Part I: A synthesis of jiadifenolide; Part II: Efforts toward a synthesis of pleurotin

Abstract

Jiadifenolide, isolated in 2009, is a pentacyclic sesquiterpenoid natural product with a densely oxidized architecture. Because of both the challenge of constructing this unique structure as well as its ability to promote neurite outgrowth in primary cultured rat cortical neurons, we were drawn to jiadifenolide as a synthetic target. The hallmarks of our strategy for synthesis include the reliance on the time-honored Robinson annulation to build the cyclohexane ring, the use of a catalytic, palladium-mediated C-H oxidation to generate local asymmetry at a carbon atom bearing a geminal methyl motif, and the incorporation of an iodoso Pummerer-like rearrangement of an α-iodo lactone to produce the corresponding α-keto lactone. The successful implementation of this strategy resulted in a successful, eighteen step synthesis of the natural product.

The intriguing chemical structure of pleurotin posed an additional opportunity for creativity in chemical synthesis. We have demonstrated through a series of model studies that the venerable Diels-Alder reaction can be used to construct two adjacent cyclohexane ring systems while establishing the configuration of four stereogenic carbon atoms. Our efforts to address the two cycloaddition reactions in the full structural context required for the total synthesis are also discussed.