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 rule out more established mechanisms and shed 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).