Synthesis of 3'-C-(Hydroxymethyl)thymidine: Introduction of a Novel Class of Deoxynucleosides and Oligodeoxynucleotides

Important requirements for antisense or antigene oligonucleotides are enhanced stability against destructive nucleases and efficient hybridization to target nucleic acids. As a consequence, such oligonucleotides need to be chemically modified in the nucleobase, the carbohydrate, or the internucleoside linkage. We consider the development of oligonucleotide analogues containing carbohydrate-modified nucleoside monomers as the most promising strategy, as modifications in the phosphate moiety (e.g., phosphorothioates, phosphoramidates, and methylphosphonates) often result in highly heterogeneous oligomers because of introduction of uncontrolled chirality at phosphorus. Besides, routine preparation of oligonucleotide sequences containing neutral achiral dephospho linkages requires often laborious syntheses of up to 16 different dimeric building blocks compared to only four when using monomeric building blocks. This communication describes the synthesis of the first 3'-C-hydroxymethyl deoxyribonucleoside 4 and its incorporation using the phosphoramidite synthon 6 into novel oligodeoxynucleotide analogues showing promising properties.