A Practical and Scalable-Oriented Enantioselective Synthesis of (S)-Autumnaline

A process-friendly and enantioselective total synthesis of (S)-autumnaline, a key biosynthetic precursor to the colchicine alkaloids, is reported. The strategy relies on a Bischler–Napieralski cyclization–asymmetric imine reduction sequence to construct the chiral isoquinoline core. Significant process innovations include a cyanide-free homologation using a Darzens reaction and a chromatography-free purification strategy via d-tartrate salt formation. The absolute configuration was definitively confirmed through a combination of circular dichroism (CD) spectroscopy and computational modeling. This developed process affords (S)-autumnaline in 11 steps (nine-step longest linear sequence) with a 13% overall yield.