Multigram Synthesis of Chiral Cyclopropane Carboxylic Acids via Tandem Diastereoselective Wadsworth-Emmons Cyclopropanation-Hydrolysis in Continuous Flow

Here, we present a novel continuous flow approach for the Wadsworth-Emmons cyclopropanation of alkyl-substituted chiral epoxides into chiral cyclopropane carboxylic acids. The developed flow process circumvents the risks associated with the harsh conditions (high T/P) required, considering the highly volatile nature of the epoxide-SM. Additionally, the flow reactors offer increased efficiency, as their reduced headspace contributes to keeping a higher concentration of the low-boiling-point reactants in the liquid phase and thus enhanced reactivity, contrary to the use of sealed vessels in batch. The cyclopropane formation process is coupled with in-line workup and hydrolysis transformations to yield the desired enantiomerically pure cyclopropane carboxylic acids in good yields up to the 100 g scale.