Switching up tertiary stereocenters

Small stereochemical changes can bring big distinctions to molecules like drugs, fragrances, and propellants. Switching the stereochemistry of a single substituent can change a rose-scented substance into a molecule with a mildly minty odor, for example. But depending on the surrounding substituents, changing a single stereocenter can a require complex, multistep synthesis—essentially making the molecule from scratch.

Chemists at the Massachusetts Institute of Technology led by Alison E. Wendlandt now report a stereochemical editing method that can switch unactivated tertiary C–H bonds, which are typically tough to switch (or epimerize, in chemical parlance), in a single step using a mild, light-catalyzed process with a decatungstate polyanion and disulfide cocatalyst (Science 2022, DOI: 10.1126/science.add6852).

“We basically found a tool that allows us to invert these kinds of stereocenters, and what that really let us do was re-envision how we might construct molecules as a result,” Wendlandt says.

The reaction proceeds via a radical mechanism, plucking off a hydrogen atom from a nonacidic C–H bond and then adding back a hydrogen atom so that the stereocenter is inverted. The MIT team shows how the reaction can be used to stereochemically edit myriad molecules, including the fragrance compound (+)-cedrol (shown). Because the transformation tolerates many functional groups, chemists can use it on complex molecules or late in a synthetic sequence, opening up molecular space that was previously difficult to access.

“This work greatly augments the current toolbox of radical C–H epimerization reactions with a more efficient and broadly applicable protocol via photocatalysis,” says Gong Chen, a chemistry professor at Nankai University who develops stereochemical editing methods, in an email. “The performance of this protocol in complex molecular settings is particularly exciting.”

Wendlandt says she’s particularly interested in how the reaction can be used on existing complex molecules from nature. “In just a step or a couple of steps, we now have this dramatically expanded access to chiral molecules because of targeted stereoinversion reactions.”