Phosphotriester approach to the synthesis of oligonucleotides: a reappraisal (original) (raw)

1993, Journal of the Chemical Society, Perkin Transactions 1

The phosphotriester approach to the synthesis of oligodeoxyribo-and oligoribo-nucleotides in solution has been reinvestigated. The efficacy of mesitylene-2-sulfonyl chloride (MSCI) 15a, 2,4,6triisopropylbenzenesulfonyl chloride (TrisCI) 1 5b, 4bromobenzenesulfonyl chloride 1 5c. naphthalene-1-sulfonyl chloride 39, and 2-and 4-nitrobenzenesulfonyl chlorides 40a and 40b, respectively, as activating agents has been examined. The latter arenesulfonyl chlorides have been used in conjunction with the following nucleophilic catalysts: 1-methylimidazole, 3-nitro-I H-1,2,4-triazole 19, 5-(3-nitrophenyl)-l H-tetrazole 20a, 5-(3.5-dinitrophenyl)-l H-tetrazole 20b. 5-(1-methylimidazol-2y l)-I H-tetrazole 21, 5-[ (1-methylimidazol-2-yl)methyl]-1 H-tetrazole 22, 4-ethoxypyridine 1-oxide 14a. 4,6-dinitro-l-hydroxybenzotriazole 29a, 1-hydroxy-4-nitro-6-(trifluoromethyl) benzotriazole 29b. 1-hydroxy-5-phenyltetrazole 30a and 1-hydroxy-5-(3-nitrophenyl) tetrazole 30b. The rates of formation and yields of the fully protected dideoxyribonucleoside and diribonucleoside phosphates 37 and 47, respectively, were determined using various combinations of activating agents and nucleophilic catalysts. Although 2-and 4-nitrobenzenesulfonyl chlorides 40a and 40b. respectively, proved to be the most powerful activating agents, their use in the deoxy-series led to the formation of by-products and hence to unsatisfactory isolated yields of the dideoxyribonucleoside phosphate 37. I I +-0 ii. iii /o 3 4 Ar = 2-chlorophenyl; B and B' are protected in substrates 1, 2 and 3, and unprotected base residues in product 4