A Michaelis‐Arbuzov‐Type pathway to a protected 2ʹ‐deoxy‐2ʹ‐selenomethyl‐adenosine‐3ʹ,5ʹ‐phosphoroselenolate guanosine dinucleotide for use in modified m7G cap synthesis

In this paper, a solution‐phase total synthesis is described of the 5ʹ‐O‐phosphorylated 2ʹ‐deoxy‐2ʹ‐selenomethyl‐adenosine 3ʹ,5ʹ‐phosphoroselenolate guanosine dinucleotide (4) using a rt, 2,6‐lutidine‐mediated, nucleoside 3ʹ‐H‐phosphonate/5ʹ‐selenocyanate Michaelis‐Arbuzov ligative coupling, whose potential mechanism is discussed herein. Our route to 4 is predicated upon the highly efficient new 2ʹ‐O‐triflate selenocyanate anion displacement of 10 in MeCN, to obtain the 2ʹ‐selenocyanate 9, which was allied with an Amosova NaBH₄/MeI mediated reductive selenomethylation in MeOH. A novel solid CPR II‐mediated 5ʹ‐O‐phosphitylation of the dinucleotide alcohol 6 and a 70% aqueous t‐BuO₂H oxidation successfully installed the 5ʹ‐O‐phosphate moiety within 4 without oxidizing the 2ʹ‐selenomethyl group. It is envisaged that 4 will be of value for a future total synthesis of the m7G cap 1; a molecule of potential utility for therapeutic mRNA manufacture.