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

• William H. Hersh

Beilstein J. Org. Chem. 2015, 11, 184–191, doi:10.3762/bjoc.11.19

• 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. Keywords: acylphosphine; acyl phosphite; chiral; DFT; NMR; nucleic acids; oligonucleotides; Introduction Antisense

• required dynamic kinetic resolution, it was hypothesized that acylphosphonites 1 might undergo rapid epimerization by comparison to their known acylphosphine analogs 2 (Figure 1). Mislow previously showed that trialkyl and triarylphosphines slowly undergo epimerization only at temperatures above

• , chiral acylphosphine 19, and chiral phosphite 20 (Scheme 4) were each minimized by DFT using Gaussian (see Supporting Information File 1 for details), and the vibrational calculation confirmed a local minimum for each structure. While the phosphites are complicated by multiple local minima, which depend