Letermovir is a potent DNA terminase inhibitor (EC50 = ca 5 nM) with no observed dose-dependent toxicity, and has been awarded both fast track and orphan drug status in 2011. The first generation synthesis of letermovir involving a classical resolution was considered sufficient for initial clinical supplies; however, in view of its racemic mode and significant raw material costs, a more efficient and cost effective route, appropriate for sustainable long-term supply, was desirable. This presentation will describe our recent chemistry development efforts toward a concise and efficient asymmetric synthesis which culminated in the development of a novel catalytic asymmetric aza-Michael cyclization reaction exploiting two classes of organocatalysis, bis-quaternized phase-transfer catalysis and hydrogen-bonding catalysis.<br/>

Asymmetric hydrogen bonding catalysis for the synthesis of dihydroquinazoline-containing antiviral, letermovir

254th National Meeting (2017)

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