Total synthesis of (+)-spiroindimicin A and congeners unveils their antiparasitic activity

Zhen Zhang, Sneha Ray, Leah Imlay, Lauren T. Callaghan, Hanspeter Niederstrasser, Prema Latha Mallipeddi, Bruce A. Posner, Dawn M. Wetzel, Margaret A. Phillips, Myles W. Smith

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

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 Pd-catalyzed asymmetric 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.

Original languageEnglish (US)
Pages (from-to)10388-10394
Number of pages7
JournalChemical Science
Volume12
Issue number30
DOIs
StatePublished - Aug 14 2021

ASJC Scopus subject areas

  • Chemistry(all)

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