Copper-catalyzed asymmetric 1,3-dipolar cycloaddition of azomethine ylides with β-trifluoromethyl-substituted alkenyl heteroarenes

Copper-catalyzed asymmetric 1,3-dipolar cycloaddition of azomethine ylides and beta-trifluoromethyl-substituted alkenyl heteroarenes was developed for the first time. A wide range of enantioenriched pyrrolidines containing both heteroarenes and trifluoromethyl group with multiple stereogenic centers could be readily accessible by this method with good to high yields and excellent levels of both stereo- and regioselectivity (up to 99% yield, >20:1 rr, >20:1 dr, and up to 95% ee). Notably, substratecontrolled umpolung-type dipolar cycloaddition was also disclosed in this protocol to achieve regiodivergent synthesis with aaryl substituted aldimine esters as the dipole precursors. Systematic DFT studies were conducted to explore the origin of the stereo- and regioselectivity of this 1,3-dipolar cycloaddition, and suggest that copper(II) salt utilized in this catalytic system could be reduced in-situ to the active copper(I) species and might be responsible for the observed high stereo- and regioselectivity.

Automated summary

A copper-catalyzed asymmetric 1,3-dipolar cycloaddition method was developed for the synthesis of enantioenriched pyrrolidines with trifluoromethyl group. The reaction shows good to high yields and excellent levels of stereo- and regioselectivity. In addition, a substrate-controlled umpolung-type dipolar cycloaddition reaction was also discovered. DFT studies suggest that the observed high stereo- and regioselectivity may be attributed to the in-situ reduction of copper(II) salt to active copper(I) species.