Enantioselective Formal Synthesis of (-)-Aflatoxin B₂ Enabled by Pd-Catalyzed Carboetherification of 2,3-Dihydrofuran

We report a short formal synthesis of the natural product (-)-aflatoxin B₂ enabled by a highly enantioselective Pd/sSPhos-catalyzed carboetherification reaction of 2,3-dihydrofuran; we also describe the application of the key reaction to several other substrates. This key step enantioselectively forges the complex tricyclic core of the natural product directly from commercially available substrates in 99% ee. An enabling aspect is that our chiral phosphine ligand sSPhos, which operates through electrostatically directed catalysis, permits a substituent to be incorporated at the 4 position of the resulting tetrahydrobenzofuran: (-)-aflatoxin B₂ and other natural products based on this polycyclic motif also contain a substituent in this position. Post-functionalization completes one of the most concise (-)-aflatoxin B₂ formal syntheses reported to date while also delivering the key intermediate with the highest enantiomeric excess. We also demonstrate sSPhos to be effective in an analogous enantioselective carboamination reaction.