Dialkyl phosphites triesters

The chemical basis for the phosphite triester approach is the observation, that dialkyl phos-phorochloridites such as (CjHjOJjPCI react very rapidly at the 3 -OH of nucleosides in pyridine even at low temperatures. In contrast, the reactions of analogous chloridates, e.g. (C2HjO)2POCIi require several hours at room temperature. It was later found that phosphite esters can be oxidized quantitatively to the phosphates by using iodine in water and that clean condensation of phosphorochloridites with nucleosides can be achieved in THF at -78 °C. To develop this chemistry into a useful synthetic procedure it was necessary to establish which... 

A common method for DNA synthesis is the phosphite triester method (Fig. 7-6). A single-stranded oligonucleotide is formed by the sequential creation of diester bonds between the 5 -hydroxyl of one residue and the 3 -phosphate of the next. The 3 -phosphate is activated by substitution by dialkyl phosphoamidite (DPA) and reacts readily with the free 5 -OH of the first nucleotide. To prevent the formation of unwanted linkages the first nucleotide is linked, by the 3 -OH, to a solid support (often silica gel) in a column or funnel the 5 -OH of the second nucleotide is prevented from reacting by a dimethoxytrityl group (DMT). 

The interaction of an ethenyl ether and a trialkyl phosphite (trimethyl phosphite was actually used) under dry acid conditions (HCl gas in MeOH) leads to a phosphonic diester according to Scheme 2. Little dealkylation of the phosphite triester appears to occur, and the reaction appears therefore not to involve addition of dialkyl hydrogenphosphonate (the product of phosphite dealkylation), all the more so since triphenylphosphine also reacts under the same conditions to give related triphenylphosphonium salts. Ethenyl ethyl ether, 2,3-dihydrofuran and 2,3-dihydropyran were used as substratesThe ease of reaction under mild conditions, coupled with high yields, testifies to the importance of a cationic intermediate species. 

Although it might be expected that reactions which employed triarylmethyl halides would occur very readily, such reactions are rendered potentially more complex by the known nature of the halides and their propensity for involvement in free radical reactions. Whereas normal alkylation proceeds between sodium diethyl phosphite and diphenyl-methyl halides, success, or otherwise, in the use of the triphenylmethyl halides depends to some extent on the individual halide and on the metal in the phosphite salt. Thus, in an early study (in 1939), Arbuzov found that in reactions between silver dialkyl phosphites and triphenylmethyl bromide, dialkyl triphenylmethylphosphonates were indeed formed, but the use of the corresponding alkyl chloride provided the phosphite triester instead (metal dialkyl phosphites possess ambident anions ). A later study confirmed the behaviour of the silver salts towards the chloride, but also showed that, whereas dialkyl phophites with primary alkyl groups yielded phosphonic diesters (as had already been found), those with secondary alkyl groups afforded phosphite triesters moreover, the presence and nature of aromatic substituents were also able to control the course of the reaction. Reactions which involve triarylmethyl halides and sodium dialkyl phosphites may well be of a free radical nature since repeated studies have demonstrated the forma-... 

A parallel series of reactions has been observed for tris(2-chloroethyl)phosphite . The formation of diethyl (2-oxoalkyl)phosphonates by the oxidation (by m-chloroperoxyben-zoic acid) of the products from the interaction of triethyl phosphite and nitroalkenes in the presence of TiCl4, is consistent with the intermediate formation of C-phosphorylated aci-nitro complexes When the phosphite triester species is a dialkyl trimethylsilyl phosphite. 

The use of oxirane together with Na2HP03 to prepare (2-hydroxyethyl)phosphonic acid as its disodium salt is of historical interest. Other poorly exploited, yet interesting and potentially valuable, reactions include the combination of a trialkyl phosphite and dialkyl chlorophosphate with an oxirane to yield O-phosphorylated derivatives of (2-hydrox-yalkyl)phosphonic diesters (reaction 10)" and, following the initial reaction of an a,j8-unsaturated ketone with a phosphorus(III) triester to give the cyclic phosphorane 272, the subsequent further reaction of the latter with an aldehyde followed by hydrolysis (reaction 11)" Dialkyl acetyl phosphites are reported to react with oxirane through anionic intermediate species with the formation, albeit in low yields, of dialkyl (2-acetyloxyethyl)phos-phonates hydrolysable with concentrated HCl, to give (2-hydroxyethyl)phosphonic acid ... 

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