Mechanistic Studies of Highly Enantio- and Diastereoselective Aza-Petasis–Ferrier Rearrangement Catalyzed by Chiral Phosphoric Acid

Abstract

The precise mechanism of the highly anti- and enantioselective aza-Petasis-Ferrier (APF) rearrangement of hemiaminal vinyl ethers catalyzed by a chiral phosphoric acid was investigated by undertaking experimental and theoretical studies. The APF rearrangement is characterized by the following unique mechanistic features: (i) efficient optical kinetic resolution of the starting racemic hemiaminal vinyl ether, (ii) enantioconvergent process from racemic hemiaminal vinyl ethers to optically active β-amino aldehyde products, and (iii) anomalous temperature effects on the enantioselectivity (enantioselectivity increases as reaction temperature increases). The following experiments were conducted to elucidate the unique mechanistic features as well as to uncover the overall scheme of the present rearrangement: (A) X-ray crystallographic analysis of the recovered hemiaminal vinyl ether to determine its absolute configuration, (B) rearrangements of enantiomerically pure hemiaminal vinyl ethers to validate the stereochemical relationship between the hemiaminal vinyl ethers and β-amino aldehydes, (C) theoretical studies on the transition states of the C-O bond cleavage and C-C bond formation steps to gain an insight into the optical kinetic resolution of the hemiaminal vinyl ether and the origin of the stereoselectivity, as well as to elucidate the overall scheme of the present rearrangement, and (D) crossover experiments of two hemiaminal vinyl ethers having different vinyl ether and aliphatic substituents to comprehend the mechanism of the anomalous temperature effect and the enantioconvergent process. The results of experiments and theoretical studies fully support the proposed mechanism of the present anti- and enantioselective APF rearrangement.

Selecting Chiral BINOL‐Derived Phosphoric Acid Catalysts: General Model To Identify Steric Features Essential for Enantioselectivity

“…However, whether the reaction benefits from large proximal sterics or small depends on the sterics of the nucleophile. For smaller displaced nucleophiles, large proximal sterics are advantageous, disfavouring Type I E pathways 29, 33, 35, 36, 37, 38, 72, 73, 74, 75, 76, 77, 78. However, if the nucleophile is large, small proximal sterics are essential 32, 34, 39, 79, 80.…”

“…The reactants and the phosphoric acid moiety of the catalyst were included in the high‐layer, and the remaining regions of the catalyst were treated as the low‐layer. This method has previously been shown to give excellent results when used to describe reactions catalyzed by chiral phosphoric acids 4, 16, 18, 34, 35, 36, 37…”

Advances in Stereoconvergent Catalysis from 2005 to 2015: Transition-Metal-Mediated Stereoablative Reactions, Dynamic Kinetic Resolutions, and Dynamic Kinetic Asymmetric Transformations

“…The authors later disclosed a thorough mechanistic evaluation to further probe this reaction and account for the anomalous temperature effect. 89 They found that the CPA catalyst serves two purposes, acting both as a hydrogen-bond donor to the N -Boc-imine and a hydrogen-bond acceptor from the transient enol. This scaffolding bifunctionality is responsible for both the large degree of anti -selectivity as well as the high enantioselectivities the authors typically observed.…”

Aminocatalytic Cross‐Coupling Approach via Iminium Ions to Different CC Bonds

“…The advantage of the latter reaction is the formation of ortho-coupled products of phenols and b-naphthol (5 and 6, respectively), whereby the same sort of reactive three-component intermediate TN 2 is generated by reaction of iminium ion II with a nucleophilic carbon center of phenol/naphthol, and subsequent deamination followed by aerobic oxidation generates 10 and 11, respectively. Generation of 12 can be explained by three-component intermediate TN 3 , produced by attack of aryl nucleophile (R À ) on the iminium ion. The aryl nucleophile is generated by the action of OH À on aryl boronic acid.…”

“…[1] Among different reactions, activation due to secondary-amine-promoted iminium ions has dominated the field and has been exploited in two different directions: 1) reactions, in which amines are used as reagents, such as Mannich, [2] Petasis, [3] and KabachnikFields reactions [4] and 2) iminium-catalyzed reactions, for example, Stork enamine, [5] Knoevenagel, [6] and trans-amination [7] reactions (Figure 1 b). Recently, we established a method based on iminium ions for the synthesis of a-ketoamides.…”