Palladium(II)-Catalyzed Oxidation Reactions in Natural Product Synthesis: Efforts toward Bielschowskysin and Phalarine

Citation

Meyer, Michael Elliott (2011) Palladium(II)-Catalyzed Oxidation Reactions in Natural Product Synthesis: Efforts toward Bielschowskysin and Phalarine. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/J3YQ-SP42. https://resolver.caltech.edu/CaltechTHESIS:08042010-151446303

Abstract

Two types of oxidative transformations, an oxidative kinetic resolution and an oxidative heterocyclization, have been developed by several laboratories using palladium(II)-catalysis to provide enantioenriched products. The main drawback of these asymmetric transformations is the limited substrate scope for each set of conditions. To address this, the Stoltz laboratory developed a unique platform utilizing palladium(II)-catalysis that provides a highly effective oxidative kinetic resolution of secondary alcohols and an asymmetric oxidative heterocyclization of phenols. Key to this platform is the use of (–)-sparteine as the chiral ligand and O₂ as the stoichiometric oxidant. Both of these methodologies will be featured in this thesis as they were applied toward the total synthesis of complex natural products.

Our palladium(II)-catalyzed oxidative kinetic resolution was used to access an enantioenriched intermediate in our efforts toward the synthesis of bielschowskysin, a polycyclic diterpenoid. A key disconnection in our strategy was formation of the cyclobutane core of bielschowskysin from a cyclopropane intermediate. After considerable experimentation, we were able to synthesize a cyclopropane intermediate that could be used for future research.

In separate work, we hoped to use two palladium(II)-catalyzed oxidative heterocyclization reactions to provide the core of phalarine, a polycyclic alkaloid. The synthesis of a key intermediate relied on a Stille coupling reaction of a complex 4,5,7-substituted indole and a nitro-arene. Model cyclization studies on an aniline substrate gave inconclusive results, while a model of a phenolic substrate has shown that cyclization onto styrenyl olefins is possible.

Thesis Files