Stereochemistry of Dbu-Assisted Reaction of Nucleoside 3'-O-(2-Thiono-1.3.2-Oxathiaphospholanes) with 5'-Hydroxynucleosides

It has been demonstrated that reaction of diastereomerically pure 5'-O-DMT-nucleoside-3'-O-(2-thiono-1.3.2-oxathiaphospholanes) with 5'-O-unprotected nucleosides occurs, assisted by DBU, with high stereospecificity providing diastereomerically puredinucleoside(3',5')phosphorothioates. 1 Model studies involving 2-N(α-naphthylethyl)amino-2-thiono-1.3.2-oxathiaphospholane evidentlyindicatedthat DBU-assisted methanolysis provides O-methyl-N(α-naphthylethyl)-phosphoroamidothioate with net retention of configuration. 2 This result, promptly documented by X-ray crystallography of substrates and products of aforementioned conversion, allowed to anticipate that 1.3.2-oxathiaphospholane ring-opening process occurs via "adjacent" type mechanism involving an attack of MeOH on phosphorus collinear with endocyclic P-O bond; pentacoordinate phosphorane intermediate before collapse has to undergo the single pseudorotation process, placing endocyclic P-S bond in apical position. Such analysis allowed for implication that reaction of 5'-O-DMT-nucleoside-3'-O-(2-thiono-1.3.2-oxathiaphospholane) with 5'-unprotected nucleoside or nucleotide occurs according the same rules and prediction, that diastereomerically pure oxathiaphospholane substrate for [Rp]-dinucleoside (3',5')-phosphorothioate has to be of [Rp]-configuration. 2