Our previous studies and others have proven 2',5'-linked ribonucleotides (2',5'-RNA) are not only interesting from a structural point of view but also potentially useful for therapeutic applications. The distinct structural feature of 2',5'-RNAs is that their duplexes (2',5'-RNA:2',5'-RNA) favor A-type conformations with C2' endo compact sugar puckers, whereas the native RNA duplexes (RNA:RNA) exhibit A-type structures with dominant C3' endo compact pucker form. The intra phosphate-phosphate distance in the minor groove of 2',5'-RNA duplexes is shorter compared to the RNA duplexes, which may be a factor that destabilizes duplexes containing 2',5'-linked nucleotide residues. This prompted us to incorporate a methylene (-CH₂) bridge between the C2' and O2' atoms of 2',5'-RNA, thus obtaining 2'-deoxy-2'-a-C-hydroxymethyl 2',5'-linked RNA. We anticipated that lengthening the sugar-phosphate backbone by one methylene unit would not only diminish putative P-P repulsions in 2',5'-RNA:RNA duplexes, but would also provide a ‘compact' nucleotide conformation favoring tighter RNA binding. Herein we describe the synthesis of 1-(2-Deoxy-2-a-C-hydroxymethyl-b-D-ribofuranosyl)thymine (2'-hm-dT, abbreviated in this work as H) as well as 2',5'-RNA strands containing one or more H units. These compounds are being evaluated as inhibitors of HIV-1 RT RNase H, and as probes to determine the substrate specificity of the yeast debranching enzyme.