Copper-Catalyzed Asymmetric Nucleophilic Addition to Ketones

Key words

copper catalysis - asymmetric reaction - 1,2-addition - silane reagents

Significance

Enantioenriched alcohols represent a recurring structural motif in biologically active molecules and pharmaceuticals. The synthesis of this class of compounds usually relies on the addition of nucleophiles to carbonyl compounds. The limitations of this approach in terms of functional-group tolerance and versatility prompted the authors to develop a novel copper-catalyzed asymmetric addition of nucleophiles, generated in situ from olefins, to ketones.

Comment

A chiral copper catalyst promoted the reaction between a number of enyne substrates with ketones. (MeO)₂MeSiH and t-BuOH are required to generate the nucleophile in situ and to terminate the catalytic cycle, respectively. The reaction delivers the corresponding chiral alcohols in good yields and excellent enantioselectivities. A 13 gram scale reaction, derivatizations of the final products and applications in the synthesis of pharmaceutical agents were provided. Furthermore, computational studies were carried out to explain the observed enantio- and diastereoselectivity.