Catalytic Aerobic Carbooxygenation for the Construction of Vicinal Tetrasubstituted Centers: Application to the Synthesis of Hexasubstituted γ‐Lactones

Abstract

Strategic design for the construction of contiguous tetrasubstituted carbons represents a daunting challenge in synthetic organic chemistry. Herein, we report a combined experimental and computational investigation aimed at developing catalytic aerobic carbooxygenation, involving the intramolecular addition of tertiary radicals to geminally di‐substituted‐alkenes followed by aerobic oxygenation. This reaction provides a straightforward route to various α,α,β,β‐tetrasubstituted γ‐lactones, which can be readily transformed into hexasubstituted γ‐lactones through allylation/translactonization. Computational analysis reveals that the key mechanistic foundation for achieving the developed aerobic carbooxygenation involves the design of endothermic (energetically uphill) C–C bond formation followed by exothermic (energetically downhill) oxygenation. Furthermore, we highlight a unique fluorine‐ induced stereoelectronic effect that stabilizes the endothermic stereo‐determining transition state.