Nickel-Catalyzed Cross-Electrophile Coupling to Access Polysubstituted Cyclobutenes

Abstract

The synthesis of cyclobutenes remains inefficient owing to inherent ring strain and poor regioselectivity. We describe herein a nickel-catalyzed cross-electrophile coupling (XEC) between readily accessible homopropargyl halides and commercially available aryl/vinyl electrophiles for direct access to polysubstituted cyclobutenes. This approach provides the first reductive 4-endo-dig cyclization with high chemo- and regioselectivity, which paves the way for the synthesis of diverse cyclobutene containing compounds (including synthetically challenging macrocycles). The synthesis of an antitumor-active combretastatin A-4 analog has been significantly optimized; the original six-step procedure yielding 14% has been streamlined into a three-step process with a markedly improved yield of 51%. Experimental data and computational studies support a mechanism involving an alkenyl nickel(I) intermediate, which undergoes facile back-side S_H2 attack to produce the strained cyclobutene ring with overall stereoinversion at the homopropargylic position.