This proposal will detail studies directed towards the total synthesis of (+)- and (-)-Spiroxins A-E, new members of the bisnaphthospiroketal class of natural products. Spiroxin A has been shown to possess very promising biological activity, exhibiting antitumor activity in nude mice against ovarian carcinoma (59 percent inhibition after 21 days) at 1mg/kg dosing and cytotoxicity with a mean IC50 value of 0.09 mg/mL against a panel of 25 diverse cell lines. The mechanism of this activity is not known, nor are the biological activities of spiroxins B-E. The spiroxins are therefore very attractive targets for synthesis and analog preparation. Furthermore, the absolute stereochemistry of these natural products is not known, nor are the relative stereochemistries of Spiroxins D and E. The syntheses proposed herein would therefore also serve to provide critical stereochemical information by accessing the unnatural enantiomers and diastereomers which may themselves possess important biological activity. The proposed synthetic route is convergent, incorporates new methodology for the asymmetric preparation of naphthoquinols, and expands the utility of existing biaryl ether-forming methodologies.
