Electrochemical control enables high-concentration, one-pot macrolactonization

Abstract

State-of-the-art macrolactone synthesis predominantly relies on the end-to-end cyclization of seco-acids, a strategy that requires high-dilution conditions (<5 mM) to suppress oligomerization. To address this limitation, we report an electrochemical macrolactonization protocol that operates at a significantly higher concentration (50 mM). Leveraging an iodide/PPh₃ dual-mediation system, this method provides access to 5- to 21-membered lactones and accommodates O-, S-, and N-heteroatom functionalization. Its efficacy originates from the gradual, charge-consumption-dependent formation of an acyloxyphosphonium intermediate, which maintains a relatively low local concentration despite high substrate loading.