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

Abstract

Enantioselective C–H oxidation is a standing chemical challenge foreseen as a powerful tool to transform readily available organic molecules into precious oxygenated building blocks. Here, we describe a catalytic enantioselective hydroxylation of tertiary C–H bonds in cyclohexane scaffolds with H2O2, an evolved manganese catalyst that provides structural complementary to the substrate similarly to the lock-and-key recognition operating in enzymatic active sites. Theoretical calculations unveil that enantioselectivity is governed 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 a single-step generation of multiple stereogenic centers (up to 4) that can be orthogonally manipulated by conventional methods providing rapid access, from a single precursor to a variety of chiral scaffolds.

%VBur index and steric maps: from predictive catalysis to machine learning

“…In 2023, Osuna, Bietti, Costas and coworkers used the steric maps to enhance the enantioselective hydroxylation at unactivated tertiary C–H Bonds. 256 Here, the challenge of achieving those enantioselective C–H oxidations has been endeavoured. In detail, the hydroxylation of tertiary C–H bonds within cyclohexane structures using H 2 O 2 as the oxidant combined with a manganese catalyst, exhibited a structural congruence with the substrate, much like the lock-and-key recognition mechanism observed in enzymatic active sites.…”

Catalytic Enantioselective Hydroxylation of Tertiary Propargylic C(sp3)–H Bonds in Acyclic Systems: a Kinetic Resolution Study

“…Second, tertiary carbon radicals might be prone to racemization more easily than secondary ones, thus resulting in partial or complete loss of stereochemistry during the oxygen recombination stage . To date, only one efficient asymmetric hydroxylation of endocyclic, unactivated tertiary C–H bonds of meso - cis -3,5-dimethyl trisubstituted cyclohexanes for cyclic tertiary alcohol synthesis has been established (Scheme c) . To our knowledge, either enzymatic or nonenzymatic asymmetric hydroxylation of tertiary C–H bonds in acyclic systems with enhanced conformational mobility has proven elusive (Scheme c) …”