C-H Bonds as Functional Groups: Simultaneous Generation of Multiple Stereocenters by Enantioselective Hydroxylation at Unactivated Tertiary C-H Bonds

EnantioselectiveC-H oxidation is a standing chemical challengeforeseen as a powerful tool to transform readily available organicmolecules into precious oxygenated building blocks. Here, we describea catalytic enantioselective hydroxylation of tertiary C-Hbonds in cyclohexane scaffolds with H2O2, anevolved manganese catalyst that provides structural complementaryto the substrate similarly to the lock-and-key recognition operatingin enzymatic active sites. Theoretical calculations unveil that enantioselectivityis governed by the precise fitting of the substrate scaffold intothe catalytic site, through a network of complementary weak non-covalentinteractions. Stereoretentive C(sp (3))-Hhydroxylation results in a single-step generation of multiple stereogeniccenters (up to 4) that can be orthogonally manipulated by conventionalmethods providing rapid access, from a single precursorto a variety of chiral scaffolds.

Automated summary

This study describes a catalytic enantioselective hydroxylation method of tertiary C-H bonds in cyclohexane scaffolds using an evolved manganese catalyst and H2O2. The catalytic system provides structural complementarity to the substrate similarly to lock-and-key recognition in enzymatic active sites. Theoretical calculations reveal that enantioselectivity is determined by the precise fitting of the substrate scaffold into the catalytic site through a network of complementary weak non-covalent interactions. Stereoretentive C(sp(3))-H hydroxylation results in the generation of multiple stereogenic centers in a single step, which can be orthogonally manipulated to obtain a variety of chiral scaffolds from a single precursor molecule.