Copper-catalysed enantioconvergent alkylation of oxygen nucleophiles

Because carbon–oxygen bonds are commonplace in organic molecules, including chiral bioactive compounds, the development of new methods for their construction with simultaneous control of stereoselectivity is an important objective in synthesis. The Williamson ether synthesis, first reported in 1850 (1), is the most widely used approach to the alkylation of an oxygen nucleophile, but it has significant limitations (scope and stereochemistry) due to its reaction mechanism (S_N2 pathway). Transition-metal catalysis of the coupling of an oxygen nucleophile with an alkyl electrophile has the potential to address these limitations, but progress to date has been very limited (2–7), especially with regard to controlling enantioselectivity. Herein we establish that a readily available copper catalyst can achieve an array of enantioconvergent substitution reactions of α-haloamides, a useful family of electrophiles, by oxygen nucleophiles; the reaction proceeds under mild conditions in the presence of a wide variety of functional groups. The catalyst is uniquely effective in being able to achieve enantioconvergent alkylations not only of oxygen nucleophiles, but also of nitrogen nucleophiles, furnishing support for the potential of transition-metal catalysts to provide a solution to the pivotal challenge of achieving enantioselective alkylations of heteroatom nucleophiles.