Copper-catalysed enantioconvergent alkylation of oxygen nucleophiles

Carbon-oxygen bonds are commonplace in organic molecules, including chiral bioactive compounds; therefore, the development of 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) owing to its reaction mechanism (S(N)2 pathway). Transition-metal catalysis of the coupling of an oxygen nucleophile with an alkyl electrophile has the potential to address these limitations, but progress so far has been limited(2-7), especially with regard to controlling enantioselectivity. Here we establish that a readily available copper catalyst can achieve an array of enantioconvergent substitution reactions of a-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 of not only oxygen nucleophiles but also nitrogen nucleophiles, giving support for the potential of transition-metal catalysts to provide a solution to the pivotal challenge of achieving enantioselective alkylations of heteroatom nucleophiles.

Automated summary

Carbon-oxygen bonds are common in organic molecules, making methods for their construction with control of stereoselectivity important. The widely used Williamson ether synthesis has limitations in terms of scope and stereochemistry due to its reaction mechanism. Transition-metal catalysis has the potential to overcome these limitations but progress has been limited, especially in controlling enantioselectivity. We demonstrate that a readily available copper catalyst can achieve enantioconvergent substitution reactions of α-haloamides with oxygen nucleophiles, offering a promising solution to the challenge of enantioselective alkylations of heteroatom nucleophiles.