Origin of Stereocontrol in Guanidine-Bisurea Bifunctional Organocatalyst That Promotes α‑Hydroxylation of Tetralone-Derived β‑Ketoesters: Asymmetric Synthesis of β- and γ‑Substituted Tetralone Derivatives via Organocatalytic Oxidative Kinetic Resolution

The mechanism of asymmetric α-hydroxylation
of tetralone-derived
β-ketoesters with guanidine-bisurea bifunctional organocatalyst
in the presence of cumene hydroperoxide (CHP) was examined by means
of DFT calculations to understand the origin of the stereocontrol
in the reaction. The identified transition-state model was utilized
to design an enantioselective synthesis of β- or γ-substituted
tetralones by catalytic oxidative kinetic resolution reaction of tetralone-derived
β-ketoesters. This kinetic resolution reaction proceeded with
high selectivity, and selectivity factors (s value)
of up to 99 were obtained. The potential utility of this oxidative
kinetic resolution method for synthesis of natural products was confirmed
by applying it to achieve an enantioselective synthesis of (+)-linoxepin
(13) from β-substituted tetralone rac-7 in only six steps.