A P" coupling reagent 3 containing indole group is described. Its usefulness is demonstrated by the synthesis of dinucleoside methylphosphonates and methylthiophosphonates. 8 1997 Elsevier Science Ltd. The oligonucleoside methylphosphonates (MP) show significant potential for antisense therapy.' The intemucleoside methylphosphonate linkage was first prepared by using activated nucleoside methylphosphonates, 2-7 but the coupling reactions were slow. Later, methylphosphoramidite approaches were utilized.8,9,'o Unfortunately, all these methods yield a mixture of diastereoisomers. Stec and his coworkers have described a route using tetracoordinate phosphorus to synthesize stereoregular MP linkages by using pnitrophenoxy",'2 and methylselenenylb as the leaving group, but the coupling yields were low, and each step required chromatographic purification of the MP products. We wish to report a very efficient synthesis of 3'S'dithymidine methylphosphonate and its sulfur analogue with a novel intemucleoside coupling procedure based on tricoordinate phosphorus reagent 3. tBDMS MePC12 ? /ph \ CH3 d ' : 2 3 Scheme 1 i) Indole (1 eq.), Et,N/CH,Cl,. ii) Indole (2 eq.), Et,N/CH,CI,. iii) S-0-tBDMS-thymidine. The coupling reagent 3 was easily prepared by a one-flask procedure, shown in Scheme 1. Dichloromethylphosphorine reacted with one equivalent of indole in the presence of triethylamine to give quantitatively methyl indolphosphorochloridite 1, which was then reacted with one equivalent of S-O-tBDMSthymidine (T"OH). After filtering out triethylammonium chloride and drying in vacua , two diastereoisomers 3a, 3b were obtained in quantitative yield as established by "P NMR. The product did not need further purification and could be stored under argon for a long time. When dichloromethylphosphorine reacted with