A catalytic process enables efficient and programmable access to precisely altered indole alkaloid scaffolds

Youming Huang, Xinghan Li, Binh Khanh Mai, Emily J. Tonogai, Amanda J. Smith, Paul J. Hergenrother, Peng Liu, Amir H. Hoveyda

Research output: Contribution to journalArticlepeer-review

Abstract

A compound’s overall contour impacts its ability to elicit biological response, rendering access to distinctly shaped molecules desirable. A natural product’s framework can be modified, but only if it is abundant and contains suitably modifiable functional groups. Here we introduce a programmable strategy for concise synthesis of precisely altered scaffolds of scarce bridged polycyclic alkaloids. Central to our approach is a scalable catalytic multi-component process that delivers diastereo- and enantiomerically enriched tertiary homoallylic alcohols bearing differentiable alkenyl moieties. We used one product to launch progressively divergent syntheses of a naturally occurring alkaloid and its precisely expanded, contracted and/or distorted framework analogues (average number of steps/scaffold of seven). In vitro testing showed that a skeleton expanded by one methylene in two regions is cytotoxic against four types of cancer cell line. Mechanistic and computational studies offer an account for several unanticipated selectivity trends. (Figure presented.)

Original languageEnglish (US)
JournalNature Chemistry
DOIs
StateAccepted/In press - 2024

ASJC Scopus subject areas

  • General Chemistry
  • General Chemical Engineering

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