Computational investigation on tunable enantioselectivity of asymmetric 1,4-additions by chiral sulfoxide-olefin chelated rhodium complex

This computational study investigates the tunable enantioselectivity of rhodium-catalyzed asymmetric 1,4-additions of phenylboronic acids to cyclohexenone using chiral sulfoxide-olefin hybrid ligands. The roles of non-chiral alkene substituents and their positional variations in stereocontrol were elucidated by comparing the free-energy differences in enantio‑determining carborhodation transition states and quantifying the steric effect with the percentages of buried volume. The results revealed that substituent position and steric bulk significantly influenced enantioselectivity, enabling inversion of 1,4-addition product configuration through ligand structural modifications. A revised stereocontrol model, contrasting prior proposals, highlighted the impact of minor conformational isomers and geometric variation of the chiral pocket. The computational results also predicted that replacing the tert‑butyl substituent with the bulkier 1-adamantyl group in the chiral sulfoxide fragment did not enhance selectivity, underscoring the dominant role of alkene substituents. This work provides mechanistic insights into ligand design for enantiodivergent catalysis, emphasizing the interplay between steric hindrance and conformational flexibility in asymmetric synthesis.