Synthesis of Etrasimod (APD334): Al₂O₃-Promoted Decarboxylative Rearrangements of Cyclopentenones with Stereochemical Inversion

This study presents an efficient synthesis pathway for etrasimod, starting from (+)-<i>cis</i>-4-acetoxy-2-cyclopenten-1-ol, yielding 5.6% overall with 98% enantiomeric excess. The crucial intermediate, (4<i>R</i>)-anilinocyclopent-2-enone, was derived from the (<i>S</i>)-alcohol/isocyanate adduct through a concerted, Al₂O₃-promoted decarboxylative rearrangement, which inverted the configuration. A tetracyclic fused lactam was formed via a one-pot acylation-Michael addition, followed by keto α-arylation. Subsequent removal of the oxo group facilitated the synthesis of cyclopenta[<i>b</i>]indol-3-ylacetic acid through a series of reactions, including methanolysis, indoline oxidation, and hydrolysis.