A Chiral Pentafluorinated Isopropyl Group via Iodine(I)/(III) Catalysis

An I(I)/(III) catalysis strategy to construct an enantioenriched fluorinated isostere of the Pr-i group is reported. The difluorination of readily accessible alpha-CF3-styrenes is enabled by the in situ generation of a chiral ArIF2 species to forge a stereocentre with the substituents F, CH2F and CF3 (up to 95 %, >20:1 vicinal:geminal difluorination). The replacement of the metabolically labile benzylic proton results in a highly preorganised scaffold as was determined by X-ray crystallography (pi ->sigma* and stereoelectronic gauche sigma ->sigma* interactions). A process of catalyst editing is disclosed in which preliminary validation of enantioselectivity is placed on a structural foundation.

Automated summary

This study introduces a catalysis strategy to construct an enantioenriched fluorinated isostere of the Pr-i group by enabling the difluorination of alpha-CF3-styrenes. By in situ generation of a chiral ArIF2 species, a stereocentre with F, CH2F, and CF3 substituents is forged with high selectivity, leading to a highly preorganized scaffold as confirmed by X-ray crystallography. The study also discloses a catalyst editing process which places initial validation of enantioselectivity on a structural basis.