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

Abstract

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. Preliminary investigations into a catalytic asymmetric spirocyclization towards an enantioselective SPM synthesis are also described. Further studies of the antiparasitic properties of this class have revealed promising activity against T. brucei for certain congeners. Together with our prior approach to the 6/5-family members, our work constitutes a synthetic solution to all known spiroindimicin natural products.