Copper-catalyzed asymmetric addition of olefin-derived nucleophiles to ketones

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Science  08 Jul 2016:
Vol. 353, Issue 6295, pp. 144-150
DOI: 10.1126/science.aaf7720

Olefins enlisted to attack ketones

The reaction of C=O groups in ketones with organometallic compounds is a common method to form carbon-carbon bonds. One drawback to this approach, however, is that the organometallics, such as magnesium-derived Grignard reagents, are difficult to handle and susceptible to side reactions. Yang et al. present an alternative method, whereby a copper catalyst activates stable olefins (C=C double bonds) to attack ketones at room temperature. An added silane functions as a reducing agent, and a chiral phosphine ligand renders the reaction highly enantioselective.

Science, this issue p. 144


Enantioenriched alcohols found in an array of bioactive natural products and pharmaceutical agents are often synthesized by asymmetric nucleophilic addition to carbonyls. However, this approach generally shows limited functional-group compatibility, requiring the use of preformed organometallic reagents in conjunction with a stoichiometric or substoichiometric amount of chiral controller to deliver optically active alcohols. Herein we report a copper-catalyzed strategy for the stereoselective nucleophilic addition of propargylic and other alkyl groups to ketones, using easily accessible (poly)unsaturated hydrocarbons as latent carbanion equivalents. Our method features the catalytic generation of highly enantioenriched organocopper intermediates and their subsequent diastereoselective addition to ketones, allowing for the effective construction of highly substituted stereochemical dyads with excellent stereocontrol. Moreover, this process is general, scalable, and occurs at ambient temperature.

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