Concise and Stereoselective Total Syntheses of Annotinolides C, D, and E

The annotinolides are one of the most recent additions to the Lycopodium family of alkaloids, with its members possessing challenging, caged structures that include a [3.2.1]-bicyclic core bearing six contiguous stereocenters, including four that are fully substituted. Herein, we document a concise and stereoselective route that achieves the first total syntheses of three of its members: annotinolides C, D, and E. Key operations include a gold(I)-catalyzed Conia-ene reaction that fashions much of the main core in a single operation, as well as a number of other challenging and chemoselective transformations to generate the remaining elements. Moreover, efforts utilizing the natural products themselves, seeking adjustments in their oxidation states and the rearrangement of individual ring systems, shed light on their potential biogenesis with some outcomes counter to those originally proposed. Finally, formal enantioenriched syntheses of the target molecules are also presented.

Automated summary

The newly added annotinolides in the Lycopodium family have complex structures, and we have successfully achieved the total synthesis of three members using key operations such as gold(I)-catalyzed Conia-ene reaction and other challenging transformations. Furthermore, efforts to adjust the oxidation states and rearrange ring systems of the natural products shed light on their potential biogenesis.