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

ABSTRACT

This study presents an efficient synthesis pathway for etrasimod, starting from (+)-cis-4-acetoxy-2-cyclopenten-1-ol, yielding 5.6% overall with 98% enantiomeric excess. The crucial intermediate, (4R)-anilinocyclopent-2-enone, was derived from the (S)-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[b]indol-3-ylacetic acid through a series of reactions, including methanolysis, indoline oxidation, and hydrolysis.