A Michaelis-Arbuzov-Type Pathway to a Protected 2'-Deoxy-2'-Selenomethyl-Adenosine-3',5'-Phosphoroselenolate
K Lawrence E Hale1, Helen O McCarthy2, Mark G McLaughlin1
1School of Chemistry and Chemical Engineering, Queen's University Belfast, Belfast, Northern Ireland, UK.
Abstract:
In this paper, a solution-phase total synthesis is described of the 5'-O-phosphorylated 2'-deoxy-2'-selenomethyl-adenosine 3',5'-phosphoroselenolate guanosine dinucleotide (4) using a rt, 2,6-lutidine-mediated, nucleoside 3'-H-phosphonate/5'-selenocyanate Michaelis-Arbuzov ligative coupling, whose potential mechanism is discussed herein. Our route to 4 is predicated upon the highly efficient new 2'-O-triflate selenocyanate anion displacement of 10 in MeCN, to obtain the 2'-selenocyanate 9, which was allied with an Amosova NaBH4/MeI mediated reductive selenomethylation in MeOH. A novel solid CPR II-mediated 5'-O-phosphitylation of the dinucleotide alcohol 6 and a 70% aqueous t-BuO2H oxidation successfully installed the 5'-O-phosphate moiety within 4 without oxidizing the 2'-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.
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