Ligand-Metal Cooperation Enables Net Ring-Opening C-C Activation/Difunctionalization of Cyclopropyl Ketones

Reactions that cleave C-C bonds and enable functionalizationat both carbon sites are powerful strategic tools in synthetic chemistry.Stereodefined cyclopropyl ketones have become readily available andwould be an ideal source of 3-carbon fragments, but general approachesto net C-C activation/difunctionalization are unknown. Herein,we demonstrate the cross-coupling of cyclopropyl ketones with organozincreagents and chlorotrimethylsilane to form 1,3-difunctionalized, ring-openedproducts. A combination of experimental and theoretical studies rulesout more established mechanisms and sheds light on how cooperationbetween the redox-active terpyridine (tpy) ligand and the nickel atomenables the C-C bond activation step. The reduced (tpy(& BULL;-))Ni-I species activates the C-Cbond via a concerted asynchronous ring-opening transition state. Theresulting 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 byconjugate addition methods, such as & beta;-allylated and & beta;-benzylated enol ethers. The utility of this approach is demonstratedin the synthesis of a key (& PLUSMN;)-taiwaniaquinol B intermediate andthe total synthesis of prostaglandin D-1.

Automated summary

Cyclopropyl ketones can be cross-coupled with organozinc reagents and chlorotrimethylsilane to form 1,3-difunctionalized, ring-opened products. The redox-active terpyridine ligand and the nickel atom cooperate to enable the C-C bond activation step. This approach allows for quick access to difficult-to-make products.