Origins of enantioselectivity in the chiral Brønsted acid catalyzed hydrophosphonylation of imines

Abstract

The results of an experimental and ONIOM-based computational investigation of the mechanism and the origins of enantioselectivity in the asymmetric synthesis of alpha-amino phosphonates by an enantioselective hydrophosphonylation of imines catalyzed by chiral Brønsted acids are reported. It was found that the enantioselectivity observed in the enantioselective hydrophosphonylation of the imine with a benzothiazole moiety was poor. A detailed computational study with a two-layer ONIOM (B3LYP/6-31G(d)/AM1) method on the mechanism of the investigated reaction was carried out to explore the origins of the enantioselectivity. Calculations indicate that the investigated reaction is a two-step process involving proton-transfer and nucleophilic addition, which is the stereo-controlling step. The investigated reaction prefers a di-coordination pathway to a mono-coordination pathway. The different enantioselectivities exhibited by three kinds of catalyst and two kinds of nucleophile were rationalized. Calculations indicate that si-facial attack is higher in energy than re-facial attack by only 0.1 kcal/mol, which accounts well for the low ee value observed in the enantioselective hydrophosphonylation of the imine with a benzothiazole moiety. The energy barrier for phosphonate-phosphite tautomerism catalyzed by chiral Brønsted acid in toluene is only 1.8 kcal/mol, which could explain why the investigated reaction can take place at room temperature.

A Chiral N‐Phosphinyl Phosphoramide: Another Offspring for the Sage Phosphoric Acid Progenitor

“…This model is consistent with the configuration of the products, but mechanistic studies for these catalysts remain limited. [7] That an acylimine is a key intermediate is consistent with the demonstration that the e.r. of the product formed is the same, whether the substrate is an ortho-hydroxy benzamide-aldehyde combination, or an N-acyl enamide (Scheme 3).…”

Mechanistic Investigation of Chiral Phosphoric Acid Catalyzed Asymmetric Baeyer–Villiger Reaction of 3‐Substituted Cyclobutanones with H2O2 as the Oxidant

“…[49][50][51]58] Such a bifunctional catalysis pattern has also been demonstrated to be viable in several recent theoretical studies on the mechanisms of phosphoric acid catalyzed nucleophilic addition reactions of imines, including Hantzsch ester transfer hydrogenations, [59,60] Strecker reactions, [61] and hydrophosphonylation. [62][63] Computational details: All calculations in this work were performed with density functional theory (DFT) [64] and MP2 [65] implemented in the Gaussian 03 program. [66] For the exploration of the reaction pathway shown in Scheme 5 and the following reactivity calculations, (R)-H 8 -BINOL-derived phosphoric acid (1 c) was used as the model catalyst, in which the initial conformation of the binaphthyl rings was kept the same as that in the H 8 -BINOL/Ti complex, which has been characterized by X-ray crystallography.…”

The mechanism investigation of chiral phosphoric acid-catalyzed Friedel–Crafts reactions – How the chiral phosphoric acid regains the proton

“…Therefore, computational studies for the organocatalysis reactions of BINOLphosphoric acid have received much more attention by some research groups, like those of the Goodman et al [8], You et al [9], Yamanaka et al [10], Himo et al [11] and Shi groups [12]. The chiral phosphoric acid bearing both Brønsted acidic and Lewis basic sites potentially allows for bifunctional catalysis to activate simultaneously both electrophiles and nucleophiles.…”