Method for Preparing New Flavin Derivatives:  Synthesis of Flavin−Thymine Nucleotides and Flavin−Oligonucleotide Adducts

In order to link to the 5‘-end of oligonucleotides the flavin analogs <b>9a</b>,<b>b</b> possessing only one terminal hydroxy group on the side chain, the phosphoramidite and the H-phosphonate coupling methods were developed. Surprisingly, after reaction of compounds <b>9a,b</b> with 2-cyanoethyl <i>N</i>,<i>N</i>-diisopropylchlorophosphoramidite, the flavin phosphoramidates <b>11a,b </b>were isolated instead of the expected phosphoramidite derivatives <b>10a,b</b>. A very efficient photooxidation process occurred probably during the isolation of the products. From the prepared flavin H-phosphonates <b>12a,b</b>, flavin−thymine nucleotides and flavin−oligonucleotide adducts were synthesized for the first time. The versatility of the method was demonstrated in the oxidation step with the synthesis of the flavin−thymine nucleotides <b>15</b>−<b>17</b> possessing a phosphodiester, a phosphorothioate, and a methyl phosphate linkage, respectively. This method is of general interest with regard to the extensive research developed for preparing flavin analogs and modified oligonucleotides possessing interesting biological or/and catalytic properties.