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Stereospecific Nickel-Catalyzed Cross-Coupling Reactions

  • Author(s): Johnson, Aaron George
  • Advisor(s): Jarvo, Elizabeth R
  • et al.

Transition metal catalyzed cross-coupling reactions have become a staple of organic synthesis and are frequently the most practical strategy for the preparation of medicinal agents and fine chemicals. Catalysts based on the precious metal palladium are commonly used in cross-coupling reactions. Replacing palladium catalysts with nickel catalysts is an active area of research as such advances present significant benefits including increasing the sustainability of transformations and new mechanisms for control of stereochemistry in the construction of Csp3–Csp3 bonds.

In Chapter 1, a stereospecific nickel-catalyzed cross-coupling reaction of secondary benzylic ethers with a variety of aliphatic and aryl Grignard reagents is presented. The method is highly stereospecific and proceeds with inversion at the benzylic carbon. Products prepared by this method were subject to biological testing, and a thiophene-containing product was shown to selectively inhibit the growth of MCF-7 breast cancer cells.

In Chapter 2, mechanistic studies that provide insight into the mechanism of oxidative addition as well as the mechanisms of major side reactions, hydrogenolysis and β-hydride elimination, are presented. Experiments presented provide evidence that the mechanisms of cross-coupling, hydrogenolysis, and β-hydride elimination reactions all include a step of oxidative addition with inversion at the benzylic center. Hydrogenolysis was also shown to be stereospecific, proceeding with overall inversion at the stereogenic center.

In Chapter 3, the application of nickel-catalyzed cross-coupling reactions to the synthesis of either enantiomer of a bioactive triaryl methane from a single enantiomer of a precursor alcohol is presented. In the key cross-coupling step a Kumada protocol allows for cross-coupling with inversion at the benzylic carbon, while a Suzuki reaction allows for cross-coupling with retention.

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