STEREOSPECIFIC GRIGNARD-ACTIVATED SOLID-PHASE SYNTHESIS OF DNA METHYLPHOSPHONATE DIMERS

Stereoregular R(p) or S-p DNA methylphosphonate dimers have been synth esized on a solid phase support. A deprotected 5'-hydroxyl-N-2-isobuta noyldeoxyguano sine 3'-O-succinate coupled to high-loaded polyethylene glycol (PEG) coated polystyrene beads (HLP) was activated with a Grig nard reagent, t-BuMgCl. After activation was complete, a pure diastere oisomer of 5'-(dimethoxytrityl) N-benzoyldeoxynucleoside 3'-(p-nitroph enyl methylphosphonate) p-nitrophenyl ester (R(p) or S-p) was added. C oupling of the activated 5'-hydroxyl to the 3'-methylphosphonate ensue d, releasing nitrophenol, yielding the R(p) or S-p dimer, respectively . The dimers were then cleaved from the solid support, deprotected, an d purified, yielding methylphosphonate DNA dimers of defined stereoche mistry.