title: To be or not to be butterfly: New mechanistic insights in the Aza-Michael asymmetric addition of lithium (R)-N-benzyl-N-(α-methylbenzyl)amide.
abstract: The asymmetric Aza-Michael addition of homochiral lithium benzylamides to α,β-unsaturated esters represents an extended protocol to obtain enantioenriched β-amino esters. An exhaustive mechanistic revision of the originally proposed mechanism is reported, developing a quantum mechanics/molecular mechanics protocol for the asymmetric Aza-Michael reaction of homochiral lithium benzylamides. Explicit and implicit solvent schemes were considered, together with a proper account of long-range dispersion forces, evaluated through a density functional theory benchmark of different functionals. Theoretical results showed that the diastereoselectivity is mainly controlled by the N-α-methylbenzyl moiety placing, deriving a Si/Re 99:1 diastereoselective ratio, in good agreement with reported experimental results. The main transition state geometries are two transition state conformers in a "V-stacked" orientation of the amide's phenyl rings, differing in the tetrahydrofuran molecule arrangement coordinated to the metal center. Extensive conformational sampling and quantum-level refinement give reasonable good speed/accuracy results, allowing this protocol to be extended to other similar Aza-Michael reaction systems.
authors: Departamento de Química Orgánica, Universidad de Salamanca, Pza de la Merced 1-5, 37007, Salamanca, Spain.
authors: Carlos T
authors: CT
authors: Nieto
authors: David
authors: D
authors: Díez
authors: Narciso M
authors: NM
authors: Garrido
keywords: Aza-Michael reaction; DFT; QM; asymmetric addition; lithium amides