Total Synthesis of Kopsimaline A

Scripps Research Institute, The, La Jolla CA

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Abstract

DESCRIPTION (provided by applicant): This proposal presents a plan for an enantioselective total synthesis of the natural product kopsimaline A and its structural analogues. Kopsimaline A has been found to be effective at reversing multidrug resistance in vincristine-resistant human cancer KB cells. Due to structural similarities between kopsimaline A and vincristine, efflux transporter proteins may preferentially bind kopsimaline A instead of vincristine, effectively inhibiting the export of vincristine out of cancer cells, reversing multidrug resistance. The synthetic plan involves a 22 step synthetic route from commercially available materials. Key steps include a [4 + 2]/[3 + 2] intramolecular cycloaddition cascade, a double conjugate addition of an enamine onto a vinyl sulfone and a ring expansion via a modified von Braun reaction. The proposed route is conducive to the creation of a library of synthetic analogues that will help identify key structural features responsible for the biological activity of the compound. Kopsimaline A will also be tested in concert with a number of vinblastine analogues that have already been synthesized by the Boger laboratory in search of an effective combination for use in chemotherapy.