Ligand–Metal Cooperation Enables Net Ring-Opening C–C Activation/Difunctionalization of Cyclopropyl Ketones
Michael M. Gilbert, Michael J. Trenerry, Victoria Longley, Anthony J. Castro, John F. Berry, Daniel J. Weix
Abstract
Reactions that cleave C–C bonds and enable functionalization at both carbon sites are powerful strategic tools in synthetic chemistry. Stereodefined cyclopropyl ketones have become readily available and would be an ideal source of 3-carbon fragments, but general approaches to net C–C activation/difunctionalization are unknown. Herein, we demonstrate the cross-coupling of cyclopropyl ketones with organozinc reagents and chlorotrimethylsilane to form 1,3-difunctionalized, ring-opened products. A combination of experimental and theoretical studies rules out more established mechanisms and sheds light on how cooperation between the redox-active terpyridine (tpy) ligand and the nickel atom enables the C–C bond activation step. The reduced (tpy ·– )Ni I species activates the C–C bond via a concerted asynchronous ring-opening transition state. The resulting alkylnickel(II) intermediate can then be engaged by aryl, alkenyl, and alkylzinc reagents to furnish cross-coupled products. This allows quick access to products that are difficult to make by conjugate addition methods, such as β-allylated and β -benzylated enol ethers. The utility of this approach is demonstrated in the synthesis of a key (±)-taiwaniaquinol B intermediate and the total synthesis of prostaglandin D 1 .