This proposal presents methodology for the synthesis of two newly- reported cembranoid diterpene natural products, pseudoplexaurol (1) and 14-deoxycrassin (2). These compounds show cytotoxicity in the range of IC50 =20.0 - 0.15 mug/mL against a variety of human cell lines. Both natural products will be accessible from a common, advanced intermediate. The key steps in the proposed synthesis include: a palladium-catalyzed allyl/allyl coupling reaction to form the 14-membered ring, a novel alkyne homologation/methylation sequence, the Eschenmoser fragmentation reaction of an epoxy ketone and the Buchi rearrangement of an optically active cyclohexenone. The requisite absolute stereochemistry will be established on small, well-defined systems prior to the formation of the 14-membered ring. The methodology presented should be applicable to the asymmetric synthesis of other natural and unnatural cembranoid diterpenes.
