ABSTRACT
The Covid-19 pandemic highlights the urgent need for cost-effective processes to rapidly manufacture antiviral drugs at scale. Here we report a concise biocatalytic process for Molnupiravir, a nucleoside analogue recently approved as an orally available treatment for SARS-CoV-2. Key to the success of this process was the development of an efficient biocatalyst for the production of N-hydroxy-cytidine through evolutionary adaption of the hydrolytic enzyme cytidine deaminase. This engineered biocatalyst performs >85â¯000 turnovers in less than 3 h, operates at 180 g/L substrate loading, and benefits from in situ crystallization of the N-hydroxy-cytidine product (85% yield), which can be converted to Molnupiravir by a selective 5'-acylation using Novozym 435.
Subject(s)
Antiviral Agents , COVID-19 Drug Treatment , Cytidine Deaminase/metabolism , Cytidine/analogs & derivatives , SARS-CoV-2 , Biocatalysis , Cytidine/biosynthesis , Cytidine/metabolism , Cytidine Deaminase/genetics , Escherichia coli/enzymology , Escherichia coli/genetics , Hydroxylamines , Metabolic Engineering , Protein Engineering , Uridine/metabolismABSTRACT
Corsifuran A has been prepared in an enantiomerically pure form for the first time by an asymmetric reduction procedure, allowing confirmation of the absolute stereochemistry of the natural product as (R).
Subject(s)
Benzofurans/chemical synthesis , Boron Compounds/chemistry , Benzofurans/chemistry , Hepatophyta/chemistry , Molecular Structure , Oxidation-Reduction , StereoisomerismABSTRACT
A procedure is described that greatly simplifies the use of an oxazaborolidine catalyst derived from (1R,2S) cis-1-amino-indan-2-ol. This B-OMe catalyst has been employed in the asymmetric reduction of a number of structurally diverse prochiral ketones, in particular the reduction of alpha-amino acetophenone and its derivatives. A method for reducing the effective catalyst loading by "in situ recycling" is also presented. [structure: see text]
