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Desymmetrization of Pibrentasvir for Efficient Prodrug Synthesis
preprintsubmitted on 22.04.2021, 12:48 and posted on 28.04.2021, 14:42 by Eric Voight, Stephen Greszler, John Hartung, Jianguo Ji, Russell C. Klix, John T. Randolph, Bhadra Shelat, Jan E. Waters, David A. DeGoey
A novel and practical desymmetrization tactic is described to access a new class of pibrentasvir prodrugs. The homotopic benzimidazoles of pibrentasvir (PIB) are differentiated via a one-pot di-Boc/mono-de-Boc selective N-Boc protection and formaldehyde adduct formation sequence, both enabled by crystallization-induced selectivity. The first step represents the only known application of the Horeau principle of statistical amplification for C2-symmetric polyheterocycle regioselective functionalization. The resulting versatile intermediate is employed in the high-yielding preparation of several pibrentasvir prodrug candidates.