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Total Synthesis of (+)-Spiroindimicin A via Asymmetric Palladium-Catalyzed Spirocyclization

preprint
submitted on 29.04.2021, 18:38 and posted on 03.05.2021, 04:46 by Zhen Zhang, Sneha Ray, Leah Imlay, Lauren Callaghan, Hanspeter Niederstrasser, Prema Latha Mallipeddi, Bruce A. Posner, Dawn Wetzel, Margaret Phillips, Myles Smith

The spiroindimicins are a unique class of chlorinated indole alkaloids characterized by three heteroaromatic rings structured around a congested spirocyclic stereocenter. Here, we report the first total synthesis of (+)-spiroindimicin A, which bears a challenging C-3’/C-5’’-linked spiroindolenine. We detail our initial efforts to effect a biomimetic oxidative spirocyclization from its proposed natural precursor, lynamicin D, and describe how these studies shaped our final abiotic 9-step solution to this complex alkaloid built around a key asymmetric Pd-catalyzed spirocyclization. Scalable access to spiroindimicins A, H, and their congeners has enabled discovery of their activity against several parasites relevant to human health, providing potential starting points for new therapeutics for the neglected tropical diseases leishmaniasis and African sleeping sickness.

History

Email Address of Submitting Author

myles.smith@utsouthwestern.edu

Institution

UT Southwestern Medical Center

Country

United States

ORCID For Submitting Author

0000-0002-0231-0059

Declaration of Conflict of Interest

No conflict of interest

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