Rapid Multikilogram Scale-Up of Di- and Trifluoromethoxy Proline Derivatives

This report describes the synthesis, development, and scale-up (up to 10 kg) of di- and trifluoromethoxy prolines, key fragments evaluated in the development of potential antiviral SARS-CoV2 Mpro inhibitors. We first demonstrate a scalable route to 1-tert-butyl 2-methyl (2S,4R)-4-(difluoromethoxy)pyrrolidine-1,2-dicarboxylate employing a Cu-catalyzed difluoromethylation of alcohols using 2,2-difluoro-2-(fluorosulfonyl)acetic acid. We then demonstrate the optimization and scale-up of challenging 1-tert-butyl 2-methyl (2S,4R)-4-(trifluoromethoxy)pyrrolidine-1,2-dicarboxylate through silver-mediated oxidative trifluoromethylation of the corresponding alcohol. Finally, we report on the oxidative fluoro-desulfurization of xanthates as a potentially scalable route to access chiral aliphatic trifluoromethoxy ethers.