ABSTRACT
Remdesivir has become an important compound for the treatment of COVID-19. Here, we describe the catalytic asymmetric synthesis of this anti-COVID-19 drug. First, the P-racemic phosphoryl chloride is synthesized in a facile procedure. Then, it is possible to obtain the protected remdesivir via the organocatalytic asymmetric phosphorylation of protected nucleoside GS441524 with P-racemic phosphoryl chloride catalyzed by chiral bicyclic imidazole. Finally, remdesivir is easily prepared by deprotection. © 2021 Wiley Periodicals LLC. Basic Protocol 1: Synthesis of 2-ethylbutyl (chloro(phenoxy)phosphoryl)-L-alaninate rac-4 Basic Protocol 2: Synthesis of chiral bicyclic imidazole Ad-DPI Basic Protocol 3: Synthesis of remdesivir.
Subject(s)
COVID-19 Drug Treatment , Pharmaceutical Preparations , Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/therapeutic use , Humans , SARS-CoV-2ABSTRACT
Asymmetric Synthesis The first catalytic asymmetric synthesis of remdesivir by the coupling of the P‐racemic phosphoryl chloride with protected nucleoside GS441524 is described by W. Zhang et al. in their Communication on page 20814.
ABSTRACT
Asymmetrische Synthese Die erste katalytische asymmetrische Synthese von Remdesivir durch die Kupplung von P‐racemischem Phosphorylchlorid mit dem geschützten Nukleosid GS441524 wird von W. Zhang et al. in der Zuschrift auf S. 21000 vorgestellt.
ABSTRACT
The catalytic asymmetric synthesis of the anti-COVID-19 drug Remdesivir has been realized by the coupling of the P-racemic phosphoryl chloride with protected nucleoside GS441524. The chiral bicyclic imidazole catalyst used is crucial for the dynamic kinetic asymmetric transformation (DyKAT) to proceed smoothly with high reactivity and excellent stereoselectivity (96 % conv., 22:1 SP :RP ). Mechanistic studies showed that this DyKAT is a first-order visual kinetic reaction dependent on the catalyst concentration. The unique chiral bicyclic imidazole skeleton and carbamate substituent of the catalyst are both required for the racemization process, involving the phosphoryl chloride, and subsequent stereodiscriminating step. A 10â gram scale reaction was also conducted with comparably excellent results, showing its potential for industrial application.