Insights into the Unexpected Chemoselectivity for the N‑Heterocyclic Carbene-Catalyzed Annulation Reaction of Allenals with Chalcones

Lewis base N-heterocyclic carbene (NHC)-catalyzed annulation is the subject of extensive interest in synthetic chemistry, but the reaction mechanisms, especially the unexpected chemoselectivity of some of these reactions, are poorly understood. In this work, a systematic theoretical calculation has been performed on NHC-catalyzed annulation between allenals and chalcone. Multiple possible reaction pathways (A–E) leading to three different products have been characterized. The calculated results reveal that NHC is more likely to initiate the reaction by nucleophilic attack on the center carbon atom of the allene group but not the carbonyl carbon atom in allenals leading to the Breslow intermediate, which is remarkably different from the other NHC-catalyzed annulations of unsaturated aldehydes with chalcones. The computed energy profiles demonstrate that the most energetically favorable pathway (A) results in polysubstituted pyranyl aldehydes, which reasonably explains the observed chemoselectivity in the experiment. The observed chemoselectivity is demonstrated to be thermodynamically but not kinetically controlled, and the stability of the Breslow intermediate is the key for the possibility of homoenolate pathway D and enolate pathway E. This work can improve our understanding of the multiple competing pathways for NHC-catalyzed annulation reactions of unsaturated aldehydes with chalcones and provide valuable insights for predicting the chemoselectivity for this kind of reaction

Computational Study on γ‑C–H Functionalization of α,β-Unsaturated Ester Catalyzed by N‑Heterocyclic Carbene: Mechanisms, Origin of Stereoselectivity, and Role of Catalyst

The N-heterocyclic carbene (NHC)-catalyzed γ-C–H deprotonation/functionalization of α,β-unsaturated esters with hydrazones leading to the δ-lactams has been theoretically investigated by using density functional theory. Three possible reaction mechanisms including Mechanism A, for which the NHC catalyst serves as a nucleophilic catalyst to attack on the carbonyl carbon atom to initiate the reaction, Mechanism B, in which NHC triggers the reaction through the hydrogen bond, and Mechanism C, which is the direct deprotonation/functionalization process without the presence of NHC, have been suggested and studied in detail. The most favorable Mechanism A was identified to proceed through the following processes: nucleophilic attack on the carbonyl carbon of the ester by NHC, γ-deprotonation, formal [4 + 2] cycloaddition of dienolate with hydrazone, and regeneration of NHC. Multiple possible deprotonation pathways were explored, and the additive base such as K₂CO₃ would significantly lower the energy barrier. The formal [4 + 2] cycloaddition step is the stereoselectivity-determining step, and <i>R</i>-configured rather than <i>S</i>-configured product was preferentially generated. In addition, the C–H···O, C–H···N, LP···π, and C–H···π interactions have been identified in the most energetically favorable transition state involved in the stereoselectivity-determining step. The additional analysis indicates that NHC strengthens the acidity and electrophilicity to promote the deprotonation, indicating this is not a simple NHC-catalyzed umpolung carbonyl reaction. The mechanistic insights and the significant role of NHC obtained in this study should provide valuable insights for understanding the organocatalytic γ-C­(sp³)–H bond functionalization reaction

Theoretical Study on DBU-Catalyzed Insertion of Isatins into Aryl Difluoronitromethyl Ketones: A Case for Predicting Chemoselectivity Using Electrophilic Parr Function

The possible mechanisms of 1,8-diazabicyclo[5.4.0]­undec-7-ene (DBU)-catalyzed chemoselective insertion of <i>N</i>-methyl isatin into aryl difluoronitromethyl ketone to synthesize 3,3-disubstituted and 2,2-disubstituted oxindoles have been studied in this work. As revealed by calculated results, the reaction occurs via two competing paths, including α and β carbonyl paths, and each path contains five steps, that is, nucleophilic addition of DBU to ketone, C–C bond cleavage affording difluoromethylnitrate anion and phenylcarbonyl–DBU cation, nucleophilic addition of difluoromethylnitrate anion to carbonyl carbon of <i>N</i>-methyl isatin, acyl transfer process, and dissociation of DBU and product. The computational results suggest that nucleophilic additions on different carbonyl carbons of <i>N</i>-methyl isatin via α and β carbonyl paths would lead to different products in the third step, and β carbonyl path associated with the main product 3,3-disubstituted oxindole is more energetically favorable, which is consistent with the experimental observations. Noteworthy, electrophilic Parr function can be successfully applied for exactly predicting the activity of reaction site and reasonably explaining the chemoselectivity. In addition, the distortion/interaction and noncovalent interaction analyses show that much more hydrogen bond interactions should be responsible for the lower energy of the transition state associated with β carbonyl path. The obtained insights would be valuable for the rational design of efficient organocatalysts for this kind of reactions with high selectivities

Insights into Stereoselective Aminomethylation Reaction of α,β-Unsaturated Aldehyde with N,O-Acetal via N‑Heterocyclic Carbene and Brønsted Acid/Base Cooperative Organocatalysis

A theoretical investigation has been performed to interrogate the mechanism and stereoselectivities of aminomethylation reaction of α,β-unsaturated aldehyde with N,O-acetal, which is initiated by N-heterocyclic carbene and Brønsted acid (BA). The calculated results disclose that the reaction contains several steps, i.e., formation of the actual catalysts NHC and Brønsted acid Et₃N·H⁺ coupled with activation of C–O bond of N,O-acetal, nucleophilic attack of NHC on α,β-unsaturated aldehyde, formation of Breslow intermediate, β-protonation for the formation of enolate intermediate, nucleophilic addition on the Re/Si face to enolate by the activated iminium cation, esterification coupled with regeneration of Et₃N·H⁺, and dissociation of NHC from product. Addition on the prochiral face of enolate should be the stereocontrolling step, in which the chiral <i>α-</i>carbon is formed. Furthermore, NBO, GRI, and FMO analyses have been performed to explore the roles of catalysts and origin of stereoselectivity. Surprisingly, the added Brønsted base (BB) Et₃N plays an indispensable role in the esterification process, indicating the reaction proceeds under NHC-BA/BB multicatalysis rather than NHC-BA dual catalysis proposed in the experiment. This theoretical work provides a case on the exploration of the special roles of the multicatalysts in NHC chemistry, which is valuable for rational design on new cooperative organocatalysis

Theoretical Investigations toward the Asymmetric Insertion Reaction of Diazoester with Aldehyde Catalyzed by N‑Protonated Chiral Oxazaborolidine: Mechanisms and Stereoselectivity

In recent years, the N-protonated chiral oxazaborolidine has been utilized as the Lewis acid catalyst for the asymmetric insertion reaction, which is one of the most challenging topics in current organic chemistry. Nevertheless, the reaction mechanism, stereoselectivity, and regioselectivity of this novel insertion reaction are still unsettled to date. In this present work, the density functional theory (DFT) investigation has been performed to interrogate the mechanisms and stereoselectivities of the formal C–C/H insertion reaction between benzaldehyde and methyl α-benzyl diazoester catalyzed by the N-protonated chiral oxazaborolidine. For the reaction channel to produce the <i>R</i>-configured C–C insertion product as the predominant isomer, the catalytic cycle can be characterized by four steps: (i) the complexation of the aldehyde with catalyst, (ii) addition of the other reactant methyl α-benzyl diazoester, (iii) the removal of nitrogen concerted with the migration of phenyl group or hydrogen, and (iv) the dissociation of catalyst from the products. Our computational results show that the carbon–carbon bond formation step is the stereoselectivity determining step, and the reaction pathways associated with [1, 2]-phenyl group migration occur preferentially to those pathways associated with [1, 2]-hydrogen migration. The pathway leading to the <i>R</i>-configured product is the most favorable pathway among the possible stereoselective pathways. All these calculated outcomes align well with the experimental observations. The novel mechanistic insights should be valuable for understanding this kind of reaction

Fundamental Reaction Pathway and Free Energy Profile for Inhibition of Proteasome by Epoxomicin

First-principles quantum mechanical/molecular mechanical free energy calculations have been performed to provide the first detailed computational study on the possible mechanisms for reaction of proteasome with a representative peptide inhibitor, Epoxomicin (EPX). The calculated results reveal that the most favorable reaction pathway consists of five steps. The first is a proton transfer process, activating Thr1-O^γ directly by Thr1-N^z to form a zwitterionic intermediate. The next step is nucleophilic attack on the carbonyl carbon of EPX by the negatively charged Thr1-O^γ atom, followed by a proton transfer from Thr1-N^z to the carbonyl oxygen of EPX (third step). Then, Thr1-N^z attacks on the carbon of the epoxide group of EPX, accompanied by the epoxide ring-opening (S_N2 nucleophilic substitution) such that a zwitterionic morpholino ring is formed between residue Thr1 and EPX. Finally, the product of morpholino ring is generated via another proton transfer. Noteworthy, Thr1-O^γ can be activated directly by Thr1-N^z to form the zwitterionic intermediate (with a free energy barrier of only 9.9 kcal/mol), and water cannot assist the rate-determining step, which is remarkably different from the previous perception that a water molecule should mediate the activation process. The fourth reaction step has the highest free energy barrier (23.6 kcal/mol) which is reasonably close to the activation free energy (∼21–22 kcal/mol) derived from experimental kinetic data. The obtained novel mechanistic insights should be valuable for not only future rational design of more efficient proteasome inhibitors but also understanding the general reaction mechanism of proteasome with a peptide or protein

Fundamental Reaction Pathway for Peptide Metabolism by Proteasome: Insights from First-Principles Quantum Mechanical/Molecular Mechanical Free Energy Calculations

Proteasome is the major component of the crucial non-lysosomal protein degradation pathway in the cells, but the detailed reaction pathway is unclear. In this study, first-principles quantum mechanical/molecular mechanical free energy calculations have been performed to explore, for the first time, possible reaction pathways for proteasomal proteolysis/hydrolysis of a representative peptide, succinyl-leucyl-leucyl-valyl-tyrosyl-7-amino-4-methylcoumarin (Suc-LLVY-AMC). The computational results reveal that the most favorable reaction pathway consists of six steps. The first is a water-assisted proton transfer within proteasome, activating Thr1-O^γ. The second is a nucleophilic attack on the carbonyl carbon of a Tyr residue of substrate by the negatively charged Thr1-O^γ, followed by the dissociation of the amine AMC (third step). The fourth step is a nucleophilic attack on the carbonyl carbon of the Tyr residue of substrate by a water molecule, accompanied by a proton transfer from the water molecule to Thr1-N^z. Then, Suc-LLVY is dissociated (fifth step), and Thr1 is regenerated <i>via</i> a direct proton transfer from Thr1-N^z to Thr1-O^γ. According to the calculated energetic results, the overall reaction energy barrier of the proteasomal hydrolysis is associated with the transition state (TS3^b) for the third step involving a water-assisted proton transfer. The determined most favorable reaction pathway and the rate-determining step have provided a reasonable interpretation of the reported experimental observations concerning the substituent and isotopic effects on the kinetics. The calculated overall free energy barrier of 18.2 kcal/mol is close to the experimentally derived activation free energy of ∼18.3–19.4 kcal/mol, suggesting that the computational results are reasonable

Theoretical Investigations toward the [4 + 2] Cycloaddition of Ketenes with <i>N</i>‑Benzoyldiazenes Catalyzed by N‑Heterocyclic Carbenes: Mechanism and Enantioselectivity

Density functional theory (DFT) calculations have been performed to provide the first detailed computational study on the mechanism and enantioselectivity for the [4 + 2] cycloaddition reaction of ketenes with <i>N</i>-benzoyldiazenes catalyzed by N-heterocyclic carbenes (NHCs). Two possible mechanisms have been studied: first is the “ketene-first” mechanism (mechanism A), and second is the novel “diazene-first” mechanism (mechanism B). The calculated results reveal that mechanism B is more favorable than mechanism A because it is not only of lower energy barrier but also more consistent with the provided general experimental procedure (Huang, X.-L.; He, L.; Shao, P.-L.; Ye, S. <i>Angew. Chem., Int. Ed.</i> <b>2009</b>, <i>48</i>, 192–195). The enantioselectivity-determining step is demonstrated to present during the first process of cycloaddition, and the main product configuration is verified to agree with the experimental ee values very well. This study should be of some worth on forecasting how different substituent groups of catalysts and/or reactants affect the enantioselectivity of products. The obtained novel mechanistic insights should be valuable for not only rational design of more efficient NHC catalysts but also understanding the general reaction mechanism of [4 + 2] cycloaddition of ketenes

N‑Heterocyclic Carbene (NHC)-Catalyzed sp³ β‑C–H Activation of Saturated Carbonyl Compounds: Mechanism, Role of NHC, and Origin of Stereoselectivity

Activation of inert sp³ β-C–H bonds has attracted widespread attention and been developed with significant progress in recent years, but understanding the mechanism of this kind of reaction continues to be one of the most challenging topics in organic chemistry. In this paper, the possible reaction mechanisms and origin of stereoselectivity in the reaction between saturated carbonyl compounds with enones generating cyclopentenes catalyzed by N-heterocyclic carbene (NHC) have been investigated using density functional theory. The computational results show that the additive DBU plays an important role in NHC-catalyzed C–H activation. Analyses of the natural bond orbital charge and global reaction index indicate that NHC can lower the energy barrier of the entire reaction by activating the α/β-C–H bond rather than by strengthening the nucleophilicity of the reactant as a Lewis base. This is remarkably at variance from previous reports. In addition, the π···π stacking between the phenyl of the enone and the conjugated system of the NHC-bounded enolate intermediate has been found by the analyses of distortion/interaction and atom-in-molecule to be responsible for the stereoselectivity. These results shed light on the detailed reaction mechanism and the significant role of the NHC organocatalyst and offer valuable insights into the rational design of potential catalysts for this kind of highly stereoselective reaction

DFT Study on the Mechanisms and Diastereoselectivities of Lewis Acid-Promoted Ketene–Alkene [2 + 2] Cycloadditions: What is the Role of Lewis Acid in the Ketene and C = X (X = O, CH₂, and NH) [2 + 2] Cycloaddition Reactions?

The detailed mechanisms and diastereoselectivities of Lewis acid-promoted ketene–alkene [2 + 2] cycloaddition reactions have been studied by density functional theory (DFT). Four possible reaction channels, including two noncatalyzed diastereomeric reaction channels (channels A and B) and two Lewis acid (LA) ethylaluminum dichloride (<b>EtAlCl</b>_<b>2</b>) catalyzed diastereomeric reaction channels (channels C and D), have been investigated in this work. The calculated results indicate that channel A (associated with product R-configurational cycloputanone) is more energy favorable than channel B (associated with the other product S-configurational cyclobutanone) under noncatalyzed condition, but channel D leading to S-configurational cyclobutanone is more energy-favorable than channel C, leading to R-configurational cycloputanone under a LA-promoted condition, which is consistent with the experimental results. And Lewis acid can make the energy barrier of ketene–alkene [2 + 2] cycloaddition much lower. In order to explore the role of LA in ketene and C = X (X = O, CH₂, and NH) [2 + 2] cycloadditions, we have tracked and compared the interaction modes of frontier molecular orbitals (FMOs) along the intrinsic reaction coordinate (IRC) under the two different conditions. Besides by reducing the energy gap between the FMOs of the reactants, our computational results demonstrate that Lewis acid lowers the energy barrier of the ketene and C = X [2 + 2] cycloadditions by changing the overlap modes of the FMOs, which is remarkably different from the traditional FMO theory. Furthermore, analysis of global reactivity indexes has also been performed to explain the role of LA catalyst in the ketene–alkene [2 + 2] cycloaddition reaction