Divergent syntheses of indole alkaloids enabled by a tandem cycloaddition cascade

Divergent synthesis was first defined by Boger group in 1984, as the conversion of an advanced common intermediate to at least two members of the class of compounds. This synthetic strategy has been widely adopted in the recent decades, allowing for efficient access of different classes of natural products and their analogs from a common intermediate. Most notably, the divergent synthetic strategy is frequently applied in drug discovery, where a common functionalized scaffold is diversified to a library of compounds to facilitate screening for bioactive small molecules.
The work herein describes the divergent total syntheses of the indole alkaloids (-)-pseudocopsinine, (-)-minovincinine and (-)-strempeliopine from a common intermediate. Key to their divergent syntheses was the recognition of the common underlying Aspidosperma carbon skeleton for these three natural products, from which they can be accessed through late-stage formation of strategic bonds unique to their respective skeleton. Central to the assemblage of the Aspidosperma core of the common intermediate was the [4+2]/[3+2] cycloaddition cascade of a 1,3,4-oxadiazole, forging the desired pentacyclic carbon skeleton in a single step with the diastereoselective formation of six contiguous stereocenters. This work complements earlier syntheses of (+)-fendleridine, (-)-kopsinine, (-)-deoxoapodine, and (-)-kopsifoline D to culminate in the total syntheses of seven different classes of alkaloid natural products from a common intermediate, demonstrating the power of divergent synthetic strategy and the importance of strategic bond disconnections.