Stereochemistry of the DBU/LiCl-Assisted Nucleophilic Substitution at Phosphorus in Nucleoside-3‘-<i>O</i>-(<i>Se</i>-methyl Methanephosphonoselenolate)s

Abstract

The crystal and molecular structure of diastereomerically pure N 4 -benzoyl-2‘-deoxycytidine 3‘- O -( Se -methyl methanephosphonoselenolate (FAST-eluted) ( 4, R = H, B = C Bz ) and 5‘- O -pixylthymidine 3‘- O -( S -methyl methanephosphonothiolate (FAST-eluted) ( 5 ) have been elucidated by X-ray crystallography. The absolute configuration at the phosphorus atom in both compounds is S P . Each FAST-4 ‘ (R = DMT, B = C Bz ) and FAST-5 (R = Px, B = Thy) in the process of DBU/LiCl-assisted condensation with 3‘- O -acetyl- N 4 -benzoylcytidine and 3‘- O -acetylthymidine gave after deprotection ( S P )-dicytidine-(3‘,5‘)-methanephosphonate and ( S P )- dithymidine-(3‘,5‘)-methanephosphonate, respectively. Unambiguous assignment of the absolute configuration at the phosphorus in 4 (R = H, B = C Bz ) and 5 (R = Px, B = Thy) allows for stereochemical correlation and the conclusion that DBU/LiCl-assisted nucleophilic substitution at phosphorus occurs with net inversion of configuration, in contrast to our earlier erroneous deduction. 5 Moreover, the knowledge of the absolute configuration at the phosphorus atom in both 4 (R = H, B = C Bz ) and 5 (R = Px, B = Thy) allows for assignment of the absolute configuration at phosphorus in precursors of 4 ‘ and 5, such as 5‘- O -DMT-nucleoside 3‘- O - methanephosphonothioanilidates ( 6 ), methanephosphonoanilidates ( 8 ), and methanephosphonoselenoanilidates ( 9 ).