Total Synthesis of the Tetracyclic Antimalarial Alkaloid (±)-Myrioneurinol

The first total synthesis of the tetracyclic antimalarial Myrioneuron alkaloid (±)‐myrioneurinol has been accomplished using three highly diastereoselective reactions as pivotal steps: 1) an intramolecular Michael addition of a benzyloxycarbonyl‐protected lactam titanium enolate to an α,β‐unsaturated ester for construction of the spirocyclic C5 quaternary center and the a/d rings, 2) a malonate anion conjugate addition to a transient nitrosoalkene to install the requisite functionality and configuration at the C7 position, and 3) an intramolecular sulfonyliminium aza‐Sakurai reaction to form the b ring and the attendant C9/C10 configuration of the natural product. Malaria's worst nightmare: A total synthesis of the tetracyclic antimalarial Myrioneuron alkaloid (±)‐myrioneurinol features three highly diastereoselective reactions as the key steps: an intramolecular Michael addition of a lactam titanium enolate to an α,β‐unsaturated ester, a conjugate addition of a malonate enolate to a nitrosoalkene, and an intramolecular aza‐Sakurai reaction.