Metaphosphates synthesis

Kornberg, A. Kornberg, S.R. Simms, E.S. Metaphosphate synthesis by an enzyme from Escherichia coli. Biochim. Biophys. Acta, 20, 215-227 (1956)... 

The intermediacy of a nucleoside metaphosphate in this synthesis was first discussed by Todd122). It could arise from the anhydrides 179 a-c formal as primary products and should effect phosphorylation of the nucleoside component. 

P-NMR spectroscopic studies on the reaction course of the dinucleotide synthesis from 3 -0-acetylthymidine 5 -phosphate (pT-Ac) (180a) and 5 -0-trityl-thymidine (Tr-T) in the presence of triisopropylbenzenesulfonyl chloride (TPS) confirm the metaphosphate hypothesis 123,124). Successive addition of 0.5 equiv. 

On use of N,N -dicyclohexylcarbodiimide instead of sulfonyl chlorides as condensation reagent in oligonucleotide synthesis, then the pyro-, tri- and tetraphosphate stages are again involved 124). The metaphosphate 183 a is found in small amounts by 3iP-NMR spectroscopy, but again no cyclic trimetaphosphate 184 can be detected, which would also be a possible phosphorylation reagent. 

It is still unclear how much general validity attaches to the metaphosphate mechanism as formulated for the present variant for the oligonucleotide synthesis. Depending upon the reaction conditions, preparative method, activating reagent, and length of the nucleotide block, other mechanisms may dominate. 

As early as 45 years ago, G. Schramm et al. (1962) carried out the synthesis of AMP, ADP and ATP using ethyl metaphosphate as the phosphorylating agent. These successful syntheses led to the formation of longer nucleotide chains however, they by no means correspond to the conditions present on the primordial Earth. Thus, the question as to the source of the phosphates remains paramount. According to Schwartz (1998), the following phosphate sources deserve consideration ... 

As discussed in Chapter 3, though phosphates exist in three structural forms, orthophosphates, pyrophosphates and metaphosphates, they are found in nature mainly as orthophosphates. The acid phosphates used in the synthesis of CBPCs, as well as the resulting products that constitute CBPCs are also orthophosphates, and therefore, this chapter is focused on orthophosphate minerals. Readers interested in other types of phosphates are referred to the excellent review by Corbridge et al. [1]. 

Keywords. Carbonylphosphonate, Ketone, Carboxylate, Bisphosphonate, Synthesis troika acid, Phosphorylation, Monomeric metaphosphate, Nucleotide... 

Synthesis of Phosphoric Acids and their Derivatives. - Among various approaches to phosphate esters the phosphorylation of phenols with dialkyl cyanophosphonate and the synthesis of triaryl phosphates under phase-transfer conditions are worthy of mention. Mixed trialkyl phosphates are also reported to be formed by brief cathodic electrolysis of the reaction of dialkyl phosphonates with aromatic aldehydes and ketones, presumably by rearrangement of the initial a-hydroxy compounds. Further reports have appeared of the generation of metaphosphates by various methods. The synthesis of analogues 1 of famesyl pyrophosphate which incorporate photoactive esters has been reported both compounds are competitive inhibitors of farnesyl transferase. 

Although phosphate monoesters chiral by virtue of oxygen isotope substitutions cannot be used in stereochemical studies of phosphate monoester hydrolysis (since there are only three stable isotopes of oxygen), they have been used profitably in studies of phosphoryl transfer reactions relevant to the question of the intermediacy of monomeric metaphosphate anion in phosphoryl transfer reactions (see Section III,A). The laboratories of Knowles and Lowe have reported general methods for the synthesis of phosphate monoesters chiral by virtue of oxygen isotope substitution, and these syntheses are summarized in this section. 

Considerable research effort has been focused on the preparation of compounds of biochemical interest, using electrophilic reactions of phosphoramidites and phosphorochloridites to prepare modified phosphates of nucleosides or lipids. Intense interest has been shown in the synthesis of myoinositol phosphates, and also of aminoalkylphosphonic acids and their derivatives and analogues. Away from the biological emphasis, however, the first (recorded) syntheses of acetylenic phosphates have been described, and so have the first 1-alkoxyphosphole, the first cis amino-iminophosphine, and the first dithiaphospholium ions ex Phosphorus semper aliquid novi The use of silyl phosphites for synthetic purposes seems to be an increasing trend, while the number of papers on metaphosphate seems to be in decline. 

Oximes, which are valuable intermediates for the conversion of oxoalkyl phosphonic diesters into those of aminoalkylphosphonic acids (Chapter 4, Section IV.C. 1. d), are also readily available, although it is necessary to prepare them with some care. Nevertheless, the feature of interest here is their ready degradability, particularly under aqueous conditions, and which has been intensively investigated by Breuer and coworkers. The necessity for care in the preparation of oximes of acylphosphonic diesters, is illustrated by the synthesis of dimethyl [a-(hydroxyimino)benzyl]phosphonate this compound exists in the thermodynamically more stable ( ) form which, under the influence of acid is converted into the less stable (Z) form, and both forms have been separately characterized by X-ray crystallography. The geometric isomers of the oxime differ in their behaviour under basic conditions with NaOH-MeOH, the ( ) form undergoes monodealkylation, whereas the (Z) isomer decomposes to dimethyl phosphate and benzonitrile. In aqueous solution, ( )-[a-(hydroxyimino)benzyl]phosphonic acid also decomposes into benzonitrile together with phosphoric acid, in a manner which is pH dependent, and consistent with a dissociative mechanism that involves the early formation of monomeric metaphosphate. ... 

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