Enantioselective Synthesis of (+)-Chamaecypanone C a Novel Microtubule Inhibitor

摘要

A number of bicyclo[2.2.2]octenone-containing natural products have been isolated from the heartwood of Chamaecyparis obtusa var. formosana () including the Diels-Alder adducts[] obtunone (>1),[] chamaecypanone C (>2),[] and the [4+2] dimer (+)->3.[],[] Compound (+)->2 was shown to exhibit potent cytotoxicity against several human cancer cells including human oral epidermoid carcinoma (KB) (IC50 = 190 nM).[] The biosynthesis of >2 was proposed[] to occur via endo [4+2] cycloaddition between 1-hydroxymentha-3,5-dien-2-one >4 () and 1,3-bis-arylcyclopenta-1,3-diene >5, followed by oxidation to an enone in accord with literature reports of cyclopentadienes as biosynthetic precursors to natural products.[] An alternative possibility involving the corresponding cyclopentadienone >6 as dienophile may also be considered in light of known biosyntheses involving reactive cyclopentadienones.[] Herein, we report a concise synthesis of both enantiomers of chamaecypanone C involving a retro-DA/DA cascade of dimer >3, obtained utilizing copper-mediated asymmetric oxidative dearomatization,[] as well as biological studies documenting that the cytotoxic action of (+)->2 involves mitotic arrest as a consequence of its binding in the colchicine site of tubulin.Representative Bicyclo[2.2.2]octenone-Containing Natural Products