Divergent Total Synthesis of Denudatine Alkaloids Cochlearenine, Macrocentrine, Dictizine, 15‐Veratroyl‐17‐Acetyl‐19‐Oxodictizine, and the Proposed Structure of Acochlearine

The first asymmetric total syntheses of four denudatine alkaloids, cochlearenine, macrocentrine, dictizine, and 15-veratroyl-17-acetyl-19-oxodictizine, along with the asymmetric synthesis of the proposed structure of acochlearine, were accomplished in a divergent manner. Highly fused tetracyclic skeletons (A/B/E/F rings) with different N-alkyl groups (Me and Et) were constructed by Brønsted acid promoted intramolecular Mannich reactions. The bicyclo[2.2.2]octane C/D rings were constructed via two-fold intermolecular Diels-Alder reactions. By utilizing these key processes, the common intermediates, possessing the complex cage-like hexacyclic skeleton, were constructed. From these common intermediates, the four denudatine alkaloids were synthesized through late-stage, chemo- and stereoselective modifications around the A/C rings. The spectroscopic data of the proposed structure of acochlearine were inconsistent with those of natural acochlearine.