Development of a Convergent Enantioselective Synthetic Route to (-)-Myrocin G

Martin Tomanik, Christos Economou, Madeline C. Frischling, Mengzhao Xue, Victoria A. Marks, Brandon Q. Mercado, Seth B. Herzon

Research output: Contribution to journalArticlepeer-review


Myrocins are a family of antiproliferative antibiotic fungal metabolites possessing a masked electrophilic cyclopropane. Preliminary chemical reactivity studies imputed the bioactivity of these natural products to a DNA cross-linking mechanism, but this hypothesis was not confirmed by studies with native DNA. We recently reported a total synthesis of (-)-myrocin G (4), the putative active form of the metabolite myrocin C (1), that featured a carefully orchestrated tandem fragment coupling-annulation cascade. Herein, we describe the evolution of our synthetic strategy toward 4 and report the series of discoveries that prompted the design of this cascade coupling. Efforts to convert the diosphenol (-)-myrocin G (4) to the corresponding 5-hydroxy-γ-lactone isomer myrocin C (1) are also detailed. We present a preliminary evaluation of the antiproliferative activities of (-)-myrocin G (4) and related structures, as well as DNA cross-linking studies. These studies indicate that myrocins do not cross-link DNA, suggesting an alternative mode of action potentially involving a protein target.

Original languageEnglish (US)
Pages (from-to)8952-8989
Number of pages38
JournalJournal of Organic Chemistry
Issue number14
StatePublished - Jul 17 2020

ASJC Scopus subject areas

  • Organic Chemistry


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