Scaleable formal synthesis of R + etomoxir without pyrophopric reagents enabled by benchtop NMR

Department of Chemistry, Biochemistry & Physics Scalable formal synthesis of (R)-(+)-etomoxir without pyrophoric reagents enabled by benchtop NMR Etomoxir is a covalent inhibitor of CPT1, a transmembrane mitochondrial protein that acts as the rate-limiting enzyme for fatty acid oxidation. This enzyme plays a major role in metabolic diseases such as diabetes, where regulation of fatty acid biosynthesis and β-oxidation kinetics through CPT1 are effective treatments for such diseases. The 4-Cl phenolic ether on (R)-(+)-etomoxir is a key SAR hotspot for enabling isoform selective inhibition of CPT1. Previously reported syntheses either require early installation of a 4-Cl phenolic ether which precludes the potential for late stage aryl substitution, or employ large scale pyrophoric reactions in early synthetic operations which are challenging to scale. We demonstrate the scalability of a new synthetic route to intercept a late-stage allylic alcohol in route to (R)-(+)-etomoxir. Notably, our alternate retrosynthetic disconnection, which proceeds through a catalytic aerobic oxidation and a one-flask tandem aldol condensation- reduction sequence, to install a key allylic methylene, avoids pyrophoric materials such as n-butyllithium. With a scalable synthesis of a key diversifiable intermediate in hand, our laboratory is currently preparing a library of diverse (R)-(+)-etomoxir analogs to more fully interrogate the SAR of the aryl ring in CPT1 inhibitory activity. RESEARCHERS: Jacqueline Shan, The King's Academy '26; Sophia Bagley, The Harker School '26 ADVISOR: Njoo Lab Synthesis | Physical Organic Chemistry | Catalysis | Chemical Biology | Spectroscopy | Medicinal Chemistry KEYWORDS: Formal Synthesis | Catalysis | Spectroscopy