Â鶹ÒùÔº

Copper radical mimics enzyme for highly efficient C-H oxidation

Optically pure alcohols are prevalent motifs in natural products and pharmaceuticals, driving the development of effective methods for their synthesis. Since the first reports of the Kharasch-Sosnovsky reaction in 1958, the copper-catalyzed radical-mediated sp³ C-H oxidation has emerged as an important method for the selective oxidation of allylic, propargylic, and other sp³ C-H bonds.

Despite progress in developing enantioselective Kharasch-Sosnovsky reactions, most reported reactions have limitations, including a narrow substrate scope on the simple cyclic alkenes, low-to-moderate enantioselectivities, poor reactivities, and the necessity for large excesses of alkenes.

There is also a long-standing challenge to achieving site- and enantioselective sp³ C-H oxidation toward substrates bearing multiple similar C-H bonds. Organic chemists have been seeking more efficient and selective methods for over 60 years.

published in Nature Catalysis, Prof. Lin Zhenyang at Hongkong University of Science and Technology and Prof. Liu Guosheng at Shanghai Institute of Organic Chemistry of the Chinese Academy of Sciences describe how a copper-bound tert-butoxy radical (Cu(II)-bound OCR) intermediate facilitates site- and enantio-selectively oxidation of C(sp³)-H on a range of alkenes and alkynes.

Researchers found that employing fluoro-containing alcohols (e.g., trifluoroethanol, TFE) as solvents is crucial for the enhancement of reaction efficiency and selectivity. They proposed a Cu(II)-bound OCR as a key intermediate for the hydrogen atom abstraction (HAA), which behaves like an active site of a copper-based enzyme both structurally and functionally.

"The chiral and bulky environment built by ligand has endowed this Cu(II)-bound OCR with an increased HAA ability as well as the capabilities to precisely distinguish similar C-H bonds," explained Prof. Liu.

Compared to the predominantly quenching process of free tert-butoxy radical by the Cu(I)-catalyst, the developed Cu(II)-bound OCR system undergoes an effective HAA process owing to the bulky steric effect, which enables highly efficient C-H oxidation with C-H substrates as the limiting reagent.

This method demonstrates a broad substrate scope, highlighting its utility and effectiveness. Alkenes and alkynes bearing a wide array of functional groups could be readily transformed into targeting enantiomeric-enriched esters with good yields and excellent enantioselectivities. Therefore, bioactive molecules, including natural products and drugs, could be oxidized with high site-selectivity.