Stereoselective Synthesis of Chiral α-SCF3-β-Ketoesters Featuring a Quaternary Stereocenter

The development of new and efficient methods, reagents, and catalysts for the introduction of fluorine atoms or fluorinated moieties in molecular scaffolds has become a topic of paramount importance in organic synthesis. In this framework, the incorporation of the SCF3 group into organic molecule has often led to beneficial effects on the drug's metabolic stability and bioavailability. Here we report our studies aimed to the stereoselective synthesis of chiral alpha-SCF3-beta-ketoesters featuring a tetrasubstituted stereocenter. The use of a chiral auxiliary was crucial to synthesize enantiopure enamines that were reacted with N-trifluoromethylthio saccharin or phthalimide, to afford enantioenriched alpha-SCF3-tetrasubstitued beta-keto esters. By using a readily available, inexpensive chiral diamine, such as trans-1,2-diaminocyclohexane, the fluorinated products could be obtained in modest to good yields, and, after the removal of the chiral auxiliary, alpha-substituted- alpha trifluoromethylthio-beta-ketoesters were isolated with high enantioselectivity (up to 91% ee).

Automated summary

The development of new methods for introducing fluorine atoms or fluorinated moieties in molecular scaffolds is crucial in organic synthesis. The incorporation of the SCF3 group into organic molecules has shown beneficial effects on drug stability and bioavailability. By using a chiral auxiliary, enantioenriched alpha-SCF3-tetrasubstitued beta-keto esters can be synthesized in good yields with high enantioselectivity.