Trials into Triumphs: The Emergence of a Concise Total Synthesis of Hinckdentine A

Nonintuitive retrosynthetic disconnections can offer valuable insights for devising efficient synthetic routes to complex natural products. When such disconnections involve skeletal rearrangements, they often allow advanced intermediates to be traced back to much simpler building blocks. Guided by this paradigm and motivated by the aspiration to achieve the "ideal synthesis", we have undertaken multiple generations of development to accomplish a concise synthesis of the unique, propeller-shaped natural product hinckdentine A. At the core of our strategy is a novel dearomative indolic-Claisen rearrangement that efficiently transfers the chirality of a readily introduced alcohol to a newly formed, fully substituted chiral center. The resulting densely substituted tertiary amide intermediate was pivotal for progressing toward the final target. The route, however, was far from straightforward, and several pathways were explored, and numerous challenges were overcome before successfully advancing this intermediate to hinckdentine A. This comprehensive account details the evolution of our synthetic campaign, highlighting the unforeseen obstacles encountered and strategic maneuvers devised to surmount them en route to a concise synthesis of the natural product.