Amaryllidaceae isocarbostyril alkaloids

Tanner W. Bingham, Lucas W. Hernandez, David Sarlah

Research output: Chapter in Book/Report/Conference proceedingChapter


The highly potent anticancer natural products, the Amaryllidaceae isocarbostyril alkaloids, have been a desirable target for total synthesis over the past few decades. However, while many elegant approaches have been reported previously, scalable access to these important medicinal compounds has remained unrealized. Here, we describe our efforts toward these antineoplastic agents in detail, including failed routes and how we overcame them. The brevity and scalability of our synthesis was due to the development of the nickel-catalyzed asymmetric dearomative carboamination reaction, allowing for olefin difunctionalization reactions to install the contiguous stereocenters of the cyclitol core. Upon completion of our synthesis, we synthesized a series of analogs, some of which displayed equipotent activity and increased aqueous solubility, a major inhibitor of these alkaloids' preclinical evaluation. We then synthesized isotopologs of the natural products to identify the potential sites of metabolism, leading to increased stability over the parent compounds. With this synthetic blueprint, we hope to enable the preclinical evaluation of these important cytotoxic natural products.

Original languageEnglish (US)
Title of host publicationStrategies and Tactics in Organic Synthesis
EditorsMichael Harmata
PublisherAcademic Press Inc.
Number of pages52
ISBN (Print)9780128222126
StatePublished - Jan 2022


  • Alkaloids
  • Analogs
  • Anticancer
  • Aqueous solubility
  • Dearomatization
  • Natural products
  • Nickel catalysis
  • Structure–activity relationship
  • Total synthesis

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry


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