In 2014, Li and coworkers reported the isolation of the tetramic acid-derived natural product cladosin C from the marine fungus Cladosporium sphaerospermum. Preliminary screening of cladosin C against influenza A subtype H1N1 revealed potentially promising antiviral activity when compared to the known anti-influenza drug ribavirin. The increasing resistance of H1N1 to current treatments and the severe side effects of currently prescribed H1N1 antiviral agents have created a dire need for the discovery of more viable treatments. Further evaluation of cladosin C is limited by the scarcity of this compound, and our goal is to synthesize enough material for meaningful characterization of this compound’s bioactivity against H1N1. Our original synthetic route towards cladosin C involved a five-step linear sequence to form the full carbon skeleton of the natural product, starting from commercially available methyl (R)-3-hydroxybutanoate. Key steps in this route include a trans-selective Wittig olefination, a dioxinone thermolysis / acylketene trapping step using a protected derivative of L-valine, and a Lacey-Dieckmann cyclization to form the tetramic acid. However, difficulties with the late-stage oxidative removal of a 2-bromobenzyl protective group under radical conditions led us to explore an alternative convergent route to this natural product. Synthetic analogs of cladosin C produced via this route will be submitted for further biological testing through our collaboration with Eli Lilly’s Open Innovative Drug Discovery program.

Total synthesis of cladosin C

253rd National Meeting (2017)

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