Phosphorofluoridates synthesis

It should be emphasized that the phosphorus oxydichlorofluoride method for preparing esters of phosphorofluoridic acid cannot compare in speed with the hydrogen phosphite method already described (p. 46). Furthermore, it is not very suitable for very large-scale work. On the other hand, once the apparatus is set up and a supply of POCl2F is obtained, one has a simple, clear-cut, method for producing a large variety of phosphorus compounds, not only esters but amino compounds (p. 87) and mixed compounds (p. 90). In other words, the method is extremely valuable for exploratory purposes and where an unequivocal synthesis is required. 

Trimethylsilyl phosphorohalidates (6) and (7) have been synthesized from phosphoryl dihalogenofluoride (8) and hexamethyldisiloxane (9). An alternative approach to (7) using bis(trimethylsilyl) phosphorofluoridate (10) has been also elaborated (Scheme 1). Compounds (6) and (10) are involved in a new synthesis of bis(trimethylsilyl) diphosphorodifluoridate (11). ... 

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. ... 

In order to examine the stereochemical implications in the synthesis of (largely) phosphinic acids (but also tertiary phosphine oxides), Inch and coworkers " employed carbohydrate frameworks as chiral templates. As primary substrates, the cyclic phospho-rochloridate 161 and the corresponding phosphorofluoridate 162 were prepared from methyl 1,2,3-di-O-methyl-a-D-glucopyranoside, each phosphoryl halide being obtained as a mixture of diastereoisomers, anomeric at phosphorus, and from which, in each case, the major component (thought to have an equatorial P=0 bond) was isolated. Configurations in both substrates and reaction products were assigned with the aid of proton and NMR... 

Michalski and coworkers have shown that sulphuryl chloride fluoride (25) is a convenient reagent for preparing both simple phosphorofluoridates and more complex carbo-hydrate-substituted phosphorofluoridates for use in polynucleotide synthesis. Using phosphorus (III) trimethylsilyl esters (equation 20), products of very high purity are obtained in excellent yields under mild reaction conditions. Alternatively, phosphorus(V) thionophosphate or selenophosphate esters (equation 21) and 25 also give the corresponding phosphorofluoridates in high yields. ... 

H. Falius, Angew. Chem., Int. Ed. 1970,9,733-734. Simple synthesis of phosphorofluoridous acid, HIPHO2F]. 

As regards the modification of intemucleosidic links, bis(deoxynucleosidyl)-trimethylsilyl phosphites 190 can be converted to phosphorofluoridates 191 by the use of S02C1F,230 and dibenzoyltetrasulfide has been advocated as a rapid sulfur transfer agent in the synthesis of nucleoside phosphorothioates, being used to prepare a phosphorothioate after each cycle of a phosphoramidite synthesis.231 Oxidation of intemucleosidic H-phosphonothioates (2 -deoxy series) with iodine in aqueous acetonitrile in the presence of trimethylamine gives... 

Nucleoside phosphorofluoridates salts 1 are stable compounds resistant to hydrolysis, but unstable in the presence of a vicinal hydroxy group in ribonucleosides (7). Compound 1 has been used in nucleotide synthesis under somewhat drastic conditions. Suitably protected nucleotides and nucleosides react in the presence of tertiary butoxide as the base and the fluoride as the leaving group of the phosphate fie, g). Biological properties of 1 and3 were described by various authors (2,3b,d,h,5b,6,8,10a-c). 

Phosphitylation of suitably protected nucleosides by the trimethylsilyl ester 6 proceeds in the presence of pyridine. Synthesis of the intermediate trimethylsilyl esters 8 (16a,c) and 9 (16a, c) and their conversion by the sulfuryl chloride fluoride into fluoridates 10 (16a,c) and 11 (16a,c) are presented in Scheme 7. Trimethylsilyl phosphites 8 and 9 prepared in situ are treated in a dry pyridine solution with the excess of sulfuryl chloride fluoride at -50°C, using a simple vacuum-line technique. The reaction can also be performed in other nonprotic solvents in the presence of pyridine. The methodology described in Scheme 7 is limited to synthesis of mononucleoside phosphorofluoridates 10 and 11, because the phosphites 8 and 9 are poor phosphitylating reagents (14,16c). This limitation can be avoided by employing the reagent 7, which allows the selective formation of trime ylsilyl esters 12(13,16a-c) and 13 (13,16a-c) as well as the esters 14 (13,16a c), which contain two... 

Monasterio, O and Timasheff, S N. (1987) Biochemistry 26,6091 11a. For synthesis of phosphorofluoridates, see Orgemischen Phosphorverbin-dungen. Parts I and II in Methoden der Organischen Chemie (Houben Weyl) (Regita, M, ed.) (1982) Georg Thieme Verlag, Stuttgart. 

Michalski, J., Dabkowski, W., Lopusinski, A., and Cramer, F. (1991) Stereoselective synthesis of nucleoside phosphorofluoridates. Nucleosides Nucleotides 10, 283-286. 

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