d1 Imidate-umpolung addition to activated imines for the asymmetric synthesis of amino acid derivatives: a combined DFT and experimental study.

Herein, we report the asymmetric synthesis of highly enantioenriched amino acid derivatives exploiting a lithiated Ellman-derived imidate as a nucleophilic d1 umpolung synthon. While traditional d1 strategies focus on aldehyde-derived acyl anions, this reagent acts as a formal ester anion equivalent. While unactivated imines fail to react, the addition to non-enolizable Ellman sulfinimines-including aromatic and α,β-unsaturated derivatives-proceeds in good yields and with excellent stereocontrol enabled by double stereodifferentiation. The matched stereoisomeric combination provides the corresponding adducts in good chemical yields (up to 96%) and almost complete diastereoselectivity (dr >99 : 1), while the mismatched pair leads to complex mixtures and much lower conversions. A comprehensive Density Functional Theory (DFT) study revealed the structural origins of both the substrate scope and the absolute stereocontrol, while also identifying a low-barrier self-condensation pathway that rationalizes the strict requirement for an in situ one-pot protocol to suppress nucleophile decomposition.