Nucleosides 5 -phosphates from 5 -phosphites

Phosphorus is abundant on Earth, both as an element (the llth-most abundant atom in Earth s crust) and as phosphate. Meteorites hold a variety of phosphate-containing minerals and some phosphide minerals.10 Scientists at the University of Arizona have recently suggested that Fe3P, the mineral schreibersite, leads to the formation of phosphate and phosphite when corroded in water. Although phosphorylation of alcohols was not demonstrated, mechanistic considerations suggest that it should be possible. It is noteworthy that a clear prebiotic pathway for the chemical incorporation of phosphate into RNA or DNA has not been found. No nucleosides (nucleobases joined to sugars) have been reported from meteorites. Nor has evidence been found in any meteorite of the presence of nucleosides or nucleotides (nucleosides attached to phosphates). That suggests that nucleic acids were first formed as products of metabolism. 

The thermal synthesis of nucleoside-5 -phosphite monoester using (NH HPCb was carried out under relatively mild conditions (60°C, reaction time about 24 h) by A. W. Schwartz s group in Nijmegen, Holland in the case of uridine, the yield was 20%. Ammonium phosphate, however, cannot be used it gave yields of only 0.15% after very long reaction times (46 days). This confirms earlier suggestions that nucleoside-H-phosphonates, and condensation products possibly derived from them, would have been formed more readily on the primeval Earth than nucleotides (de Graaf and Schwartz, 2005). 

Bis(trimethylsilyl) peroxide, (CH3)3SiOOSi(CH3)3, is prepared from trimethylsilyl chloride, l,4-diaza[2,2,2]bicyclooctane, and Dabco s complex with 2 mol of hydrogen peroxide [127]. It is used alone [228] or in the presence of catalysts such as pyridinium dichromate [236] trimethylsilyl trifluoromethanesulfonate, CF3S03Si(CH3)3 [228, 237] or tris-(triphenylphosphine)ruthenium dichloride, [(C6H5)3P]3RuCl2 [236]. This reagent oxidizes primary alcohols to aldehydes (in preference to the oxidation of secondary alcohols to ketones [236]), ketones to esters or lactones Baeyer-Villiger reaction) [238], and nucleoside phosphites to phosphates [228]. All these oxidations require anhydrous conditions. 

Synthesis of Phosphoric Acids and their Derivatives.-New approaches to the preparation of dialkyl phosphorofluoridates include the treatment of a vinyl phosphate, e.g.,(l), or an irninophosphace, e.g.,(2), with triethylamine tris(hydrogen fluoride) when the alkyl group consists of a suitably protected nucleoside, the reaction between mono(crimethylsilyl) phosphite in pyridine and sulphuryl chloride fluoride at -30° has been successfully explored. Dibenzyl phosphorofluorldate, hitherto unreported, has been obtained from tecrabenzyl diphosphate and caesium fluoride, and also from the reaction between dibenzyl hydrogen phosphate and 2-fluoro-N-methylpyridinlum tosylate. ... 

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. 

Basic hydrolysis of the products from the reaction of 3-P-D-ribofuranosyl-adenine with phosphorus oxychloride in trimethyl phosphite gave the cyclic phosphoramidate (620) as well as the expected 5 -phosphate. Phosphoramid-ates e.g. (621)] have been obtained from the reaction between nucleoside 5 -azides and 3 -silylphosphites the silylation reaction and azide condensation were conducted simultaneously (Scheme 95). ... 

Phosphonate analogues of nucleotides continue to attract attention. S -Hydrogen-phosphonates and 5 -methylphosphonates of various anti-HIV nucleosides have been made, and the H-phosphonates from AZT and 3 -deoxy-3 -fluorothymidine were highly active. 5 -Fluoro-methyl- and -difluoromethyl-phosphonatcs have been prepared from d4T,26 AZT,264,265 gnj various other nucleosides and deoxynucleosides,265 and phosphonates 199 (n = 1,2) were prepared from the 5 -bis(TMS)phosphite by Arbusov or Michael reaction. The non-hydrolysable analogue 200 of phosphoadenosine phosphosulfate ( active sulfate ) has been described. The 3 -phosphale was put on in the last step using trimetaphosphate, and the desired product was sq>arated from die 2 -phosphate by hplc.267... 

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