Biocatalytic Oxidative Desymmetrization of the Substituted Pyrrolidine Intermediate of MK-7845: An Investigational Antiviral Therapy for COVID-19

An important structural motif in MK-7845, the Merck & Co., Inc., Rahway, NJ, USA experimental antiviral treatment for COVID-19, is the bicyclic substituted pyrrolidine moiety. During the discovery stages and the first GMP production of MK-7845, this key fragment was introduced from the commercially available but costly precursor (1S,3aR,6aS)-ethyl octahydrocyclopenta[c]pyrrole-1-carboxylate hydrochloride salt through sequential peptide couplings. Aiming to achieve a green and sustainable commercial manufacturing route, the team explored an enzymatic oxidative desymmetrization of bicyclic amine 1 to generate chiral imine 2 that was utilized as the crystalline trimer in a three-component Ugi-coupling penultimate step to prepare MK-7845. Monoamine oxidase was selected as the biocatalyst to perform this transformation under aqueous conditions, with oxygen (supplied as compressed air) as the terminal oxidant. While this chemoenzymatic transformation offers high enantioselectivity and low environmental footprint, challenges were encountered during process development due to lower enzyme activity at a practical substrate concentration, competing pathways of oxygen consumption, and imine volatility. In this paper, we describe our efforts to utilize process analytical technology (PAT) to track the enzymatic oxidation and sulfonation reaction profiles to develop an efficient gram scale desymmetrization toward bisulfite-adduct 3.