Negishi Cross-Coupling Reaction

In 1972, after the discovery of the nickel-catalyzed cross-coupling of alkenyl and aryl halides with Grignard reagents (Kumada cross-coupling), improvements in functional group tolerance were sought. It was realized that the answer lay in the use of organometallic substrates with metals less electropositive than lithium and magnesium. From the first studies in 1976, extensive research by E. Negishi demonstrated that the best results in terms of reactivity, yield, and stereoselectivity were obtained when organozinc compounds are used in the presence of palladium catalysts. Today, the palladium- or nickel-catalyzed cross-coupling of organozinc compounds with aryl, alkenyl, or alkynyl halides is known as the Negishi cross-coupling reaction.

The use of organozinc reagents allows for a much greater variety of functional groups to be present in both coupling partners than is possible with the Kumada cross-coupling.

Other advantages of the Negishi cross-coupling reaction include high reactivity, high regio- and stereoselectivity, usability in a wide range of applications, few side reactions, and limited toxicity.

The total synthesis of motuporin, a cyclic pentapeptide that is a potent cytotoxin and protein phosphatase-1 inhibitor, utilized the Negishi cross-coupling reaction.