Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Epublish
PubMed: 39504114 DOI: 10.1039/d4ob01552e
Synthesis of the 5/5-spiroindimicin alkaloids: development of a general synthetic approach and biological investigations.
Org Biomol Chem 22(48):9413-9425
Authors: Ankush Banerjee, Tiffany A Brisco, Sneha Ray, Arani Datta, Xiaoyu Zhang, Zhen Zhang, Alexander A Busse, Hanspeter Niederstrasser, Krissty Sumida, Bruce A Posner, Dawn M Wetzel, Margaret A Phillips, Myles W Smith
Affiliations
- Department of Biochemistry, UT Southwestern Medical Center, Dallas, Texas 75390, USA.
- Department of Pediatrics, UT Southwestern Medical Center, Dallas, Texas 75390, USA.
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 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.
MeSH
Chemistry, Organic, Alkaloids, Biochemistry