Silvestrol is a novel rocaglamide derivative (flavagline) that has demonstrated potent cytotoxic activity (low nM IC50 values) in vitro against numerous human cancer cell lines.  Moreover, silvestrol has displayed this potent cytotoxicity against both acute and chronic lymphoblastic leukemia while exhibiting selectivity for malignant B-cells.  Structurally, silvestrol contains the densely functionalized cyclopenta<b>benzofuran core, which is characteristic of all flavaglines, but also possesses an unprecedented C6 dioxanyloxy side chain that makes silvestrol unique.  In order to access the C6, C8 differentially functionalized cyclopenta<b>benzofuran core required to synthesize silvestrol, we have utilized a CAN mediated oxidative addition of 1,3-cyclohexadine derivatives into an allylic ether to construct the core ring system.  This methodology has permitted the development of a rapid, versatile, and modular synthesis of this system, and provides access to the flavagline class of natural products as a whole. This ongoing effort has facilitated the synthesis of two classes of structurally distinct flavagline analogues designed to explore structure activity relationships, delineate the mechanism of action, and ultimately improve the pharmacological profile of these compounds.

Synthesis of the differentially functionalized cyclopenta[<i>b</i>]benzofuran core of silvestrol through a CAN mediated oxidative cyclization

248th National Meeting (2014)

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Synthesis of the differentially functionalized cyclopenta[b]benzofuran core of silvestrol through a CAN mediated oxidative cyclization