A pilot-scale synthesis of (1R)-trans-2-(2,3-dihydro-4-benzofuranyl)cyclopropanecarboxylic acid: a practical application of asymmetric cyclopropanation using a styrene as a limiting reagent

Asymmetric cyclopropanation of styrene 1 (as the limiting reagent) was demonstrated using excess ethyl diazoacetate and catalytic Ru(ip-Pybox). Selective hydrolysis of the resulting 90:10 trans:cis mixture of cyclopropane 4 generated cyclopropyl acid 2 as a 96:4 trans:cis mixture with 84% e.e. for the trans-cyclopropane. Further purification and enantiomeric enrichment was achieved by diastereoselective crystallization with (+)-dehydroabeitylamine to afford the (R,R)-isomer with ≥99.9% e.e in 60–65 M% yield starting from styrene 1.