Synthesis of Enzymatically and Chemically Non-hydrolyzable Analogues of Dinucleoside Triphosphates Ap3A and Gp3G

Dinucleoside polyphosphates are ubiquitous compounds tightly involved in the regulation of a number of key biological processes. Hydrolysis-resistant analogues of Ap(3)A and Gp(3)G, two important members of that family of nucleotides, have been synthesized. P(1),P(2):P(2),P(3)-Bis-methylene diadenosine and diguanosine triphosphates were prepared from O,O-dialkyl methaneselenophosphonates using an original methodology. Whereas the 2-fold addition of the methanephosphonate anion to the activated phosphorus species cannot be performed, multiple condensation of lithiated methaneselenophosphonate with electrophilic trivalent phosphorus compounds is revealed to be very effective. A one-pot condensation/esterification/oxidation sequence involving O,O-dialkyl methaneselenophosphonates provides a highly efficient route to the PCH(2)PCH(2)P backbone. This new development in selenophosphonate chemistry offers a great potential for further regioselective functionalization of polyphosphate mimics.