In-Depth Insights into the Enantioselective Ketyl-Olefin Cyclizations Promoted by Reductive Multisite Proton-Coupled Electron Transfer

The enantioselective ketyl-olefin cyclization reaction is a powerful synthetic tool to synthesize azaarene-functionalized cyclic alcohols, but the detailed mechanism and the origin of stereoselectivities have yet to be established. Herein, we proposed and confirmed the activation model reductive multisite proton-coupled electron transfer (MS-PCET) for the generation of ketyl radicals. Subsequent protonation, enantioselective radical cyclization, and the sequential processes of single-electron transfer and proton transfer lead to the enantioselective formation of various kinds of cyclic alcohols. The transform of Hantzsch ester plays an important role in the reaction, not only as a reducing agent but also in providing additional proton to the chiral phosphoric acid (CPA) anion, thereby ensuring that the stereoselective step proceeds via a dual activation mode. This is critical to ensuring sufficient rigidity in the enantioselective transition state structures. Computational studies reveal that the origin of the enantioselectivity is differential distortion of the chiral catalyst and substrate in the divergent cyclization transition states. This work should be important for understanding the general principle and detailed mechanism of enantioselective intramolecular radical cyclization reactions.