Recently, the research team led by Chen Zhu at the Frontiers Science Center for Transformative Molecules, Shanghai Jiao Tong University, has achieved significant research progress. Their work, entitled " Central-to-Axial Chirality Transfer to Construct Atropisomeric Isothiazoles", has been published in Chem.

Article abstract:

The bigger picture

Axially chiral molecules are important in asymmetric catalysis, pharmaceuticals, and materials science. Herein, we disclose a central-to-axial chirality transfer strategy using radical homolytic substitution and the Pummerer rearrangement, achieving the first enantioselective synthesis of axially chiral isothiazole frameworks. This method employs photoredox-neutral radical substitution for precise enantiocontrol, facilitating efficient chirality transfer. Density functional theory (DFT) calculations provide mechanistic insights, elucidating axial chirality formation. The strategy accommodates diverse 5,6- and 5,5-biaryl skeletons and exhibits broad functional group tolerance. Additionally, the synthesized product can be converted into an axially chiral P, N-ligand, which demonstrates exceptional catalytic performance in palladium-catalyzed asymmetric reactions. This work establishes a versatile platform for axial chirality generation, paving the way for new applications in asymmetric catalysis.

Summary

Axially chiral molecules play a pivotal role across diverse scientific disciplines, yet the enantioselective synthesis of pentatomic bi(hetero)aryls remains a significant challenge due to their inherently low rotational energy barriers. Here, we devise a method of central-to-axial chirality transfer, leveraging a cascade of radical homolytic substitution and the Pummerer rearrangement to achieve the enantioselective synthesis of axially chiral isothiazole frameworks for the first time. The intramolecular radical homolytic substitution proceeds under photoredox-neutral conditions, generating chiral cyclic sulfinamides that render precise enantiocontrol in the subsequent chirality transfer during the Pummerer rearrangement. Comprehensive density functional theory (DFT) calculations provide mechanistic insights, elucidating the origination of axial chirality. This approach provides a versatile platform for the asymmetric synthesis of isothiazole atropisomers with broad structural diversity and excellent enantioselectivities.