Development of Nickel-Catalyzed Cycloaddition and Coupling Reactions.

Abstract

Nickel-catalyzed carbon-carbon bond-forming reactions provide a potentially useful strategy to generate a variety of organic compounds efficiently,regioselectively, chemoselectively, and stereoselectively. The versatility of these types of reactions makes them a powerful tool in organic synthesis. This dissertation mainly focuses on methodology development involving nickel catalysis. In this work, a number of highly selective reactions of readily available precursors, such as alkynes, enals and enones were developed. In one application, a novel, nickel-catalyzed [3+2] cycloaddition of enals and alkynes was explored. This reaction provides a diastereoselective and chemoselective entry to five-membered rings, which are a common structural motif in many architecturally complex and biologically active natural products. In another application, a novel, nickel-catalyzed intermolecular reductive coupling of enones and alkynes was developed. The key feature of this reaction is the chemoselective coupling of two potential Michael acceptors such as enones and alkynoates. The direct participation of alkynes as an alternative to preparing and handling sensitive vinyl cuprate reagents provides potentially significant improvements in accessing γ,δ-unsaturated ketones. An intriguing, nickel-catalyzed, intermolecular reductive coupling of enals and alkynes has also been developed. The unique features of this reaction are the construction of geometrically pure Z-enol silanes and high functional group tolerance. The direct participation of enals, alkynes and silanes as an alternative to existing methods provides potentially significant improvements in accessing enol silanes. Additionally, this reaction provides direct evidence for the catalytic involvement of a seven-membered oxametallacycle intermediate. A novel, nickel-catalyzed intermolecular three-component coupling of aldehydes, alkynes, and enones has been developed. This new process involves an internal redox mechanism and proceeds in the absence of reducing agents that have previously been required in related nickel-catalyzed couplings. The high extent of chemoselectivity is unusual, particularly for aldehyde, enone, alkyne couplings that involve three different π-components. Together, these new methods provide access to interesting chemical scaffolds and greatly expand the versatility of nickel-catalyzed reactions.