Vicinal difluorides have drawn much interest from chemists and chemical biologists due to the gauche effect and the rotationally restrained C(F)–C(F) backbone. However, the stereoselective synthesis of vicinal difluorides is still underdeveloped. Existing methods often employ toxic reagents, require enantioenriched starting materials and suffer from limited substrate scope. Herein, we report the stereodivergent synthesis of vicinal difluorides via asymmetric allylic substitution between a prochiral, α-fluoroenolate nucleophile and a fluorinated cinnamyl-typed electrophile in the presence of a chiral Cu/bisphosphine Lewis acid catalyst and a chiral Ir-phosphoramidite catalyst. This method produces the desired vicinal difluorides in good yield, high diastereoselectivity, and excellent enantioselectivity. Moreover, by controlling the combinations of the chiral Cu/bisphosphine Lewis acid and the chiral Ir catalyst, we can synthesize all four stereoisomers of the vicinal difluoride from the same, racemic starting materials. This method tolerates α-fluoroacetamides, acetates and ketones that contain a large variety of nitrogen-containing heteroaromatics. A carboxylic acid that contains a diazirine and an alkyne handle can be tethered to the vicinal difluoride products to afford potentially bioactive probes.

Stereodivergent synthesis of vicinal difluorides via synergistic Cu/Ir catalysis

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