The Design and Development of Palladium-Catalyzed Aerobic Oxidative Transformations

Citation

Ferreira, Eric Matthew (2005) The Design and Development of Palladium-Catalyzed Aerobic Oxidative Transformations. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/Z9K64G2R. https://resolver.caltech.edu/CaltechETD:etd-05252005-205358

Abstract

Oxidation is a fundamental process in chemistry and biology. In synthetic chemistry, several developments have been made in catalytic asymmetric oxidative transformations that involve a heteroatom transfer from a reagent to a substrate (e.g., epoxidations, dihydroxylations). Enantioselective oxidations that do not involve a heteroatom transfer have been relatively less explored. These types of oxidative transformations were investigated using a general palladium(II) catalyst system.

A palladium-catalyzed oxidative kinetic resolution of secondary alcohols was developed. This catalytic system utilizes (–)-sparteine as the chiral ligand and molecular oxygen as the sole stoichiometric oxidant. Benzylic and allylic alcohols can be resolved to high enantiomeric excesses in excellent yields. The same selective process has been applied to the desymmetrization of meso diols.

This general palladium(II) oxidative system was applied to intramolecular Wacker oxidations to form a variety of heterocycles. Lactones, lactams, tetrahydrofurans, dihydrobenzofurans, and dihydrobenzopyrans were all accessed by this methodology. Importantly, this work provided entry into the development of asymmetric variants. Highly enantioselective cyclizations of phenolic substrates were realized with a palladium-sparteine catalyst, analogous to the kinetic resolution chemistry. The heterocyclization chemistry was employed in the context of the total synthesis of the Cephalotxaxus alkaloids.

Oxidative annulations for the synthesis of carbocycles were developed utilizing this general palladium system. Indoles with pendant olefin tethers were oxidatively cyclized under palladium(II) catalysis to form annulated indoles. Electron-rich aromatic systems were also investigated, culminating in the syntheses of benzofurans and dihydrobenzofurans. These reactions were demonstrated to proceed by an initial C-H bond functionalization event, followed by olefin insertion and beta-hydride elimination.

Enantioselective heterocyclizations using the general oxidative system were further explored. Promising results were realized in the heterocyclizations of sulfonamide-based compounds. Key experiments allowed for a firmer understanding of how the reaction was progressing, and specifically, how enantioselectivity was being induced by the palladium catalyst.

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