How can fluctional chiral lanthanide (III) complexes achieve a high stereoselectivity in aqueous mukaiyama-aldol reaction?

The aqueous Mukaiyama-Aldol reaction catalyzed by lanthanide (Ln) Lewis acid is one of the most attractive reactions for green chemistry. One of the chiral catalysts that achieved a high stereoselectivity is Ln³⁺ complexed with fluctional DODP, (2R,2′R)-dialkyl 2,2′-(1,7-dioxa-4,10-diazacyclododecane-4,10-diyl)dipropanoates. In this study, we theoretically studied the structure of the Ln³⁺-DODP (Ln = Eu) complex and the transition states (TSs) for stereodetermining C-C bond formation step between benzaldehyde and silyl enol ether catalyzed by this complex to elucidate the origin of stereoselectivity of the reaction. To explore the local minima and TSs exhaustively, we used an automated exploration method, called the Global Reaction Root Mapping (GRRM) strategy. Unlike conventional rigid chiral catalysts, three conformers of the Eu³⁺-DODP (the lowest A, the second lowest B, and the third lowest C) coexisted in the reaction system. Considering all the TSs obtained from the three conformers, we reproduced the experimental enantio excess and diastereomeric ratio quantitatively. The most stable TS for the C-C bond formation producing the major stereoisomer (R,R) was obtained from the second lowest conformer B. The lowest TS producing the enantiomer (S,S) was obtained from the conformer C; the similar (S,S) TS obtained from the conformer B was 0.4 kcal/mol less stable. Thus, to improve the enantioselectivity, the existing probability of the conformer C had to be reduced. The easiest way to achieve this is replacing Eu³⁺ by other Ln³⁺ with larger ionic radii, which was consistent with the experimental facts.