Unveiling the mechanism and origin of stereocontrol in dinuclear-zinc-catalyzed reductive desymmetrization of malonic esters

Abstract

The recently described reductive desymmetrization of malonic esters, which is enabled by a dinuclear zinc (Zn) complex with a chiral tetradentate ligand, provides an efficient method for the formation of all-carbon quaternary stereocenters. Herein, DFT calculations were conducted to unveil the mechanism and selectivity of catalytic desymmetrization of malonic esters. The transformation begins with a pre-catalyst initiation via ligand coordination, followed by consecutive σ-bond metatheses to produce an active dinuclear Zn–H species. Then, one of the carbonyls of malonic esters is reduced to aldehyde by a six-membered migratory insertion of carbonyl into Zn–H and β-ethoxy elimination. After the regeneration of the active Zn–H catalyst, the aldehyde undergoes a six-membered migratory insertion, σ-bond metatheses, and acid hydrolysis to produce an α-quaternary β-hydroxy ester product. Catalyst regeneration after aldehyde formation is the rate-determining step. The stereoselectivity is mainly controlled by the ester carbonyl migratory insertion, wherein the large substitute orients toward the vacancy near pyrrolidine contributing to minimizing ligand–substrate steric repulsions and gaining more ligand–substrate dispersion interactions. The chemoselectivity originates from the stronger polarity of the aldehyde CO than its ester counterpart, which is preferentially reduced by reaction with Zn–hydride. The study provides molecular-level insights into how two Zn centers that are linked by a multidentate ligand collaborate to perform the catalytic activity in the hydrosilylation of carbonyls and how the ligand-casted chiral scaffolding can be intentionally employed to differentiate symmetry elements in desymmetrization.