Stereoselective Synthesis of the IDO Inhibitor Navoximod
Frédéric St-Jean, Rémy Angelaud, Stephan Bachmann, Diane E. Carrera, Travis Remarchuk, Katarzyna A. Piechowicz, Katrin Niedermann, Hans Iding, Roland Meier, Haiyun Hou, Lauren E. Sirois, Jie Xu, Martin Olbrich, Pankaj D. Rege, Maud Guillemot-Plass, Francis Gosselin
Abstract
A highly efficient asymmetric synthesis of the IDO inhibitor navoximod, featuring the stereoselective installation of two relative and two absolute stereocenters from an advanced racemic intermediate, is described. The stereocenters were set via a crystallization-induced dynamic resolution along with two selective ketone reductions: one via a biocatalytic ketoreductase transformation and one via substrate-controlled hydride delivery from LiAlH(Ot-Bu)3. Following this strategy, navoximod was synthesized in 10 steps from 2-fluorobenzaldehyde and isolated in 23% overall yield with 99.7% ee and high purity.