Enantioselective Synthesis of β-l-5-[()-2-Bromovinyl)-1-((2,4)-2-(hydroxymethyl)-1,3-(dioxolane-4-yl) Uracil)] (l-BHDU) Chiral Pure l-Dioxolane.

β-l-5-(()-2-Bromovinyl)-1-((2,4)-2-(hydroxymethyl)-1,3-(dioxolane-4-yl) uracil (l-BHDU, ) is a potent and selective inhibitor of the varicella-zoster virus (VZV). l-BHDU () has demonstrated excellent -VZV activity and is a preclinical candidate to treat chickenpox, shingles (herpes zoster), and herpes simplex virus 1 (HSV-1) infections. Its monophosphate prodrug (POM-l-BHDU-MP, ) demonstrated an enhanced pharmacokinetic and antiviral profile. POM-l-BHDU-MP (), , effectively reduced the VZV viral load and was effective for the topical treatment of VZV and HSV-1 infections. Therefore, a viable synthetic procedure for developing POM-l-BHDU-MP () is needed. In this article, an efficient approach for the synthesis of l-BHDU () from a readily available starting material is described in 7 steps. An efficient and practical methodology for both chiral pure l- & d-dioxolane and were developed diastereomeric chiral amine salt formation. Neutralization of the amine carboxylate salt of l-dioxolane provides enantiomerically pure l-dioxane (ee ≥ 99%). Optically pure was utilized to construct the final nucleoside l-BHDU () and its monophosphate ester prodrug (POM-l-BHDU-MP, ). Notably, the reported process eliminates expensive chiral chromatography for the synthesis of chiral pure l- & d-dioxolane, which offers avenues for the development and structure-activity relationship studies of l- & d-dioxolane-derived nucleosides.