Impact of the Difluoromethylene Group in the Organocatalyzed Acylative Kinetic Resolution of α,α-Difluorohydrins

Due to the omnipresence of chiral organofluorine compounds in pharmaceutical, agrochemical, and material chemistry, the development of enantioselective methods for their preparation is highly desirable. In the present study, the enantioselective organocatalyzed acylation of alpha,alpha-difluorohydrins using a commercially available chiral isothiourea is reported through a kinetic resolution (KR) process. It reveals that the difluoromethylene moiety (C(sp(3))F-2) can serve as a directing group through electrostatic fluorine-cation interactions, greatly improving the enantioselectivity of the KR. In this context, a broad range of fluorinated alcohols such as valuable 4,4-difluoro-1,3-diols could be synthesized with exquisite enantiocontrol (typically >99:1 er). Turning to 2,2-difluoro-1,3-diols, we also demonstrated that aromatic and fluorinated groups were mutually compatible to provide the expected enantioenriched adducts with >99:1 er.

Automated summary

This study reported an enantioselective organocatalyzed acylation of alpha,alpha-difluorohydrins using a commercially available chiral isothiourea, greatly improving the enantioselectivity of the kinetic resolution process through electrostatic fluorine-cation interactions. The method allows for the synthesis of various fluorinated alcohols with exquisite enantiocontrol, such as 4,4-difluoro-1,3-diols, as well as demonstrated compatibility between aromatic and fluorinated groups in providing enantioenriched adducts.