Endergonic synthesis driven by chemical fuelling

Spontaneous chemical reactions proceed energetically downhill to either a local or global minimum, limiting possible transformations to those that are exergonic. Endergonic reactions do not proceed spontaneously and require an input of energy. Light has been used to drive a number of deracemisations and thermodynamically unfavourable bond-forming reactions, but is restricted to substrates that can absorb, directly or indirectly, energy provided by photons. In contrast, anabolism involves energetically uphill transformations powered by chemical fuels. Here we report on the transduction of energy from an artificial chemical fuel to drive a thermodynamically unfavourable Diels–Alder reaction. Carboxylic acid catalysed carbodiimide-to-urea formation is chemically orthogonal to the reaction of the diene and dienophile, but transiently brings the functional groups into close proximity, causing the otherwise prohibited cycloaddition to proceed in modest (12%) yield and with high levels of regio- (>99%) and stereoselectivity (92:8 exo:endo). At the chemically fuelled steady state, kinetic asymmetry in the fuelling cycle ratchets the Diels–Alder reaction away from the equilibrium distribution of the Diels–Alder:retro-Diels–Alder products. The driving of the endergonic reaction away from equilibrium occurs through a ratchet mechanism, reminiscent of how molecular machines directionally bias motion. Ratcheting synthesis has the potential to expand the synthetic chemistry toolbox, offering new paradigms in reactivity, complexity and control.