Hindered ether synthesis shocked to life

Abstract

Hindered ethers are tricky little buggers. They’re important precursors for many products, especially in the synthesis of certain drugs. The bulkiness of the compounds helps prevent the body’s enzymes from metabolizing the drug molecule before it reaches its target. But this bulkiness also means the compounds are hard to make. Now Phil Baran of Scripps Research in California and coworkers have resurrected an old electrochemical method to zap new life into hindered dialkyl ether synthesis, making 80 ethers through zippier routes while also boosting yields (Nature 2019, DOI: 10.1038/s41586-019-1539-y). Traditionally, chemists make ethers using the Williamson synthesis, which involves an oxygen nucleophile attacking a carbon center to kick off a leaving group through an SN2-type mechanism. In the case of hindered ethers, bulky groups on the attacking nucleophile get in the way, slowing down the reaction and cutting yields. Baran’s team wanted to find a faster route to hindered ethers