Copper-catalyzed asymmetric allylic alkylation of racemic inert cyclic allylic ethers under batch and flow conditions

Highly enantioselective Cu-catalyzed asymmetric allylic alkylation of racemic inert cyclic allylic ethers is accomplished in this work. The use of Grignard reagents in combination with BF3.OEt2 and CuBr.SMe2/ L2 is the key to enable employment of long-challenging low reactive allylic substrates in this AAA reaction. In addition, the approach exhibited a remarkable superiority in the construction of a stereogenic center involving challenging sterically hindered nucleophiles for both primary and secondary alkyl groups. Extension of this method under continuous flow conditions was also performed with excellent enantioselectivity in a short residence time. Mechanistic experiments indicated that the reaction proceeded through an in situ generated allylic bromide intermediate. All these advantages demonstrated that this chiral catalytic system is a valuable complement for existing asymmetric catalytic methods.

Automated summary

Highly enantioselective Cu-catalyzed asymmetric allylic alkylation of racemic inert cyclic allylic ethers is achieved in this work. The use of Grignard reagents in combination with BF3.OEt2 and CuBr.SMe2/ L2 plays a key role in enabling the employment of low reactive allylic substrates. The approach also demonstrates advantages in constructing a stereogenic center involving sterically hindered nucleophiles.