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

Abstract

SummaryThe 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.

Improving the accuracy of 31P NMR chemical shift calculations by use of scaling methods

“…l Combined MAD/RMSD for all compounds in Table 2 and Table 3 with no multiple P-C bonds. 13 C NMR spectrum by analogy to amides, but was instead observed at 228 ppm and confirmed by a calculated (unscaled) value of 242 ppm [81]! Such a result demonstrates the value of DFT calculations for structures not having any experimental NMR precedent.…”

“…The case for multiple P–C bonding in compound 25 is supported by the amide-like CO infrared stretching frequency of 1654 cm −1 . This compound further warrants mention since one might suppose that the carbonyl carbon atom would be found near 170 ppm in the 13 C NMR spectrum by analogy to amides, but was instead observed at 228 ppm and confirmed by a calculated (unscaled) value of 242 ppm [ 81 ]! Such a result demonstrates the value of DFT calculations for structures not having any experimental NMR precedent.…”