Synthesis of the 5/5-spiroindimicin alkaloids: development of a general synthetic approach and biological investigations.

We describe the development of a unified synthetic strategy for the preparation of all known 5/5-spirocyclic spiroindimicin (SPM) alkaloids, namely spiroindimicins B-G. The present synthetic route relies on four fundamental transformations: Grignard-based fragment coupling between halogenated pyrrolemetal and isatin partners, Suzuki coupling to generate a triaryl scaffold encompassing all requisite skeletal atoms of the natural products, Lewis acid-mediated spirocyclization to construct the 5/5-spirocyclic core, and chemoselective lactam reduction. The developed syntheses are step-economic (6-7 steps from commercial materials), scalable, and amenable to analogue synthesis.

Modular Total Synthesis of the 5/5-Spirocyclic Spiroindimicins.

Total syntheses of the 5/5-spirocyclic indoline alkaloids (±)-spiroindimicins B, C, D, E, F, and G have been achieved via a modular approach. Our route features direct coupling of halogenated pyrrolemetal and isatin partners, Suzuki coupling to append the indole unit, Lewis acid-mediated spirocyclization, and divergent functionalization to give various family members. These syntheses are concise (six or seven steps from commercial materials) and highly amenable to analogue synthesis.