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

Abstract

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.