Phosphite method

The following sections primarily describe many of the methods used for the cleavage of some of the more common phosphate protective groups. Since most of these groups are introduced by either the phosphate or phosphite method, little information is included here about their formation. The cited references generally describe the means that were used to introduce the protective group. In some cases, methods of formation are described, but this is done only when alternative methods to the phosphate or phosphite procedure were used. 

Further modifications were then made in this hydrogen phosphite method of preparing di-isopropyl phosphorofluoridate in order to put it on an industrial scale. 

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. 

We found that the toxicity and myotic activity of di-isopropyl phosphorofluoridate (XI) were far greater than that of di- propyl phosphorofluoridate. In Report no. 6 on fluoro-phosphonates to the Ministry of Supply3 we described the preparation of di aec.-butyl phosphorofluoridate (XII) by the hydrogen phosphite method (p. 6). The compound was found to be very toxic and to produce severe myosis in man and animals. The symptoms displayed during and after exposure were identical with those produced by di-isopropyl phosphorofluoridate. The L.c. 50 for di-sec.-butyl phosphorofluoridate for mice for deaths within 2 hr. was 0-6 mg./l., and that for deaths within 48 hr. was 0-54 mg./l. 

Steroidal amides. Herz and Mantccon- have prepared amides from lithocholic acid 3-foimate in sati.sfactory yields by the triphenyl phosphite method of Mitin and Glinskaya (3,322 323). 

Hashimoto and coworkers successfully applied their phosphite method to selective -manno-sylation [63,64,65] (O Scheme 21), Similar to the case of Crich s mannosylation, cyclic protection at the 4- and 6-positions is essential. Mannosyl phosphate and phosphoramidate were also investigated [65,66]. Toshima et al. used the glycosyl phosphites activated with a solid acid catalyst to give -mannoside predominantly [67,68]. 

The phosphite method is effective for the synthesis of DNA oligomers, because the preparation requires no protection of the phosphoric acid moieties. ... 

These cycloadditions are more sensitive to the quality of the catalyst, the major side reaction being protodesilylation of the allylsilane subunit. Since this can not be measured readily either in the case of the tetrakis(triphenylphosphane)palladium(0) or the palladium acetate/triisopropyl phosphite methods, an improved method for generating the palladium(O) species has been developed22. This involves in situ preparation of tetrakis(triisopropyl phos-phite)palladium(O) by direct reduction of palladium acetate with butyl lithium. This method is illustrated by the addition of the methyl-substituted TMM-Pd complex to eyelopentenone. 

If R = arylalkyl or alkyl, then R X must be more reactive than RX unless RX can be removed continuously from the reaction mixture. The triphenyl phosphite method gives first a quasi-phosphonium compound (A), which is then transesterified (b) ... 

Katzhendler J, Cohen S, Weisz M, Ringel I, Camerini-Oetrio RD, Deutsch A. Spacer effect on the synthesis of oligodeoxynucleotides by the phosphite method. R ct Polym 6 175-187, 1987. 

Although nucleoside phosphoramidites with improved stability thus have been developed it is still a drawback of the phosphite method that solutions of the monomers (91)—(96) have to be prepared and stored. Two approaches to circumvent this have been described. One uses methoxydichlorophosphine (98) to prepare the 5 -0-phosphorchloridite in situf the other approach uses methoxybis(tetrazolyl)phosphine (99) in a similar way (Scheme 9). Both seem to work well for larger oligonucleotides and are promising for their simplicity. 

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