Torquoselectivity in the Nazarov cyclization of facially biased dienones and their application toward total synthesis of taxinine

The Nazarov cyclization has emerged as a powerful method for formation of five-membered carbocyclic rings from simple dienone precursors. Its mechanism was shown to proceed by initial conrotatory ring closure of the activated dienone-Lewis acid complex affording an intermediate oxyallyl zwitterions that collapses during eliminative termination to furnish the corresponding cyclopentenone products as a mixture of stereoisomers. The presented studies demonstrate that stereochemical control in the Nazarov cyclization can be achieved in complex facially biased dienone systems.; Lewis-acid initiated Nazarov cyclizations of bicyclic dienones are found to provide complex tricyclic 2-cyclopentenones in good yields and in most cases high diastereoselectivity. The substitution pattern around the dienone system was found to be crucial to the stereochemical outcome of the reaction. In addition, a new modification of the Stille coupling was developed as an efficient method for constructing such elaborate cross-conjugated ketones.; Taxinine is a member of the taxane class of natural products and structurally very similar to taxol. Although less potent than taxol, it displays anticancer activity and is a suspected multidrug resistance (MDR) reversing agent. Described herein is our approach to a highly substituted bicyclic taxane intermediate. This route is highlighted by a torquoselective Nazarov cyclization in which high levels of endo selectivity are observed. In addition, assembly of the central eight-membered ring is achieved via an oxidative fragmentation reaction of a tetrasubstituted double bond. Furthermore, installation of the bridgehead olefin is accomplished through a base-induced elimination of an E-epoxy ketone.