Shearinines are indole triterpenoids isolated from a variety of fungi.¹ They were selected as targets both because of their complex molecular scaffolds and their interesting bioactivities. Among others, Cichewicz and coworkers found shearinine D and shearinine E to be potent inhibitors of biofilm formation by Candida albicans. They additionally observed synergistic effects when the alkaloids were employed in combination with amphotericin B,² a compound which has a long history in our research group.³ Our highly convergent synthetic strategy relies on the late-stage assembly of two complex fragments and allows for the straightforward implementation of various modifications enabling a structure–activity relationship study on the shearinine natural products.

Shearinines D and E present a formidable synthetic challenge due to their complex nonacyclic structures bearing eight stereocenters, wherein two are vicinal quaternary carbons. Our campaign has led to the completion of the first total synthesis of shearinine D.

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[2] Jianlan You, Lin Du, Jarrod B. King, Brian E. Hall, Robert H. Cichewicz, ACS Chem. Biol., 2013, 8, 840-848.
[3] For a complete list of related publications, see http://www.carreira.ethz.ch/research/chemical-biology.html.