Catalytic enantioselective desymmetrizing functionalization of alkyl radicals via Cu(i)/CPA cooperative catalysis

In contrast with abundant methods for the asymmetric functionalization of alkyl radicals to generate stereogenic centres at reaction sites, catalytic enantioselective desymmetrizing functionalization of alkyl radicals for forging multiple stereocentres—including positions that are remote from the reaction sites—with both high enantio- and diastereoselectivity remains largely unexplored. The major challenge for such reactions is the high reactivity of open-shell alkyl radicals. Here, we describe a strategy to address this challenge: the use of Cu(ii) phosphate to immediately associate with the in situ-generated reactive alkyl radical species, creating a compact and confined chiral microenvironment for effective stereocontrol. With this strategy, we have developed a general and efficient catalytic enantioselective desymmetrizing functionalization of alkene-tethered 1,3-diols. It provides various tetrahydrofurans and analogues bearing multiple stereocentres with remarkably high levels of enantio- and diastereocontrol. Density functional theory calculations and mechanistic experiments revealed a reaction mechanism involving an enantiodetermining outer-sphere C–O bond formation step. The high reactivity of open-shell alkyl radicals makes their use in asymmetric catalysis challenging. Here the authors report a catalytic enantioselective desymmetrizing reaction of alkyl radicals and diols, forming stereocentres at the reaction site and at sites remote from it.