Combining nickel and squaramide catalysis for the stereodivergent α-propargylation of oxindoles

Stereoisomers of drugs can have different therapeutic outcomes or side effects, and regulatory agencies require the bioactivity of all stereoisomers of pharmaceutical candidates to be evaluated during the drug discovery and development process. However, relatively few methods can lead to all possible stereoisomers of molecules containing contiguous stereocentres. Here we report a combination of nickel and squaramide catalysis as a versatile strategy for stereodivergent α-propargylation of oxindoles. Effective with both primary and secondary propargylic ammonium salt substrates, the reported process gives a range of α-propargylated oxindole products with excellent regio- and stereocontrol. The stereochemical outcome of the reaction can be programmed through choice of the appropriate enantiomers of the nickel and squaramide catalysts. The synthetic utility of this stereodivergent methodology is demonstrated through its application to the synthesis of a number of natural products, (−)-physovenine, (−)-esermethole and (−)-physostigmine.