A new approach to the synthesis of Anti-Reverse Cap Analog (ARCA) <sup>2m</sup>GpppG

A new approach to the synthesis of Anti-Reverse Cap Analog (ARCA) of the classical structure – dimethylated guanosine dinucleotide 2mGpppG is proposed. The classical approach to obtaining consists in condensation of activated 5′-diphosphate of 7,3′-O-dimethylguanosine with 5′-guanosine monophosphate. We suggest to use a commercially available 3′-O-methylguanosine for the synthesis of 5′-monophosphate of dimethylated guanosine only, and to use an activated 5′-guanosine diphosphate in the condensation. The conditions of 3′-O-methylguanosine phosphorylation were determined to avoid the formation of a side product 3′-O-methyl-5′-deoxy-5′-chloroguanosine-3′-phosphate. ARCA was synthesized with a high yield (89% at the condensation stage). Our approach to the synthesis is easily scaled and can be used for a preparative synthesis of ARCA (several grams).