This review summarizes recent advancements in catalytic direct transformation of unactivated C(sp3)–H bonds into C(sp3)–C(sp3) bonds.

A poly trifluoromethylated chiral spirocyclic phosphoric acid was developed and employed with hexafluoroisoproyl alcohol (HFIP) to render the catalytic asymmetric Mukaiyama-Mannich reaction of difluoroenoxysilanes with in situ formed ketimines. This unique multiple-fluorine system provides rapid access to difluoromethylated tetrasubstituted stereocenters in isoindolones with wide substrate scope under mild conditions. Further synthetic transformations to enantioenriched CF2H-isoindolones and CF2-decorated fused isoindolones were also implemented with good efficiency.

A zinc-/quinine-mediated enantioselective Aldol-type reaction of trifluorodiazoethane (CF 3 CHN 2 ) with various aldehydes is described. This study demonstrated the feasibility of utilizing CF 3 CHN 2 as an effective hard nucleophile in catalytic asymmetric transformations. Furthermore, the synthetic utility of this protocol is exemplified by the construction of a diverse set of chiral β-trifluoromethylated alcohols, including a valuable HDAC inhibitor precursor.