic models, i.e. hydroxide ion attack on the monoanion, can be rejected on the grounds that the required rate coefficients far exceed that found for alkaline hydrolysis of phosphate triesters. At pH > 9 two new reactions appear, one yielding a 1,6-a.nhydro sugar by nucleophilic attack through a five-membered transition state of the 1-alkoxide ion upon C-6 with expulsion of phosphate trianion. The second is apparently general-base catalysis by 1-alkoxide of water attack on C-6 or phosphorus through greater than six-membered cyclic transition states. 

The product l-phospho-(S)-propane-l/2-diol 1 (here shown as R at phosphorus) is converted by in-line ring closure to an equimolar mixture of three cyclic diesters. These are methylated to give six cyclic triesters. Of these, only 3 and 6 give sharp 31P resonance because the 170 in the others broadens the lines. 

Predicted and observed 31P NMR spectra of the mixtures of syn and anti cyclic triesters derived from labeled samples of 1 phospho-(S)-propane-l/2-diols that are R and S at phosphorus. 

Here the subsequent oxidation can be neglected, and the products were readily separated by distillation. Again, low yields of triester were obtained when equivalent quantities of thioalkoxide and phosphorus were used. Evidence of incomplete conversion was obtained from the 31P NMR spectra of the reaction mixtures using... 

Phosphonic acid esters are derived from phosphonic acid (often erroneously called phosphorous acid), which is shown with some of its esters in Figure 18.3 Only two of the H atoms of phosphonic acid are ionizable, and hydrocarbon groups may be substituted for these atoms to give phosphonic acid esters. It is also possible to have esters in which a hydrocarbon moiety is substituted for the H atom that is bonded directly to the phosphorus atom. An example of such a compound is dimethylmethylphosphonate, shown in Figure 18.3. This type of compound has the same elemental formula as triesters of the hypothetical acid P(OH)3, phosphorous acid. Examples of triesters of phosphorous acid, such as trimethylphosphite, are shown in Figure 18.3. 

The phosphorus-based nerve gases and insecticides act by deactivating acetylcholinesterase. Note that all of these compounds have a good leaving group on the phosphorus. They react readily with the nucleophilic hydroxy group of the enzyme to form a phosphate triester in a reaction that is very similar, both in its mechanism and its product, to the reaction of an acyl chloride with an alcohol to form an ester ... 

Tissue esterases have been divided into two classes the A-type esterases, which are insensitive, and the B-type esterases, which are sensitive to inhibition by organo-phosphorus esters. The A esterases include the arylesterases, whereas the B esterases include cholinesterases of plasma, acetylcholinesterases of erythrocytes and nervous tissue, carboxylesterases, lipases, and so on. The nonspecific arylesterases that hydrolyze short-chain aromatic esters are activated by Ca2+ ions and are responsible for the hydrolysis of certain organophosphate triesters such as paraoxon (Figure 10.10B). 

This acid, PH(0)(0H)2, is obtained by treating PC13 or P406 with water when pure, it is a deliquescent colorless solid (mp 70.1°C, pK = 1.3). It can be oxidized to orthophosphate by various agents, but the reactions are slow and complex. The mono-, di-, and triesters can be obtained from reactions of alcohols or phenols with PC13 alone or in the presence of an organic base as hydrogen chloride acceptor. They can also be obtained directly from white phosphorus by the reaction... 

In no small measure because of the importance of such substances and processes as those just mentioned, the hydrolysis of phosphate esters has received much fundamental study. Triesters are attacked by OH at phosphorus and by H20 at carbon ... 

Shaw has reviewed the various approaches to the synthesis of organophos-phate-oligonucleosides and has further commented on their chemical and biophysical properties along with their interactions with various enzymes such as DNA-polymerases, and compared them to other members of the family of phosphorus modified nucleic acids. She also reported the synthesis of P-tyrosinyl(P-0)-5 -P-nucleosidyl boranophosphates (23a,b), as antiviral and anticancer prodrug candidates. The P-boranophosphates were prepared by reacting a phosphoramidite intermediate obtained from protected tyrosine and the protected nucleoside in the presence of IH-tetrazole, followed by in situ borona-tion of the phosphite triester intermediate. The two diastereomers were then separated by reverse-phase HPLC. ... 

Phosphorus oxychloride is a suitable reagent for preparation of the symmetrically substituted phospho-triesters of type (RO)3PO. The preparation is easily achieved by treatment of phosphorus oxychloride with 3 equiv. of alcohols or their metal salts. The reaction is generally promoted by a base or acid. Titanium trichloride is a particularly effective catalyst for the reaction. Conversion of POCI3 to unsymmetri-cally substituted phosphotriesters is achievable with difficulty. Phosphorochloridates and phosphorodichloridates have been used for the preparation of mixed tertiary phosphoric esters of type (ROlmPOfOROn (ffi = 1, n = 2, or m = 2, n = 1) in a very wide variety. Reaction of phosphorus oxychloride and 1 or 2 equiv. of alcohols followed by hydrolysis forms phosphomonoesters or phosphodi-esters, respectively. The hydrolysis may be generally effected by dilute aqueous alkali. Some phosphoFodichlori te intermediates are easily hydrolyzed by water. For example, the phosphorylation of a ribonucleoside (1 equation 4) with phosphorus oxychloride in an aqueous pyridine-acetonitrile mixture furnishes the nucleoside S -monophosphate (2) in excellent yield. ... 

After distilling off the excess phosphorus(V) oxychloride, the alkyl ester dichloride is reacted with an aqueous solution of sodium phenolate to the triester in a two-phase reaction ... 

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