Monofluoroalkene is recognized as mimetic of the peptide bond and widely used as a structural or mechanistic probe in biological studies. Moreover, as fluorine is an isostere of hydrogen, monofluoroalkenes are promising alternatives to their non-fluorinated analogues when pursuing novel bioactive compounds. Olefination of carbonyl compounds is one of the most straightforward methods to prepare various alkenes. Although both Z and E non-fluorinated alkenes are easily accessible through the Wittig, Horner–Wadsworth–Emmons or modified Julia reaction, tuning the Z/E selectivity of a monofluoroolefination reaction remains challenging. Furthermore, as a result of the difficulty in separation, monofluoroalkene products are often obtained and characterized as a inseparable mixture of Z and E isomers. Extractive separation of Z- and E-monofluoroalkenes generated from carbonyl olefination reaction via the above-mentioned strategy is very appealing; however, the realization of this idea is hampered by the lack of selective phase labeling reaction of the E- or Z- monofluoroalkene. Herein, we report a spontaneous resolving reaction that simultaneously addresses the challenges in the synthesis and separation of Z- and E-monofluoroalkenes. The reaction is accompanied by a highly efficient spontaneous kinetic resolution and phase labeling of a pair of diastereomeric monofluoroalkene precursors which allows the separation of Z- and E- monofluoroalkenes by liquid-liquid extraction. We would also like to report the first highly stereoselective carbonyl monofluoroolefination with a fluorosulfoximine reagent. The potential application of this method is demonstrated by the synthesis of MDL 72161 and by the late-stage monofluoromethylenation of complex molecules such as haloperidol and steroid derivatives.

Stereoselective carbonyl fluoroolefinations with fluorinated sulfone and sulfoximine reagents

253rd National Meeting (2017)

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