Total Synthesis of (-)-Calyciphylline N

The dissertation herein describes the first total synthesis of the complex Daphniphyllum alkaloid, (-)-calyciphylline N. This alkaloid was chosen as the target in our synthetic program due its unprecedented structure, the inherent challenges associated with its synthesis, and limited reports of synthetic studies towards members of this family of natural products. An initial unsuccessful approach is discussed, followed by a revised, ultimately successful approach. Highlights of the synthesis include a substrate controlled, intramolecular Diels-Alder reaction to build the bicyclo[2.2.2]octane core and set four contiguous stereocenters, a transannular enolate alkylation to secure ring D, a highly efficient Stille carbonylation/Nazarov cyclization sequence to construct ring E with concomitant activation of a hindered silyl group towards Fleming-Tamao oxidation, and an unprecedented, homogeneous hydrogenation of an exceptionally hindered diene ester to complete the eastern hemisphere, a structural motif that is common to a variety of the Daphniphyllum alkaloids.