Computational Studies on Reaction Mechanisms and Origin of Stereoselectivity in the [1,3]‐Rearrangement of Ene‐Aldimines

Abstract

The mechanism of Brønsted acid‐initiated formal [1,3]‐rearrangement was rationalized using density functional theory (DFT) calculations. The computed mechanism comprises I) fragmentation: (a) imino‐nitrogen protonation, (b) proton transfer to olefin, (c) 1,2‐shift, and (d) C−C bond cleavage, and II) product formation: (e) methylene addition, (f) azonia‐[3,3]‐sigmatropic rearrangement, and (g) methylene elimination. The ene‐aldimine fragmentation to the 2‐azaallenium cation was found to be a highly reactive intermediate and the real catalyst species. The stereoselectivity for asymmetric formal [1,3]‐rearrangement of optically pure ene‐aldimine is in good agreement with chair transition state of azonia‐[3,3]‐sigmatropic rearrangement step and is supported by DFT calculation. Our computational study provides important mechanistic insights for ene‐aldimine rearrangements and guides the design of chiral catalysts for rearrangement process.

Chiral Counteranion-Directed Catalytic Asymmetric Methylene Migration Reaction of Ene-Aldimines

“…In 2006, Kobayashi et al reported the first highly asymmetric aza-Cope rearrangement, with catalytic asymmetric versions subsequently developed by three research groups (Figure a). − Previously, we developed a protocol for Brønsted acid-initiated asymmetric methylene migration in β-disubstituted ene-aldimines and thus provided access to the previously inaccessible 2,2,4-homoallylic amines . Considering the key intermediates suggested for the methylene migration step, one expects the application of ACDC to greatly enhance the value of this transformation for asymmetric synthesis. Herein, we report the catalytic asymmetric methylene migration reaction of ene-aldimines initiated by chiral Brønsted acids and apply it to β 2 -amino acid synthesis (Figure b).…”

“…The above results directed our attention to the origin of stereoselectivity in the catalytic asymmetric reaction initiated by 1e . On the basis of a previous study of the reaction mechanism (Figure a) and the results of density functional theory (DFT) calculations, we proposed an asymmetric induction model relying on steric hindrance between the phenyl groups of 2 and phosphate 1e – . In this model, si -facial carbon–carbon bond formation in the methanaminium- 1e – complex leads to the S -product, whereas re -facial bond formation affords the R -product (Figure b).…”