Divergent Total Syntheses of Bisnicalaterine Alkaloids Enabled by a Stereocontrolled Geissoschizol Synthesis.

Bisnicalaterine alkaloids are structurally complex and biologically significant bisindole natural products. Herein, we report the first enantioselective total syntheses of bisnicalaterines B, C, and their N4' epimers using an eight-step longest linear sequence. Central to this strategy is a site- and stereoselective bioinspired Friedel-Crafts-type coupling between the eburnamine and geissoschizol fragment, enabling a highly selective formation of the bisindole core. The geissoschizol framework is efficiently assembled using a stereocontrolled Bischler-Napieralski cyclization/reduction sequence and an organocatalytic enantioselective Michael addition, which establishes the C3 and C15 stereocenters with high fidelity. In addition, the stereochemical relationship between the cis- and trans-fused indoloquinolizidine cores is delineated, offering new insight into conformational control within this alkaloid family. This concise synthetic route not only provides the first laboratory access to these unique natural products but also establishes geissoschizol as a versatile platform for the synthesis of other monoterpenoid indole alkaloids (MIAs) and bisindole alkaloids.