Synthesis of dinucleoside acylphosphonites by phosphonodiamidite chemistry and investigation of phosphorus epimerization

نویسنده

  • William H Hersh
چکیده

The reaction of the diamidite, (iPr2N)2PH, with acyl chlorides proceeds with the loss of HCl to give the corresponding acyl diamidites, RC(O)P(N(iPr)2)2 (R = Me (7), Ph (9)), without the intervention of sodium to give a phosphorus anion. The structure of 9 was confirmed by single-crystal X-ray diffraction. The coupling of the diamidites 7 and 9 with 5'-O-DMTr-thymidine was carried out with N-methylimidazolium triflate as the activator to give the monoamidites 3'-O-(P(N(iPr)2)C(O)R)-5'-O-DMTr-thymidine, and further coupling with 3'-O-(tert-butyldimethylsilyl)thymidine was carried out with activation by pyridinium trifluoroacetate/N-methylimidazole. The new dinucleoside acylphosphonites could be further oxidized, hydrolyzed to the H-phosphonates, and sulfurized to give the known mixture of diastereomeric phosphorothioates. The goal of this work was the measurement of the barrier to inversion of the acylphosphonites, which was expected to be low by analogy to the low barrier found in acylphosphines. However, the barrier was found to be high as no epimerization was detected up to 150 °C, and consistent with this, density functional theory calculations give an inversion barrier of over 40 kcal/mol.

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عنوان ژورنال:

دوره 11  شماره 

صفحات  -

تاریخ انتشار 2015