PREPARATION OF OLIGODEOXYRIBONUCLEOSIDE PHOSPHORODITHIOATES BY A TRIESTER METHOD

A method to prepare thymidine phosphorodithioate dimers (ref. 1) has b een extended to allow the preparation of oligo-2'-deoxyribonucleotide phosphorodithioates containing all four bases. The method is suitable for large-scale synthesis and gives phosphorodithioates without phosph orothioate impurities (P-31 nmr, detection limit 0.5 to 1%). Oligonucl eotides up to octamers which contain -O-(PS2-)-O- linkages at all posi tions have been prepared by block synthesis in solution. The phosphoro dithioate linkage is introduced by the reaction of a 5'-O, N-protected nucleoside (or oligonucleotide) with a dithiophosphorylating agent RS P(S)(ODhbt)(2), R = 2,4-dichlorobenzyl, Dhbt = 3,4-dihydro-4-oxo-benzo triazin-3-yl, followed by coupling of the product to a 3'-O,N-protecte d nucleoside (or oligonucleotide). This method gives pure protected ol igodeoxyribonucleoside phosphorodithioates, and phosphorothioate linka ges are only introduced if contact with cone. aqueous ammonia during o r after deblocking is unduly prolonged.