The phainanoids were isolated from the plant Phyllanthus hainanensis and their potent bioactivities (e.g. inhibition of T-cell and B-cell proliferation) were also reported (J. Am. Chem. Soc. 2015, 137, 138–141.). We are applying a pharmacophore-directed retrosynthesis strategy (Nat. Chem. 2019, 11, 342-350) that was recently applied to rameswaralide (J. Am. Chem. Soc. 2022, 144, 18575–18585.) to the phainanoids and derivatives. While we predict that most of this natural product is required for potent bioactivity, our initial target is the C-D-E-F ring system to determine strategies for constructing this ring system while also providing simplified derivatives for initial biological testing. In collaboration with Prof. Jun Liu’s group (Johns Hopkins), we will determine the immunosuppressive activity of simplified versions of the top right sector of the molecule to develop an SAR profile and ultimately the minimum structure required for potent bioactivity. We will describe synthetic strategies to construct the key C-C bond between the the 5,5-spirolactone and the 5,6-bicyclic enone.

Structure of phainanoid F isolated and reported by Fan et al. (<i>J. Am. Chem. Soc.</i> <b>2015</b>, <i>137</i>, 138–141)

Structure of phainanoid F isolated and reported by Fan et al. (J. Am. Chem. Soc. 2015, 137, 138–141)

Evan Woods

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