Kinetically Controlled aza-Michael/Epimerization Cascade Enables a Scalable Total Synthesis of Putative (+)-Fumigaclavine F

Abstract

The first total syntheses of putative (+)-fumigaclavine F (seven pots, 16% overall yield, 400 mg scale) and its proposed biosynthetic precursor (seven pots, 21% overall yield, 400 mg scale) have been achieved. The stereochemistry of both was unambiguously verified via XRD. The synthesis features a decagram-scale asymmetric intramolecular Mannich reaction, followed by an aza-Michael/epimerization cascade that constructs the cis-fused tetracyclic scaffold. The synthesis provides an excellent approach to probe the bioactivity of clavine alkaloids.