Design, Development, and Scale-Up of a Stereoselective Synthesis of (1R,3R)-3-(3,5-Bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane Carboxylic Acid

This report describes the design, development, and scale-up of a stereoselective synthesis of (1R,3R)-3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane carboxylic acid (1), a key intermediate toward the synthesis of a promising developmental agrochemical. The synthesis features d-mannitol as a sustainable chiral pool starting material, a double Heck coupling reaction, and the invention of diastereoselective dichlorocyclopropanation. Details disclosed include the route design, development of enabling steps, and learnings from a kilogram-scale campaign. The nine-step route was used to produce 1.5 kg of (1R,3R)-3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane carboxylic acid in 13% overall yield, 97.8% purity, and excellent enantiopurity (>99.5% ee).