Asymmetric C-H Functionalization Through Cobalt-Salox Catalysis

Asymmetric C–H functionalization offers a direct and efficient approach for constructing chiral C–C and C–X bonds, streamlining access to complex molecules. Traditionally, this transformation relies on transition metal catalysis using noble metals such as iridium and rhodium, however their scarcity and high cost limit widespread application. To address these challenges, the Cramer group explored cobalt(III) as a more abundant alternative, demonstrating its potential for asymmetric C–H functionalization. However, the cobalt complexes still require a multi-step synthesis that can limit scalability. In 2014, the Daugulis group reported an innovative method involving in situ oxidation of a cobalt(II) salt to generate a cobalt(III) octahedral complex, facilitated by a bidentate directing group. This system successfully promoted C–H activation, but it lacked enantioselectivity. Building on this foundation, the Shi group introduced the first enantioselective cobalt-catalyzed C–H functionalization using a Co(II)/Salox catalytic system. Salicyloxazoline (Salox), a chiral monoanionic bidentate ligand, plays a dual role by both generating the active cobalt(III) catalyst in situ and controlling the stereochemistry of the reaction.

In 2022, the Shi group employed cobalt(II) and Salox catalysis to access highly enantioenriched chiral phosphorus centers through intramolecular annulation. The Sundararaju group in 2024 successfully reversed the regioselectivity of intramolecular annulation of arylphosphinamides by utilizing haloalkynes. Most recently, in 2025, the Shi group revisited this catalysis to achieve atroposelective intramolecular annulation, simultaneously generating two chiral C–N axes.

1. Yao, Q.-J.; Shi, B.-F. Acc. Chem. Res. 2025, 58 , 971.. 
2. Woźniak, Ł.; Cramer, N. Trends Chem. 2019, 1, 471.
3. Ozols, K.; Jang, Y.-S.; Cramer, N. J. Am. Chem. Soc. 2019, 141, 5675.
4. Grigorjeva, L.; Daugulis, O., Angew. Chem. Int. Ed. 2014, 53, 10209.
5. Yao, Q.; Chen, J.; Song, H.; Huang, F.; Shi, B. Angew. Chem. Int. Ed. 2022, 61,      e202202892.
6. Das, A.; Mandal, R.; Ravi Sankar, H. S.; Kumaran, S.; Premkumar, J. R.; Borah, D.; Sundararaju, B. Angew. Chem. Int. Ed. 2024, 63, e202315005.
7. Qian, P.-F.; Wu, Y.-X.; Hu, J.-H.; Chen, J.-H.; Zhou, T.; Yao, Q.-J.; Zhang, Z.-H.; Wang, B.-J.; Shi, B.-F. J. Am. Chem. Soc. 2025, 147, 10791.