Stereoselective Synthesis of Linustedastat Via Deoxy-Aromatization Strategy

An efficient and stereoselective synthesis of Linustedastat (1) is reported, commencing from inexpensive and commercially available sitolactone. The route features a highly chemoselective Grignard addition, followed by sequential double aldol condensations to construct the core steroidal framework. A key step involves a novel deoxy-aromatization of a fluorinated steroid intermediate, setting the stage for a stereoselective hydrogenation and a 1,4-conjugate addition to further elaborate the molecule. This strategically designed sequence delivers the complex and electron-deficient fluorinated steroidal architecture in 16 steps with an 11.0% overall yield.