Enantioselective synthesis of hetisine

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DESCRIPTION (provided by applicant): Hetisane-type alkaloids (which comprise a family of over 100 compounds isolated from plants of the genre Aconitum, Delphinium, Thalictrum, Consolida, and Spirea) have been shown to possess antiarrhythmic properties. To date, none of the hetisane alkaloids have been synthesized. The current need for novel antiarrhythmic agents, coupled with the known antiarrhythmic properties of these compounds makes this class of molecule a worthwhile target. Proposed here is the enantioselective synthesis of hetisine. This synthesis would lay the groundwork for developing novel structural variants based on the hetisane carbon skeleton. In this respect, the intermediates generated throughout this synthesis would be important unto themselves. Not only would they provide a basis for the synthesis of novel compounds, but they themselves could be used to generate valuable structure-activity relationship data. The key step in this synthesis will be an unusual aza-Cope-Mannich transformation in which conformational and steric restrictions drive the reaction through a normally unfavored boat transition state. Establishing the ability to control product formation through structural restrictions in this manner would enhance the scope and generality of this already proven reaction.