Highly Efficient Synthesis of Artificial Nucleic Acids Having New Functions

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New methods for the highly efficient synthesis of artificial nucleic acids, which are useful as drugs or functional materials, were developed. Boranophosphate DNAs are regarded as potentially useful antisense molecules or stable nucleic acid-based functional materials. We developed a new method for the synthesis of the boranophosphate DNAs on the basis of a new boranophosphorylation reaction (boranophosphotriester approach). We also developed a new reaction for the transformation of the boranophosphate DNAs into the corresponding H-phosphonate DNAs, which are useful intermediates for the synthesis of a wide variety of backbone-modified DNA analogs. Among these DNA analogs, phosphorothioate DNAs are most widely used for antisense drugs to date. However, the currently used phosphorothioate DNAs are random mixtures of diastereomers owing to the phosphorous chirality. We developed a new method for the stereocontrolled synthesis of phosphorothioate DNAs by the use of nucleoside 3'-oxazaphospholidine derivatives as monomers (oxazaphospholidine approach). The method was successfully applied to the stereocontrolled synthesis of phosphorothioate RNAs as well as other backbone-modified nucleic acid analogs.