Design and Synthesis of Isonucleosides Constructed on a 2-Oxa-6-thiabicyclo[3.2.0]heptane Scaffold

A novel method for the design and synthesis of an isonucleoside containing a 2-oxa-6-thiobicyclo[3.2.0]heptane skeleton is described. 2,2-Dimethy1-1,3-dioxan-5-one 13 was converted into a dioxabicyclohexane derivative in six steps. After cleavage of the epoxide group with a thiol (thiophenol or PM B mercaptan), the resulting product was subjected to the Mitsunobu reaction in the presence of a nucleobase. The reaction proceeded via the migration of the thiosullide groups and gave the desired isonucleoside derivatives. In the case of a phenyl sulfide derivative, radical desulfurization followed by deprotection gave 4'-substituted 2',3'-dideoxyisonucleosides. A PM B sulfide derivative, on the other hand, was converted into the corresponding dimesylate, which was then treated with mercury acetate and trifluoroacetic acid to remove the PM B group. The resulting thiol derivative was treated with DBU to give the desired isonucleoside constructed on a 2-oxa-6-thiobicyclo[3.2.0]heptane scaffold after deprotection. The optimized conformer of the isonucleoside was calculated using DFT at the B3LYP/6-31G** level and was compared with that of lamivudine using model compounds.

See More