PHOSPHOTRIESTER APPROACH TO THE SYNTHESIS OF OLIGONUCLEOTIDES - A REAPPRAISAL

The phosphotriester approach to the synthesis of oligodeoxyribo- and o ligoribo-nucleotides in solution has been reinvestigated. The efficacy of mesitylene-2-sulfonyl chloride (MSCl) 15a, 2,4,6-triisopropylbenze nesulfonyl chloride (TrisCl) 15b, 4-bromobenzenesulfonyl chloride 15c, naphthalene-1-sulfonyl chloride 39, and 2- and 4-nitrobenzenesulfonyl chlorides 40a and 40b, respectively, as activating agents has been ex amined. The latter arenesulfonyl chlorides have been used in conjuncti on with the following nucleophilic catalysts: 1-methylimidazole, 3-nit ro-1H-1,2,4-triazole 19, 5-(3-nitrophenyl)-1H-tetrazole 20a, 5-(3,5-di nitrophenyl)-1H-tetrazole 20b, 5-(1-methylimidazol-2-yl)-1H-tetrazole 21, 5-[(1-methylimidazol-2-yl)methyl]-1H-tetrazole 22, 4-ethoxypyridin e 1-oxide 14a,4,6-dinitro-1-hydroxybenzotriazole 29a, 1-hydroxy-4-nitr o-6-(trifluoromethyl)benzotriazole 29b, 1-hydroxy-5-phenyltetrazole 30 a and 1-hydroxy-5-(3-nitrophenyl)tetrazole 30b. The rates of formation and yields of the fully protected dideoxyribonucleoside and diribonuc leoside phosphates 37 and 47, respectively, were determined using vari ous combinations of activating agents and nucleophilic catalysts. Alth ough 2- and 4-nitrobenzenesulfonyl chlorides 40a and 40b, respectively , proved to be the most powerful activating agents, their use in the d eoxy-series led to the formation of by-products and hence to unsatisfa ctory isolated yields of the dideoxyribonucleoside phosphate 37.