Computational Prediction and Experimental Validation of a Bridged Cation Intermediate in Akanthomycin Biosynthesis

Here we report a computation-driven chemoenzymatic synthesis and biosynthesis of the natural product deoxyakanthomycin, an atropisomeric pyridone natural product that features a 7-membered carbocycle with five stereocenters, one of which a quaternary center. The one-step synthesis from a biosynthetic precursor is based on computational analysis that predicted a σ-bridged cation mediated cyclization mechanism to form deoxyakanthomycin. The σ-bridged cation rationalizes the observed substrate-controlled selectivity; diastereoselectivity arises from attack of water anti to the σ-bridging, as is generally found for σ-bridged cations. Our studies also reveal a unifying biosynthetic strategy for 2-pyridone natural products that derive from a common o-quinone methide to create diverse structures.