Desymmetrization of Pibrentasvir for Efficient Prodrug Synthesis

Autor:	Jan E. Waters, Russell C. Klix, Jianguo Ji, John T. Randolph, Eric A. Voight, Greszler Stephen N, David A. Degoey, Bhadra H. Shelat, John Hartung
Rok vydání:	2021
Předmět:	010405 organic chemistry Chemistry Regioselectivity General Chemistry Prodrug 010402 general chemistry 01 natural sciences Combinatorial chemistry Desymmetrization Pibrentasvir 0104 chemical sciences Adduct Selectivity
Zdroj:	Chemical Science
DOI:	10.26434/chemrxiv.14456259.v1
Popis:	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. Horeau principle statistical amplification and solubility-driven selectivities allow C2-desymmetrization of pibrentasvir without typically required internal functionalization or steric proximity effects.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3a0d187ca8e4c54e2d10be7865a28bdb https://doi.org/10.26434/chemrxiv.14456259.v1 Zobrazit plný text záznamu