6'-carbon-substituted carbocyclic analogs of 2'-deoxyribonucleosides synthesis and effect on DNA/RNA duplex stability

6'-alpha-Methyl and 6'-alpha-hydroxymethyl carbocyclic thymidines 11 and 22 have been synthesized via bicyclic lactone 2 and amines 9 and 19, respectively, as key intermediates. Both nucleoside analogs were subsequently elaborated into 5'-O-DMTr protected 3'-phosphoramidites of 6'-alpha-methyl and 6'-alpha-hydroxymethyl carbocyclic thymidines as well as appropriately base protected 5-methyl 2'-deoxycytidines. Analysis of the RNA-binding affinity of modified oligodeoxyribonucleotides incorporating these 6'-substituted carbocyclic nucleoside analogs revealed a strongly position dependent effect on DNA/RNA duplex stability. While duplex stability is significantly reduced by point modifications at separated sequence positions, it is only marginally affected by stretches of contiguous modified building blocks. Copyright (C) 1996 Elsevier Science Ltd