Stereoselective Total Synthesis of Eburnane-Type Alkaloids Enabled by Conformation-Directed Cyclization and Rearrangement

Controlling the cis C20/C21 relative stereochemistry remains an unsolved issue in the synthesis of eburnane-type indole alkaloids. Provided herein is a simple solution to this problem by developing a unified and diastereoselective synthesis of four representative members of this class of natural products, namely, eburnamonine, larutensine, terengganensine B, and melokhanine E. The synthesis features the following key steps: a) an alpha-iminol rearrangement transforming the 3-hydroxyindolenine into spiroindolin-3-one, b) a highly diastereoselective conformation-directed cyclization leading to the melokhanine skeleton with the desired C20/C21 cis stereochemistry, and c) either an aza-pinacol or an unprecedented alpha-aminoketone rearrangement converting spiroindolinone back into the indole skeleton.