Convenient Reagent for the Copper-Catalyzed Asymmetric Methyl 1,4-Addition Reaction

Key words

copper catalysis - asymmetric reaction - 1,4-conjugate addition - stable zirconium reagent

Significance

Tertiary and quaternary stereocenters bearing a methyl group are common structural units in a wide array of natural products and pharmaceuticals. The synthesis of such compounds is usually performed by the asymmetric conjugate methyl addition to α,β-unsaturated ­carbonyl compounds. Unfortunately, this approach usually relies on the use of impractical reagents (e.g. pyrophoric reagents, low functional group compatibility). In this work, the authors disclosed the use of Cp₂ZrMeCl as an efficient and operationally friendly reagent in copper-catalyzed methyl 1,4-addition reactions.

Comment

The use of Cp₂ZrMeCl as a methyl source in combination with a chiral copper catalyst allowed the formation of β- and δ-tertiary and quaternary centers in generally good yields and excellent enantioselectivities. The reaction was applied to a variety of cyclic and acyclic carbonyl compounds, allyl chlorides and in the synthesis of (R)-(–)-muscone. The zirconium reagent was prepared on a 10 g scale reaction from Cp₂ZrCl₂ and was demonstrated to be stable for up to six months when stored under inert gas at room temperature.