Measurement of the barrier to inversion of configuration in acyclic phosphite triesters

Synthesis of three acyclic chiral phosphites is reported, in the form of dithymidine phosphite triesters. These diastereomerically pure P-stereogenic phosphites undergo epimerization at a measurable rate at 150 °C. When the alcohols on the deoxyribose moieties are protected as acyls, decomposition is minimized and by computer fitting, rate constants for epimerization can be extracted. These allow for the first time calculation of the barrier to inversion of configuration in phosphite triesters, giving ΔG†(150 °C) = 33.0 ± 0.2 kcal mol−1, comparable to the inversion barrier seen for phosphines.

Graphical abstractDiastereomerically pure P-stereogenic phosphites undergo epimerization at a measurable rate at 150 °C. The barrier to inversion of configuration in acyclic phosphite triesters has been measured for the first time, giving ΔG†(150 °C) = 33.0 ± 0.2 kcal mol−1, comparable to the inversion barrier seen for phosphines.Figure optionsDownload full-size imageDownload as PowerPoint slideResearch highlights► Separation of P-epimers of chiral dinucleoside phosphite triesters. ► Phosphite epimerization at 150 °C with activation barrier of 33 kcal mol−1. ► Rate constants measured by computer fitting. ► Inversion barrier for phosphites is comparable to that for phosphines.