Synthesis of 2,6,7-trichloro-1-(β-D-ribofuranosyl)naphtho[2,3-d]imidazole:: A linear dimensional analogue of the antiviral agent TCRB

Human cytomegalovirus (HCMV) remains a significant clinical problem in neonates and immunocompromised individuals such as those undergoing transplantation as well as individuals with acquired immune deficiency syndrome (AIDS). Recently in our laboratory, 2,5,6-trichloro-1-(beta-D-ribofuranosyl)benzimidazole (TCRB, 1a) and 2-bromo-5,6-dichloro-1-(beta-D-ribofuranosyl)benzimidazole (BDCRB, 1b) were found to have better activities in cell culture studies against HCMV than the clinically used agents ganciclovir and foscarnet. These benzimidazole compounds appear to act by a unique mechanism. However, as the biological target of TCRB and BDCRB has not been completely identified, 2,6,7-trichloro-1-(beta-D-ribofuranosyl)naphthol[2,3-d]imidazole (2) was designed as a linear dimensional analogue of TCRB for a study on the spatial limitation of the binding site in the target enzyme. In the synthesis, a convenient route was developed for the synthesis of 2-substituted 6,7-dichloronaphtho[2,3-d]imidazoles involving a Diels-Alder reaction of 4,5-dichloro-o-quinodimethane (8) as the key step. 6,7-Dichloro-1,4-dihydro-2,3-benzoxathiin 3-oxide (15) was found to be an ideal precursor for the generation of the elusive intermediate 8. The ribosylation of 6,7-dichloronaphtho[2,3-d]imidazoles was influenced by the functional group at the 2-position and 6,7-dichloro-2-methylthionaphtho[2,3-d]imidazole (3c) was found to smoothly undergo ribosylation. The 2-methylthio group of the unprotected nucleoside 25 was converted into a chloro group under mild conditions to give nucleoside 2 in high yield.