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Catalytic asymmetric addition of Grignard reagents to alkenyl-substituted aromatic N-heterocycles

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Science  22 Apr 2016:
Vol. 352, Issue 6284, pp. 433-437
DOI: 10.1126/science.aaf1983

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Copper adds alkyls asymmetrically

Nitrogen-bearing rings are very common features in the molecular structures of modern drugs. Reactions that can modify these N heterocycles selectively are thus especially useful to optimize pharmaceutical properties. Jumde et al. developed a method to append alkyl groups in a single mirror-image orientation to substituted C=C double bonds dangling from N heterocycles. The copper-catalyzed reaction, which relies on Grignard reagents to introduce the alkyl groups, manifests high selectivity across a broad range of substrates, with no interference from the nitrogen.

Science, this issue p. 433

Abstract

Catalytic asymmetric conjugate addition reactions represent a powerful strategy to access chiral molecules in contemporary organic synthesis. However, their applicability to conjugated alkenyl-N-heteroaromatic compounds, of particular interest in medicinal chemistry, has lagged behind applications to other substrates. We report a highly enantioselective and chemoselective catalytic transformation of a wide range of β-substituted conjugated alkenyl-N-heteroaromatics to their corresponding chiral alkylated products. This operationally simple methodology can introduce linear, branched, and cyclic alkyl chains, as well as a phenyl group, at the β-carbon position. The key to this success was enhancement of the reactivity of alkenyl-heteroaromatic substrates via Lewis acid activation, in combination with the use of readily available and highly reactive Grignard reagents and a copper catalyst coordinated by a chiral chelating diphosphine ligand.

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