Thermal -Sigmatropic Shift of Previtamin D3 to Vitamin D3: Synthesis and Study of Pentadeuterio Derivatives

Article abstract of DOI:10.1021/jo00055a011

Specifically pentadeuteriated previtamin D₃ 11 has been synthesized to impart thermal stability to the otherwise labile material.A 12-step synthesis of the trideuteriated A-ring 14b from p-methoxyphenol was developed and employed the addition of (methyl-d3)magnesium iodide to either the keto thiomethylene intermediate 23 or the keto dioxane 27.The enantiomerically pure trideuterio A-ring (-)-14b was then coupled with the deuteriated CD fragment 13b followed by hydrogenation to afford pentadeuteriated previtamin D₃ 11.A primary deuterium kinetic isotope effect (KIE) study of the <1,7>-sigmatropic hydrogen migration in the conversion of previtamin D₃ to vitamin D₃ indicated a more "normal" primary deuterium isotope effect (as compared to a previously reported literature value of ca. 45).At 80 deg C, a k_H/k_D for the previtamin D₃ to vitamin D₃ isomerization was determined to be ca. 6.2.At 25 deg C, this <1,7>-sigmatropic hydrogen migration proceeds with a k_H/k_D of ca. 11.4.The revisible, first-order <1,7>-sigmatropic hydrogen shift of previtamin D₃ to D₃, determined over the temperature range 60.1-85.5 deg C is characterized by the following activation parameters: log A^H = 8.8 and E_a^H = 19.6 kcal/mol.Deuteriated pre-D₃, which rearranges over this temperature range, is characterized by the activation parameters log A^D = 9.5 and E_a^D = 21.9 kcal/mol.